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CARDIOLOGY
1
Contents
I. Atrial fibrillation.....................................................................................................................................3
Dr. Csaba Herczku, Dr. Laszlo Czopf, Dr. Miklos Rabai, Dr. Barbara Sandor
II. The diagnosis and management of heart failure..................................................................................29
Dr. Tamas Habon, Dr. Robert Halmosi, Dr. Roland Gal, Dr.Barbara Sandor
III. Ischemic heart disease, stable coronary artery disease (SCAD), angina pectoris................................51
Prof. Dr. Kalman Toth, Dr. Laszlo Czopf, Dr. Peter Kenyeres, Dr.Katalin Biro
Supported by the grant of TAMOP 4.1.1. C
2015
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I. Atrial fibrillation
Dr. Csaba Herczku1, Dr. Laszlo Czopf2, Dr. Miklos Rabai2, Dr. Barbara Sandor2
1
Gottsegen Gyorgy Hungarian Institute of Cardiology, Budapest, Hungary
2 st
1 Department of Medicine, Medical School, University of Pecs, Pecs, Hungary
1. Definition
Atrial fibrillation (AF) is defined as a cardiac arrhythmia with the following characteristics:
(1) The surface ECG shows absolutely irregular RR intervals (AF is therefore sometimes known as
arrhythmia absoluta), i.e. RR intervals that do not follow a repetitive pattern.
(2) Instead of distinct P waves on the surface ECG, f waves can be seen. Some apparently regular atrial
electrical activity may be seen in some ECG leads, most often in lead V1.
(3) The atrial cycle length (when visible), i.e. the interval between two atrial activations, is usually
variable and <200 ms (>300 bpm).
2. Types of atrial fibrillation
Clinically, it is reasonable to distinguish five types of AF based on the presentation and duration of the
arrhythmia: first diagnosed, paroxysmal, persistent, long-standing persistent and permanent AF.
(1) Every patient who presents with AF for the first time is considered a patient with first diagnosed
AF, irrespective of the duration of the arrhythmia or the presence and severity of AF-related symptoms.
(2) Paroxysmal AF is self-terminating, usually within 48 h. Although AF paroxysms may continue for up
to 7 days, the 48 h time point is clinically important. After this first 48 h the likelihood of spontaneous
conversion is low and anticoagulation must be considered.
(3) Persistent AF is present when an AF episode either lasts longer than 7 days or requires termination
by cardioversion, either with drugs or by direct current cardioversion (DCC).
(4) Long-standing persistent AF has lasted for ≥1 year when it is decided to adopt a rhythm control
strategy.
(5) Permanent AF is said to exist when the presence of the arrhythmia is accepted by the patient (and
physician). Hence, rhythm control interventions are not pursued in patients with permanent AF. If rhythm
control strategy is adopted, the arrhythmia will be redesignated as long-standing persistent AF.
This classification is useful for clinical management of AF patients, especially when AF-related
symptoms are also considered. Therapeutic decisions require careful consideration of additional individual
factors and co-morbidities.
Silent AF (asymptomatic) may manifest as an AF-related complication (ischaemic stroke or
tachycardiomyopathy) or may be diagnosed by an opportunistic ECG. Silent AF may present as any of the
temporal forms of AF.
In lone AF neither structural heart disease nor thrombotic risk factors can be found.
It is conventional to divide AF into cases which are described as “valvular” or “non-valvular”. The term
valvular AF is used to imply that AF is related to rheumatic valvular disease (predominantly mitral stenosis)
or prosthetic heart valves.
3. Epidemiology
Atrial fibrillation is the most common sustained cardiac arrhythmia, occurring in 1-2% of the general
population; over 6 million Europeans suffer from this arrhythmia. AF may long remain undiagnosed (silent
AF), and many patients with AF will never present to hospital. Hence, the true prevalence of AF is probably
closer to 2% of the population. The prevalence of AF increases with age, from 0.5% at 40-50 years, to 5-15%
at 80 years, and its prevalence is expected to at least double in the next 50 years as the population ages.
Men are more often affected than women.
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Much earlier detection of the arrhythmia might allow the timely introduction of therapies to protect
the patient, not only from the consequences of the arrhythmia, but also from the progression of AF from an
easily treated condition to an utterly refractory problem.
4. Mechanisms of atrial fibrillation
4.1. Atrial factors
Any kind of structural heart disease may trigger a slow but progressive process of structural
remodelling in both the ventricles and the atria. In the atria, proliferation and differentiation of fibroblasts
into myofibroblasts and enhanced connective tissue deposition and fibrosis are the hallmarks of this
process. Structural remodelling results in electrical dissociation between muscle bundles and local
conduction heterogeneities facilitating the initiation and perpetuation of AF. This electroanatomical
substrate permits multiple small re-entrant circuits that can stabilize the arrhythmia.
4.2. Electrophysiological mechanisms
The initiation and perpetuation of a tachyarrhythmia requires both triggers for its onset and a
substrate for its maintenance. These mechanisms are likely to co-exist at various times.
Focal mechanisms potentially contribute to the initiation and perpetuation of AF. Cellular mechanisms
of focal activity might involve both triggered activity and re-entry. Because of shorter refractory periods as
well as abrupt changes in myocyte fibre orientation, the pulmonary veins (PVs) have a stronger potential to
initiate and perpetuate atrial tachyarrhythmias.
According to the multiple wavelet hypothesis, AF is perpetuated by continuous conduction of several
independent wavelets propagating through the atrial musculature in a seemingly chaotic manner.
Fibrillation wavefronts continuously undergo wavefront-waveback interactions, resulting in wavebreak and
the generation of new wavefronts, while block, collision, and fusion of wavefronts tend to reduce their
number. As long as the number of wavefronts does not decline below a critical level, the multiple wavelets
will sustain the arrhythmia.
4.3. Genetic predisposition
AF has a familial component, especially AF of early onset. During the past years, numerous inheritable
cardiac syndromes associated with AF have been identified. Both short and long QT syndromes and
Brugada syndrome are associated with supraventricular arrhythmias, often including AF.
It also frequently occurs in a variety of inherited conditions, including hypertrophic cardiomyopathy, a
familial form of ventricular pre-excitation, and abnormal LV hypertrophy associated with mutations in the
PRKAG gene. Other familial forms of AF are associated with mutations in the gene coding for atrial
natriuretic peptide, loss-of-function mutations in the cardiac sodium channel gene SCN5A, or gain of
function in a cardiac potassium channel.
5. Atrial flutter
Atrial flutter is similar to AF caused by a re-entrant rhythm in either the right or left atrium. It is
typically initiated by a premature electrical impulse arising in the atria and propagated due to differences in
refractory periods of atrial tissue resulting in a localized self-perpetuating loop. In atrial flutter the atrial
cycle length is longer than in AF (e.g. ≥200 ms). While on ECG leads F waves can be identified, the pulse is
regular or regularly irregular.
In type I (typical or common) atrial flutter the reentrant loop circles in the right atrium, passing
through the cavo-tricuspid isthmus (e.g. a body of fibrous tissue in the lower atrium between the inferior
vena cava, and the tricuspid valve). Type I atrial flutter is divided into two subtypes: counterclockwise atrial
flutter and clockwise atrial flutter depending on the direction of the current passing through the loop.
Counterclockwise atrial flutter is more commonly seen. The flutter waves in this rhythm are inverted in ECG
leads II, III, and aVF, while in the clockwise atrial flutter F waves are upright in leads II, III, and aVF.
Type II flutter follows a re-entry pathway different from that in type I flutter, and is typically faster and
has a rare appearance. Left atrial flutter is common after incomplete left atrial ablation procedures.
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Atrial flutter is associated with similar clinical manifestations and consequences to AF. Although, there
are some specific considerations particular to treatment of atrial flutter, in general, it should be managed in
the same way as atrial fibrillation.
6. Clinical consequences
6.1. Atrial fibrillation-related cardiovascular consequences
AF is associated with increased rates of hospitalizations, haemodynamic changes - left ventricular (LV)
dysfunction, degraded quality of life, reduced exercise capacity, stroke and other thrombo-embolic events
and death.
Hospitalizations due to AF account for one-third of all admissions for cardiac arrhythmias.
Haemodynamic changes affected by different factors in patients with AF involve loss of coordinated
atrial contraction, high ventricular rates, irregularity of the ventricular response, and decrease in
myocardial blood flow, as well as long-term alterations such as atrial and ventricular cardiomyopathy.
Acute loss of coordinated atrial mechanical function after the onset of AF reduces cardiac output by 515%. This effect is more pronounced in patients with reduced ventricular compliance since atrial
contraction contributes significantly to ventricular filling. High ventricular rates limit ventricular filling due
to the short diastolic interval. Rate-related interventricular or intraventricular conduction delay may lead to
dyssynchrony of the left ventricle and reduce cardiac output further. Moreover, these changes are often
associated with angina and symptomatic heart failure.
Persistent elevation of ventricular rates above 120-130 bpm may produce ventricular
tachycardiomyopathy. Reduction of the heart rate may restore normal ventricular function and prevent
further dilatation and damage to the atria.
In addition, irregularity of the ventricular rate can reduce cardiac output. Fluctuations of the RR
intervals cause a large variability in the strengths of subsequent heart beats, often resulting in pulse deficit.
In patients with pre-excitation syndromes, fast and potentially life-threatening ventricular rates may
occur (FBI arrhythmia).
Quality of life and exercise capacity are impaired in patients with AF. Patients with AF have a
significantly poorer quality of life compared with healthy controls, the general population, or patients with
coronary heart disease in sinus rhythm.
Thrombo-embolic events are associated with flow abnormalities in AF which are evidenced by stasis
within the left atrium, with reduced left atrial appendage (LAA) flow velocities, and visualized as
spontaneous echo-contrast on transoesophageal echocardiography (TEE). The LAA is the dominant source
of embolism (90%) in non-valvular AF. Abnormalities of blood constituents are well described in AF and
include haemostatic and platelet activation, as well as inflammation and growth factor abnormalities.
Ischaemic strokes in association with AF are often fatal, and those patients who survive are left more
disabled by their stroke and more likely to suffer a recurrence than patients with other causes of stroke. AF
confers a 5-fold risk of stroke, and one in five of all strokes is attributed to this arrhythmia. Undiagnosed,
silent AF is a likely cause of some cryptogenic strokes. Paroxysmal AF carries the same stroke risk as
permanent or persistent AF.
Cognitive dysfunction, including vascular dementia, may be related to AF. Small observational studies
suggest that asymptomatic embolic events may contribute to cognitive dysfunction in AF patients in the
absence of an overt stroke.
Death rates are doubled by AF, independently of other known predictors of mortality. Only
antithrombotic therapy has been shown to reduce AF-related deaths.
6.2. Cardiovascular and other conditions associated with atrial fibrillation
AF is associated with a variety of cardiovascular conditions. Conditions associated with AF are also
markers for global cardiovascular risk and/or cardiac damage rather than simply causative factors.
Ageing increases the risk of developing AF, possibly through age-dependent loss and isolation of atrial
myocardium and associated conduction disturbances.
Hypertension is a risk factor for incident (first diagnosed) AF and for AF-related complications such as
stroke and systemic thrombo-embolism.
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Symptomatic heart failure (New York Heart Association (NYHA) classes II-IV) is found in 30% of AF
patients and AF is found in up to 30-40% of heart failure patients, depending on the underlying cause and
severity of heart failure. Heart failure can be both a consequence of AF (e.g. tachycardiomyopathy or
decompensation in acute onset AF) and a cause of the arrhythmia due to increased atrial pressure and
volume overload, secondary valvular dysfunction, or chronic neurohumoral stimulation.
Tachycardiomyopathy should be suspected when LV dysfunction is found in patients with a fast
ventricular rate but no signs of structural heart disease. It is confirmed by normalization or improvement of
LV function when good AF rate control or reversion to sinus rhythm is achieved.
Valvular heart diseases are found in 30% of AF patients. AF caused by left atrial (LA) distension can be
an early manifestation of mitral stenosis and/or regurgitation. AF occurs in later stages of aortic valve
disease. While rheumatic valvular disease associated with AF was a frequent finding in the past, it is now
relatively rare in Europe.
Cardiomyopathies carry an increased risk for AF, especially in young patients. Relatively rare
cardiomyopathies are found in 10% of AF patients.
Atrial septal defect is associated with AF in 10-15% of patients. This association has important clinical
implications for the antithrombotic management of patients with previous stroke or transient ischaemic
attack (TIA) and an atrial septal defect.
Other congenital heart defects at risk of AF include patients with single ventricle, after Mustard
operation for transposition of the great arteries, or after Fontan surgery.
Coronary artery disease is present in ≥20% of the AF population. Whether uncomplicated coronary
artery disease per se (atrial ischaemia) predisposes to AF and how AF interacts with coronary perfusion are
uncertain.
Overt thyroid dysfunction can be the sole cause of AF and may predispose to AF-related
complications. In recent surveys, hyperthyroidism or hypothyroidism was found to be relatively uncommon
in AF populations, but subclinical thyroid dysfunction may contribute to AF.
Obesity is found in 25% of AF patients, and the mean body mass index was 27.5 kg/m 2 in a large,
German AF registry (equivalent to moderately obese).
Diabetes mellitus requiring medical treatment is found in 20% of AF patients, and may contribute to
atrial damage.
Chronic obstructive pulmonary disease (COPD) is found in 10-15% of AF patients, and is possibly more
a marker for cardiovascular risk in general than a specific predisposing factor for AF.
Sleep apnoea, especially in association with hypertension, diabetes mellitus, and structural heart
disease, may be a pathophysiological factor for AF because of apnoea-induced increases in atrial pressure
and size, or autonomic changes.
Chronic renal disease is present in 10-15% of AF patients. Renal failure may increase the risk of AFrelated cardiovascular complications.
7. Diagnosis
The risk of AF-related complications is not different between short AF episodes and sustained forms of
the arrhythmia. It is therefore important to detect paroxysmal AF in order to prevent AF-related
complications (e.g. stroke).
An irregular pulse should always raise the suspicion of AF, but an ECG recording is necessary to
diagnose AF. Clinical symptoms such as palpitations or dyspnea should trigger ECG monitoring to
demonstrate AF. More intense and prolonged monitoring is justified in highly symptomatic patients (with
recurrent syncope, and with a potential indication for anticoagulation especially after cryptogenic stroke).
In patients with rhythm or rate control treatment, the frequency of 12-lead ECG recording depends on the
type of antiarrhythmic drug treatment, the potential side effects, complications, and risks of
proarrhythmia. When arrhythmia or therapy-related symptoms are suspected, monitoring using Holter
recordings, transtelephonic recordings, patient- and automatically activated devices, or external loop
recorders should be considered. Implantable devices capable of intracardiac atrial electrogram recording
such as dual-chamber pacemakers and defibrillators can detect AF appropriately.
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Any arrhythmia that has the ECG characteristics of AF and lasts sufficiently long for a 12-lead ECG to be
recorded, or at least 30 s on a rhythm strip, should be considered as AF. The heart rate in AF can be
calculated from a standard 12-lead ECG by multiplying the number of RR intervals on the 10 s strip
(recorded at 25 mm/s) by six.
8. Management
8.1. Diagnostic evaluation
A thorough medical history should be obtained from the patient with AF. The acute management of AF
patients should concentrate on relief of symptoms and assessment of AF-associated risk. Clinical evaluation
should include determination of AF-related symptoms (EHRA score), estimation of stroke risk (CHA2DS2VASc score), estimation of bleeding risk (HAS-BLED score) and search for conditions that predispose to AF
(see section 6.2.) and for complications of the arrhythmia (see section 6.1.).
Management of AF patients is aimed at reducing symptoms and at preventing severe complications of
AF. The EHRA score provides a simple clinical tool for assessing symptoms during AF (Table 1).
EHRA I
no symptoms
EHRA II mild symptoms; normal daily activity not affected
EHRA III severe symptoms; normal daily activity affected
EHRA IV disabling symptoms; normal daily activity discontinued
Table 1. The EHRA score system
The EHRA score only considers symptoms that are attributable to AF and reverse or reduce upon
restoration of sinus rhythm or with effective rate control.
Prevention of AF-related complications relies on antithrombotic therapy, control of ventricular rate,
and adequate therapy of concomitant cardiac diseases. These therapies may already alleviate symptoms,
but symptom relief may require additional rhythm control therapy by cardioversion, antiarrhythmic drug
therapy, electrical cardioversion or ablation therapy.
Patients with AF and signs of acute heart failure require urgent rate control and often cardioversion.
An urgent echocardiogram should be performed in haemodynamically compromised patients to assess LV
and valvular function and right ventricular pressure. Patients with stroke or TIA require immediate stroke
diagnosis, usually via emergency computed tomography (CT) and adequate cerebral revascularization.
The time of onset of the arrhythmia episode should be established to define the type of AF (see
section 2.). Most patients with AF <48 h in duration can be cardioverted on low molecular weight heparin
(LMWH) without risk for stroke. If AF duration is >48 h or there is doubt about its duration, TEE may be
used to rule out intracardiac thrombus prior to cardioversion. The transthoracic echocardiogram can
provide useful information to guide clinical decision making, but cannot exclude thrombus in the LAA.
Patients with AF should be assessed for risk of stroke and risk of bleeding. Most patients with acute AF
will require anticoagulation unless they are at low risk of thrombo-embolic complications (no stroke risk
factors) and no cardioversion is necessary (e.g. AF terminates within 24-48 h).
After the initial management of symptoms and complications, underlying causes of AF should be
sought. The 12-lead ECG should be inspected for signs of structural heart disease. An echocardiogram is
useful to detect ventricular, valvular, and atrial disease as well as rare congenital heart disease. Thyroid
function tests, a full blood count, a serum creatinine measurement and analysis for proteinuria,
measurement of blood pressure, and a test for diabetes mellitus are useful. A serum test for hepatic
function may be considered in selected patients.
A stress test is reasonable in patients with signs or risk factors of coronary artery disease. Patients with
persistent signs of LV dysfunction and/or signs of myocardial ischaemia are candidates for coronarography.
8.2. Antithrombotic management
8.2.1. Risk of thrombo-embolism
As it was mentioned before AF is associated with increased thrombotic tendency due to stasis in the
left atrium with decreased left atrium appendage flow which is the dominant source of embolism in nonvalvular AF. During AF management risk stratification for stroke and thrombo-embolism is required.
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Major risk factors are prior stroke or TIA, or thrombo-embolism, and older age (≥75 years). The
presence of some types of valvular heart disease (mitral stenosis or prosthetic heart valves) would also
categorize such valvular AF patients as high risk. Clinically relevant non-major risk factors are heart failure
(moderate to severe systolic LV dysfunction, defined as left ventricular ejection fraction ≤40%),
hypertension, or diabetes. Other non-major risk factors include female sex, age 65-74 years, and vascular
disease (specifically, myocardial infarction, complex aortic plaque and peripheral artery disease).
Risk factors are cumulative and the simultaneous presence of two or more non-major risk factors
would justify a stroke risk that is high enough to require anticoagulation. This risk factor-based approach in
non-valvular AF can also be expressed as an acronym: CHA2DS2-VASc score (Table 2).
Letter
Risk factors
Score CHA2DS2-VASc score Stroke rate (%/year)
C
congestive heart failure/LV dysfunction
1
0
0%
H
hypertension
1
1
1.3%
A2
age >75
2
2
2.2%
D
diabetes mellitus
1
3
3.2%
S2
stroke/TIA/thrombo-embolism
2
4
4%
V
vascular disease
1
5
6.7%
A
age 65-74
1
6-7
9.6-9.8%
Sc
sex category (i.e. female sex)
1
8
6.7%
Maximum score
9
9
15.2%
Table 2. The CHA2DS2-VASc score system
8.2.2. Risk of bleeding
An assessment of bleeding risk should be part of the patient evaluation before anticoagulation. Rates
of intracranial haemorrhage are considerably lower than in the past, typically between 0.1 and 0.6%. This
may reflect lower anticoagulation intensity, careful dose regulation, or better control of hypertension.
Various bleeding risk scores have been validated for bleeding risk in anticoagulated patients, but all
have different modalities in evaluating bleeding risks and categorization into low-, moderate-, and high-risk
groups, usually for major bleeding risk. Using the results of a cohort of 3,978 European subjects with AF
from the EuroHeart Survey, a new simple bleeding risk score (HAS-BLED score) has been derived (Table 3).
The HAS-BLED score has a good predictive value, correlates well with the intracranial haemorrhage events
and highlights risk factors that can be actively managed to reduce the bleeding risk.
Letter
Clinical characteristics
Score
H
hypertension
1
A
abnormal renal and liver function (1 point each)
1 or 2
S
stroke
1
B
bleeding
1
L
labile INRs
1
E
elderly (e.g. age >65 years)
1
D
drugs or alcohol (1 point each)
1 or 2
Maximum score
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Table 3. The HAS-BLED score system
Hypertension is defined as systolic blood pressure >160 mmHg. Abnormal kidney function is defined
as the presence of chronic dialysis, renal transplantation or serum creatinine ≥200 mmol/L. Abnormal liver
function is defined as chronic hepatic disease (e.g. cirrhosis) or biochemical evidence of significant hepatic
derangement (e.g. bilirubin >2 x upper limit of normal, in association with aspartate
aminotransferase/alanine aminotransferase/alkaline phosphatase >3 x upper limit normal, etc.). Bleeding
refers to previous bleeding history and/or predisposition to bleeding, e.g. bleeding diathesis, anaemia, etc.
Labile INRs (international normalized ratio) refers to unstable/high INRs or poor time in therapeutic range
(e.g. <60%). Drugs/alcohol use refers to concomitant use of drugs, such as antiplatelet agents, nonsteroidal anti-inflammatory drugs, or alcohol abuse, etc.
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8.2.3. Antithrombotic therapy
The CHA2DS2-VASc and HAS-BLED scores are useful score systems to aid practical decision-making for
thromboprophylaxis in non-valvular AF. Decision-making needs to balance the risk of stroke against the risk
of major bleeding, especially intracranial bleeding, which is the most feared complication of anticoagulation
therapy and confers a high risk of death and disability. Thus, a formal bleeding risk assessment is
recommended for all patients with AF, and in patients with a HAS-BLED score ≥3, caution and regular
review are appropriate, as well as efforts to correct the potentially reversible risk factors for bleeding. The
HAS-BLED score per se should not be used to exclude patients from antithrombotic therapy but allows
clinicians to make an informed assessment of bleeding risk and makes them think of the correctable risk
factors for bleeding.
In the absence of thrombotic risk factors (CHA2DS2-VASc score <1) (e.g. patients aged <65 with lone
AF) antithrombotic therapy is not recommended. Thus, female patients with gender alone as a single risk
factor (still a CHA2DS2-VASc score of 1) would not need anticoagulation if they clearly fulfill the criteria of
age <65 and lone AF.
8.2.3.1. Vitamin K antagonist therapy
In atrial fibrillation with at least 1 risk factor for stroke and thrombo-embolism (CHA2DS2-VASc score
≥1) oral anticoagulation (OAC) therapy, such as vitamin K antagonist (VKA) (warfarin, acenocumarol)
treatment adjusted to intensity range of INR 2.0-3.0 is suggested. VKA blocks the formation of vitamin Kdependent coagulation factors (factors II, VII, IX, and X), and the onset of the therapy should overlap with
LMWH administration (increased thrombotic risk due to VKA-induced inhibition of antithrombotic factors,
such as protein C and S) which should be continued until INR reaches the therapeutic range.
In a meta-analysis, the relative risk reduction with VKA was highly significant and amounted to 64%,
corresponding to an absolute annual risk reduction in 2.7% of all strokes. This reduction was similar for
both primary and secondary prevention and for both disabling and non-disabling strokes. Of note, many
strokes occurring in the VKA treated patients occurred when patients were not taking therapy or were
subtherapeutically anticoagulated. One of the many problems with anticoagulation with VKA is the high
interindividual and intraindividual variation in INRs. VKAs also have significant drug, food, and alcohol
interactions. On average, patients may stay within the intended INR range of 2.0-3.0 for 60-65% of the time
in controlled clinical trials, but many studies suggest that this figure may be <50%. Indeed, having patients
below the therapeutic range for <60% of the time may completely offset the benefit of VKA.
Although rate of intracranial bleeding increases with INR values >3.5-4.0, there is no increment in
bleeding risk with INR values between 2.0 and 3.0 compared with lower INR levels. The fear of falls may be
overstated, as a patient may need to fall 3̴ 00 times per year for the risk of intracranial haemorrhage to
outweigh the benefit of OAC in stroke prevention.
In the presence of high INR values without any bleeding VKA therapy should be suspended until INR
reaches the therapeutic range. When bleeding is associated with high INR levels administration of
parenteral antidote (vitamin K) and transfusions (fresh frozen plasma and red blood cells) would be
essential. In a life-threatening situation immediate hemodynamic stabilization as well as appropriate
interventions (neurosurgical, gastroenterological, surgical, urological, pulmonological or otolaryngological)
are required.
8.2.3.2. Novel oral anticoagulants
Several novel oral anticoagulant (NOAC) drugs have been developed for stroke prevention: the oral
direct thrombin inhibitors (dabigatran) and the oral factor Xa inhibitors (rivaroxaban, apixaban,
edoxaban). In contrast to VKAs, these drugs block the activity of one single step in coagulation.
The RE-LY trial compared two doses of dabigatran (110 mg b.i.d. or 150 mg b.i.d.) to warfarin aiming
for an INR of 2.0-3.0. For the primary efficacy endpoint of stroke and systemic embolism, high dose of
dabigatran was superior to warfarin, with no significant difference in the primary safety endpoint of major
bleeding. Lower dose of dabigatran was non-inferior to warfarin, with 20% fewer major bleedings.
In the ROCKET-AF trial high-risk patients with AF were randomized to either treatment with
rivaroxaban 20 mg o.d. (15 mg daily for those with estimated creatinine clearance: 30-49 mL/min) or
warfarin. Rivaroxaban was non-inferior to warfarin for the primary endpoint of stroke and systemic
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embolism. There was no reduction in rates of mortality or ischaemic stroke, but a significant reduction in
haemorrhagic stroke and intracranial haemorrhage could be observed. The primary safety endpoint was
the composite of major- and clinically relevant non-major bleeding, there was no significant difference
between rivaroxaban and warfarin but, with rivaroxaban, there was a significant reduction in fatal bleeding,
as well as an increase in gastrointestinal bleeds requiring transfusion.
The ARISTOTLE trial compared apixaban (5 mg b.i.d. with a dose adjustment to 2.5 mg b.i.d. in
patients ≥80 years, weight ≤60 kg or with a serum creatinine ≥133 mmol/L) to a dose-adjusted warfarin
therapy aiming for an INR of 2.0-3.0. There was a significant reduction in the primary efficacy outcome of
stroke or systemic embolism by 21% with apixaban compared with warfarin, with a 31% reduction in major
bleeding and a significant 11% reduction in all-cause mortality. Rates of haemorrhagic stroke and
intracranial haemorrhage were significantly lower in patients treated with apixaban than with warfarin.
Gastrointestinal bleeding was similar between the treatment arms.
The ENGAGE AF-TIMI 48 trial has shown that both edoxaban daily dosages (60 mg and 30 mg) were
non-inferior to warfarin for preventing stroke or systemic embolism in AF patients with moderate to high
risk for stroke, meanwhile edoxaban therapy was associated with significantly less major bleeding than VKA
treatment.
At a CHA2DS2-VASc score of 1, apixaban and both doses of dabigatran had a positive net clinical
benefit, while in patients with CHA2DS2-VASc score ≥2, all NOACs were superior to warfarin, with a positive
net clinical benefit, irrespective of bleeding risk. When switching from a VKA to a NOAC, the INR should be
allowed to fall to about 2.0 before starting the NOAC, all of which have rapid onset of anticoagulation
effect. All NOACs can be given in fixed doses without routine laboratory monitoring and have fewer drugdrug and food-drug interactions than VKAs.
8.2.3.3. Antiplatelet therapy
The ACTIVE A trial found that major vascular events were reduced in patients receiving aspirin plus
clopidogrel, compared with aspirin monotherapy, primarily due to a 28% relative reduction in the rate of
stroke with combination therapy.
The BAFTA study showed that VKA (target INR 2-3) was superior to aspirin 75 mg daily in reducing the
fatal or disabling stroke (ischaemic or haemorrhagic), intracranial haemorrhage, or clinically significant
arterial embolism by 52%, with no difference in the risk of major haemorrhage between warfarin and
aspirin.
In the ACTIVE W trial, anticoagulation therapy with warfarin was superior to the combination of
clopidogrel plus aspirin with no difference in bleeding events between treatment arms. Major bleeding was
similar to that seen with VKA therapy only.
Thus, in case on stroke risk factors (CHA2DS2-VASc score ≥1) antiplatelet therapy with aspirin plus
clopidogrel, or - less effectively - aspirin only, should only be considered in AF patients who refuse any OAC,
or cannot tolerate anticoagulants for reasons unrelated to bleeding. In case of no risk factors (CHA2DS2VASc score <1) no antithrombotic therapy is preferred rather than antiplatelet therapy.
8.2.3.4. Antithrombotic and antiplatelet therapy - special situations
Many anticoagulated AF patients have stable coronary or carotid artery disease and/or peripheral
artery disease, and common practice is to treat such patients with VKA plus one antiplatelet drug, usually
aspirin. Adding aspirin to VKA does not reduce the risk of stroke or vascular events (including myocardial
infarction), but substantially increases bleeding events. Thus, in patients with stable vascular disease (e.g.
with no acute ischaemic events or PCI/stent procedure in the preceding year), VKA monotherapy should be
used, and concomitant antiplatelet therapy should not be prescribed, since VKA therapy for secondary
prevention in patients with coronary artery disease is at least as effective as aspirin.
In AF patients undergoing elective percutaneous coronary intervention (PCI), drug-eluting stents
should be limited to clinical and/or anatomical situations, such as long lesions, small vessels, diabetes, etc.,
where a significant benefit is expected compared with bare-metal stents, and triple therapy (OAC, aspirin,
and ADP receptor blocker) should be used for 4 weeks followed by long-term therapy (up to 12 months)
with OAC plus ADP receptor blocker daily (or aspirin in case of intolerance). In case of drug-eluting stent
implantation, triple therapy should be administered for 3-6 months following OAC and ADP receptor
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blocker therapy. When anticoagulated AF patients are at moderate to high risk of thrombo-embolism, an
uninterrupted anticoagulation strategy can be preferred during PCI, and radial access should be used as the
first choice even during therapeutic anticoagulation (INR 2-3).
In patients with acute coronary syndrome (ACS) and/or percutaneous coronary intervention, dual
antiplatelet therapy with aspirin plus an ADP receptor blocker thienopyridine (clopidogrel or prasugrel or
ticagrelor) is recommended. In AF patients hospitalized with ACS and treated by PCI, bare-metal stent
implantation is recommended instead of drug-eluting stents plus instead of dual antiplatelet therapy, triple
therapy should be given. In this special case VKA non-treatment was associated with an increase in
mortality and major adverse cardiac events, with no significant difference in bleeding rates between VKAtreated and non-treated patients. The prevalence of major bleeding with triple therapy is 2.6-4.6% at 30
days, which increases to 7.4-10.3% at 12 months. Thus, short term triple therapy (3-6 months) seems to
have an acceptable risk-benefit ratio, which could be extended in selected patients at low bleeding risk
(HAS-BLED score <3). Following this initial treatment, longer therapy (up to 12 months) with OAC plus ADP
receptor blocker (or aspirin in case of intolerance) has to be given. At high bleeding risk (HAS-BLED score
≥3) 1 month long triple therapy is suggested followed by combination of OAC and ADP receptor blocker up
to 12 months. After 1 year treatment lifelong OAC only is recommended. Gastric protection with a proton
pump inhibitor should be considered (in almost all cases).
8.2.3.5. Cardioversion
Increased risk of thrombo-embolism following cardioversion is well recognized. Therefore,
anticoagulation is considered mandatory before elective (electrical and pharmacological) cardioversion for
AF of >48 h or AF of unknown duration. Antithrombotic treatment should be given for at least 3 weeks
before cardioversion and should be continued for a minimum of 4 weeks after cardioversion because of risk
of thrombo-embolism due to post-cardioversion left atrial dysfunction (so-called atrial stunning). In
patients with risk factors for stroke or AF recurrence, antithrombotic treatment should be continued
lifelong irrespective of apparent maintenance of sinus rhythm following cardioversion.
The mandatory 3-week period of thromboprophylaxis prior to cardioversion can be shortened if
transoesophageal echocardiogram (TEE) measurement reveals no LA or LAA thrombus. TEE may not only
show thrombus within the LAA, but may also identify spontaneous echo-contrast (sign of slow circulation)
or complex aortic plaque. If no LA thrombus is detected LMWH should be started prior to cardioversion and
continued thereafter until the OAC therapy. If TEE detects a thrombus in the left atrium or LAA, VKA (INR
2.0-3.0) treatment is required for at least 3 weeks and TEE should be repeated. If thrombus resolution is
evident, cardioversion can be performed, and post-cardioversion OAC is continued lifelong. If thrombus is
still evident, the planned rhythm control strategy may be changed to a rate control strategy.
In patients with a definite AF onset <48 h, cardioversion can be performed expediently under the cover
of LMWH. In patients with risk factors for stroke, OAC therapy should be started after cardioversion and
continued lifelong. No OAC is required in patients without thrombo-embolic risk factors.
In patients with AF <48 h with haemodynamic instability (angina, myocardial infarction, shock, or
pulmonary oedema), immediate DC cardioversion should be performed with LMWH administration before
and OAC therapy after the cardioversion.
8.2.3.6. Acute stroke
An acute stroke is a common first presentation of a patient with AF. There are limited trial data to
guide their management, and there is concern that patients within the first 2 weeks after cardioembolic
stroke are at greatest risk of recurrent stroke because of further thrombo-embolism. However,
anticoagulation in the acute phase may result in intracranial haemorrhage or haemorrhagic transformation
of the infarct. In patients with AF presenting with an acute stroke or TIA, uncontrolled hypertension should
be appropriately managed before antithrombotic treatment is started, and cerebral imaging, CT or
magnetic resonance imaging (MRI), should be performed to exclude haemorrhage. In the absence of
haemorrhage, anticoagulation should begin after 2 weeks, but, in the presence of haemorrhage,
anticoagulation should not be given. In patients with AF and acute TIA, anticoagulation treatment should
begin as soon as possible in the absence of cerebral infarction or haemorrhage.
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8.2.3.7. Valvular AF
In patients with AF related to valvular disease (e.g. mitral stenosis and prosthetic valves) only VKA
therapy is approved, since the RE-ALIGN trial with dabigatran has shown increased risk in thrombo-embolic
and bleeding events in the NOAC arm compared to warfarin therapy.
8.2.3.8. Atrial flutter
The risk of stroke in atrial flutter is similar to that seen in atrial fibrillation. Thus, thromboprophylaxis in
patients with atrial flutter should follow the same guidelines as in atrial fibrillation patients.
8.2.3.9. Non-pharmacological methods to prevent stroke
The left atrial appendage is thought to be the main site of atrial thrombogenesis. Thus, AF patients
with contraindications to chronic anticoagulation therapy might be considered as candidates for LAA orifice
occlusion which may reduce atrial thrombus formation and development of stroke.
Participants in the PROTECT AF trial received either percutaneous closure of the LAA (using a
WATCHMAN device) plus subsequent discontinuation of warfarin or VKA treatment (INR range 2-3) without
any intervention. In case of the primary efficacy endpoint (stroke, systemic embolism and cardiovascular
death) WATCHMAN device was considered non-inferior to that of VKA treatment.
8.3. Rate and rhythm management
The acute management of patients with AF is driven by acute protection against thrombo-embolic
events and acute improvement of cardiac function. The severity of AF-related symptoms should drive the
decision for acute restoration of sinus rhythm (in severely compromised patients) or acute management of
the ventricular rate (in most other patients).
8.3.1. Rate control
8.3.1.1. Acute rate control
An inappropriate ventricular rate and irregularity of the rhythm can cause symptoms (i.e. palpitations,
dyspnea, fatigue, and dizziness) and severe haemodynamic distress in AF patients. Patients with a rapid
ventricular response usually need acute control of their ventricular rate leading to reduced symptoms and
improved haemodynamics, by allowing enough time for ventricular filling and prevention of
tachycardiomyopathy.
In stable patients, this can be achieved by oral administration of beta-blockers or non-dihydropyridine
calcium channel antagonists. In severely compromised patients, i.v. verapamil or metoprolol can be useful
to slow atrioventricular node conduction rapidly. In the acute setting, the target ventricular rate should
usually be 80-100 bpm. In selected patients, amiodarone may be used, especially in those with severely
depressed LV function.
AF with slow ventricular rates may respond to atropine (0.5-2 mg i.v.), but many patients with
symptomatic bradyarrhythmia may require either urgent cardioversion or placement of a temporary
pacemaker lead in the right ventricle.
8.3.1.2. Long-term rate control
Acute initiation of rate control therapy should usually be followed by a long-term rate control strategy.
The optimal level of heart rate control with respect to morbidity, mortality, quality of life, and symptoms
remains unknown. Previous guidelines recommended strict rate control aiming at a resting heart rate
between 60-80 bpm and 90-115 bpm during moderate exercise. On the other hand, strict rate control
therapy sometimes required implantation of a pacemaker for symptomatic bradycardia, while higher
resting heart rates were not associated with an adverse prognosis. The recently published RACE II trial did
not identify a benefit of strict rate control over lenient rate control therapy. The trial suggests that an
initially lenient rate control approach should be used, aiming at a resting heart rate of <110 bpm. The dose
of rate control drugs can be increased and drugs can be combined until this target has been achieved. If
patients remain symptomatic, especially if complaints relate to excessive rate or irregularity, a stricter rate
control target (resting heart rate <80 bpm and a target heart rate of <110 bpm during moderate exercise)
should be pursued. The ventricular rate should be reduced until the patient becomes asymptomatic or
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symptoms become tolerable. In case of strict rate control a 24 h Holter monitor should be performed to
assess pauses and bradycardia. In patients who remain symptomatic on strict rate control therapy, rhythm
control therapy may be considered.
8.3.1.3. Pharmacological rate control
The main determinants of the ventricular rate during AF are the conduction characteristics and
refractoriness of the atrioventricular node and the sympathetic and parasympathetic tone. Drugs
commonly used are beta-blockers, digitalis and non-dihydropyridine calcium channel antagonists.
Furthermore, amiodarone may be suitable for some patients with otherwise refractory rate control.
Combinations of drugs may be necessary.
Beta-blockers (i.e. metoprolol, bisoprolol, atenolol, carvedilol) may be especially useful in the
presence of high adrenergic tone or symptomatic myocardial ischaemia occurring in association with AF.
Digoxin and digitoxin are effective in controlling heart rate at rest, but not during exercise. In
combination with a beta-blocker either may be effective in patients with or without heart failure. Digoxin
treatment normally affects ECG morphology causing ST depression and T wave inversion. On the other
hand digoxin may cause adverse effects including life-threatening situations (i.e. nausea, vomiting,
diarrhea, blurred vision, dizziness, confusion, agitation, delirium, psychosis, ECG changes: PQ interval
prolongation, bradycardia, AV block, bigeminia, ventricular tachycardia and fibrillation) due to its narrow
therapeutic index. Regular daily dose is 125 µg, while the therapeutic range in serum is 0.5-1.0 ng/ml. In
case of abnormal renal function digitoxin should be used instead of digoxin.
Amiodarone is an effective rate control drug. Intravenous amiodarone is effective and well tolerated
in haemodynamically ill patients. It may also be instituted for chronic treatment when conventional
measures are ineffective. Amiodarone, usually initiated for rhythm control, may continue to be used
inadvertently for rate control when patients have lapsed into permanent AF. Unless safer agents are
unsuitable, amiodarone should be discontinued in this setting.
Dronedarone (e.g. deiodined amiodarone) is effective as a rate-controlling drug for chronic treatment,
significantly decreasing the heart rate at rest and during exercise. The effects of dronedarone are additive
to those of other rate control agents.
Non-dihydropyridine calcium channel antagonists (verapamil and diltiazem) are effective for acute
and chronic rate control of AF. The drugs should be avoided in patients with systolic heart failure because
of their negative inotropic effect.
8.3.2. Pharmacological rhythm control and electrical cardioversion
8.3.2.1. Pharmacological cardioversion
The main motivation to initiate rhythm control therapy is relief of AF-related symptoms. Conversely,
asymptomatic patients (or those who become asymptomatic with adequate rate control therapy) should
not generally receive antiarrhythmic drugs.
Many episodes of AF terminate spontaneously within the first hours or days. If medically indicated
(e.g. in severely compromised patients), in patients who remain symptomatic despite adequate rate
control, or in patients in whom rhythm control therapy is pursued and the chance for a successful
cardioversion is fairly high, pharmacological cardioversion of AF may be initiated by a bolus administration
of an antiarrhythmic drug. Most patients who undergo pharmacological cardioversion require continuous
medical supervision and ECG monitoring during the drug infusion and for a period afterwards (usually
about half the drug elimination half-life) to detect proarrhythmic events such as ventricular proarrhythmia,
sinus node arrest, or atrioventricular block.
Flecainide (Na+ channel blocker, class Ic) given i.v. to patients with AF of short duration (especially <24
h) has an established effect (67-92% at 6 h) on restoring sinus rhythm. The usual dose is 2 mg/kg over 10
min. The majority of patients convert within the first hour after i.v. administration. It is rarely effective for
termination of atrial flutter or persistent AF.
Propafenone (Na+ channel blocker, class Ic) is an effective antiarrhythmic drug in converting recentonset AF to sinus rhythm. Within a few hours, the expected conversion rate was between 41 and 91% after
i.v. use (2 mg/kg over 10-20 min). The time to conversion varies from 30 min to 2 h. Propafenone has only a
limited efficacy for conversion of persistent AF and for atrial flutter.
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Flecainide and propafenone should be avoided in patients with underlying heart disease involving
abnormal LV function and ischaemia. In addition, owing to its weak beta-blocking properties, propafenone
should be avoided in severe obstructive lung disease. These drugs with their high proarrhythmic effect may
prolong QRS duration causing polymorphic ventricular tachycardia. Furthermore they may inadvertently
increase the ventricular rate due to conversion to atrial flutter and 1:1 conduction to the ventricles. Thus,
they should be combined with beta-blocker therapy which enhances the AV node conduction delay.
Cardioversion with amiodarone (K+ and other channel blocker, class III) occurs several hours later than
with flecainide or propafenone. The conversion rate at 24 h is 80-90% after amiodarone treatment.
Treatment should be started with a loading dose (5 mg/kg i.v. over 1 h) followed by a continuous perfusion
for 24 h. It may cause phlebitis, hypotension and decreased ventricular rate as side effects.
In patients with recent-onset AF, ibutilide (K+ and other channel blocker, class III) in one or two
infusions of (1 mg over 10 min each, with a wait of 10 min between doses), has a conversion rate ̴50%
within 90 min. The most important side effect of ibutilide is most often non-sustained polymorphic
ventricular tachycardia, while the QTc interval is expected to increase by ̴60 ms. Ibutilide is more effective
for conversion of atrial flutter than AF.
In summary, in suitable patients with recent-onset AF (generally <48 h duration), a trial of
pharmacological cardioversion to sinus rhythm can be recommended with i.v. flecainide or propafenone
(when there is little or no underlying structural heart disease) or amiodarone (when there is structural
disease). The anticipated conversion rate is ≥50% within ̴15-120 min.
8.3.2.2. Pill-in-the-pocket approach
Oral administration of flecainide or propafenon (conversion between 2 and 6 h) may be effective in
case of recent-onset AF. According to a trial, oral propafenone (450-600 mg) or flecainide (200-300 mg) can
be administered by the patient safely and effectively out of hospital.
This approach may be used in selected, highly symptomatic patients with infrequent (e.g. between
once per month and once per year) recurrences of AF and they could be instructed to take flecainide or
propafenone when symptoms of AF occur. In order to implement the pill-in-the-pocket technique, patients
should be screened for indications and contraindications, and the efficacy and safety of oral treatment
should be tested in hospital.
8.3.2.3. Electrical cardioversion - direct current cardioversion (DCC)
The conversion rate with DCC is higher than with antiarrhythmic drugs. It requires the presence of a
trained physician initiating appropriate conscious sedation or anaesthesia and the use of biphasic external
defibrillators because of their lower energy requirements and greater efficacy compared to those of
monophasic defibrillators. The defibrillator has to be in synchronized mode. Currently, two conventional
positions are commonly used for electrode placement. Several studies have shown that anteroposterior
electrode placement is more effective than anterolateral placement.
DCC is usually defined as termination of AF, documented as the presence of two or more consecutive P
waves after shock delivery. If initial shocks are unsuccessful for terminating the arrhythmia, the electrodes
should be repositioned and cardioversion repeated (maximum 2-3 times).
In pacemaker-dependent patients the electrode paddle should be at least 8 cm from the pacemaker
battery and an increase in pacing threshold should be anticipated. These patients should be monitored
carefully. After cardioversion, the device should be interrogated and evaluated to ensure normal function.
Outpatient/ambulatory DCC can be undertaken in patients who are haemodynamically stable and do
not have severe underlying heart disease. At least 3 h of ECG and haemodynamic monitoring are needed
after the procedure, before the patient is allowed to leave the hospital.
The risks and complications of cardioversion are associated primarily with thrombo-embolic events,
post-cardioversion arrhythmias, and the risks of general anaesthesia. The procedure is associated with 12% risk of thrombo-embolism, which can be reduced by adequate anticoagulation in the weeks prior to
cardioversion or by exclusion of left atrium thrombi before the procedure (e.g. TEE examination). Skin
burns are a common complication.
In patients with sinus node dysfunction, especially in elderly patients with structural heart disease,
prolonged sinus arrest without an adequate escape rhythm may occur. A pacing catheter or external pacing
14
pads may be needed if asystole or bradycardia occurs after the electric shock. Dangerous arrhythmias, such
as ventricular tachycardia and fibrillation may arise in the presence of hypokalaemia, digitalis intoxication,
or improper synchronization. The patient may become hypoxic or hypoventilated from sedation, but
hypotension and pulmonary oedema are rare.
Although atrial flutter is relatively resistant to chemical cardioversion, and often deteriorates into
atrial fibrillation prior to spontaneous return to sinus rhythm, it is considerably more sensitive to DCC than
AF, and usually requires a lower energy shock.
8.3.2.4. Long-term rhythm control
Antiarrhythmic treatment is mostly motivated and initiated by attempts to reduce AF-related
symptoms. In case of recurrent AF, long-term rhythm control is recommended on the basis of choosing
safer, although possibly less efficacious medication before resorting to more effective but less safe therapy.
Clinically successful antiarrhythmic drug therapy may reduce rather than eliminate recurrence of AF which
is associated with frequent drug-induced proarrhythmia or extra-cardiac side effects.
Beta-blockers are only modestly effective in preventing recurrent AF except in the context of
thyrotoxicosis and exercise-induced AF. The perceived antiarrhythmic effect may also be explained by
improved rate control that may render recurrent AF silent. Thus, beta-blockers (class II in Vaughan Williams
classification) are not considered effective antiarrhythmic drugs in AF.
In a recent meta-analysis of 44 randomized controlled trials comparing antiarrhythmic drugs against
control (placebo or no treatment), sodium channel blockers with fast (disopyramide, quinidine) or slow
(flecainide, propafenone) binding kinetics, and agents causing either pure potassium channel blockade
(dofetilide), potassium channel blockade plus beta-blockade (sotalol), or mixed ion channel blockade plus
antisympathetic effects (amiodarone) significantly reduced the rate of recurrent AF.
Overall, the likelihood of maintaining sinus rhythm is doubled by the use of antiarrhythmic drugs.
Amiodarone was superior to class I agents and sotalol. The number of patients needed to be treated was 3
with amiodarone, 4 with flecainide, 5 with dofetilide and propafenone, and 8 with sotalol.
In the meta-analysis, the number of patients needed to be treated for 1 year was 2-9. Withdrawal due
to side effects was frequent (1 in 9-27 patients), and all drugs except amiodarone increased the incidence
of proarrhythmia. Most of the trials enrolled relatively healthy patients without severe concomitant cardiac
disease. Although mortality was low in all studies (0-4.4%), rapidly dissociating sodium channel blockers
(disopyramide phosphate, quinidine sulfate) were associated with increased mortality (e.g. QT-prolonging
effect associated with risk for drug-induced torsades de pointes).
Flecainide approximately doubles the likelihood of maintaining sinus rhythm. Flecainide was initially
evaluated for paroxysmal AF, but is also used to maintain sinus rhythm after DCC. It can be safely
administered to patients without significant structural heart disease, but should not be used in patients
with coronary artery disease or in those with reduced LVEF (e.g. prolonging QRS duration causing potential
risk of proarrhythmia). Concomitant AV node blockade is recommended because of the potential of
flecainide to convert AF to atrial flutter, which then may be conducted rapidly to the ventricles.
Propafenone also prevents recurrent AF. In addition, propafenone has a weak beta-blocker effect. It
can be safely administered in patients without significant structural heart disease. Precautions similar to
those for flecainide should also be observed with propafenone as well.
Amiodarone is a good therapeutic option in patients with frequent, symptomatic AF recurrences
despite therapy with other antiarrhythmic drugs. Unlike most other agents, amiodarone can be safely
administered to patients with structural heart disease, including patients with heart failure. The risk of
drug-induced torsade de pointes is lower with amiodarone than with other potassium channel blockers,
possibly due to its multiple ion channel inhibition. However, drug-induced proarrhythmia is seen with
amiodarone, and the QT interval should be monitored closely. Amiodarone can cause several non-cardiac
side effects such as abnormalities in the thyroid gland function (e.g. hypo and hyperthyroidism), interstitial
lung disease (e.g. pulmonary fibrosis), elevation in the liver enzyme levels (jaundice, hepatomegaly and
hepatitis are rare), symptomless corneal micro-deposits and light-sensitive blue-grey discoloration of the
skin (patients should avoid exposure to the sun and use of suncream).
Sotalol less effectively prevents recurrent AF than amiodarone, although in the SAFE-T study, the
efficacy of sotalol to maintain sinus rhythm was not inferior to amiodarone in the subgroup of ischaemic
15
heart disease patients. Drug-induced proarrhythmia with sotalol is due to excessive prolongation of the QT
interval and/or bradycardia. Careful monitoring for QT prolongation and abnormal TU waves is mandatory.
In patients reaching a QT interval 500 ms, sotalol therapy should be stopped.
Dronedarone is a multichannel blocker that inhibits the sodium, potassium, and calcium channels, and
has non-competitive antiadrenergic activity. Similarly to sotalol, propafenone, and flecainide, its efficacy to
maintain sinus rhythm is lower than that of amiodarone. In the DIONYSOS study in patients with persistent
AF, dronedarone was less effective but also less toxic than amiodarone (e.g. fewer thyroid, neurological,
skin, and ocular events). The safety profile of dronedarone is advantageous in patients without structural
heart disease and in stable patients with heart disease. Specifically, dronedarone appears to have a low
potential for proarrhythmia.
8.3.2.5. Choice of antiarrhythmic drugs
AF occurring in patients with little or no underlying cardiovascular disease can be treated with almost
any antiarrhythmic drug that is licensed for AF therapy. In these patients, beta-blockers represent a logical
first attempt to prevent recurrent AF when the arrhythmia is clearly related to mental or physical stress.
Since beta-blockers are not very effective in many other patients with lone AF, flecainide, propafenone,
sotalol or dronedarone are usually prescribed.
Cardiovascular diseases have conventionally been divided into a variety of pathophysiological
substrates: hypertrophy, ischaemia, and congestive heart failure. For each of these it has been
recommended that specific drugs be avoided.
In patients with LV hypertrophy, sotalol is thought to be associated with an increased incidence of
proarrhythmia. Flecainide and propafenone may be used, but there is some concern about proarrhythmic
risk, especially in patients with marked hypertrophy (LV wall thickness >14 mm), and associated with
coronary artery disease. Dronedarone was demonstrated to be safe and well tolerated in patients with
hypertension and possible LV hypertrophy, although definitive data do not exist. Amiodarone should be
considered when symptomatic AF recurrences continue to impact on the quality of life of these patients.
In coronary artery disease, the CAST trial proved that flecainide and propafenone are contraindicated
since they increased the mortality after myocardial infarction. Studies on post-myocardial infarction
patients suggest that sotalol may be used relatively safely in coronary artery disease. In view of the better
safety and potential outcome benefit, dronedarone may be preferable as the first antiarrhythmic option, in
patients with symptomatic AF and underlying cardiovascular disease. If dronedarone fails to control
symptoms, amiodarone therapy might then be necessary, which is considered as the drug of last resort in
this population due to its extra-cardiac side effect profile.
In patients with heart failure dronedarone and amiodarone are the only agents available in Europe
that can be safely administered to patients with stable NYHA class I-II heart failure. Dronedarone is
contraindicated in patients with NYHA class III-IV or recently (within the previous 4 weeks) decompensated
heart failure. In such patients, amiodarone should be used.
It is challenging to make recommendations concerning the choice between amiodarone and
dronedarone for patients with structural heart disease. Dronedarone was tested in the ATHENA trial which
has shown numerical, but not significant reduction in cardiovascular mortality and in overall deaths in the
dronedarone treated AF patients. Amiodarone has not been evaluated in a large-scale randomized
controlled trial similar to ATHENA, but several meta-analyses have failed to identify a beneficial effect on
cardiovascular outcomes (e.g. amiodarone dose not decrease cardioivascular mortality). In its favour,
amiodarone has been used for many years without the emergence of any consistent and obvious cardiac
toxicity. On the other hand, general toxicity relating to amiodarone is considerable when used at higher
doses, but less when given at ≤200 mg per day.
8.3.3. Rhythm control with left atrial catheter ablation
In general, catheter ablation should be reserved for patients with AF which remains symptomatic
despite optimal medical therapy, including rate and rhythm control. Whether to undertake an ablation
procedure in a symptomatic patient the following should be taken into account:
(1) The stage of atrial disease (i.e. AF type, LA size, AF history)
(2) The presence and severity of underlying cardiovascular disease
16
(3) Potential treatment alternatives (antiarrhythmic drugs, rate control)
(4) Patient preference
Operator experience is an important consideration when considering ablation as a treatment option
since the possible complications in relation with a radiofrequency ablation are potentially life threatening
or disabling. The overall death rate related to the procedure is 0.7%. The EURObservational Research
Programme demonstrated that acute severe complication rates were 0.6% for stroke, 1.3% for tamponade,
1.3% for peripheral vascular complications, and around 2% for pericarditis. The incidence of silent cerebral
infarctions varies significantly among different ablation technologies, ranging from 4% to 35%.
Catheter ablation is usually undertaken in patients with symptomatic paroxysmal AF that is resistant
to at least one antiarrhythmic drug, however depending on the patients choice, it can be a first-line therapy
in patients with no or minimal structural heart disease and paroxysmal AF.
Studies and meta-analyses of studies performed mostly in patients with paroxysmal AF, comparing
antiarrhythmic drugs and catheter ablation and have shown a clearly better rhythm outcome after
catheter ablation. The MANTRA-PAF and RAAFT II trials compared catheter ablation of AF to
antiarrhythmic drug therapy as a first-line rhythm control intervention and demonstrated that significantly
more patients in the ablation group were free from any AF and symptomatic AF. The one year AF free
survival after catheter ablation varied between 56-89%, while with antiarrhythmic drugs it was found to be
between 7.3 and 43%.
For patients with either persistent AF or long-standing persistent AF, and no or minimal organic
heart disease, extensive and frequently repeated ablation procedures may be necessary. Ablation therapy
should be maintained for those who are refractory to antiarrhythmic drug treatment but ablation can be an
alternative to amiodarone treatment in younger patients.
For symptomatic paroxysmal and persistent AF in patients with relevant organic heart disease
antiarrhythmic drug treatment (e.g. amiodarone) is recommended before catheter ablation. Ablation
strategy in these patients may result significant improvement in ejection fraction and functional endpoints.
The benefit of AF-ablation has not been demonstrated in asymptomatic patients.
8.3.3.1. Ablation considerations and concepts in AF
Before ablation 12-leads ECG and Holter recording should be performed to demonstrate the
arrhythmia. Transthoracic echocardiogram can identify structural heart disease. CT or MRI imaging can
help to design the ablation strategy by revealing anatomical alterations and can be used for merge
procedures where the image is integrated into the electroanatomical map during ablation. It is now
possible to visualize atrial fibrosis before ablation by MRI, which helps in detecting the localization of
possible conductive gaps before a repeated procedure. LA thrombus (usually within the LAA) should be
excluded (by TEE or CT/MRI).
The concept behind the treatment of AF with catheter ablation includes partly the elimination of the
triggers mainly from the pulmonary veins (PVs) which may induce and sustain AF and to modify the
arrhythmia substrate that is the left atrium itself.
8.3.3.2. Trigger elimination by PV ablation
Triggered AF episodes initiated by focal firing from within the PVs led to the strategy of electrically
isolating these triggers from atrial substrate. This was achieved by circumferential mapping catheter that
was positioned within the PV ostia to guide ablation and target the connecting fibers by segmental ablation
until the elimination of PV potentials. This ablation method carries a risk for ostial stenosis and occlusion
hence the ablation is performed close to the PV ostia.
8.3.3.3. Linear PV isolation and circumferential PV ablation, complex fractionated electrograms
To reduce the risk of PV stenosis ablation sites were moved further towards the atrial side forming a
long lesion around one or both ipsilaterel PVs. This ablation technique not simply electrically isolates the
pulmonary veins but also the antral left atrial tissue which may serve as a substrate for maintenance of AF.
The PVs and the antrum are critical for maintenance of AF. Left atrial macroreentrant or focal tachycardias
are more common after this type of ablation due to incomplete lines or circles which makes a challenge
both for pharmacological and invasive treatment.
17
Ablation strategies that target the PVs and/or the PV antrum are the cornerstone for the most AF
ablation procedures. Patients with persistent or long-standing persistent AF or with left atrial
macroreentrant tachycardias may need additional linear ablation on the posterior left atrium between the
pulmonary veins or from the left inferior pulmonary vein to the mitral isthmus. Thus, a
compartmentalization of the left atrium can be achieved.
The ablation of complex fractionated electrograms (CFAEs) as a complementary technique can be
useful in patients with persistent AF.
8.3.3.4. Technical possibilities, ablation tools
The elimination of the pulmonary vein potentials by segmental ablation required only a circumferential
and an ablation catheter. The recently applied technique with widespread ablation round the pulmonary
veins in the antrum requires the application of electroanatomical mapping systems which provide detailed
information about the left atrial anatomy and pulmonary veins. The integration of CT or MRI images into
the system is also possible. To overcome the limitations of the sequential point-by-point ablations several
single-shot devices have been developed using cryoenergy and balloon technology or expandable
circumferential catheters and radiofrequency. The learning curve for the operator is shorter with these
devices but their potential collateral damage is still under investigation.
Left atrial ablation is also possible as a part of cardiac surgery or as a standalone operation. The cutand-sew technique is also known as the maze-procedure. Freedom from AF is 75-95% up to 15 years after
the procedure. Alternative energy sources, like radiofrequency, cryoablation, high-intensity focused
ultrasound can replicate the maze lines. The FAST trial compared the outcome of catheter ablation and
surgical ablation and the rhythm outcome was better after surgical ablation.
8.3.3.5. Anticoagulation therapy peri-ablation
Catheter ablation of AF may be performed with fewer complications when OAC therapy is continued.
VKA should be kept at low therapeutic levels (such as an INR of 2 to 2.5) throughout ablation, but
experience with NOAC is limited. Intravenous heparin administration with activated clotting time control
during the procedure is mandatory even with uninterrupted OAC therapy. This regimen helps to reduce
peri-procedural thrombo-embolic events (strokes). Continuation of long-term OAC therapy post-ablation is
recommended in all patients with a CHA2DS2-VASc score ≥2, irrespective of apparent procedural success.
For those patients with lower risk score anticoagulation should be continued for a minimum of 3 months
after the ablation.
8.3.3.6. Monitoring for atrial fibrillation recurrences
Symptom-based follow-up may be sufficient as symptom relief is the main aim of AF ablation. More
standardized ECG monitoring, 12-leads ECG, Holter recordings, transtelephonic recordings, loop recorders,
or implantable devices capable of intracardiac atrial electrogram recording (if they were implanted by
standard device implantation indications) may be necessary to compare different procedures and ablation
methods.
Expert consensus recommends an initial follow-up visit at 3 months, with 6 monthly intervals
thereafter for at least 2 years. Besides reconnection of previously isolated PVs iatrogenic atrial re-entrant
tachycardia due to incomplete lines of ablation is the major cause of post-ablation arrhythmia which may
require another ablation procedure. The most important predictor for a late recurrence appears to be early
recurrence of AF after the ablation procedure.
The technology behind AF ablation and the follow up tools of these patients evolve rapidly mainly
focusing on reducing the risk of peri-procedural complications and on reducing the learning curve of this
complex procedure. The relatively lower success rate that can be achieved in comparison with other
invasive electrophysiological procedures are due to the nature of the disease. Further investigation to
understand the mechanism and pathophysiology of AF is also mandatory.
Very important messages of the recent guidelines are that AF ablation has only indication in
symptomatic patients and the postprocedural anticoagulation management is based on the stroke risk
stratification rather than on the apparent success of the procedure.
18
8.3.3.7. Atrial flutter - catheter ablation in the right atrium
Because of the reentrant nature of atrial flutter, it is often possible to ablate the circuit that causes
atrial flutter. In case of type I atrial flutter a linear lesion to produce bidirectional block at the cavo-tricuspid
isthmus (e.g. the inferior right atrial isthmus connecting the tricuspid annulus to the inferior caval vein) can
block the conduction and terminate the arrhythmia. The recurrence rate of atrial flutter after isthmus
ablation is lower than 5%.
In patients with AF ablation who also have documented atrial flutter an additional isthmus ablation is
recommended. It is not uncommon to experience atrial flutter after the initiation of antiarrhythmic
medication (sodium channel blockers) for atrial fibrillation. In this case a hybrid therapy (antiarrhythmic
medication + isthmus ablation) can be successful.
8.3.4. Rate versus rhythm control
The initial therapy after onset of AF should always include adequate antithrombotic treatment and
control of the ventricular rate. The decision to add rhythm control therapy to the management of AF
requires individual decision and should therefore be discussed at the beginning of AF management. Before
choosing rate control alone as a long-term strategy, the clinician should consider how much permanent AF
is likely to affect the individual patient in the future and how successful rhythm control is expected to be.
Symptoms related to AF are an important determinant in making the choice between rate and rhythm
control (e.g. EHRA score) in addition to factors that may influence the success of rhythm control (i.e. long
history of AF, older age, more severe associated cardiovascular diseases, other associated medical
conditions, and enlarged LA size).
Several randomized trials (AFFIRM, RACE, AF-CHF, PIAF, STAF) compared outcomes of rhythm vs. rate
control strategies in patients with AF. The AFFIRM, RACE and AF-CHF found no difference in all-cause
mortality between patients on rhythm and rate control therapy. The AFFIRM database analysis has
suggested that harmful effects of antiarrhythmic drugs (a mortality increase of 49%) may have offset the
benefits of sinus rhythm (associated with a 53% reduction in mortality), while an analysis of the RACE
database suggested that underlying heart disease impacts prognosis more than AF itself.
In the AFFIRM, RACE, or AF-CHF trials, development of heart failure was not different between rate
control and rhythm control therapy. The RACE trial with highly selected patients with heart failure
undergoing extensive catheter ablation for AF suggests that LV function may deteriorate less or even
improve in patients undergoing rhythm control management.
The AFFIRM, RACE, STAF and PIAF trials found no differences in quality of life with rhythm control
compared with rate control. The quality of life is significantly impaired in patients with AF compared with
healthy controls and post-hoc analyses suggest that maintenance of sinus rhythm may improve quality of
life and associated with improved survival.
There is a clear lack of connection between the negative outcome of AF patients compared with those
in sinus rhythm (see section 6.1.) and the outcome of all rate vs. rhythm trials. The outcome of the ATHENA
(e.g. a trial with AF patients on dronedarone treatment found numerical reduction in cardiovascular
mortality and in overall deaths) trial is the first signal that safely maintained sinus rhythm may prevent
relevant outcomes in AF, but this trial alone cannot reconcile the lack of connection.
It may be concluded that rate control is a reasonable strategy in elderly patients, in whom the level of
symptoms related to AF is acceptable (EHRA score is 1). Rhythm control therapy is reasonable for
ameliorating symptoms, but should not result in cessation of antithrombotic therapy, rate control therapy,
or therapy of underlying heart disease. There is a clear need for a controlled trial to assess the effects of
catheter ablation and safe antiarrhythmic drugs as novel means for sinus rhythm maintenance on severe
cardiovascular outcomes compared with rate control.
9. Acknowledgement
This summary about atrial fibrillation represents the current opinion of the European Society of
Cardiology and based on its management guidelines of 2010 and on the focused update of 2012.
19
10. Quiz
1. In atrial fibrillation f waves and absolutely regular RR intervals can be seen on surface ECG:
A: true
B: false
2.
Valvular atrial fibrillation is associated with (2 right answers):
A: aortic stenosis
B: aortic regurgitation
C: mitral stenosis
D: prosthetic heart valves
E: heart failure
3.
Prevalence of atrial fibrillation in Europe (1 right answer):
A: 0.1-0.5%
B: 0.5-1.0%
C: 1.0-2.0%
D: 2.0-3.0%
E: 4.0-5.0%
4.
Features of persistent atrial fibrillation (2 right answers):
A: lasts longer than 7 days
B: self-terminating
C: presence of the arrhythmia is accepted, no rhythm control is employed
D: cardioversion e.g. by amiodarone (not spontaneously)
E: lasted for ≥1 year when rhythm control therapy is decided
5.
Features of atrial flutter (3 right answers):
A: ventricular rate is ≥200/min
B: F waves are positive in clockwise atrial flutter
C: reentrant loop circles can be detected mostly in the right atrium
D: regular or regularly irregular pulse
E: atrial cycle length is <200 ms
6.
Possible clinical consequences of atrial fibrillation (3 right answers):
A: cognitive dysfunction
B: embolism of the left lower limb
C: pulmonary embolism
D: heart failure
E: ishaemic heart disease
7.
The most common location of the thrombus in atrial fibrillation (1 right answer):
A: right atrium appendage
B: left atrium appendage
C: apical region of the left ventricle
D: atrial surface of the mitral valve
E: ventricular surface of the aortic valve
20
8.
Features of paroxysmal atrial fibrillation (2 right answers):
A: associated with right sided heart failure
B: cardioversion could be achieved after bisoprolol
C: does not last longer than 7 days
D: cardioverted by propafenone
E: does not require anticoagulation
9.
Diagnostic tools of atrial fibrillation (3 right answers):
A: Holter monitoring
B: transtelephonic ECG
C: loop recorders
D: stress echocardiography
E: OGTT
10. Conditions frequently associated with atrial fibrillation (3 right answers):
A: chronic prostatitis
B: ischaemic heart disease
C: overt thyroid dysfunction
D: aging
E: claudication intermittens
11. Risk factors of stroke in atrial fibrillation (2 right answers):
A: male sex
B: diabetes mellitus
C: frequent alcohol consumption
D: heart failure
E: anticoagulation therapy
12. CHA2DS2-VASc and HAS-BLED score of a female, 67 year old atrial fibrillation patient with obesity,
hypertension, stones in the gallbladder, fibromas in the left breast, COPD, left sided nephrectomy,
elevated creatinin level and prior right sided stroke (1 right answer):
A: CHA2DS2-VASc score: 3, HAS-BLED score: 2
B: CHA2DS2-VASc score: 1, HAS-BLED score: 6
C: CHA2DS2-VASc score: 5, HAS-BLED score: 2
D: CHA2DS2-VASc score: 3, HAS-BLED score: 1
E: CHA2DS2-VASc score: 5, HAS-BLED score: 4
13. Risk factors of bleeding in atrial fibrillation (3 right answers):
A: abnormal liver function
B: prior GI bleeding
C: age >60 years
D: labile INR
E: peripheral artery disease
21
14. Possible medications for rate control therapy in atrial fibrillation (3 right answers):
A: ivabradine
B: metoprolol
C: digitoxin
D: amlodipine
E: amiodarone
15. Target frequency in lenient rate control of atrial fibrillation (1 right answer):
A: ventricular frequency <110 bpm
B: atrial frequency <110 bpm
C: ventricular frequency <80 bpm
D: atrial frequency <80 bpm
E: ventricular frequency <60 bpm
16. Features of rate control therapy in atrial fibrillation (3 right answers):
A: bisoprolol can decrease palpitation
B: strict rate control is more frequently associated with loss of consciousness
C: digoxin blocks sinus node activity
D: amiodarone is contraindicated for rate control
E: dronedarone can significantly decrease the heart rate at rest and during exercise
17. Features of digoxin therapy (4 right answers):
A: effective for rate control at rest but not during exercise
B: adverse effects of digoxin are nausea, vomiting, blurred vision, confusion, etc
C: signs of normal digoxin effect on ECG are ST depression and T inversion
D: in case of abnormal renal function digitoxin should be used instead of digoxin
E: therapeutic range in serum is 0.5-2.0 ng/ml
18. Anticoagulation therapy is indicated in (2 right answers):
A: atrial flutter
B: coronary heart disease
C: prosthetic heart valve implantation
D: carotis stenosis
E: pulmonary hypertension
19. Besides atrial fibrillation rivaroxaban can be used in (3 right answers):
A: pulmonary embolism
B: prosthetic heart valve implantation
C: deep vein thrombosis
D: peripheral artery disease
E: after hip replacement surgery
22
20. Features of vitamin K antagonist therapy in atrial fibrillation (2 right answers):
A: target INR should be between 3.0-4.0
B: alcohol consumption increases the effect of acenocumarol
C: transfusion of fresh frozen plasma reverses the effect of vitamin K antagonist therapy
D: dabigatran can cause cardioversion
E: warfarin has higher antithrombotic effect than apixaban
21. Features of dabigatran therapy in atrial fibrillation (2 right answers):
A: efficient therapy requires INR between 2.0-3.0
B: causing strict rate control
C: direct thrombin inhibition
D: intravenous administration
E: no food interaction
22. Stroke preventive medications in atrial fibrillation (3 right answers):
A: clopidogrel
B: apixaban
C: amiodarone
D: enoxaparin
E: verapamil
23. Possibilities of rhythm control therapy for atrial fibrillation patients with ischaemic heart disease (3
right answers):
A: propafenone
B: carvedilol
C: dronedarone
D: sotalol
E: direct current cardioversion
24. Possible side effects of amiodarone (3 right answers):
A: pulmonary fibrosis
B: kidney failure
C: corneal micro-deposits
D: elevated liver enzymes
E: cataract
25. Features of antiarrhythmic medications in atrial fibrillation (1 right answer):
A: flecainide can be indicated in atrial fibrillation patients with severe left ventricular hypertrophy
B: amiodarone decreases mortality
C: sotalol can prolong QT interval
D: propafenone is a potassium channel blocker
E: diltiazem can be given to atrial fibrillation patients with heart failure
23
26. Features of electrical cardioversion (3 right answers):
A: atrial flutter is more sensitive to electrical cardioversion than atrial fibrillation
B: the conversion rate with direct current cardioversion is lower than with antiarrhythmic drugs
C: the defibrillator has to be in synchronized mode
D: electrical cardioversion may cause prolonged sinus arrest
E: there is no risk for thrombo-embolic events during direct current cardioversion
27. The approximate one year arrhythmia free survival after atrial fibrillation ablation (1 right answer):
A: ≤14%
B: 15-33%
C: 34-55%
D: 56-89%
E: ≥90%
28. Anatomical structures which provide mainly the trigger and the substrate of atrial fibrillation (2 right
answers):
A: caval veins
B: pulmonary veins
C: right and left atrial appendage
D: peri-mitral atrial tissue
E: antral left atrial tissue
29. It is not recommended to perform ablation therapy in asymptomatic paroxysmal atrial fibrillation:
A: true
B: false
30. False allegation regarding atrial fibrillation ablation (1 right answer):
A: after atrial fibrillation ablation expert consensus recommends an initial follow-up visit at 3 months,
with 6 monthly intervals thereafter for at least 2 years
B: continuation of long-term anticoagulation therapy is recommended in all patients with a CHA2DS2VASc score ≥2 irrespective of apparent procedural success
C: symptom-based follow-up may be sufficient as symptom relief is the main aim of ablation
D: the most important predictor for a late recurrence appears to be the early recurrence of atrial
fibrillation after the ablation procedure
E: a permanent pacemaker implantation with atrial lead can be recommended for the follow-up after
AF ablation to be able to evaluate the success rate precisely
24
11. Right answers
1. B
2. C,D
3. C
4. A,D
5. B,C,D
6. A,B,D
7. B
8. B,C
9. A,B,C
10. B,C,D
11. B,D
12. E
13. A,B,D
14. B,C,E
15. A
16. A,B,E
17. A,B,C,D
18. A,C
19. A,C,E
20. B,C
21. C,E
22. A,B,D
23. C,D,E
24. A,C,D
25. C
26. A,C,D
27. D
28. B,E
29. A
30. E
25
12. References
[1]
[2]
[3]
[4]
[5]
[6]
[7]
[8]
[9]
[10]
[11]
[12]
[13]
[14]
[15]
[16]
[17]
[18]
[19]
[20]
[21]
[22]
[23]
[24]
[25]
[26]
[27]
[28]
Stewart S, Hart CL, Hole DJ, et al. Population prevalence, incidence, and predictors of atrial fibrillation in the
Renfrew/Paisley study. Heart 2001; 86: 516-521.
Go AS, Hylek EM, Phillips KA, et al. Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm
management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. JAMA
2001; 285: 2370-2375.
Kirchhof P, Auricchio A, Bax J, et al. Outcome parameters for trials in atrial fibrillation: executive summary.
Recommendations from a consensus conference organized by the German Atrial Fibrillation Competence NETwork
(AFNET) and the European Heart Rhythm Association (EHRA). Eur Heart J 2007; 28: 2803-2817.
Lip GY, Golding DJ, Nazir M, et al. A survey of atrial fibrillation in general practice: the West Birmingham Atrial
Fibrillation Project. Br J Gen Pract 1997; 47: 285-289.
Miyasaka Y, Barnes ME, Gersh BJ, et al. Secular trends in incidence of atrial fibrillation in Olmsted County, Minnesota,
1980 to 2000, and implications on the projections for future prevalence. Circulation 2006; 114: 119-125.
Heeringa J, van der Kuip DA, Hofman A, et al. Prevalence, incidence and lifetime risk of atrial fibrillation: the Rotterdam
study. Eur Heart J 2006; 27: 949-953.
Naccarelli GV, Varker H, Lin J, et al. Increasing prevalence of atrial fibrillation and flutter in the United States. Am J
Cardiol 2009; 104: 1534-1539.
Fox CS, Parise H, D’Agostino RB Sr, et al. Parental atrial fibrillation as a risk factor for atrial fibrillation in offspring.
Parental atrial fibrillation as a risk factor for atrial fibrillation in offspring. JAMA 2004; 291: 2851-2855.
Hodgson-Zingman DM, Karst ML, Zingman LV, et al. Atrial natriuretic peptide frameshift mutation in familial atrial
fibrillation. N Engl J Med 2008; 359: 158-165.
Olson TM, Michels VV, Ballew JD, et al. Sodium channel mutations and susceptibility to heart failure and atrial
fibrillation. JAMA 2005; 293: 447-454.
Chen YH, Xu SJ, Bendahhou S, et al. KCNQ1 gain-of-function mutation in familial atrial fibrillation. Science 2003; 299:
251-254.
Packer DL, Bardy GH, Worley SJ, et al. Tachycardia-induced cardiomyopathy: a reversible form of left ventricular
dysfunction. Am J Cardiol 1986; 57: 563-570.
Thrall G, Lane D, Carroll D, et al. Quality of life in patients with atrial fibrillation: a systematic review. Am J Med 2006;
119: 448 e1-e19.
Watson T, Shantsila E, Lip GY. Mechanisms of thrombogenesis in atrial fibrillation: Virchow’s triad revisited. Lancet
2009; 373: 155-166.
Knecht S, Oelschlager C, Duning T, et al. Atrial fibrillation in stroke-free patients is associated with memory impairment
and hippocampal atrophy. Eur Heart J 2008; 29: 2125-2132.
Friberg L, Hammar N, Rosenqvist M. Stroke in paroxysmal atrial fibrillation: report from the Stockholm Cohort of Atrial
Fibrillation. Eur Heart J 2010; 31: 967-975.
Stewart S, Hart CL, Hole DJ, et al. A population-based study of the longterm risks associated with atrial fibrillation: 20year follow-up of the Renfrew/Paisley study. Am J Med 2002; 113: 359-364.
Hylek EM, Go AS, Chang Y, et al. Effect of intensity of oral anticoagulation on stroke severity and mortality in atrial
fibrillation. N Engl J Med 2003; 349: 1019-1026.
Nieuwlaat R, Capucci A, Camm AJ, et al. Atrial fibrillation management: a prospective survey in ESC member countries:
the Euro Heart Survey on Atrial Fibrillation. Eur Heart J 2005; 26: 2422-2434.
Nabauer M, Gerth A, Limbourg T, et al. The Registry of the German Competence NETwork on Atrial Fibrillation: patient
characteristics and initial management. Europace 2009; 11: 423-434.
Hobbs FD, Fitzmaurice DA, Mant J, et al. A randomised controlled trial and cost-effectiveness study of systematic
screening (targeted and total population screening) versus routine practice for the detection of atrial fibrillation in
people aged 65 and over. The SAFE study. Health Technol Assess 2005; 9: iii-iv, ix-x, 1-74.
Klein AL, Grimm RA, Murray RD, et al. Use of transesophageal echocardiography to guide cardioversion in patients with
atrial fibrillation. N Engl J Med 2001; 344: 1411-1420.
Lip GY, Nieuwlaat R, Pisters R, et al. Refining clinical risk stratification for predicting stroke and thromboembolism in
atrial fibrillation using a novel risk factor-based approach: the Euro Heart Survey on atrial fibrillation. Chest 2010; 137:
263-272.
Pisters R, Lane DA, Nieuwlaat R, et al. A novel userfriendly score (HAS-BLED) to assess one-year risk of major bleeding
in atrial fibrillation patients: The Euro Heart Survey. Chest 2010; 138: 1093-1100.
Connolly S, Pogue J, Hart R, et al. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial
fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled
trial. Lancet 2006; 367: 1903-1912.
Connolly SJ, Pogue J, Hart RG, et al. Effect of clopidogrel added to aspirin in patients with atrial fibrillation. N Engl J
Med 2009; 360: 2066-2078.
Friberg L, Benson L, Rosenqvist M, et al. Assessment of female sex as a risk factor in atrial fibrillation in Sweden:
nationwide retrospective cohort study. BMJ 2012; 344: e3522.
Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have
nonvalvular atrial fibrillation. Ann Intern Med 2007; 146: 857-867.
26
[29] Connolly SJ, Ezekowitz MD, Yusuf S, et al. Newly identified events in the RE-LY trial. N Engl J Med 2010; 363: 1875-1876.
[30] Patel MR, Mahaffey KW, Garg J, et al; ROCKET AF Investigators. Rivaroxaban vs. warfarin in nonvalvular atrial
fibrillation. N Engl J Med 2011; 365: 883-891.
[31] Granger CB, Alexander JH, McMurray JJ, et al; ARISTOTLE Committees and Investigators. Apixaban vs. warfarin in
patients with atrial fibrillation. N Engl J Med 2011; 365: 981-992.
[32] Giugliano RP, Ruff CT, Braunwald E, et al; ENGAGE AF-TIMI 48 Investigators. Edoxaban versus warfarin in patients with
atrial fibrillation. N Engl J Med 2013; 369: 2093-2104.
[33] Mant J, Hobbs FD, Fletcher K, et al. Warfarin versus aspirin for stroke prevention in an elderly community population
with atrial fibrillation (the Birmingham Atrial Fibrillation Treatment of the Aged Study, BAFTA): a randomised controlled
trial. Lancet 2007; 370: 493-503.
[34] Lip GY, Huber K, Andreotti F, et al. Management of antithrombotic therapy in atrial fibrillation patients presenting with
acute coronary syndrome and/or undergoing percutaneous coronary intervention/stenting. Thromb Haemost 2010;
103: 13-28.
[35] Eikelboom JW, Connolly SJ, Brueckmann M, et al; RE-ALIGN Investigators. Dabigatran versus warfarin in patients with
mechanical heart valves. N Engl J Med 2013; 369: 1206-1214.
[36] Holmes DR, Reddy VY, Turi ZG, et al. Percutaneous closure of the left atrial appendage versus warfarin therapy for
prevention of stroke in patients with atrial fibrillation: a randomised noninferiority trial. Lancet 2009; 374: 534-542.
[37] Wyse DG, Waldo AL, DiMarco JP, et al; AFFIRM Investigators. A comparison of rate control and rhythm control in
patients with atrial fibrillation. N Engl J Med 2002; 347: 1825-1833.
[38] Van Gelder IC, Groenveld HF, Crijns HJ, et al. Lenient versus strict rate control in patients with atrial fibrillation. N Engl J
Med 2010; 362: 1363-1373.
[39] Reisinger J, Gatterer E, LangW, et al. Flecainide versus ibutilide for immediate cardioversion of atrial fibrillation of
recent onset. Eur Heart J 2004; 25: 1318-1324.
[40] Khan IA. Single oral loading dose of propafenone for pharmacological cardioversion of recent-onset atrial fibrillation. J
Am Coll Cardiol 2001; 37: 542-547.
[41] Alboni P, Botto GL, Baldi N, et al. Outpatient treatment of recent-onset atrial fibrillation with the ‘pill-in-the-pocket’
approach. N Engl J Med 2004; 351: 2384-2391.
[42] Kirchhof P, Eckardt L, Loh P, et al. Anterior-posterior versus anterior-lateral electrode positions for external
cardioversion of atrial fibrillation: a randomised trial. Lancet 2002; 360: 1275-1279.
[43] Lafuente-Lafuente C, Mouly S, Longas-Tejero MA, et al. Antiarrhythmics for maintaining sinus rhythm after
cardioversion of atrial fibrillation. Cochrane Database Syst Rev 2007; 4: CD005049.
[44] McNamara RL, Bass EB, Miller MR, et al. Management of new onset atrial fibrillation (evidence report/Technology
assessment). In: Agency for Heathcare Research and Quality 2001, Publication No. AHRQ 01-E026.
[45] Connolly SJ. Evidence-based analysis of amiodarone efficacy and safety. Circulation 1999; 100: 2025-2034.
[46] Kirchhof P, Franz MR, Bardai A, et al. Giant T-U waves precede torsades de pointes in long QT syndrome. A systematic
electrocardiographic analysis in patients with acquired and congenital QT prolongation. J Am Coll Cardiol 2009; 54:
143-149.
[47] Fetsch T, Bauer P, Engberding R, et al. Prevention of atrial fibrillation after cardioversion: results of the PAFAC trial. Eur
Heart J 2004; 25: 1385-1394.
[48] Singh BN, Singh SN, Reda DJ, et al. Amiodarone versus sotalol for atrial fibrillation. N Engl J Med 2005; 352: 1861-1872.
[49] Kaab S, Hinterseer M, Nabauer M, et al. Sotalol testing unmasks altered repolarization in patients with suspected
acquired long-QT-syndrome-a casecontrol pilot study using i.v. sotalol. Eur Heart J 2003; 24: 649-657.
[50] Le Heuzey J, De Ferrari GM, Radzik D, et al. A short-term, randomized, double-blind, parallel-group study to evaluate
the efficacy and safety of dronedarone versus amiodarone in patients with persistent atrial fibrillation: the DIONYSOS
study. J Cardiovasc Electrophysiol 2010; 21: 597-605.
[51] Hohnloser SH, Crijns HJ, van Eickels M, et al. Effect of dronedarone on cardiovascular events in atrial fibrillation. N Engl
J Med 2009; 360: 668-678.
[52] Echt DS, Liebson PR, Mitchell LB, et al; Investigators and the CAST investigators. Mortality and morbidity in patients
receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial. N Engl J Med 1991; 324: 781-788.
[53] Kober L, Torp-Pedersen C, McMurray JJ, et al. Increased mortality after dronedarone therapy for severe heart failure. N
Engl J Med 2008; 358: 2678-2687.
[54] Piccini JP, Hasselblad V, Peterson ED, et al. Comparative efficacy of dronedarone and amiodarone for the maintenance
of sinus rhythm in patients with atrial fibrillation. J Am Coll Cardiol 2009; 54: 1089-1095.
[55] Singh D, Cingolani E, Diamon GA, et al. Dronedarone for atrial fibrillation: have we expanded the antiarrhythmic
armamentarium. J Am Coll Cardiol 2010; 55: 1569-1576.
[56] Arbelo E, Brugada J, Hindricks G, et al; Atrial Fibrillation Ablation Pilot Study Investigators. ESC-EURObservational
research programme: the atrial fibrillation ablation pilot study, conducted by the European Heart Rhythm Association.
Europace 2012; 14: 1094-1103.
[57] Wilber DJ, Pappone C, Neuzil P, et al. Comparison of antiarrhythmic drug therapy and radiofrequency catheter ablation
in patients with paroxysmal atrial fibrillation: a randomized controlled trial. JAMA 2010; 303: 333-340.
[58] Calkins H, Reynolds MR, Spector P, et al. Treatment of atrial fibrillation with antiarrhythmic drugs or radiofrequency
ablation: two systematic literature reviews and meta-analyses. Circ Arrhythm Electrophysiol 2009; 2: 349-361.
27
[59] Noheria A, Kumar A, Wylie JV Jr, et al. Catheter ablation vs antiarrhythmic drug therapy for atrial fibrillation: a
systematic review. Arch Intern Med 2008; 168: 581-586.
[60] Jais P, Cauchemez B, Macle L, et al. Catheter ablation versus antiarrhythmic drugs for atrial fibrillation: the A4 study.
Circulation 2008; 118: 2498-2505.
[61] Wazni OM, Marrouche NF, Martin DO, et al. Radiofrequency ablation vs antiarrhythmic drugs as first-line treatment of
symptomatic atrial fibrillation: a randomized trial. JAMA 2005; 293: 2634-2640.
[62] Pappone C, Augello G, Sala S, et al. A randomized trial of circumferential pulmonary vein ablation versus antiarrhythmic
drug therapy in paroxysmal atrial fibrillation: the APAF Study. J Am Coll Cardiol 2006; 48: 2340-2347.
[63] Boersma LV, Castella M, van Boven W, et al. Atrial fibrillation catheter ablation vs. surgical ablation treatment (FAST): a
2-center randomized clinical trial. Circulation 2012; 125: 23-30.
[64] Van Gelder IC, Hagens VE, Bosker HA, et al. A comparison of rate control and rhythm control in patients with recurrent
persistent atrial fibrillation. N Engl J Med 2002; 347: 1834-1840.
[65] Roy D, Talajic M, Nattel S, et al. Rhythm control versus rate control for atrial fibrillation and heart failure. N Engl J Med
2008; 358: 2667-2677.
[66] Hsu LF, Jais P, Sanders P, et al. Catheter ablation for atrial fibrillation in congestive heart failure. N Engl J Med 2004;
351: 2373-2383.
[67] Khan MN, Jais P, Cummings J, et al. Pulmonary-vein isolation for atrial fibrillation in patients with heart failure. N Engl J
Med 2008; 359: 1778-1785.
[68] Carlsson J, Miketic S, Windeler J, et al; STAF Investigators. Randomized trial of rate-control versus rhythmcontrol in
persistent atrial fibrillation. J Am Coll Cardiol 2003; 41: 1690-1696.
[69] Hohnloser SH, Kuck KH, Lilienthal J. Rhythm or rate control in atrial fibrillation - Pharmacological Intervention in Atrial
Fibrillation (PIAF): a randomised trial. Lancet 2000; 356: 1789-1794.
28
II. The diagnosis and management of heart failure
Dr. Tamas Habon, Dr. Robert Halmosi, Dr. Roland Gal, Dr. Barbara Sandor
1 Department of Medicine, Medical School, University of Pecs, Pecs, Hungary
st
1. Introduction
1.1. Definition and terminology
Heart failure (HF) can be defined as an abnormality of cardiac structure or function leading to failure of
the heart to deliver oxygen at a rate commensurate with the requirements of the metabolizing tissues,
despite normal filling pressures (or only at the expense of increased filling pressures). Heart failure is
defined, clinically, as a syndrome in which patients have typical symptoms (e.g. breathlessness, ankle
swelling, and fatigue) and signs (e.g. elevated jugular venous pressure, pulmonary crackles, and displaced
apex beat) resulting from an abnormality of cardiac structure or function at rest.
The main terminology used to describe heart failure is historical and is based on the measurement of
left ventricle ejection fraction (EF). EF is the stroke volume (which is the end-diastolic volume minus the
end-systolic volume) divided by the end-diastolic volume. The EF is considered important in heart failure,
not only because of its prognostic importance (the lower is the EF the poorer is the survival) but also
because most clinical trials selected patients based upon EF.
1.1.1. Terminology related to the ejection fraction (EF)
Heart failure is divided into two different types: heart failure due to reduced ejection fraction (HFrEF)
also known as heart failure due to left ventricular systolic dysfunction or systolic heart failure (EF <40%) and
heart failure with preserved ejection fraction (HFpEF) also known as diastolic heart failure (Table 1).
Patients with an EF in the range of 40-50% therefore represent a ‘grey area’ and most probably have
primarily mild systolic dysfunction.
The diagnosis of HFrEF requires three conditions to be satisfied
(1) symptoms typical of HF
(2) signs typical of HF
(3) reduced LVEF
The diagnosis of HFpEF requires four conditions to be satisfied
(1) symptoms typical of HF
(2) signs typical of HF
(3) normal or only mildly reduced LVEF and LV not dilated
(4) structural heart disease (LV hypertrophy/LA enlargement) and/or diastolic dysfunction
Table 1. Diagnosis of heart failure
1.1.2. Terminology related to the time-course of HF
A patient who has never exhibited the typical signs or symptoms of cardiac insuffiency is described as
having asymptomatic systolic dysfunction (or whatever the underlying cardiac abnormality is). Patients who
have had heart failure for some time are often said to have ‘chronic heart failure’. A treated patient with
symptoms and signs, which have remained generally unchanged for at least a month, is said to be ‘stable’.
If chronic stable HF deteriorates, the patient may be described as ‘decompensated’ and this may happen
suddenly, i.e. ‘acutely’, usually leading to hospital admission, an event of considerable prognostic
importance.
1.1.3. Terminology related to the symptomatic severity of HF
The quantification of heart failure symptoms is useful for assessing the adequacy of therapy and
determining prognosis. The New York Heart Association (NYHA) functional classification is most often
used for this purpose (Table 2).
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The NYHA classification provides a shorthand means of detecting changes in the patient’s symptomatic
status that occur over time or in response to treatment, and it facilitates communication between various
providers about the patient’s clinical status.
The Killip classification may be used to describe the severity of the patient’s condition in the acute
setting of myocardial infarction (Table 3).
It is important to note, however, that symptom severity correlates poorly with ventricular function,
and that although there is a clear relationship between severity of symptoms and survival, patients even
with mild symptoms may still have a relatively high absolute risk of hospitalization and death.
Class
Symptoms
no limitation of physical activity
Class I (mild)
ordinary physical activity does not cause undue fatigue, palpitation, or
dyspnea (shortness of breath)
slight limitation of physical activity
Class II (mild)
comfortable at rest, but ordinary physical activity results in fatigue,
palpitation, or dyspnea
marked limitation of physical activity
Class III (moderate) comfortable at rest, but less than ordinary activity causes fatigue,
palpitation, or dyspnea
unable to carry out any physical activity without discomfort
Class IV (severe)
symptoms of cardiac insufficiency at rest
if any physical activity is undertaken, discomfort is increased
Table 2. The New York Heart Association Functional Classification (NYHA) of Heart Failure
Killip classification Cardiac decompensation Cardiac arrest (%) Hospital mortality (%)
Class I
no heart failure
5
6
Class II
heart failure
15
17
Class III
pulmonary oedema
46
38
Class IV
cardiogenic shock
77
81
Table 3. The Killip classification of heart failure in acute setting of myocardial infarction
2. Epidemiology
Heart failure prevalence is continously rising throughout the world. The worldwide prevalence and
incidence rates of heart failure (HF) are approaching epidemic proportions, as evidenced by the relentless
increase in the number of HF hospitalizations, the growing number of HF-attributable deaths, and the
spiraling costs associated with the care of HF patients. Approximately 1-2% of the adult population in
developed countries has HF, with the prevalence rising to more than 10% among persons 70 years of age or
older. Worldwide, HF affects almost 23 million people and in the United States, heart failure affects 5.8
million people, and each year 550 000 new cases are diagnosed. The prevalence of symptomatic HF in the
general European population is similar to that in the United States, and ranges from 0.4% to 2%. The
relative incidence of HF is lower in women than in men. In the Hillingdon study the incidence of heart
failure increased from 0.2/1000 person years in those aged 45-55 years to 12.4/1000 person years in those
aged >85 years. In the Rotterdam study the incidence increased from 2.5/1000 person years (age 55-64
years) to 44/1000 person years (age >85 years). The lifetime risk of developing HF is approximately one in
five for a 40-year-old person. The overall prevalence of HF is thought to be increasing, in part because our
current therapies of cardiac disorders are allowing patients to survive longer.
Approximately 50% of HF patients have a normal or preserved EF (EF >40-50%). HFpEF has a different
epidemiological and etiological profile from HFrEF. HFpEF is a systemic disorder with complex, multifactorial pathophysiology and clinical heterogeneity. Patients are older and more often female and obese
than those with HFrEF. They are less likely to have coronary heart disease and more likely to have
hypertension and atrial fibrillation (AF). HFpEF has a better prognosis than HFrEF.
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3. Etiology
Usually myocardial diseases cause systolic ventricular dysfunction. However, abnormalities of the
ventricular diastolic function or of the valves, the pericardium, endocardium, heart rhythm, and conduction
can also cause HF (and more than one abnormality can be present).
Based on population-attributable risks, hypertension has the greatest impact on the development of
HF, accounting for 39% of HF events in men and 59% in women. Despite its much lower prevalence in the
population (3-10%), myocardial infarction also has a high attributable risk in men (34%) and women (13%).
Valvular heart disease only accounted for 7% to 8% of HF.
In industrialized countries, coronary artery disease (CAD) has become the predominant cause in men
and women, and is responsible for 60% to 75% of HF cases. Both CAD and hypertension interact to
augment the risk of HF. There are many other causes of systolic HF (Table 4), which include previous viral
infection (recognized or unrecognized), alcohol abuse, chemotherapy (e.g. doxorubicin or trastuzumab) or
metabolic disorders, etc. In 20% to 30% of the HF cases with a depressed EF, the exact causative basis is not
known. These patients are referred to as having non-ischemic, dilated, or idiopathic cardiomyopathy if the
cause is unknown (although the cause is thought to be unknown, some of these cases may have a genetic
basis). Rheumatic heart disease remains a major cause of HF in Africa and Asia, especially in the young.
Myocardial disease: coronary artery disease, cardiomyopathy’s
(1) familial cardiomyopathy’s:
- hypertrophic, dilated, arrhythmogenic right ventricular, restrictive, left ventricular non-compaction
(2) acquired cardiomyopathy’s:
- myocarditis (inflammatory cardiomyopathy):
• infective: bacterial, spirochaetal, fungal, protozoal, parasitic, rickettsial, viral
• immune-mediated: vaccines, drugs, lymphocytic/giant cell myocarditis,
sarcoidosis, autoimmune, eosinophilic (Churg-Strauss)
• toxic: drugs (e.g. hemotherapy, cocaine), alcohol, heavy metals (copper, iron, lead)
- endocrine/nutritional: phaeochromocytoma, hypophosphataemia, hypocalcaemia, thyreotoxicosis,
vitamin deficiency (e.g. thiamine), selenium deficiency, beri-beri
- pregnancy
- infiltration (amyloidosis, malignancy)
Valvular heart disease: mitral, aortic, tricuspid, pulmonary
Pericardial disease: constrictive pericarditis, pericardial effusion
Endocardial disease: endomyocardial diseases with hypereosinophilia (hypereosinophilic-syndromes),
endomyocardial disease without hypereosinophilia (e.g. endomyocardial fibrosis),
endocardial fibroelastosis
Congenital heart disease
Arrhythmia: tachyarrhythmia, atrial, ventricular, bradyarrhythymia, sinus node dysfunction
Conduction disorders: atrioventricular block, LBBB
High output states: anaemia, sepsis, thyrotoxicosis, Paget’s disease
Pressure overload (hypertension)
Volume overload: renal failure, Iatrogenic (e.g. post-operative fluid infusion)
Pulmonary heart disease: cor pulmonale, pulmonary vascular disorders
Table 4. Causes of heart failure
4. Pathophysiology of heart failure
Heart failure is caused by any condition which reduces the efficiency of the myocardium, or heart
muscle, through damage or overloading (volume or pressure) (Figure 1).
HF begins after an index event (e.g. ischaemic event or high blood pressure) produces an initial decline
in pumping capacity of the heart. Following this initial decline in pumping capacity of the heart, a variety of
compensatory mechanisms are activated, including the adrenergic nervous system, the renin-angiotensin
system, and the cytokine systems. In the short term, these systems are able to restore cardiovascular
function to a normal homeostatic range with the result that the patient remains asymptomatic. However,
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with time, the sustained activation of these systems can lead to secondary end-organ damage within the
ventricle, with worsening LV remodeling and subsequent cardiac decompensation. As a result of worsening
LV remodeling and cardiac decompensation, in patients undergo the transition from asymptomatic to
symptomatic HF. One of the most important adaptations is activation of the sympathetic (adrenergic)
nervous system, which occurs early in the course of HF. It may contribute to the pathophysiologic process
of congestive heart failure by multiple mechanisms involving cardiac, renal, and vascular function. In the
heart, increased sympathetic nervous system outflow may lead to desensitization of beta-adrenergic
receptors, myocyte hypertrophy, necrosis, apoptosis, and fibrosis. In the kidneys, increased sympathetic
activation induces arterial and venous vasoconstriction, activation of the renin-angiotensin system, increase
in salt and water retention, and attenuated response to natriuretic factors. In the peripheral vessels,
neurogenic vasoconstriction and vascular hypertrophy are induced by increased sympathetic nervous
system activity.
In contrast to the sympathetic nervous system, the components of the RAAS are activated
comparatively later in HF. Renal hypoperfusion and increased sympathetic stimulation of the kidney leading
to increased renin release from the juxtaglomerular apparatus. Angiotensin II is a vasoconstrictor and
promotes Na+ resorption by increasing aldosterone secretion and by a direct effect on the tubules.
Interruption of these two compensatory mechanisms is the basis of the effective treatment of HF.
Circulating levels of different hormones including brain natriuretic peptide (BNP) and cytokines are
also elevated in HF, with a positive correlation with the severity of HF.
Figure 1. The pathophysiology of heart failure
5. Prognosis and stages of heart failure
5.1. Prognosis
Although several reports have suggested that the mortality for HF patients is improving, the overall
mortality rate remains higher than for many cancers (e.g. bladder, breast, uterus, and prostate). Before
1990, the modern era of treatment, 60-70% of patients died within 5 years of diagnosis, and the
hospitalisation (and rehospitalisation) rate was very high in many countries. Effective treatment has
improved both of these outcomes, with a relative reduction in hospitalization rate in recent years of 3050% and a smaller but significant decrease in mortality. The 1 year median survival in NYHA IV functional
stage is less than 50%. European studies have confirmed a similarly poor long-term prognosis. The
aggregate data suggest that women with HF have a better overall prognosis than men. Patients with HFpEF
have a better prognosis than those with HFrEF. Differences in survival between these two forms of HF are
variably reported but generally minimal (Figure 2).
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Figure 2. Progression of heart failure
5.2. Stages of heart failure
A new approach developed to the classification of HF, one that emphasized both the development and
progression of the disease. HF should be viewed as a continuum that comprises four interrelated stages
(Figure 3).
Figure 3. Stages of heart failure
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Stage A includes patients who are at high risk for developing HF, but without structural heart disease
or symptoms of HF (e.g., patients with diabetes or hypertension). Stage B includes patients who have
structural heart disease but without symptoms of HF (e.g., patients with a previous myocardial infarction
and asymptomatic LV dysfunction). Stages A and B patients are best defined as those with risk factors that
clearly predispose toward the development of HF. Stage C then denotes patients with current or past
symptoms of HF associated with underlying structural heart disease (most patients with HF). Stage D
includes patients with refractory HF requiring special interventions (e.g., patients with refractory HF who
are awaiting cardiac transplantation, surgical procedures, or for end-of-life care, such as hospice).
6. Diagnosis
6.1. Physical examination
A complete medical history and carefully focused physical examination serve as the core of the
diagnostic process. The diagnosis of HF can be difficult, especially in the early stages. Quantification (NYHA
functional classification) of heart failure symptoms and signs is useful for assessing the adequacy of
therapy, stability over time and determining prognosis.
6.1.1. Symptoms
Although symptoms (Table 5) bring patients to medical attention, many of the symptoms of HF are
non-specific and do not, therefore, help discriminate between HF and other problems. Symptoms that are
more specific (i.e. orthopnea and paroxysmal nocturnal dyspnea) are less common, especially in patients
with milder symptoms, and are insensitive.
Dyspnea, shortness of breath, and fatigue are common complaints of heart failure patients. Patients
with worsening heart failure frequently experience exertional dyspnea, and this symptom often triggers a
visit to the clinic or emergency department. Patients may sleep with their heads elevated to relieve
symptoms of pulmonary congestion. Classically, the patient experiences nocturnal awakenings usually
occurring at a fixed time after retiring (often in the range of 1 to 2 hours) precipitated by the subjective
feeling of air hunger, smothering, or drowning. A history of weight gain, increasing abdominal girth, and the
onset of oedema in dependent organs (extremities or scrotum) is helpful when it is present but also is
nonspecific.
Symptoms can also change rapidly; for example, a stable patient with mild symptoms can become
suddenly breathless at rest with the onset of an arrhythmia, and an acutely unwell patient with pulmonary
oedema and NYHA class IV symptoms may improve rapidly with the administration of a diuretic.
6.1.2. Signs
By observing or palpating the apical impulse and percussing the left cardiac borders, the examiner can
determine heart size. A characteristic holosystolic murmur of mitral insufficiency or aortic stenosis is heard
in many heart failure patients. Tricuspid insufficiency, which is also common, can be differentiated from
mitral insufficiency by the location of the murmur at the left sternal border. The presence of a third heart
sound suggests increased ventricular filling volume or diminished relaxation; a fourth heart sound usually
indicates ventricular stiffening. An increase in the intensity of either gallop sound during inspiration
indicates that it is derived from the right ventricle.
A key objective of the examination is to detect and to quantify pulmonary or systemic congestion.
Oedema, a common finding in volume-overloaded heart failure patients, may be the result of venous
insufficiency. A more definitive test for assessment of a patient’s volume status is by the measurement of
JVP (jugular vein pressure). Not only does an elevated JVP detect systemic congestion, but there is good
sensitivity (70%) and specificity (79%) between high JVP and elevated left-sided filling pressure.
Pulmonary congestion is detected on physical examination from signs indicating the presence of fluid
in the pleural space or lung parenchyma. Dullness to percussion and diminished breath sounds at one or
both lung bases suggest the presence of a pleural effusion. Leakage of fluid from pulmonary capillaries into
the lung parenchyma can be manifested as rales, rhonchi or wheezes. Pulmonary rales due to heart failure
are usually fine in nature and extend from the base upward. The occurrence of so-called cardiac asthma is
due to the presence of fluid in the bronchial wall as well as secondary bronchospasm.
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Detection of reduced cardiac output (CO) and systemic hypoperfusion (fatigue, somnolence or loss of
mental acuity, low body temperature, tachycardia and cool, mottled extremities, etc.) is a key component
of the examination. Whereas patients with poor systemic perfusion due to low CO usually have low systolic
and narrow pulse pressures, this relationship is not exact. Many patients with systolic blood pressure in the
range of 80 mmHg (or even lower) may have adequate perfusion. Others with reduced CO maintain blood
pressure in the normal range at the expense of tissue perfusion by greatly increasing systemic vascular
resistance.
Typical symptoms
More specific signs
breathlessness
elevated jugular venous pressure
orthopnea
hepatojugular reflux
paroxysmal nocturnal dyspnea
third heart sound (gallop rhythm)
reduced exercise tolerance
laterally displaced apical impulse
fatigue, increased time to recover after exercise
cardiac murmur
ankle swelling
Less typical symptoms
Less specific signs
nocturnal cough
peripheral oedema (ankle, sacral, scrotal)
wheezing
pulmonary crepitations
weight gain (>2 kg/week)
dullness at lung bases (pleural effusion)
weight loss (in advanced heart failure)
reduced air entry, tachypnea
bloated feeling
irregular pulse
loss of appetite
tachycardia
confusion (especially in the elderly)
hepatomegaly
depression
ascites
palpitations
tissue wasting (cachexia)
Table 5. Symptoms and signs typical of heart failure
6.2. General diagnostic tests
6.2.1. Electrocardiography
Electrocardiogram (ECG) is one of the most useful tests in patients with suspected HF. The ECG shows
the heart rhythm and electrical conduction, i.e. whether there is sinoatrial disease, atrioventricular (AV)
block, or abnormal intraventricular conduction. These findings are also important for decisions about
treatment (e.g. rate control and anticoagulation for AF, pacing for bradycardia, or CRT if the patient has left
brundle branch block). The ECG may also show evidence of LV hypertrophy or Q waves (indicating loss of
viable myocardium), giving a possible clue to the aetiology of HF. A completely normal ECG makes systolic
HF unlikely.
6.2.2. Chest X-ray
Chest radiography remains a useful component of the assessment, particularly when the clinical
presentation is ambiguous. A “butterfly” pattern of alveolar opacities that fan out bilaterally from engorged
hilar pulmonary arteries to the periphery of the lungs is the classic pattern of congestion seen in
decompensated heart failure. The most prominent chest radiographic findings in heart failure are
cardiomegaly, Kerley B lines, peribronchial cuffing, pleural effusion.
6.2.3. Natriuretic peptides
Where the availability of echocardiography is limited, an alternative approach to diagnosis is to
measure the blood concentration of a natriuretic peptide, a family of hormones secreted in increased
amounts when the heart is diseased or the load on any chamber is increased (e.g. by AF, pulmonary
embolism, and some non-cardiovascular conditions, including renal failure).
Measurement of natriuretic peptide (BNP, NT-proBNP, or MR-proANP) should be considered to
exclude alternative causes of dyspnea (if the level is below the exclusion cut-point, HF is very unlikely) and
obtain prognostic information.
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6.2.4. Routine laboratory tests
In addition to standard biochemical (Na+, K+, creatinine/estimated glomerular filtration rate (eGFR),
inflamantory parameters) and haematological tests (haemoglobin, haematocrit, ferritin, leucocytes, and
platelets), it is useful to measure thyroid-stimulating hormone (TSH) as thyroid disease can mimic or
aggravate HF. As well as a pre-treatment check, biochemical monitoring is important after the initiation of
the treatment, while the dose is being up-titrated and during longer term follow-up.
6.3. Cardiac imaging
Imaging plays a central role in the diagnosis of HF and in guiding treatment. Of the several imaging
modalities available, echocardiography is the method of choice in patients with suspected HF. It may be
complemented by other modalities, chosen according to their ability to answer specific clinical questions
and taking account of contraindications to, and risks of, specific tests.
6.3.1. Echocardiography
The echocardiogram is the most useful tests in patients with suspected HF. Transthoracic
echocardiography can be performed without risk to the patient, does not involve radiation exposure, and
can be performed at the bedside if necessary. Echocardiography may be limited in some patients because
available imaging planes and image quality depend on acoustic windows, which may be suboptimal as a
result of obesity, emphysema, or other causes.
It is particularly well suited for evaluating the structure and function of both the myocardium and
heart valves and providing information about intracardiac pressures and flows. Information about the
pericardium, endocardium and the morphology and relative sizes of the cardiac chambers may suggest
specific diagnoses. Echocardiography may also aid in deciding what treatments will help the patient, such
as medication, insertion of an implantable cardioverter-defibrillator or cardiac resynchronization therapy.
We can determine with echocardiography the stroke volume (SV, the amount of blood in the heart
that exits the ventricles with each beat), the end-diastolic volume (EDV, the total amount of blood at the
end of diastole), and the SV in proportion to the EDV, a value known as the ejection fraction (EF).
Echocardiography can also help determine if acute myocardial ischemia is the precipitating cause, and
may manifest as regional wallmotion abnormalities on echo.
Diastolic function is easily assessed by echocardiography with Doppler and Tissue Doppler
measurements. Echocardiographic measurements are also used to estimate right-sided heart pressures
noninvasively, which may be useful in assessing and managing heart failure patients.
TOE is, however, valuable in patients with complex valvular disease (especially mitral disease and
prosthetic valves), suspected endocarditis, and in selected patients with congenital heart disease. TOE is
also used to check for thrombus in the left atrial appendage of patients with AF.
Exercise or pharmacological (dobutamin) stress echocardiography may be used to identify the
presence and extent of inducible ischaemia and to determine whether non-contracting myocardium is
viable.
6.3.2. Cardiac MRI
CMR is a non-invasive technique that provides most of the anatomical and functional information
available from echocardiography, including evaluation of ischemia and viability, as well as additional
assessments. MRI is regarded as the gold standard with respect to accuracy and reproducibility of volumes,
mass, and wall motion. It is particularly valuable in identifying inflammatory and infiltrative conditions, and
in predicting prognosis in patients with these. MRI is also useful in the work-up of patients with suspected
cardiomyopathy, arrhythmias, suspected cardiac tumours (or cardiac involvement by tumor), or pericardial
diseases, and is the imaging method of choice in patients with complex congenital heart disease.
Major limitations:
(1) implanted pacemakers or defibrillators (except for newer, MRI compatible devices)
(2) claustrophobia
(3) GFR <30 mL/min/m2 (gadolinium-based contrast agent can cause nephrogenic systemic fibrosis)
(4) highly irregular rhythms
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6.3.3. Coronary angiography
Coronary angiography should be considered in patients with angina pectoris or a history of cardiac
arrest if the patient is otherwise suitable for coronary revascularization.
Coronary angiography should be strongly considered for patients with systolic left ventricular
dysfunction and a strong suspicion of hibernating myocardium based on the findings of noninvasive
evaluation. In patients with normal systolic function but otherwise unexplained episodes of acute
pulmonary edema, coronary angiography may be necessary to rule out ischemically related systolic and/or
diastolic left ventricular dysfunction.
6.3.4. Other special imagings
Single-photon emission computed tomography (SPECT) and positron emission tomography (PET) alone
or with computed tomography (PET-CT) may be useful in assessing ischaemia and viability if CAD is
suspected, and provides prognostic as well as diagnostic information.
The main use of coronary CT in patients with HF is a non-invasive means to visualize the coronary
anatomy in patients with low or intermediate cardiovascular risk.
6.4. Other investigations
Measurement of intracardiac pressures and cardiac output by right-heart catheterization is less
commonly performed now than in the past either as part of the diagnostic workup or for guiding therapy
because biomarkers and noninvasive imaging techniques provide much of the information.
In patients with suspected constrictive or restrictive cardiomyopathy, cardiac catheterization used in
combination with other noninvasive imaging techniques may help to establish the correct diagnosis. In
patients with suspected myocarditis and infiltrative diseases (e.g. amyloidosis, endomyocardial biopsy may
be needed to confirm the diagnosis.
Exercise testing allows objective evaluation of exercise capacity and exertional symptoms, such as
dyspnea and fatigue. The 6-min walking test and a variety of treadmill and bicycle protocols are available.
When more precise information is needed (e.g. before cardiac transplantation), cardiopulmonary exercise
testing (spiroergometry) is also often used because it provides better quantification of exercise capacity
and can determine whether the cause of exercise limitation is cardiac.
The role of genetic testing in ‘idiopathic’ dilated and hypertrophic cardiomyopathy is described in
detail elsewhere. Currently this is recommended in patients with ‘idiopathic’ dilated and hypertrophic
cardiomyopathy and AV block or a family history of premature unexpected sudden death.
7. Therapy
7.1. Treatment of heart failure with reduced ejection fraction (systolic heart failure - HFrEF)
Medical care for heart failure (HF) includes a number of nonpharmacologic, pharmacologic, and
invasive strategies to limit and reverse the manifestations of heart failure. The goals of treatment in
patients with established HF are to relieve symptoms and signs (e.g. oedema), prevent hospital admission,
and improve survival. It is important to recognize that LV dysfunction may develop transiently in various
different clinical settings, which may not lead invariably to the development of the clinical syndrome of HF.
7.1.1. Prevention of heart failure
Depending on the severity of illness, nonpharmacologic therapies include dietary Na+ and fluid
restriction; physical activity as appropriate; and attention to weight gain. Identification and correction of
the condition(s) responsible for the cardiac structural and/or functional abnormalities are critical, insofar as
some conditions that provoke LV structural and functional abnormalities are potentially treatable and/or
reversible.
Clinicians should aim to screen for and treat aggressively comorbidities such as hypertension, diabetes
and coronary heart disease, which are thought to underlie the structural heart disease.
HF patients should be advised to stop smoking and to limit daily alcohol consumption.
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Certain drugs are known to make HF worse and should also be avoided. For example, nonsteroidal
anti-inflammatory drugs (NSAIDs), including cyclooxygenase 2 (COX-2) inhibitors, are not recommended in
patients with chronic HF.
Although heavy physical labor is not recommended in HF, routine modest exercise has been shown to
be beneficial in patients with NYHA Classes I to III. Caloric supplementation is recommended for patients
with advanced HF and unintentional weight loss or muscle wasting (cardiac cachexia). Dietary restriction of
Na+ (3 g daily) is also recommended for all patients with the clinical syndrome of HF and preserved or
depressed EF.
7.1.2. Pharmacological treatment
7.1.2.1. Treatments recommended in potentially all patients with systolic heart failure - first line therapy
Angiotensin-converting enzym inhibitors (ACEIs), angiotensin receptor blockers (ARBs), betaadrenergic receptor blockers (beta-blockers) and mineralocortico-steroid receptor inhibitors (MRA) have
emerged as cornerstones of modern first line HF therapy for systolic heart failure patients (EF ≤40%) to
reduce the risk of HF hospitalization and the risk of premature death and to improve survival (Figure 4,
Table 6).
Figure 4. Treatments for patients with chronic symptomatic systolic heart failure (NYHA class II-IV)
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Initial dose (mg)
Target dose (mg)
ACEIs
captopril
6.25 (3x)
50 (3x)
enalapril
2.5 (2x)
10-20 (2x)
lisinopril
2.5-5 (1x)
20-35 (1x)
ramipril
2.5 (1x)
5 (2x)
Beta-blockers
bisoprolol
1.25 (1x)
10 (1x)
carvedilol
3.125 (1x)
25-50 (2x)
metoprolol (CR/XL)
12.5/25 (1x)
200 (1x)
nebivolol
1.25 (1x)
10 (1x)
ARBs
candesartan
4-8 (1x)
32 (1x)
valsartan
40 (2x)
160 (2x)
losartan
50 (1x)
150 (1x)
MRAs
eplerenone
25 (1x)
50 (1x)
spironolactone
25 (1x)
25-50 (1x)
Table 6. Titration of first line therapy
7.1.2.1.1. Renin-angiotensin-aldosterone system inhibitors (RAAS inhibitors)
There is overwhelming evidence that angiotensin-converting enzym inhibitors (ACEIs) should be used
in symptomatic and asymptomatic patients with a reduced EF (<40%). ACEIs interfere with the RAAS by
inhibiting the enzyme that is responsible for the conversion of angiotensin I to angiotensin II. However,
because ACEIs also inhibit kininase II, they may lead to the upregulation of bradykinin, which may further
enhance the effects of angiotensin suppression.
ACEIs stabilize LV remodeling, improve symptoms, prevent hospitalization, and prolong life. ACE
inhibitors are also beneficial in asymptomatic LV systolic dysfunction (NYHA class I). It should be start as
early as possible in the course of disease and should be initiated in low doses, followed by increments in
dose if lower doses have been well tolerated. Titration (Table 6) is generally achieved by doubling the
dosage every 3 to 5 days. The dose of ACE inhibitor should be increased until the doses used are similar to
those that have been shown to be effective in clinical trials. For stable patients, it is acceptable to add
therapy with beta-blocking agents before full target doses of ACEIs are reached. Blood pressure, renal
function, and K+ level should be evaluated within 1 to 2 weeks after initiation of ACEIs.
The efficacy of ACEIs has been consistently demonstrated in clinical trials with patients with
asymptomatic and symptomatic LV dysfunction. These trials recruited a broad variety of patients and the
consistency of data from some studies has shown that asymptomatic patients with LV dysfunction will have
less development of symptomatic HF and fewer hospitalizations when treated with an ACEI. ACEIs have also
consistently shown benefit for patients with symptomatic LV dysfunction. The CONSENSUS and the SOLVD
trial showed that ACE inhibitor therapy reduces mortality (relative risk reduction: 27% in CONSENSUS and
16% in SOLVD-Treatment).
ACE inhibitors occasionally cause worsening of renal function, hyperkalaemia, symptomatic
hypotension, cough, and, rarely, angioedema. ACE inhibitor treatment should only be used in patients with
normal - to moderately compromised renal function (creatinine ≤221 mmol/L or eGFR ≥30 mL/min/1.73
m2) and a normal serum K+ level (<5.0 mmol/l).
Angiotensin receptor blockers (ARBs) are well tolerated in patients who are intolerant of ACEIs
because of the development of cough, skin rash, and angioedema and should therefore be used in same
indications (in symptomatic and asymptomatic patients with an EF less than 40%), who are ACE-intolerant
for reasons other than hyperkalemia or renal insufficiency.
Clinical trials have demonstrated that ARBs are as effective as ACEIs in reversing the process of LV
remodeling, improving symptoms, preventing hospitalization, and reducing HF morbidity and mortality.
39
Spironolactone and eplerenone are synthetic mineralocorticoid receptor antagonists (MRAs) that act
on the distal nephron to inhibit Na+-K+ excretion at the site of aldosterone action. Although spironolactone
and eplerenone are both weak diuretics, clinical trials have shown that both of these agents have profound
effects on cardiovascular morbidity and mortality. An MRA is recommended for all patients with persisting
symptoms (NYHA class II-IV) and an EF ≤35%, in spite of ACEI plus beta-blocker treatment to reduce the risk
of HF hospitalization and the risk of premature death. They can cause hyperkalaemia and worsening renal
function. Spironolactone has antiandrogenic and progesterone-like effects, which may cause gynecomastia
(1-10%) or impotence in men and menstrual irregularities in women. Eplerenone has greater selectivity for
the mineralocorticoid receptor than for steroid receptors, and has less sex hormone side effects.
One direct renin inhibitor (aliskiren) is currently being evaluated in some morbidity-mortality trials. It
is not presently recommended as an alternative to an ACE inhibitor or ARB.
7.1.2.1.2. Beta-adrenergic receptor blockers (beta-blockers)
Beta-blocker therapy represents a major advance in the treatment of HF. Beta-blockers interfere with
the harmful effects of the sympathetic nervous system by competitively antagonizing one or more
adrenergic receptors. Beta-blockers cause time-dependent improvements in ventricular structure (LV
remodelling) and function (ejection fraction). Other beneficial actions include reductions in heart rate and
blood pressure, prolonging left ventricular diastolic filling time, inhibition of the renin-angiotensin system,
reduction of arrhythmias, and anti-ischemic effects (improving the myocardial oxygen support).
Beta-blockers indicated in symptomatic heart failure patients (EF ≤40%), since many trials have shown
that beta-blockers reduce mortality (relative risk reduction: ̴34%), HF hospitalization ( 2̴ 8-36%) and
improves quality of life within 1 year of starting treatment. Three beta-blockers have been shown to be
effective in reducing the risk of death in patients with chronic HF. Bisoprolol and sustained-release
metoprolol succinate are cardio selective beta-blockers acting primarily on beta-1 receptors, and carvedilol
is a non-selective beta-blocker with additional alpha-receptor blocking and antioxidant properties.
It should be started as early as possible in the course of disease. The dose should be increased until the
doses used are similar to those that have been reported to be effective in clinical trials. The dose titration
of beta-blockers should proceed no sooner than at 2-week intervals, because the initiation and/or suddenly
increased dosing of these agents may lead to worsening heart failure (fluid retention).
Side effects of the therapy with beta-blockers are bradyarrhythmias, prolonged intraventricular
conduction (AV-block), bronchoconstriction (rare side effect), hypotension and worsening renal function.
Treatment can be accompanied by feelings of general fatigue or weakness.
7.1.2.1.3. Other treatments recommended in selected patients with systolic heart failure
Ivabradine is a drug that inhibits the If channels in the sinus node. It’s only known pharmacological
effect is to slow the heart rate in patients with sinus rhythm (it does not slow the ventricular rate in AF).
Ivabradine should be considered to reduce the risk of HF hospitalization in patients in sinus rhythm with an
EF ≤35%, a heart rate remaining ≥70 b.p.m., and persisting symptoms (NYHA class II-IV) despite treatment
with an evidence-based dose of beta-blocker (or maximum tolerated dose), ACE inhibitor (or ARB), and an
MRA (or ARB). If beta-blockers are contraindicated, ivabradine may be considered.
The primary mechanism of cardiac glycosides (digoxin and digitoxin) involves inhibition of the Na+/K+
ATPase, mainly in the myocardium. This inhibition causes an increase in intracellular Na+ levels, resulting in
a reversal of the action of the Na+/Ca2+ exchanger leading to increased contractility. The inhibition of the
sodium pump may also improve baroreceptor sensitivity in HF and may explain some of the neurohormonal
effects of digoxin. Digoxin has important parasympathetic effects, leading to an increase in vagal tone that
counterbalances the increased activation of the adrenergic system in advanced HF (negative chronotrop).
In patients with symptomatic HF and AF, digoxin may be used to slow the ventricular rate, although other
treatments are preferred. It reduces the risk of HF hospitalization in patients with an EF ≤45% despite
treatment of beta-blockers or who are unable to tolerate beta-blockers. The use of digoxin should be
restricted to heart failure with AF already on beta-blocker, and there are low levels of evidence to use in
sinus rhythm. The principal cardiac adverse effects of digoxin are the atrial and ventricular arrhythmias,
particularly in the context of hypokalaemia, heart block and ectopic and reentrant cardiac rhythms.
40
7.1.2.2. Other pharmacological treatment
Combination of hydralazine and isosorbide dinitrate (H-ISDN) may be considered as an alternative to
an ACE inhibitor or ARB, if neither is tolerated, to reduce the risk of HF hospitalization and risk of premature
death in patients with an EF ≤45% and symptomatic heart failure (NYHA class II-IV).
Omega-3 polyunsaturated fatty acids (n-3 PUFAs) have favorable effects on inflammation, platelet
aggregation, blood pressure, heart rate, and LV function. The GISSI-HF study has shown that long-term
administration of omega-3 fatty acids results in a significant reduction in both all-cause mortality.
Novel, promising therapeutical option is the usage of angiotensin receptor blocker-neprylisin inhibitor
(ARNI).
7.1.2.3. Management of fluid status - diuretics
Many clinical manifestations of heart failure result from excessive salt and water retention that leads
to an inappropriate volume expansion of the vascular and extravascular space causing symptoms of the
disease. Although both digitalis and low doses of ACEIs enhance urinary Na+ excretion, only few volumeoverloaded HF patients can maintain proper Na+ and fluid balance without the use of diuretic drugs.
The effects of diuretics on mortality and morbidity have not been studied in patients with HF, unlike
ACE inhibitors, beta-blockers, and MRAs (and other treatments). However, diuretics relieve dyspnea and
oedema and are recommended for this reason in patients with signs and symptoms of congestion,
irrespective of EF (Figure 2).
Classification of diuretics in heart failure:
(1) loop diuretics (e.g. furosemide, torasemide)
(2) tiazides (e.g. hidrochlorotiazide) and tiazide-like diuretics (e.g. indapamide)
(3) K+-sparing diuretics (e.g. MRAs, amiloride, triamterene)
The loop diuretics have emerged as the preferred diuretic (moderate to severe symptoms or renal
insufficiency) agents for use in most patients with HF. The aim of using diuretics is to achieve and maintain
euvolaemia (the patient’s ‘dry weight’) using the lowest achievable therapy dose. Diuretics should be
initiated in low doses and then titrated upward to relieve signs and symptoms of fluid overload. A typical
starting dose of furosemide for patients with systolic HF and normal renal function is 20-40 mg, although
doses of 80 to 160 mg are often necessary to achieve adequate diuresis. Because of the steep doseresponse curve and effective threshold for loop diuretics, it is critical to find an adequate dose of loop
diuretic that leads to a clear-cut diuretic response. Once patients have achieved an adequate diuresis, it is
important to document their dry weight and make certain that patients weigh themselves daily to maintain
their dry weight.
Loop diuretics produce a more intense and shorter diuresis than thiazides, which cause a more gentle
and prolonged diuresis. Thiazides may be less effective in patients with reduced kidney function. Loop
diuretics are usually preferred to thiazides in HFrEF although they act synergistically and the combination
may be used (usually on a temporary basis) to treat resistant oedema. Intravenous administration of
diuretics may be necessary to relieve congestion acutely. In symptomatic patients, diuretics should always
be used in combination with ACEIs (or ARB), beta-blockers and MRA if it is possible.
The major complications of diuretic use include electrolyte (hypokalaemia) and metabolic
disturbances, volume depletion, and worsening of renal function (azotemia). The interval for reassessment
should be individualized based on the severity of illness and underlying renal function, past history of
electrolyte imbalances, and/or need for more aggressive diuresis.
7.1.2.4. Treatments that may cause harm in symptomatic systolic heart failure (NYHA class II-IV)
Most calcium channel blockers (with the exception of amlodipine, felodipine, lercanidipine) should
not be used as they have a negative inotropic effect and can cause worsening HF.
NSAIDs and COX-2 inhibitors should be avoided if possible as they may cause Na+ and water retention,
worsening renal function and worsening HF.
Finally, the addition of an ARB (or renin inhibitor) to the combination of an ACE inhibitor and a
mineralocorticoid receptor antagonist is not recommended because of the risk of renal dysfunction and
hyperkalaemia.
41
7.2. Treatment of heart failure with preserved ejection fraction (diastolic heart failure - HFpEF)
Heart failure with preserved ejection fraction (HFpEF) is a complex syndrome characterized by heart
failure (HF) signs and symptoms and a normal or near-normal left ventricular ejection fraction (LVEF). More
specific diagnostic criteria have evolved over time and include signs/symptoms of HF, objective evidence of
diastolic dysfunction, disturbed left ventricular (LV) filling, structural heart disease, and elevated brain
natriuretic peptides. However, multiple cardiac abnormalities are often present apart from diastolic LV
dysfunction, including subtle alterations of systolic function, impaired atrial function, chronotropic
incompetence, or haemodynamic alterations, such as elevated pre-load volumes. Extracardiac
abnormalities and comorbidities, such as hypertension, atrial fibrillation, diabetes, renal or pulmonary
disease, anaemia, obesity and deconditioning may contribute to the HFpEF syndrome (Figure 5). Lowgrade
inflammation with endothelial dysfunction, increased reactive oxygen species production, impaired nitric
oxide (NO) bioavailability, and the resulting adverse effects on cardiac structure and function are
considered a mechanistic link between frequently encountered comorbidities and the evolution and
progression of HFpEF.
Figure 5. Heterogenity of the heart failure with preserved ejection fraction (HFpEF)
In contrast to the treatment of HF with reduced EF, information to guide the pharmacologic therapy
for patients with HFpEF is lacking. Present treatment strategies for HFpEF are largely based on assumptions
of its pathophysiologic mechanisms and on extrapolations from proven strategies used in HF with a
reduced EF.
The pharmacological therapy of diastolic heart failure is based mainly on empiric data, and aims to the
normalization of blood pressure, reduction of left ventricular dimensions and increased heart rate,
maintenance of normal atrial contraction and treatment of symptoms caused by congestion.
Beneficial effects of ACEIs and ARBs may be utilized in patients with diastolic dysfunction, especially in
those with hypertension. Beta-blockers appear to be useful in lowering heart rate and thereby prolonging
left ventricular diastolic filling time. Diuretics are used to control Na+ and water retention and relieve
reathlessness and oedema as in HFrEF. Adequate treatment of hypertension and myocardial ischaemia is
also considered to be important, as is control of the ventricular rate in patients with AF.
The drugs that should be avoided in HFrEF should also be avoided in HFpEF, with the exception of
calcium channel blockers.
7.3. Non-pharmacological (device, surgery) therapy of heart failure
7.3.1. Implantable cardioverter defibrillator (ICD)
Approximately half of the deaths in patients with HF, especially in those with milder symptoms, occur
suddenly and unexpectedly, and many, if not most, of these are related to ventricular arrhythmias.
Prevention of sudden death is an important goal in HF.
42
While the optimal pharmacological therapy mentioned earlier reduce the risk of sudden death, they do
not abort it and the specific antiarrhythmic drugs do not decrease the mortality (and may even increase it).
In primary prevention an ICD is recommended in a patient with symptomatic HF (NYHA class II-III) and
an EF ≤35% despite ≥3 months of treatment with optimal medical therapy, who is expected to survive for
more than 1 year with good functional status, to reduce mortality (the risk of sudden death).
ICDs reduce mortality in survivors of cardiac arrest (secondary prevention) and in patients with
sustained symptomatic (haemodinamic instability) ventricular arrhythmias. Consequently, an ICD is
recommended in such patients, irrespective of EF, with good functional status, a life expectancy of more
than 1 year.
7.3.2. Cardiac resynchronization therapy (CRT)
Several conduction abnormalities are commonly seen in association with chroni heart failure. Among
these are abnormalities of ventricular conduction, such as bundle branch blocks, that alter the timing and
pattern of ventricular contraction so as to place the already failing heart at a further mechanical
disadvantage. These ventricular conduction delays produce suboptimal ventricular filling, a reduction in left
ventricular contractility, prolonged duration of mitral regurgitation, and paradoxical septal wall motion.
Taken together, these mechanical manifestations of altered ventricular conduction have been termed
ventricular dysynchrony.
Ventricular dysynchrony may now be addressed with pacing therapy through the implantation of
pacing leads to both the right and left ventricles. This form of pacing therapy has come to be known as
cardiac resynchronization therapy (CRT). It reduces the risk of HF hospitalization and the risk of premature
death (reduce motality).
CRT-P (biventricular pacemaker) or CRT-D (CRT+ICD) is recommended in patients with NYHA II-IV:
(1) in sinus rhythm or in atrial fibrillation
(2) left brundle branch block (LBBB) QRS morphology on ECG (with a QRS duration of ≥120 ms, optimal
in QRS duration ≥150 ms), or irrespective of QRS morphology (with a QRS duration of ≥150 ms)
(3) patients with uncontrolled heart rate (in atrial fibrillation) who are candidates for AV junction
ablation for rate control.
(4) low EF (≤35%)
(5) who are expected to survive with good functional status for more than 1 year
7.3.3. Surgical Therapy
The surgical therapy of heart failure includes coronary revascularization, aneurysmectomy, valve
surgery (repair or replacement), ventricular assist device implantation (LVAD, RVAD, BIVAD) and heart
transplantation.
7.4. Treatment of acute heart failure
Although not ‘evidence based’ in the same way as treatments for chronic HF, the key drugs are oxygen
(oxigen saturation <90%), diuretics and vasodilators. Opiates and inotropes are used more selectively, and
mechanical support of the circulation is required only rarely. Non-invasive ventilation (NIV) is used
commonly in many centres, but invasive ventilation is required in only a minority of patients.
Most patients with dyspnea caused by pulmonary oedema obtain rapid symptomatic relief from
administration of an i.v. diuretic, as a result of both an immediate venodilator action and subsequent
removal of fluid. Opiates such as morphine may be useful in some patients with acute pulmonary oedema
as they reduce anxiety, relieve distress associated with dyspnea, reducing preload and may also reduce
sympathetic drive. Vasodilators such as nitroglycerine reduce preload and afterload and increase stroke
volume, and are probably most useful in patients with hypertension. Use of an inotrope such as
dobutamine, levosimendan should usually be reserved for patients with such severe reduction in cardiac
output that vital organ perfusion is compromised.
Systolic blood pressure, heart rhythm and rate, saturation of peripheral oxygen (SpO2) using a pulse
oxymeter, and urine output should be monitored on a regular and frequent basis until the patient is
stabilized.
43
8. Quiz
1. The true statement in relation to the prevalence of heart failure:
A: the prevalence of heart failure among adults is between 1-2% and shows a downward trend
B: the prevalence of heart failure among adults is between 4-5% and shows an upward trend
C: the prevalence of heart failure among adults is between 1-2% and shows an upward trend
D: the prevalence of heart failure among adults is between 4-5% and shows a downward trend
2.
Characteristics of patients in functional class IV. according to the NYHA classification:
A: ordinary physical activity cause fatigue, palpitation, or dyspnea
B: the patient's condition can only be stabilized via intravenous inotropic therapy
C: unable to do any physical activity without discomfort, symptoms of cardiac insufficiency at rest
D: ACE inhibitor and beta-blockers can not be applied in this case
3.
Characteristics of skeletal muscle in a heart failure patient:
A: stuctural changes in the sceletal muscle with increase of type IIb fibers
B: biochemical alteration
C: ergoreflex alteration
D: all of the above
4.
The false sentence:
A: BNP is mainly released from the right ventricle at elevated filling pressure
B: ARBs are act on ATII AT1 receptors
C: in heart failure beta-receptor down regulation is observed
D: excessive diuretic treatment enhance the activation of the sympathetic nervous system
5.
Brain natriuretic peptide (BNP) is secreted primarily from the brain during heart failure, therefore it
is considered important in the diagnosis of heart failure.
A: true-true
B: false-false
C: true-false
D: false-true
6.
The true sentence:
A: RAAS system activation is crucial in the pathogenesis of heart failure
B: during heart failure the number of beta-receptors rises (upregulation)
C: sympathetic nervous system activation only occurs in end-stage disease
D: all 3 statements above are true
7.
In the treatment of heart failure the following statement is true:
A: digitals therapy improve survival, and patients become less symptomatic
B: ACE inhibitors reduce the risk of HF hospitalization but increase the risk of premature death
C: beta-blocker reduce the risk of HF hospitalization and the risk of premature death
D: mineralocorticoid antagonist only indicated in severe, refractory cases
8.
In the treatment of heart failure the following statement is true:
A: digitalis is indicated in all systolic heart failure patients
B: ACE inhibitor is always indicated if no contraindication present
C: beta-blockers not indicated in high dose, because it has a negative inotropic effect
D: Ca-antagonist is always indicated
44
9.
The true statement in case of diastolic heart failure (HFpEF):
A: diastolic heart failure (HFpEF) is common, it occurs in 10-20% of heart failure cases
B: usually these patients are elderly, diabetic, obes, hypertensive and women
C: evidences are available when choosing its treatment
D: all 3 statements above are true
10. Thallium reinjection scintigraphy is mainly used in the diagnosis of heart failure:
A: the separate of viable (hibernating) myocardium from necrosis
B: detection of previous myocardial infarction
C: imaging of Coronary Artery Calcium
D: determination of left ventricular systolic function
11. Meaning of class „I. A” recommendation:
A: intervention is not useful/effective and may be harmful
B: intervention is useful and effective, data derived from multiple randomized clinical trials
C: chinidin or other class I. A type antiarrythmic medication therapy is indicated
D: intervention is useful based on expert, consensus opinion
12. In the diagnosis/prognostics of heart failure the following biomarkers can be applied:
A: natrium, CN, creatinin
B: troponin, CK
C: galectin-3, BNP, NT-ProBNP
D: blood sugar, LDL-cholesterol, CRP
13. It is important for a person with heart failure to:
A: make sure they get the flu shot every year
B: receive the pneumovax vaccination to prevent pneumonia
C: see their heart failure doctor regularly
D: all of the above
14. The recommended total daily amount of Na+ that persons with heart failure should eat is:
A: about 3,000 milligrams
B: more than 2,500 milligrams
C: less than 2,000 milligrams
D: 500 milligrams
15. The best medicine to take in case of headache or pain in person with heart failure:
A: aspirin
B: acetaminophen
C: NSAID
D: morphin
16. How often should a person with heart failure exercise?
A: every week
B: every day
C: exercise is contraindicated in heart failure
D: 2-3 times per week
45
17. Persons with heart failure should call their doctor if they have which of the following symptoms:
A: weight gain of 2-3 kg in 1-2 days
B: increased swelling of the ankles and/or stomach
C: more shortness of breath
D: all of the above
18. The best time of day for persons with heart failure to weigh themselves is:
A: at bedtime
B: upon awakening in the morning
C: at or around lunchtime
D: when they remember to do it
19. How often should a person with heart failure weigh themselves?
A: every day
B: every week
C: every month
D: once in a while
20. If a person with heart failure gains 2-3 pounds in a few days, this usually means he/she:
A: is eating too many calories and gaining weight
B: has extra water in the body
C: needs to drink more fluid
D: needs to be getting more exercise to burn calories
21. Calcium channel blocker which is contraindicated in HFrEF:
A: amlodipine
B: verapamil
C: levosimendan
D: bisoprolol
22. Resynchronization therapy (CRT) is clearly indicated (class I A):
A: for all patients with heart failure below EF 35%
B: in case of (RBBB)
C: in all cases of Left bundle branch block (LBBB)
D: in patients in sinus rhythm with QRS duration of ≥120 ms, LBBB QRS morphology and an EF ≤35%
23. In the case of heart failure it is essential to determine when examining myocardial ischemia:
A: the localization of ischemia
B: the extent of ischemia
C: the presence of necrotic or hibernating myocardium
D: all of the above
24. First-line drugs in the treatment of chronic systolic heart failure:
A: diuretics + beta-blockers + ACE inhibitors
B: digtalis + beta-blockers + mineralocorticoid receptor blockers
C: beta-blockers + ACE inhibitors + mineralocorticoid receptor blockers
D: digitalis + diuretics + ACE inhibitors
46
25. In the outpatient heart failure service, according to the ESC Long-Term Registry data, what
percentage of patients achieving target dose of ACE inhibitors/beta-blockers?
A: above 50%
B: below 30%
C: above 30%
D: below 20%
26. A contraindicated drug combination in heart failure:
A: beta-blocker + ACE inhibitor + mineralocorticoid receptor antagonist (MRA)
B: angiotensin receptor blocker + ACE inhibitor + MRA
C: beta-blocker + ACE inhibitor + ivabradine
D: digoxin + beta-blocker + ACE inhibitor
27. The recommended beta-blockers when heart failure is associated with COPD:
A: it is not recommended
B: it has no restrictions
C: beta-1 selective blockers are preferable
D: non-selective, with combined action is recommended (ie. carvedilol)
28. From the following which statement is not true? Diuretic resistance…
A: … is common and occurs in one in three heart failure patients especially from moderate to severe
heart failure
B: … may be worsened by NSAIDs, which - through the inhibition of prostaglandin synthesis - reduce
renal perfusion and this way inhibit the effect of diuretics
C: … means that on the "usual" dose diuretic therapy the hyperhydration of the extracellular space is
not reduced
D: … is very rare, only occurs when heart failure is combined with severe kidney disease
29. The strength of heart muscle contractions can be increased by:
A: reducing the concentration of intracellular Ca2+ of heart muscle cells
B: the activation of beta-adrenergic signaling system of heart muscle cells
C: increasing plasma K+ concentrations
D: increasing the concentration of intracellular inorganic phosphate of heart muscle cells
30. 64 years old woman has chronic systolic heart failure. Her ejection fraction is 30%, in NYHA II. She
received enalapril 20 mg b.i.d., bisoprolol 10 mg o.d., eplerenone 50 mg o.d. and furosemide 40 mg
at stable dose more than 3 months. Her ECG shows sinus rhythm, typical LBBB, QRS 150 msec and
her heart rate is 78 min-1. She has not fluid retention. Her NTproBNP level is 2000 pg/ml. What is the
next step?
A: to increase the dose of furosemide
B: ICD implantation
C: CRT-D implantation
D: introduction of ivabradine
31. Not part of the patient’s self-care management:
A: avoiding excessive fluid intake
B: introducing and titrating neurohormonal antagonists
C: performing exercise training regularly
D: understanding indications, dosing and effects of drugs
47
9. Right answers
1. C
2. C
3. D
4. A
5. D
6. A
7. C
8. B
9. B
10. A
11. B
12. C
13. D
14. C
15. B
16. B
17. D
18. B
19. A
20. B
21. B
22. D
23. D
24. C
25. B
26. B
27. C
28. C
29. B
30. D
31. B
48
10. References
[1]
[2]
[3]
[4]
[5]
[6]
[7]
[8]
[9]
[10]
[11]
[12]
[13]
[14]
[15]
[16]
[17]
[18]
[19]
[20]
[21]
[22]
[23]
[24]
[25]
[26]
[27]
McMurray JVJJ, Adamopoulos S, Anker SD, et al. ESC Guidelines for the diagnosis and treatment of acute and chronic
heart failure 2012. The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the
European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur
Heart J 2012; 33: 1787-1847.
Chronic heart failure: national clinical guideline for diagnosis and management in primary and secondary care: partial
update. Nat Clin Guideline Centre 2010; 19-24.
Braunwald E, Bonow R, Mann DL, et al. Braunwald’s heart disease: a textbook of cardiovascular medicine. Ninth
edition. Elservier Saunders, Philapelphia 2012; 520. ISBN: 978-0-8089-2436-4.
Khot UN, Jia G, Moliterno DJ, et al. Prognostic importance of physical examination for heart failure in non-ST-elevation
acute coronary syndromes: the enduring value of Killip classification. JAMA 2003; 290: 2174-2181.
Mosterd A, Hoes AW. Clinical epidemiology of heart failure. Heart 2007; 93: 1137-1146.
Upadhya B, Taffet GE, Cheng CP, et al. Heart failure with preserved ejection fraction in the elderly: scope of the
problem. J Mol Cell Cardiol 2015; 83: 73-87.
Braunwald E, Bonow R, Mann DL, et al. Braunwald’s heart disease: a textbook of cardiovascular medicine. Ninth
edition. Elservier Saunders, Philapelphia 2012; 557. ISBN: 978-0-8089-2436-4.
Ackerman MJ, Priori SG, Willems S, et al. HRS/EHRA expert consensus statement on the state of genetic testing for the
channelopathies and cardiomyopathies: this document was developed as a partnership between the Heart Rhythm
Society (HRS) and the European Heart Rhythm Association (EHRA). Heart Rhythm 2011; 8: 1308-1339.
Braunwald E, Bonow R, Mann DL, et al. Braunwald’s heart disease: a textbook of cardiovascular medicine. Ninth
edition. Elservier Saunders, Philapelphia 2012; 544. ISBN: 978-0-8089-2436-4.
Nohria A, Cusco JA, Creager MA. Neurohormonal, renal and vascular adjustments in heart failure. Atlas of Heart
Failure. Fourth edition. Current Medicine, Philadelphia, 2005; 106.
Stewart S, Ekman I, Ekman T, et al. Population impact of heart failure and the most common forms of cancer: a study of
1 162 309 hospital cases in Sweden (1988 to 2004). Circ Cardiovasc Qual Outcomes 2010; 3: 573-580.
Leier CV, Chatterjee K. The physical examination in heart failure. Part I-II. Congest Heart Fail 2007; 13: 41-47 and 99104.
Ewald B, Ewald D, Thakkinstian A, et al. Meta-analysis of B type natriuretic peptide and N-terminal pro B natriuretic
peptide in the diagnosis of clinical heart failure and population screening for left ventricular systolic dysfunction. Intern
Med J 2008; 38: 101-113.
Sicari R, Nihoyannopoulos P, Evangelista A, et al. Stress echocardiography expert consensus statement: European
Association of Echocardiography (EAE) (a registered branch of the ESC). Eur J Echocardiogr 2008; 9: 415-437.
Raman SV, Simonetti OP. The CMR examination in heart failure. Heart Fail Clin 2009; 5: 283-300.
Braunwald E, Bonow R, Mann DL, et al. Braunwald’s heart disease: a textbook of cardiovascular medicine. Ninth
edition. Elservier Saunders, Philapelphia 2012; 550-551. ISBN: 978-0-8089-2436-4.
McMurray J, Cohen-Solal A, Dietz R, et al. Practical recommendations for the use of ACE inhibitors, beta-blockers,
aldosterone antagonists and angiotensin receptor blockers in heart failure: putting guidelines into practice. Eur J Heart
Fail 2005; 7: 710-721.
Granger CB, McMurray JJ, Yusuf S, et al; CHARM Investigators and Committees. Effects of candesartan in patients with
chronic heart failure and reduced left ventricular systolic function intolerant to angiotensin-converting-enzyme
inhibitors: The CHARM-Alternative trial. Lancet 2003; 362: 772-776.
Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe
heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med 1999; 341: 709-717.
Braunwald E, Bonow R, Mann DL, et al. Braunwald’s heart disease: a textbook of cardiovascular medicine. Ninth
edition. Elservier Saunders, Philapelphia 2012; 574-577. ISBN: 978-0-8089-2436-4.
Swedberg K, Komajda M, Bohm M, et al. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised
placebo-controlled study. Lancet 2010; 376: 875-885.
The Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl
J Med 1997; 336: 525-533.
Braunwald E, Bonow R, Mann DL, et al. Braunwald’s heart disease: a textbook of cardiovascular medicine. Ninth
edition. Elservier Saunders, Philapelphia, 2012; 565-567. ISBN: 978-0-8089-2436-4.
Goldstein RE, Boccuzzi SJ, Cruess D, et al. Diltiazem increases late-onset congestive heart failure in postinfarction
patients with early reduction in ejection fraction. The Adverse Experience Committee; and the Multicenter Diltiazem
Postinfarction Research Group. Circ 1991; 83: 52-60.
Mamdani M, Juurlink DN, Lee DS, et al. Cyclo-oxygenase-2 inhibitors versus non-selective nonsteroidal antiinflammatory drugs and congestive heart failure outcomes in elderly patients: a population-based cohort study. Lancet
2004; 363: 1751-1756.
Czuriga I, Borbely A, Czuriga D, et al. Heart failure with preserved ejection fraction (diastolic heart failure). Orv Hetil
2012; 153: 2030-2040.
Zipes DP, Camm AJ, Borggrefe M, et al. ACC/AHA/ESC 2006 guidelines for management of patients with ventricular
arrhythmias and the prevention of sudden cardiac death - executive summary: a report of the American College of
Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice
49
Guidelines (Writing Committee to Develop Guidelines for Management of Patients with Ventricular Arrhythmias and
the Prevention of Sudden Cardiac Death) Developed in collaboration with the European Heart Rhythm Association and
the Heart Rhythm Society. Eur Heart J 2006; 27: 2099-2140.
[28] Braunwald E, Bonow R, Mann DL, et al. Braunwald’s heart disease: a textbook of cardiovascular medicine. Ninth
edition. Elservier Saunders, Philapelphia 2012; 592. ISBN: 978-0-8089-2436-4.
[29] Brignole M, Auricchio A, Baron-Esquivias G, et al. 2013 ESC Guidelines on cardiac pacing and cardiac resynchronization
therapy. The Task Force on cardiac pacing and resynchronization therapy of the European Society of Cardiology (ESC).
Developed in collaboration with the European Heart Rhythm Association (EHRA). Eur Heart J 2013; 34: 2281-2329.
50
III. Ischemic heart disease, stable coronary artery disease (SCAD),
angina pectoris
Prof. Dr. Kalman Toth, Dr. Laszlo Czopf, Dr. Peter Kenyeres, Dr.Katalin Biro
1 Department of Medicine, Medical School, University of Pecs, Pecs, Hungary
st
1. Introduction and epidemiology
In developed countries with a decline of infectious diseases, violent and accident death with an
increase in life expectancy and age, chronic diseases and their complications came into view as a death
cause. More than half of deaths are caused by cardiovascular diseases, and 75 percent of these cases are
related to ischemic heart disease. The ischemic heart disease is the leading cause of death in developed
countries and - based on epidemiological forecast - it is going to be a leading cause of death in developing
countries as well. In 2001 17 million people died due to cardiovascular disease, and this number can reach
25 million by 2020. Ischemic heart disease is a most important factor in morbidity statistics, the disease and
its complaints will require vast amounts of money, posing a huge burden on the society.
The occurrence of stable angina increases gradually with age in both genders: in the agegroup of 45-64
it is 4-7%, in the agegroup of 65-84 it can reach 10-14%. In middle aged patients, complaints more
frequently occur in women (primarily due to the higher risk of functional angina), while in the elderly the
occurrence is more frequent in men and the main cause is significant coronary artery disease. The all-cause
mortality of the disease is 1.2-2.4% annually.
The incidence of the disease, morbidity and mortality can vary considerable from region to region due
to genetics, lifestyle and public health conditions. Cardiovascular risk is lower in the Western-European
region, in the Mediterranean and Scandinavian regions, while the risk is higher in Central and Eastern
Europe (including Hungary). The prevalence of stable angina in Europe is around 20 thousand to 40
thousand in a million people.
2. Risk factors
In most cases ischemic heart disease is caused by coronary stenosis due to atherosclerosis. In the
development and progression of the disease, in the formation of complications the following factors were
identified (the most important major risk factors are in bold type):
(1) non-modifiable risk factors:
• age
• male gender
• genetics, positive family history
• already developed atherosclerosis, previous events (heart attack, stroke, peripheral artery
disease)
(2) modifiable factors partially influenced by:
• smoking
• hypertension
• diabetes mellitus
• dyslipidemia (primarily high total-, LDL- and low HDL-cholesterol level, secondarily high level of
triglyceride)
• obesity and metabolic syndrome
• physical inactivity
• stress, depression
(3) beside the above mentioned risk factors the role of some other factors includes:
• impaired hemorheological parameters (fibrinogen, hematocrit, plasma viscosity and whole
blood viscosity, leukocyte count)
• hyperuricemia
51
• hyperhomocysteinemia
• infections, chronic inflammation (increased C reactive protein)
• microalbuminuria, decreased glomerular filtration rate (GFR) (chronic kidney diseases)
• oxidative stress, air pollution
• high heart rate
The SCORE chart (Figure 1) provides an estimated risk of fatal cardiovascular events within ten years
based on gender, age, smoking habit, blood pressure and blood cholesterol level. The chart was worked out
for different European risk regions; Hungary belongs to high risk countries.
Patients have high risk when:
(1) they had a cardiovascular event
(2) they suffer from diabetes mellitus (type II, or type I with micro/macroalbuminuria)
(3) metabolic syndrome is proven
(4) the risk based on the SCORE chart is ≥5%
Figure 1. Risk chart (SCORE)
Ten-year risk of fatal cardiovascular disease in populations at high cardiovascular disease risk
3. Definition and pathophysiology of angina pectoris
Ischemic heart disease is a generic term, involving diseases and clinical conditions, when myocardial
oxygen supply is lower than oxygen demand. As a consequence, aerobic myocardial metabolism shifts to
energetically unfavorable anaerobic metabolism.
3.1. Consequences of ischemia
Lack of energy impairs different normal myocardial functions; these appear parallel but at different
levels of energy deficiency. The sequel appearance of symptoms listed below is called ischemic cascade:
(1) Levels of lactic acid produced by anaerobic metabolism and K+ stuck extracellularly due to
dysfunction of the Na/K pump are elevated in the blood coming from the ischemic region. It can be
detected by blood sampling from the coronary sinus, but invasiveness makes it unused in practice.
(2) Break-up of actin-myosin binds, muscle relaxation needs energy. Impairment of the procedure
causes diastolic dysfunction, the earliest detectable symptom.
(3) Following diastolic function, systolic function becomes impaired as well. Hypo-akinesia of the
affected region and the reduction of ejection fraction can be detected.
52
(4) Disturbance of active ion transport changes the normal electrolyte gradients, repolarization,
impulse generation and conduction get impaired. ST-T abnormalities, QRS morphology changes,
arrhythmias, blocks may appear on the ECG.
(5) Ischemia usually means the lack of oxygen, the deficiency of blood flow and wash out as well.
Cumulating metabolites irritate sensatory nerve endings and provoke ischemic pain, angina pectoris.
(6) When the most severe form of the metabolic disorder occurs, myocardial necrosis takes place.
Extensive transmural necrosis may even result in wall rupture. After healing a scar remains, without the
ability for contraction or electrical activity, with passive paradox movement caused by intraventricular
pressure, possibly with aneurysm formation, and an electric window leading to pathological Q wave.
Repeated or chronic ischemic episodes trigger adaptation mechanisms that help cells to better
tolerate a subsequent ischemia (preconditioning). Persistent weak blood supply promotes the growth of
collateral vessels; the affected region will gain blood from other large vessels as well. On the other hand,
degeneration and remodeling processes may lead to the impairment of electrical and mechanical functions.
Degeneration of the impulse generating and conducting system may lead to ectopic beats (SVES,
VES), sinus bradycardia, sick sinus syndrome, AV blocks, bundle branch and fascicular blocks, and other
ventricular conduction abnormalities. Scars and muscle fibers with different conduction velocity can be the
base of reentry tachycardias (atrial fibrillation, ventricular tachycardia, ventricular fibrillation).
Mechanical dysfunction causes hypokinesia and akinesia, pump function decreases and ventricles
dilate leading to secondary valvular insufficiency. Papillary muscle dysfunction may also contribute to that.
Severe, acute ischemia resolved in time may cause myocardial stunning. The myocardium avoids
necrosis, but its mechanical function gets severely impaired. This state is spontaneously reversible,
contractile function is usually restored within days or weeks. In chronic ischemia the mechanical and often
also the electrical function of the myocardium become impaired; it becomes hibernated, but remains
viable, able to live. Restoration from ischemia (revascularization) may improve its function.
3.2. Cause of ischemia
Ischemia is caused by reduced oxygen supply and increased oxygen demand, or most often the
combination of these.
3.2.1. Reduced oxygen supply
3.2.1.1. Reduced blood flow in the coronary arteries
(1) increased coronary vascular resistance (either in epicardial large vessels or small vessels):
• atherosclerotic stenosis of vessels
• vasospasm
• thrombus formation (temporary or permanent)
• embolism
• significant augmentation of circulating blood viscosity (e.g. polyglobulia, paraproteinaemias)
(2) Significantly reduced cardiac output
• arrhythmias
- severe/critical bradycardia
- mechanically ineffective tachycardia (ventricular tachycardia, ventricular fibrillation)
• vitiums
- flow limiting mitral stenosis, aortic valve stenosis
- significant valve insufficiency causing low effective cardiac output, left-right shunts
(3) Deteriorated circulation during diastole - nutritive circulation of left ventricular happens mostly in
diastole, in systole wall stretch constricts intramural vessels
• low diastolic pressure
- bradycardia
- hypovolemia
- hypotension
- aortic valve insufficiency
• in case of reduced diastolic time: e.g. tachycardia, significant extrasystolia
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3.2.1.2. Reduced oxygen content of blood
(1) arterial hypoxia: pulmonary edema, pulmonary diseases
(2) reduced oxygen-carrying capacity: anemia
(3) damaged oxygen delivery: CO-poisoning, alkalosis, methemoglobinemia
3.2.2. Increased oxygen demand:
(1) Conditions requiring increased cardiac output (physiological increase in heart rate and blood
pressure)
• physical activities
• fever
• hyperthyroidism
• anemia
• pregnancy
• other sympathomimetic effects (e.g. emotional stress, drugs)
(2) Increased heart rate ratio of systolic time (working period) increases, diastolic time (resting)
decreases: any kind of tachycardia
(3) Increased wall tension
• hypertension
• aortic valve stenosis
• myocardial/ventricular dilation (based on the Laplace law)
(4) Increased myocardial mass
• adaptive hypertrophy (e.g. hypertension)
• hypertrophy (HCM)
Among the factors limiting oxygen supply the most common is the narrowing of the coronary arteries.
The oxygen extraction of myocardium unlike in skeletal muscle is nearly normal in baseline. Increased
oxygen supply can be reached by increasing the dilatation of arteries resulting in improved coronary flow.
In healthy subjects coronary reserve capacity can be fivefold higher than in cardiovascular patients. Under
atherosclerotic narrowing the reserve capacity is decreasing and ischemia can occur as a result of even
smaller load or effect of any other insult.
The subendocardial myocardium lies the farthest away from epicardial vessels, the blood gets here last
with the lowest perfusion pressure, and circulation is squeezed by the contraction of the myocardium for
the longest time here. In ischemia the first injured area is typically the subendocardial myocardium.
The atherosclerotic plaque can rupture; the core lying below the endothelium is thrombogenic.
Extensive platelet aggregation and thrombus formation can occur resulting in total occlusion of the artery
and - in the lack of adequate collateral circulation - it can cause severe ischemia of the distal part of
myocardium (e.g. acute coronary syndrome). It depends on a local thrombotic-antithrombotic balance
whether the thrombus is permanent or dissolves in time. Even if the thrombus dissolves, further
progression of plaque formation is likely.
The atherosclerotic narrowing is a fixed resistance, which cannot be compensated by vasodilatation of
the distal part of the blood vessel. When in the surrounding areas vasodilatation occurs (e.g. an increase in
the blood flow by own demand), the blood flow goes toward the smaller resistance, the flow through the
narrowed vessel can be deteriorated (steal effect).
In most cases the combination of the above facts can lead to ischemia.
A few examples:
(1) An atherosclerotic stenosis is completely closed by thrombus formation due to plaque rupture,
leading to necrosis (STEMI).
(2) An atherosclerotic stenosis may lead to angina during physical activity (stable angina pectoris).
(3) In case of atherosclerotic stenosis, an additional atrial fibrillation with high ventricular may lead to
heart failure within days.
(4) In case of severe atherosclerotic coronary artery stenosis, additional atrial fibrillation with high
ventricular rate may lead to pulmonary edema and increase in necroenzyme levels.
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4. Anatomy of coronary arteries
The lesion of each coronary artery leads to perfusion disturbances in special areas (Table 1), causing
special signs and deviations in ECG and mechanical alterations. Likewise, these kind of alterations could
help to find a culprit lesion (responsible for symptoms).
Coronary artery system
Supplied areas
Left main – LM
Left anterior descendent - LAD
anterior part of the right ventricle
• septal branches
anterior part of the septum
• diagonal branches (D)
anterior part of the left ventricle
Circumflex artery - Cx
left and right atrium
• obtuse marginal (OM)
lateral part of the left ventricle
Right coronary artery - RCA
right atrium
• acut marginal (AM)
sinus node
• posterior descending artery (PDA)
lateral and posterior part of the right ventricle
posterior part of the septum
AV node
posterior and inferior wall of the left ventricle
Table 1. Coronary arteries and their supplied areas
In most cases the strong PDA branch comes from RCA (right dominance, 70%). Rarely this branch
originates from Cx (left dominance, 10%), or can originate both from RCA and Cx as well (co-dominance,
20%). Usually LM divides into two branches: LAD and Cx (bifurcation), but sometimes another third,
intermediate (IM) branch originates as well (trifurcation), supplying the anterolateral part of the left
ventricle. In chronic coronary artery narrowing strong collateral network may develop between branches
(homocollateral - between branches of the same large vessel, heterocollateral - between branches of
different large vessels):
(1) RCA-conus artery ─ LAD
(2) LAD-septal arteries ─ RCA-PDA (through the septum)
(3) LAD ─ RCA-PDA (at the apex)
(4) RCA-PDA ─ Cx (at the crux)
5. Clinical manifestation of ischemic heart disease
A distinction should be made between unstable and stable coronary heart disease. The course and the
severity of these two diseases are different, thus diagnostic procedures and therapy should be different.
5.1. Acute coronary syndromes (ACS)
The unstable coronary artery disease or acute coronary syndrome means the acute impairment of
coronary flow, the appearance of acute ischemia. Acute circulatory obstruction is usually caused by
thrombus or vasospasm over atherosclerotic narrowing. It threats or leads to myocardial necrosis, or can
result in acute heart failure, life-threatening arrhythmia, sudden cardiac death. To make a diagnosis and
start the appropriate treatment is an emergency task. Acute ischemic coronary syndrome is a work
diagnosis based on threatening symptoms, which is classified by necroenzymes and deviation of ECG.
5.1.1 Unstable angina
In unstable angina atherosclerotic plaque rupture leads to release of vasoactive and trombogenic
agents causing vasospasm and thrombotic occlusion of the vessel. The occlusion dissolves in time, necrosis
does not develop, but this may be a threatening sign for an oncoming myocardial infarct in the near future.
Unstable angina is suspected:
(1) first angina attack of the patient
(2) angina in resting position or at minimal exertion
(3) angina presenting at always smaller exertion (crescendo angina)
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(4) in acute/subacute phase of myocardial infarction after initial complaints resolve, angina may
appear (so-called postinfarction angina)
On the ECG during angina acute ischemic variations can be observed, mostly changes or movement of
ST-T phase, (ST depression (rarely elevation) coronary T wave or T wave pseudonormalization). Slight
increase in troponin level may appear in lab tests, but increase in CK(MB), GOT or LDH level cannot be
detected.
5.1.2. Myocardial infarction - heart attack
Myocardial infarction is associated with acute ischemia leading to myocardial necrosis. The laboratory
test shows typical enzyme kinetics, first increasing later on decreasing enzyme level. Among the markers
examined increase of troponin can be observed first, but in a really early phase it may still be negative as
well, therefore in ACS checking troponin within 3 hours is essential.
The complaints include resting chest pain, longer than 20-30 minutes, persisting after nitrate therapy,
possibly associated with symptoms of acute heart failure (dyspnea, pulmonary edema) and vegetative
symptoms: sweating, nausea, vomiting (in inferior myocardial infarction), tachycardia (sympathetic
excitement), bradycardia (effect of vagal verve), fear of death.
Based on the ECG morphology two different types of myocardial infarctions can be differed:
(1) ST segment elevation acute myocardial infarction (STEMI)
(2) non-ST elevation ACS (NSTEMI, NSTE-ACS)
STEMI is usually caused by total occlusion of a large epicardial artery that - in the absence of early
recanalization - leads to the necrosis in the whole wall thickness (transmural). More than 0.1 mV-t ST
elevation can be observed in connected ECG leads. New appearance of left bundle branch block is
considered as STEMI as well. Diagnosis of STEMI can be established by the clinical symptoms and ECG
alone. Do not hesitate to start a therapy, waiting for the troponin level is a mistake.
In case of NSTEMI, no ST elevation can be seen on ECG; usually ST depression and T wave alteration
may occur, but the ECG readings can be normal as well. On the other hand, the diagnosis requires elevation
of necroenzymes. In NSTEMI some blood flow still remains in the affected area, the whole area does not
die; primarily the subendocardial region suffers injury.
NSTEMI can be caused by:
(1) obstruction of a smaller coronary artery
(2) partial obstruction of a large epicardial vessels
(3) total obstruction of a large epicardial vessels if the affected area is supplied by adequate collateral
blood vessels
(4) the heart with advanced vessel stenosis is affected by another severe, spontaneously not resolving
insult (e.g. clinically significant hemorrhage, anaemia, hyperviscosity, hypoxaemia, shock or extreme
tachyarrhythmia)
5.2. Stable coronary artery disease:
In stable coronary artery disease temporary, spontaneously reversible angina episodes without
necrosis may occur, or slow deterioration in heart work may be observed. The incidences of severe
complications are less frequent, so detailed diagnosis and therapy does not justify emergency. The
prognosis is relatively good; the yearly mortality is 0.9-1.4%. When symptoms suggesting instability arises,
patients should be treated similarly to that in acute coronary syndrome. The incidence of heart attack is
0.5-2.6% annually.
The leading symptom is angina pectoris, which means discomfort, squeezing pain or pressure in the
chest. In most cases it appears in the retrosternal region and radiates to the left arm, sometimes to the
jawbone, to the neck or teeth as well. In severe cases dyspnea, weakness, nausea, restlessness may occur.
Commonly it can be provoked by physical exertion, emotional stress, breathing of cold air, heavy meal, or
waking up in the morning, but it can be triggered or aggravated by any pathophysiological factor mentioned
in the previous section. The threshold of angina varies; it can be different in the same person. Pain is rarely
longer than 10-15 minutes and attenuated or relieved by using nitrates or rest.
In case of typical angina, the three main attributes of the pain (quality of pain, provocation, relief) is
similar to the above mentioned characteristics. This kind of angina is called stable angina pectoris
56
(Heberden angina), based on chronic atherosclerotic narrowing of coronary arteries, where blood flow gets
insufficient during workload. Typically the same occurrence, duration, characteristics, localization of
complaints and cessation of pain can be anticipated.
In case of atypical angina, only two of the three main characteristics can be observed. In
microvascular angina pain usually occurs after exertion, but does not show tight correlation with the level
of load, may appear later, often develops following exercise. It is often stronger and lasts longer than stable
angina, and may remain over 30 minutes. It has a poor response to nitrate. It is caused by increased
vascular tone and spasm of the small vessels, there is no significant alteration on large vessels. In
vasospastic angina the quality of the pain is typical, but it is usually not provoked by physical exertion, it
can appear in resting position as well. It starts with mild pain, pain increases, and stagnates for up to 15
minutes, then decreases. Usually it responses well to nitrate. Ischemia is caused by dynamic narrowing due
to vasospasm. Atherosclerotic narrowing is not significant, but vasospasm usually appears near an
atherosclerotic plaque, however, sometimes normal vessels can be affected. A special form is Prinzmetal
(variant) angina, where a large epicardial artery is affected by spasm, and temporary transmural ischemia
and ST elevation may develop. Complaints usually arise at night, or in resting position, physical exertion
rarely provokes it, and it often appears at the same time. The duration of complaints can be longer than in
stable angina pectoris, and a response to nitrate can vary in patients. It is often accompanied by migraine
or Raynaud phenomenon.
If none or just one of the mentioned features of chest pain occurs, non-anginal chest pain is
considered. It often arises from extracardial cause. A wide spectrum of cardiac, pulmonary, mediastinal,
skeletal, and gastrointestinal disorders can cause chest pain.
Pain may not be the leading symptom of the ischemic attack in neuropathic, diabetic, elderly patients;
it can be moderate or even missing. Rather other symptom of ischemia e.g. dyspnea, weakness can be the
main complaint. In patients who are prone to such silent ischemia the above symptoms can be considered
angina equivalent.
In stable coronary artery disease sometimes the leading symptom is not angina, but consequences of
ischemic cardiomyopathy:
(1) chronic heart failure may develop after myocardial infarction due to left ventricular dysfunction,
postinfarction aneurysm formation or as result of hibernating myocardium; infarction of papillary muscle
may also result in mitral insufficiency
(2) acute heart failure and pulmonary edema may arise as a result of extensive myocardial ischemia global ischemia, or ischemia of the residual, intact myocardium with decreased left ventricular function - or
acute mitral regurgitation due to acute papillary muscle ischemia
(3) the result of acute ischemia can be longer due to stunning, and due to „low output failure” it can
cause fatigue
(4) temporary or permanent arrhythmias may occur during angina
(5) the threatening complication, sudden cardiac death may occure due to malignant ventricular
arrhythmias (e.g. ventricular tachycardia, ventricular fibrillation), acute bradyarrhytmia (sinus arrest, high
grade AV block) or acute heart failure
In addition, the following cases are considered stable coronary heart disease as well:
(1) patients after myocardial infarction
(2) patients became asymptomatic by revascularization or medical therapy
(3) asymptomatic patients, in whom proper investigation proved the presence of resting or provokable
ischemia or significant coronary stenosis
6. Diagnostic procedures in ischemic heart disease
6.1. Medical history
Ask the patient about known coronary disease: did he suffered a heart attack earlier, did he have
proper investigation for this reason, maybe percutaneous intervention, CABG. Is the information reliable?
There are many patients affixed with the diagnosis of myocardial infarction, without proper diagnostic
procedures and adequate therapy. Risk factors of the patients should be highlighted.
57
6.2. Complaints
Explore characteristics and frequency of chest pain, provoking and attenuating factors. Is it typical,
atypical or non-anginal chest pain? Is there any possibility for instability? Is there any dyspnea, fatigue, any
complaints referring to heart failure or angina-equivalent symptoms? Is arrhythmia present (irregular, fast
heart beat, pulse measured as fast, slow or irregular)? In non-anginal chest pain specific questions for
differential diagnosis need to be asked.
Classification of angina severity based on the Canadian Cardiovascular Society (CCS) score:
(1) CCS I - ordinary activity does not cause angina, just a rapid or high exertion at work
(2) CCS II - slight limitation of ordinary activity; hurry, climbing stairs, climbing more than one floor,
exertion after meal can provoke angina
(3) CCS III - marked limitation of ordinary physical activity; walking at regular or slow speed, walking
along a flat field causes complaints
(4) CCS IV - any kind of physical activity causes chest discomfort; angina appear on minimal exertion or
even in resting position
6.3. Physical examination
There are no typical alterations for SCAD. In acute heart failure pulmonary congestion and gallop
rhythm can be observed and during angina with papillary ischemia temporary mitral regurgitation can be
diagnosed. We have to watch risk factors and symptoms provoking angina (obesity, high blood pressure,
arrhythmias, signs of heart failure, missing peripheral pulses, heart murmur, ankle-brachial index, signs of
anemia, nodes in the thyroid gland, fever).
6.4. Lab tests, biochemical tests
Biochemical test are usually not suitable for direct diagnosis of ischemic heart disease. Necroenzymes such as troponin T and I, creatinine kinase, GOT, LDH - are used to prove myocardial infarction, to diagnose
acute/subacute stadium, to follow up the course, and to recognize a reinfection. They should be checked an
acute cases and suspected instability of SCAD. Other lab parameters give information about risk factors,
effects and side effects of the therapy, and help to detect any ischemia-provoking factor.
Electrolytes (K+, Na+, Mg2+); electrolyte-alterations can be a background in many arrhythmias. In
hypokalemia and hypomagnesaemia tachycardia and ectopic impulse generation can appear, in
hyperkalemia bradycardia and conduction abnormalities may occur. Many cardiac drugs can influence its
level (furosemide and thiazide diuretics decreases the K+ level, while spironolactone and K+
supplementation increase it), for this reason it has to be checked regularly.
Renal function (CN, creatinine, GFR); renal failure is a cardiac risk factor. Heart failure can cause
deterioration of the renal function. Numerous drugs can aggravate the renal function (spironolactone, ACE
inhibitors, ARB, overdosing of diuretics), some drugs are contraindicated is renal failure (spironolactone) or
dosage reduction is necessary (LMWH, NOAC).
Liver function (GOT, GPT, LDH); these parameters are not specific necroenzymes as well. Higher levels
of these enzymes can refer to liver congestion. Many drugs can cause liver injury (statin, amiodarone).
Blood count; acute infection, anemia, polyglobulia (hyperviscosity) can trigger ischemia.
Carbohydrate metabolism (blood sugar, HbA1c, oral glucose tolerance test); these parameters are
used in the diagnosis of diabetes or hypoglycemia and for the evaluation of therapy.
Lipids (total-, HDL-, LDL-cholesterol, triglyceride); these parameters are used in the diagnosis of
dyslipidemia and for the evaluation of the cholesterol lowering therapy.
Thyroid gland function (TSH, T3, T4); hyperthyroidism can cause arrhythmia and hyperkinetic
circulation. Hypothyroidism may lead to accelerated atherosclerosis.
BNP/NT-proBNP; marker of heart failure, it provides help in differential diagnostics.
6.5. Instrumental examinations
The anatomical imaging diagnostic procedures conclude to the degree of narrowing, an expected
severity of the disease by visualizing large coronary arteries. With their help the critical narrowing of blood
vessels, which can be a target of revascularization procedures, can be detected.
58
Functional examinations can provide information about blood flow, tissue perfusion and electric and
mechanical dysfunction of myocardium. In most cases oxygen supply can fulfil resting oxygen demand,
ischemia may only occur during exertion. Functional examinations can be carried out during exertion for
provoking and detecting ischemia under controlled conditions.
During physical examination oxygen demand is increased by physical activity. There are different
protocols used for treadmill or bicycle (rarely arm ergometer), which can quantify the patient’s capacity.
Physiological alterations during daily life routine can be better demonstrated, the patient’s capacity, and
physiological responses to the exertion (blood pressure, pulse) can be assessed.
In some patients physical exertion could not be induced due to their limited mobility, difficulty in
cooperation or low capacity, or a required work load cannot be achieved. Sometimes intensive physical
activity is not possible because of the examination method or circumstances. In these cases
pharmacological stress tests can be performed:
(1) dobutamine is a positive chronotropic and inotropic drug, increasing the work and oxygen demand
of the myocardium
(2) dypiridamole and adenosine has a vasodilating potential, they can provoke ischemia by earlier
mentioned steal effect
Ischemia provoked by stress - although with a low chance (around 0.5-25/10000 examination) - may
involve life-threatening arrhythmia and fatal complications as well; therefore it should be carried out under
proper surveillance, in emergency preparedness (defibrillation, reanimation).
6.5.1. ECG examinations
Myocardial repolarization and depolarization disturbances, injury of the impulse generation and
conducting system due to ischemia can be detected with ECG. The following alterations can refer to
ischemia, but their appearance is not mandatory, and similar alterations may occur for other reasons. The
differentiation at adequate lead can refer to the site of ischemia on 12-leading ECG.
Alterations on ECG:
(1) ST elevation: transmural ischemia, aneurysm
(2) ST depression: subendocardial ischemia
(3) coronary T (symmetric, negative T wave): ischemia, previous myocardial infarction, Wellen’s
syndrome (deep negative T wave in V2-V3, severe, sign of significant LAD stenosis threatening with
obstruction)
(4) T wave pseudonormalization: resting coronary T wave turns around (becomes positive)
(5) flat T wave
(6) hyperacute T wave (wide based, asymmetric, high, peaky T): first sign of STEMI, Prinzmetal angina
(7) pathological Q wave: previous or ongoing transmural infarction
(8) R reduction, inadequate R wave increment: non-transmural infarction
(9) left bundle branch block
• in case of new onset of left branch block the infarction is considered STEMI
• in left branch block Q wave, ST segment and T wave cannot be assessed, but
• the direction of ST segment and T wave is normally opposite of QRS (typically in V1: negative
main wave, ST elevation and positive T wave, in V6: positive main wave, ST depression, negative T); if
this relationship between QRS and T wave is upset or ST segment and T wave change significantly,
ischemia may be present
(10) QRS morphology, variation of axis
(11) frequent ventricular premature beats, nsVT, ventricular tachycardia, ventricular fibrillation
(12) atrial fibrillation
(13) sick sinus syndrome, AV blocks
6.5.1.1. Resting ECG
All patients with suspected coronary atherosclerosis should have a resting 12-lead ECG recorded.
Compare the ECG with an earlier one if available. Resting ECG will establish a baseline for comparison with
ECG during complaint or during exercise stress testing and for follow-up of the patient.
59
6.5.1.2. ECG exercise testing
Exercise ECG is a most frequently used stress test. During the most commonly used Bruce protocol the
patient is walking or running on the treadmill, whose speed and slope increases every 3 minutes. This
exercise is limited by the patient’s symptom, not stopped at a predefined level, but in optimal cases
continued up to the capability (or compliance) of the patient. The exercise should be interrupted if
continuing is dangerous, e. g. patient cannot keep up with a treadmill due to musculoskeletal diseases,
claudication or dizziness; severe angina or threatening ECG alterations appear, hemodynamic instability or
extreme increase in blood pressure is detected.
The maximal load level, blood pressure and heart rate response, arrhythmias and repolarization
alterations are assessed. At least 0.1 mV (1 mm) horizontal or downsloping ST depression at 60/80 ms after
J point in connected leads is considered significant. The evaluation is assisted by signal averaging software,
filtering out movement and respiratory artefacts, but a real time ECG assessment is essential. Mostly in
small vessel disease, ECG alterations present during the resting period after exercise. ST depression during
exercise ECG (unlike in resting ECG) refers only to the appearance of ischemia and not to its localization.
This method is unsuitable for the detection of ischemia in abnormal resting repolarization (LBBB,
ventricular pacemaker, WPW syndrome). Its limited value may give a false-positive result in left ventricular
hypertrophy, ventricular strain, intraventricular conduction disorder, electrolyte alterations and atrial
fibrillation or in digitalis effect.
If the patient does not reach 85% of the expected maximal heart rate (in sinus rhythm it is 220 minus
the age of the patient), ischemia cannot be ruled out in case of negative result. Antianginal drugs may
prevent provoking ischemia, thus if the aim of the examination is prove to SCAD, the examination should be
performed without antianginal medications; beta-blockers, calcium channel blockers, nitrates,
trimetazidine and digitalis should be suspended. If the aim of the examination is the assessment of the
therapeutic efficacy in SCAD patient and follow-up, medication should not be stopped.
6.5.1.3. Holter ECG
24-hour ECG monitoring may detect arrhythmias and ischemic periods during daily routine. It has an
importance primarily in the load-unrelated vasospastic and silent ischemia.
6.5.1.4. Transtelephonic ECG
Patients can make an ECG during chest pain with this simple ECG instrument, and send it to a call
center. Presence or lack of arrhythmia and repolarization alteration at the time of complaints can be
identified by this instrument.
6.5.2. Echocardiography
Resting two-dimensional echocardiography is recommended for all patients suspected to have
coronary artery disease. Segmental wall motion disorder (hypokinesia, akinesia, paradox movement), and
reduced ejection fraction may refer to ongoing ischemia or past infarction. The examination may identify
other disorders (hypertrophy, valvular disorders) that may contribute to the provoking and worsening of
ischemia or may be non-ischemic causes of chest pain and dyspnea.
Stress echocardiography can be performed using exercise or pharmacological stress. Exercise stress is
preferred due to the aforementioned advantages; however, imaging during movement is technically more
difficult. The latter is no issue in pharmacological stress. Pharmacological (preferably dobutamine) stress is
recommended in significant resting wall motion disorders. Imaging quality may be improved by the
application of echo-contrast agents (microbubble solution).
Possible findings in stress echo:
(1) new wall motion disorder (decrease in systolic wall thickening) during stress test refers to ischemia
(2) contrast agents help not only to better visualize wall motions, but to assess tissue perfusion as well
(3) diastolic dysfunction is an early sign of ischemia, new methods like tissue Doppler imaging and
strain rate analysis helps its better assessment
(4) dobutamine stress testing can be used to assess viability of akinetic regions. Wall segments
producing motion by low-dose dobutamine indicate viable myocardium
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6.5.3. Myocardial perfusion scintigraphy
Patients receive an intravenous bolus of isotope that distributes in the myocardium according to the
perfusion rate. Distribution is visualized by SPECT; low activity areas represent impaired perfusion. During
stress testing, the isotope is injected just before the peak of exercise or pharmacological stress, and this
image is compared to a resting one. Permanent perfusion defect that is present on both stress and resting
image indicates dead or hibernated myocardium. Transient perfusion defect indicates blood supply
sufficient at rest but insufficient during stress.
The examination is usually performed using 99mTc-MIBI isotope that supplanted the previously used
thallium-201. Longer half-life of thallium results in lower useful activity during imaging, image quality, if
worse, radiation burden of the patient and his environment is higher. Another disadvantage is the
redistribution of the isotope, as cells in poorly perfused regions start to accumulate it as a K+ analog,
making timing of injection and imaging critical. This property, on the other hand, makes it suitable to detect
hibernated but living myocardium, preserving thallium for viability examinations.
Myocardial perfusion scintigraphy can be performed using positron emitting isotopes and PET imaging
as well. Its image quality and diagnostic value is superior to SPECT, but high cost and poor availability makes
it rarely used.
6.5.4. Cardiac MR (CMR)
The method can visualize walls and cavities and more objectively assess wall motions and left
ventricular function. It may be used when transthoracic echocardiography is unable to answer the clinical
question (usually because of a restricted acoustic window). Gadolinium contrast agent can identify areas
having died due to acute or previous myocardial infarction that cumulate the contrast agent with a delay
compared to unaffected tissue (delayed/late enhancement). This is the only method to quantify the extent
and transmurality of an infarction and connected to the inspection of wall motion, most accurate
assessment of viability.
Dobutamine stress CMR to detect newly onset wall motion disorders is an alternative of stress
echocardiography in the case of restricted acoustic window. The new perfusion CMR providing information
about tissue perfusion is an alternative of SPECT. Coronary MR angiography is theoretically also possible,
but because of its worse resolution and long imaging time it is not used.
CMR is an evolving, developing method providing multimodal information about ischemia with a single
examination, unfortunately the need for expensive instrumental background makes it not widely available.
6.5.5. Chest X-ray
Chest X-ray cannot identify ischemic heart disease, but it is useful to detect other causes of chest pain
and dyspnea (pulmonary or skeletal origin) during the differential diagnosis. It is recommended in any
patient with such complaints.
6.5.6. Coronary CT
Modern multidetector row, at least 64-slice CT systems are suitable for non-invasive anatomical
imaging of coronary vessels with adequate speed and resolution. Besides, chest CT provides help in the
differential diagnosis of chest pain and dyspnea. “Triple rule-out CT” assesses coronary disease, pulmonary
embolism and aortic dissection in the background of acute chest pain during a single examination.
The amount of Ca2+ in the coronary vessels can be assessed without contrast agents (Agatston score)
(based on pixels above 130 Hounsfield unit), that indicates the extent of atherosclerosis but gives no
information about the presence of significant stenoses.
Coronary CT angiography using contrast agent displays coronary vessel walls and lumen. Magnitude of
stenoses can be quantified, significant stenoses can be identified. Imaging is based on data of several heart
beats using ECG-gating. The patient should be able to hold his breath and not move during the imaging.
Synchronization of images needs low-rate, rhythmical heartbeats; atrial fibrillation, significant extrasystolia,
tachycardia greatly worsens image quality (short acting beta-blocker may be used if necessary). Severe
obesity is a confounding factor as well. Quantification of stenoses may be inaccurate in significant
calcification (Agatston score above 400), stents and graft stenosis after CABG.
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6.5.7 Hybrid techniques: SPECT/CT, PET/CT, PET/CMR
Combination of methods allows the acquisition of both anatomical and functional information during
one examination, and the assessment of their relationship (if perfusion is sufficient despite significant
stenosis; if there is functional disorder despite non-significant lesion). Additional information from one
method may help to correct the artefacts of the other method as well (based on the chest shape displayed
by CT, it is possible to correct radiation absorption due to obesity or breasts that would otherwise appear
as perfusion defect on SPECT).
6.5.8. Coronary angiography
Coronary angiography is an invasive, anatomical imaging method; it is rarely used for diagnosis only.
Its purpose is to detect the need and possibility of revascularization, which can be done during the same
session. The examination is performed in local anesthesia by the cannulation of the radial (nowadays it is
preferred due to the less bleeding complications) or the femoral artery, through which a catheter is led to
the coronary arteries, selectively dying them with contrast agent and visualizing them with fluoroscopy.
Anatomically significant stenoses can be identified: over 50% of the area in the case of the left main, and
over 70% for other branches.
Anatomically not significant, but long or multiple stenoses may considerably hinder blood flow, and
can be hemodinamically significant. This can be assessed by FFR (fractional flow reserve) measurement
comparing pressures proximal and distal to the stenosis. A stenosis with FFR below 0.8 is considered
hemodinamically significant. The measurement is gaining recognition; recently only stenosis above 90% is
considered obviously significant, for stenoses between 50-90%, measurement of FFR is recommended.
6.6. Strategy of diagnostics in coronary artery disease
Examinations aim not only the diagnosis of coronary artery disease, but the assessment of severity,
risk stratification of the patient, follow-up of the patient and measurement of therapeutic effectiveness as
well. If at any time instability is suspected, diagnostics (complaints, ECG, troponin level) and therapy for
acute coronary syndrome should be followed.
6.6.1. Diagnosis
The following examinations should be performed in case of suspected coronary artery disease:
(1) taking case history, complaints and physical examination
(2) blood chemistry to clarify risk factors
(3) 12-lead resting ECG for diagnostic purpose and later comparison
(4) resting echocardiography
(5) chest X-ray for differential diagnosis if chest complaints are present
Knowing sex, age and characteristics of complaints, pre-test probability (PTP) of coronary artery
disease can be calculated according to population data (Table 2). Presence of risk factors and positive test
results increase this probability.
Typical angina
Atypical angina
Non-anginal chest pain
Age
Male
Female
Male
Female
Male
Female
30-39
59
28
29
10
18
5
40-49
69
37
38
14
25
8
50-59
77
47
49
20
34
12
60-69
84
58
59
28
44
17
70-79
89
68
69
37
54
24
>80
93
76
78
47
65
32
Table 2. Pre-test probability (PTP) of patients for coronary artery disease according to sex, age and
characteristics of chest pain (%)
Patients with ejection fraction below 50% and complaints of typical angina are considered high-risk,
and invasive diagnostics is indicated without any further non-invasive testing.
Further tests may help to prove or reject the diagnosis. Any examinations, however, can provide false
positive or negative results that adversely affect the decision making.
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If pre-test probability is already high, above 85% (typical angina of old male), further non-invasive
diagnostic testing is useless: positive result does not add much to decision making, while negative result is
more probable to be false than indicating the lack of coronary artery disease (based on Bayes’ theorem).
Such patients should be considered to have coronary artery disease and be referred for coronary
angiography. Non-invasive testing may still be applied for risk stratification and planning of therapy.
In low, below 15% pre-test probability (young female with atypical or non-anginal chest pain),
coronary artery disease is unlikely, further testing is unnecessary. Other causes of chest pain should be
considered. In the presence of repeated, angina-like complaints, functional coronary artery disease
(vasospasm, small vessel disease) may be suspected.
If pre-test probability is between 15-85%, further testing should be performed; the choice of method
depends on the local practice, human and instrumental resources and patient features. Keep the
mentioned limitations of tests in mind. Exercise stress testing for disabled patients, ECG based tests in the
presence of left bundle branch block, stress echocardiography for patients with restricted acoustic window,
coronary CT in atrial fibrillation, CMR or scintigraphy in claustrophobia are poor choices.
Exercise ECG is usually easily available and performable. It is the preferred method for patients with
PTP of 15-65% if they are able to do the exercise. It has a good specificity but weaker sensitivity, thus in
patients with PTP of 65-85% the number of false negative results increase. In this case the test is
recommended for diagnosis only if other methods are not available or applicable.
Stress echocardiography, stress myocardial perfusion scintigraphy, rarely stress CMR are possible
alternatives if exercise ECG is not possible or not recommended.
Coronary CT angiography has an excellent negative predictive value. It may be a first choice to rule out
coronary artery disease in patients with low to moderate risk (15-50% PTP). On the other hand, since
Agatston score above 400 or considerable focal calcification may result in inaccurate assessment of
stenoses, the method is not recommended in higher PTP; coronary angiography should be chosen for
anatomical imaging. A positive test result proves coronary artery disease. If the result is uncertain,
equivocal or uninterpretable, a second non-invasive test (stress testing or coronary CT angiography) or if
necessary (e.g. the patient is unsuitable for other tests) direct coronary angiography should be performed.
6.6.2. Risk stratification
The tests mentioned help not only to make the diagnosis, but to assess the risk of the patient as well,
which is needed for therapy planning.
During exercise ECG, poor workload capacity, onset of angina or ST depression indicate higher risk.
These are summed up in the Duke treadmill score:
Duke treadmill score = T – 5 x STmax – 4 x angina index
T: duration of exercise in minutes
STmax: maximal ST deviation in mm
Angina index:
0: no angina
1: angina that did not force termination of exercise
2: exercise limiting angina
≥+5:
low risk
-10 – +4:
moderate risk
≤-11:
high risk
Stress imaging refers to high risk, if the area of ischemia exceeds 10% of the myocardium (10% for
scintigraphy, 3 segments with induced wall motion disorder for stress echocardiography or stress CMR).
Risk is low, if no ischemia is detected. High risk is considered with anatomical imaging in significant left
main or proximal LAD stenosis or proximal three vessel disease. Other significant stenoses indicate
moderate risk. Annual mortality is below 1% in low risk, 1-3% in moderate and above 3% in high risk cases.
Beyond the aforementioned estimation, consider the presence of other risk factors and symptoms, like
hypertension, diabetes, smoking, dyslipidemia, chronic kidney disease, peripheral arterial disease, stroke,
previous myocardial infarction, symptoms of heart failure and especially intensity, frequency and
refractoriness of angina. Accordingly, more aggressive diagnostic strategy may be chosen (e.g. coronary
angiography is indicated primarily for a patient with typical angina and ejection fraction below 50%).
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7. Treatment of SCAD
In the past decades medical and instrumental therapy has made huge progress, thereby cardiovascular
death and frequency of myocardial infarction could be reduced significantly, symptoms, quality of life and
life expectancy have been improved. On the other hand it is important to remember that coronary sclerosis
is a progressive disease, progression primarily may be slowed down by the elimination of risk factors. The
treatment of modifiable risk factors is really important both in primary and secundary prevention.
7.1. Lifestyle changes
The effective treatment of the disease require a long-term change in patient attitude in relation to
smoking, nutrition, exercise, medication habits and also the adequate compliance with a patient. Education
related to the disease, complications, therapy, life style, medical information, stress management and
information about psychosocial risk factors is considered, which can be achieved by involving healthcare
professionals (nurses, psychologists, dietetics).
Cardiac rehabilitation involves control of risk factors, optimization of medication, moreover patient’s
exercise capacity is assessed under well-controlled conditions and its improvement is aimed based on a
training plan. Cardiac rehabilitation is offered not only for patients after myocardial infarction or recent
coronary intervention, but should be considered in all patients suffering from chronic angina.
Smoking is maybe the most aggressive, but the most easily eliminateable risk factor, complete and
final smoking cessation is essential. All smoking patients should be advised to quit and offered cessation
assistance, even advice on pharmacological help (bupropion, vareniclin) to stop smoking. Nicotine
replacement therapy can be useful and safe. Passive smoking should be avoided as well.
Healthy diet helps to reduce body weight, to optimize the lipid profile and carbohydrate balance and
to reduce blood pressure. Energy intake should be limited to the amount of energy needed. Saturated fatty
acids should make up no more than 10% of energy intake, use poly-unsaturated fatty acids. A good source
is to consume fish at least twice a week. Trans unsaturated fatty acids should be consumed as little as
possible, below 1%. Salt consumption per day should not exceed 5 g. 30-45 g of fiber consumption per day
is recommended from wholegrain products, fruits and vegetables. Consume 200-200 g vegetables and
fruits 2-3 times per day. To follow a Mediterranean diet, using extra virgin olive oil and consumption of oily
seeds is beneficial. Moderate alcohol consumption, primarily wine intake is beneficial, but should be not
more than 20 g/day (2 glasses) in males, and 10 g/day (1 glass) in females.
Regular physical activity helps to lose weight, improves dyslipidemia, assists glucose uptake
independently to insulin, reduces blood pressure and increases capacity. Moderate intensity aerobic
exercise training at least 3 times a week and for 30 min per session is recommended. Patients with
sedentary lifestyle should start light-intensity exercise programs. In patients having suffered from
myocardial infarction, underwent PCI or CABG, or suffering from stable angina or chronic heart failure, safe
workload level can be assessed using controlled level loading like exercise ECG.
Sexual activity refers to 6 MET physical exertion, but increase in blood pressure and pulse can be
higher. Sexual activity may provoke angina, use of nitroglycerin before sexual activity can decrease or
prevent it in SCAD patients. It may be necessary to assess safe physical workload capacity in heart failure,
angina pectoris. In vascular disease erectile dysfunction often occurs, in these cases PDE5-inhibitor potency
increasing drugs (sildenafil, tadalafil, vardenafil) are usually applicable. Their application is not advised in
hypotensive patients, in NYHA III-IV stadium, after recent cardiovascular event and in refractory angina.
Their application is absolutely contraindicated when using nitrate, because a synergist effect can cause
severe hypotension. Patients taking PDE5-inhibitor in angina cannot receive nitrate until the drug is
completely eliminated (24-48 hours).
Achieving the optimal body weight positively influences the blood pressure, dyslipidemia and glucose
metabolism. Weight reduction in overweight and obese people is recommended. The goal usually is to
reach and keep 20-25 kg/m2 BMI range, waist circumference in ladies below 80 cm, in males below 94 cm.
Lipid control is another important issue. In high risk patients to LDL-cholesterol level should be kept
below 1.8 mmol/l target value or if or possible, it should be reduced by 50% at least. Significant
hypertriglyceridemia has to be treated. If it cannot be achieved by statin monotherapy alone, other
complementary therapy (ezetimibe, fibrate, nicotine-acid, PCSK-9 inhibitor) can be used. For patients
before PCI high doses of statin is recommended.
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Blood pressure control: Usually the aim is below 140 mmHg systolic value and below 90 mmHg
diastolic value, in diabetic population below 140/85 mmHg value is recommended. Primarily, as detailed
later, drugs that prevent death and relieve angina symptoms are recommended (ACE inhibitor/ARB, betablocker, Ca channel blocker).
Control of diabetes mellitus and carbohydrate balance: The optimal glycemic control is essential. The
aim is to keep HbA1C under 7% (6.5-6.9%). ACE inhibitor and beta-blocker should be given for renal
protection if tolerated.
Psychosocial factors: In cases of clinically significant symptoms of depression, symptoms or anxiety
and hostile behavior a psychologist or psychiatrist can be involved, and appropriate psychotherapy or
medication should be considered.
Influenza vaccination is recommended annually for patients with SCAD, especially in elderly.
Hormone replacement therapy: based on epidemiological data we assumed the protective effect of
estrogen, but large randomized multicenter trials showed that in ladies over 60 years the hormone
replacement therapy did not improve, but deteriorated mortality. Preventive hormone replacement
therapy is contraindicated.
7.2. Pharmacological therapy
Pharmacological therapy of stable coronary artery disease has dual goal: on one hand to improve
prognosis by preventing myocardial infarction and cardiac death, on the other hand to improve the quality
of life by reducing the frequency and severity of complaints.
7.2.1. Antianginal medications
Antianginal, antiischemic medicines reduce the myocardial oxygen demand or improve its perfusion.
Nitrates are the longest used effective medication. As a NO donor, they dilate coronary vessels, relieve
vasospasm and improve perfusion. They reduce preload and afterload and reduce the myocardial oxygen
demand.
Short-acting sublingual nitrates are used for rapid ease of effort or vasospastic angina and for the
prevention of anticipated angina (e.g. before sexual activity). Most commonly nitroglycerine (0.3-0.6
mg/dose every 5 minutes, max. 1.2 mg) and isosorbid-dinitrate (5 mg) are applied.
Long-acting nitrates are aimed to prevent angina attacks. Prolonged, continuous application leads to
tolerance, thus a daily at least 10-12 hour-long intermission is recommended. Isosorbid-mononitrate,
isosorbid-dinitrate, and transdermal nitroglycerin belong to this group.
The most common side effects are hypotension and headache. Application with PDE5 inhibitor
potency boosters is prohibited. Administration of short-acting nitrates should be careful in the case of
severe aortic stenosis or hypertrophic obstructive cardiomyopathy limiting cardiac output since they may
lead to a drop in cerebral blood flow and collapse due to whole body steal effect.
Beta-blockers’ negative ino- and chronotropic effect decrease myocardial oxygen demand, and the
longer diastolic filling time improves oxygen supply as well. They not only reduce angina, but improve
mortality owing to their antiarrhythmic effect as well. For post-infarction and heart failure patients without
contraindication their use is compulsory, they should be used in first line, but they can be recommended
for any patients with stable coronary artery disease.
Most frequently used representatives are metoprolol, bisoprolol, nebivolol and carvedilol. Lower doses
should be administered first, then it should be up-titrated to the tolerated level. Target heart rate in stable
coronary artery disease is around 60/min.
Side effects: beta-blockers may increase vascular tone and worsen the symptoms in vasospastic angina
and severe limb ischemia, in such cases nebivolol that has direct vasodilator effect may also be applied.
Bronchospasm in COPD and asthma may be increased, which can be avoided using more selective agents
(e.g. nebivolol). Beta-blockers may lead to bradycardia or AV block, co-administration with other heart ratelowering drugs should be done carefully. Cold limbs, fatigue, depression and erectile dysfunction may rarely
occur.
Calcium channel blockers (CCB) dilate coronary arteries, open collaterals and improve the blood flow
in ischemic areas. They reduce the blood pressure, the afterload, and thus the myocardial oxygen demand.
Ankle edema is a common side effect that can be reduced with ACE inhibitors.
65
Dihydropyridine type calcium channel blockers (nifedipine, amlodipine, lercanidipine, felodipine,
lacidipine) affect the vascular smooth muscle, and have little effect on the myocardium.
Non-dihydropyridine type calcium channel blockers (verapamil, diltiazem) affect the vascular smooth
muscle and the myocardial calcium channels as well; they have both antihypertensive and antiarrhythmic
effect. They may cause bradycardia and AV block, co-administration with beta-blockers is contraindicated.
They should not be used in the presence of reduced ejection fraction because of their negative inotropic
effect.
Ivabradine, a selective If-channel inhibitor, reduces the activation rate of the sinus node, lowers the
heart rate thus prolongs diastole. It has no other significant effect or side effect, does not influence blood
pressure or contractility. It is indicated if the resting heart rate is above 70/min despite of beta-blocker
treatment (or in case of beta-blocker contraindication), and only in sinus rhythm.
Trimetazidine affects metabolism. Oxidation of fatty acids is inhibited, metabolism is shifted toward
glucose oxidation that provides the same energy using less oxygen, being more favourable during ischemia.
Ranolazine is a selective inhibitor of the late sodium channel, leading to the reduction in intracellular
Ca level, muscle contraction and wall tension. It prolongs QT, thus it should be carefully used in the
presence of long QT or with other QT prolonging agents.
Nicorandil stimulates ATP sensitive potassium channel and dilates the coronary arteries. Plaque
stabilizing effect is supposed as well.
Molsidomine is a direct NO donor, vasodilator. Nitrate-like tolerance is less common.
7.2.2. Medication for event prevention
Life expectancy can be improved by preventing acute thrombotic events and preserving left ventricular
function.
Antiplatelet agents prevent vessel occluding thrombus formation on ruptured plaques. They are used
for the prevention of myocardial infarction, atherothrombotic TIA and stroke and peripheral arterial
occlusions as well. Increased bleeding risk should be expected as a side effect (gastrointestinal, intracranial
and skin hemorrhages).
Effectiveness of antiplatelet agents can be tested in vitro, in many patients inadequate platelet
aggregation inhibition may be found (non-responders). Such methods may help drug selection in special
cases, routine application, however, it does not improve the prevention of thrombotic events, and thus is
not recommended.
Acetylsalycilic acid, aspirin irreversibly inhibits cyclooxygenase (COX)-1, prevents the synthesis of
thromboxane A2 and platelet activation. Much lower doses are enough for the cardioprotective effect than
for pain relief (75-150 mg daily), higher doses usually only increase side effects.
Thienopyridines:
(1) clopidogrel hinders the amplification of platelet aggregation by irreversible inhibition of ADP P2Y12
receptor. Long-term administration of clopidogrel is slightly more effective compared to aspirin, but cost
effectiveness and safety reasons make it only a second line choice in this indication, in cases of aspirin
intolerance or non-response.
(2) prasugrel, a new generation thienopyridine, has more reliable pharmacokinetics than its precursor.
(3) ticagrelor is a novel reversible ADP receptor inhibitor. Both proved to be more effective in
treatment and secondary prevention of STEMI compared to clopidogrel; at the cost of increased bleeding
complications. They are indicated in selected cases of STEMI.
Beta-blockers are not only antianginal agents, but reduce mortality as well. See detailed description in
the previous section.
Statins (fluvastatin, simvastatin, atorvastatin, rosuvastatin) have pleiotropic effects: they reduce
cholesterol level, slow the progression and stabilize atherosclerotic plaques, have antioxidant and
antiinflammatoric effect. Their administration is recommended even in normal cholesterol level.
Side effects involve myopathy, rarely rhabdomyolysis and liver failure (especially in hypothyroidism,
alcoholism, and taking of antimycotics), thus periodic check of liver function of CK is recommended.
Inhibition of the renin-angiotensin-aldosterone system with angiotensin converting enzyme (ACE)
inhibitors and angiotensin receptor blockers (ARB); these medications have several beneficial effects in
addition to blood pressure and afterload reduction (they inhibit myocardial and vascular remodeling, have
66
antiproliferative/antiatherogenic effect, stabilize coronary plaques, improve endothelial function, increase
fibrinolysis). They are recommended in the first line in coronary artery disease, especially in cases of
hypertension, diabetes, renal failure or heart failure with reduced ejection fraction. ACE inhibitors (e.g.
perindopril, ramipril, enalapril, fosinopril, quinapril) are preferred; in cases of intolerance (pl. dry cough)
ARBs can be a substitute (e.g. losartan, valsartan, telmisartan, irbesartan). Combination with CCBs further
improves prognosis, combination of ACE inhibitors with ARBs on the other hand has no further benefits but
increase the risk of renal failure and thus is usually contraindicated. The use of mineralocorticoid receptor
antagonists (spironolactone, eplerenone) is recommended in post-infarction patients with reduced ejection
fraction beside ACE inhibitor and beta-blocker treatment, in the presence of symptoms of heart failure or
diabetes.
7.2.3. Strategy of medical treatment in stable coronary artery disease
First of all, lifestyle modification and control of risk factors should be done.
7.2.3.1. Prevention of cardiovascular events
(1) antiplatelet agents: aspirin, or clopidogrel in aspirin intolerance
(2) statin: reduce LDL-cholesterol level below 1.8 mmol/l, or at least by 50% if target level cannot be
reached
(3) ACE inhibitors: in patients with hypertension, diabetes, renal failure, previous myocardial
infarction, ejection fraction below 40% or heart failure (majority of coronary artery disease patients)
7.2.3.2. Reducing angina symptoms:
(1) short-acting nitrates to use on demand
(2) first line:
• beta-blocker or heart rate-lowering CCB (if one is ineffective, it may be switched to the other)
• beta-blocker and dihydropyridine type CCB together
(3) second line:
• ivabradine
• long-acting nitrates
• trimetazidine
• (nicorandil, ranolazine: not marketed in Hungary)
7.2.3.3. Special cases:
(1) for 1 year after acute coronary syndrome, and for 3-12 months following PCI and stent
implantation dual antiplatelet therapy is necessary beside the standard therapy: aspirin and clopidogrel
should be used together (in selected cases prasugrel or ticagrelor may be used instead of clopidogrel)
(2) microvascular angina:
• control of risk factors
• short-acting nitrates to use on demand (usually only partially effective)
• first line beta-blockers, supplemented by CCBs and long-acting nitrates if necessary
• first line CCBs, if threshold of angina is variant
• ACE inhibitors/ARBs
• alpha-blockers are sometimes effective
• statins
• xanthine derivates (aminophylline) may reduce angina pain by adenosine receptor blockade
(3) vasospastic angina:
• Holter ECG (and transtelephonic ECG) may help diagnosis
• control of risk factors (especially smoking cessation and avoiding vasospastic drugs)
• aspirin
• short-acting nitrates to use on demand
• first line CCBs
• long-acting nitrates
• beta-blockers should be avoided (may increase spasm), if necessary, nebivolol is preferred
67
(4) in therapy refractory cases:
• high dose CCB and nitrate
• antiadrenergic agents (guanethidine, clonidine)
• stent implantation at the location of the spasm
• pharmacological or surgical sympathectomy
7.3. Myocardial revascularization
Revascularization aims to improve myocardial blood supply by elimination, dilation or bypassing
stenoses and obstructions. They are invasive, potentially dangerous interventions, which if used properly,
are able to improve patients’ life quality and life expectancy. In stable coronary artery disease, invasive
treatments do not always have benefit over optimal medical therapy. Furthermore, complications may
bring the patient in worse condition than before. Revascularisation should only be chosen in well-founded
cases and only after the start of optimal medical therapy. The first step to invasive treatment is invasive
diagnostics, coronary angiography which identifies the significant vessel stenoses. In many cases, it is
possible to solve such stenoses during the same session via the same arterial access.
Coronary angiography is recommended in the following cases:
(1) ejection fraction below 50% and typical angina complaints
(2) high pretest probability and severe symptoms
(3) high risk patient according to non-invasive testing (annual cardiovascular mortality >3%)
(4) for medium risk patients (1-3% annual cardiovascular mortality) coronary angiography or optimal
medical therapy alone may be chosen according to individual assessment, for low risk patients (annual
cardiovascular mortality below 1%) medical therapy should be preferred
(5) if complaints indicate angina that is not improved by the introduction and intensification of medical
therapy (refractory angina) coronary angiography may be performed
Only viable myocardium has reason to be revascularized. In doubtful cases (state after STEMI, akinetic
segments) viability testing should be performed. The larger the ischemic area, the more benefit can be
expected from revascularization. In cases of small endangered myocardium, the risk of complications
exceeds the potential benefit, optimal medical therapy should be continued instead of revascularization.
Based on the result of coronary angiography revascularization is recommended in the following cases:
(1) significant stenosis of the LM
(2) significant stenosis of the proximal LAD
(3) area of ischemia is over 10% of the left ventricle
(4) significant stenosis of 2 or 3 vessels with reduced left ventricular function (EF <40%)
(5) significant stenosis of any vessel in cases of limiting angina refractory to medical therapy
Stenosis is considered significant, if the area is reduced by over 90% or by 50-90% if FFR <0.8 (previous
definition considered 50% stenosis of the LM or 70% stenosis of other vessels). Non-significant stenoses
should not be revascularized, as it yields no benefit, while it has the same risk for complications.
Patients who are not candidate for invasive procedures:
(1) do not treat invasively patients, whose life expectancy (e.g. patient with end stage tumor) or
quality of life (old, bedridden patient with poor cognitive functions) can not be improved
(2) consent or rejection to the invasive procedure after getting informed should be the patient’s
decision, just as what level of invasiveness (PCI or CABG) is accepted, the decision can be changed later to
either direction (e.g. a patient refusing an elective intervention may accept it in case of an acute infarction)
(3) patients, who are not candidate for revascularization, coronary angiography should be avoided,
even in the presence of acute coronary syndrome
Complications of invasive coronary angiography:
(1) bleeding form the arterial access (especially using antiplatelet drugs), hematoma, dissection and
pseudoaneurysm formation are possible; compression bandage is applied for several hours after the
intervention to prevent these
(2) aortic dissection
(3) contrast-induced nephropathy, acute renal failure, and metformin associated lactic acidosis
(4) allergy to contrast agent
68
7.3.1. Percutaneous coronary intervention (PCI), percutaneous transluminal coronary angioplasty (PTCA)
During POBA (plain old balloon angioplasty) a deflated balloon is positioned into the stenosis using a
guide wire and fluoroscopy, and then it is inflated with high pressure (4-20 atmospheres), pressing the
plaque into the vessel wall and dilating the lumen.
Complications:
(1) coronary vessel rupture
(2) vessel dissection and subsequent occlusion is possible
(3) the vessel is occluded during inflation, which may cause angina and troponin elevation, in severe
cases myocardial infarction, acute heart failure, life threatening arrhythmias may take place
(4) plaque rupture creates thrombogenic surface and may lead to postprocedural infarction; dual
antiplatelet therapy is important after the intervention
(5) the dilated section may narrow back due to the elastic elements of the vessel
After balloon predilation or in one step with the dilation (direct stenting) a mesh tube, stent, can be
placed. The basic version is a bare metal stent (BMS). The stent supports the vessel wall and prevents
elastic recoil. It can stabilize intimal flap in cases of dissection.
Complications:
(1) stent thrombosis: the stent is a thrombogenic surface; complete occlusion, infarction may occur.
(2) in-stent restenosis: stent may irritate the vessel wall maintaining chronic inflammation, thus the
endothelium slowly grows into the stent reducing the risk of thrombosis but narrowing the lumen.
(3) stent malposition: when placing a stent in a kinking section, calcified plaque or bifurcation, or using
not ideal sized balloon or stent, the stent may not fully lean against the vessel wall. The gap increases the
risk of thrombosis. Side vessel may be occluded. Young patient may “grow out” the stent.
Drug eluting stent (DES) emits cytostatic agents into the vessel wall hindering the endothelial growth.
It reduces the risk of restenosis, but the thrombogenic surface remains open longer as well, with a longer
chance for stent thrombosis.
Application of drug eluting balloon (DEB) leaves no stent behind, but the vessel wall is impregnated
with cytostatic agent during the balloon dilation, which prevents reendothelization during the critical
period of time. There is no risk of stent thrombosis and stent malposition.
Second generation biodegradable, resorbable stents work like DES at the time of implantation, giving
adequate support to the vessel wall. Later struts break up making physiological vasoconstriction and
dilation possible, then during the years it is completely absorbed eliminating the risk of stent thrombosis
and malposition, and in case of restenosis a stent does not hinder a subsequent intervention either.
In cases of chronic total occlusion (CTO), regular dilation is not possible as guide wire cannot be led
through the occlusion. Using special techniques - special guide wire, rotablator, laser - the occlusion can be
pierced and dilated, but success rate is worse than with regular stenoses. After PCI, thrombogenic surface
of the damaged endothelium and the implanted stents requires dual antiplatelet therapy:
(1) for 12 months after acute coronary syndrome with or without PCI
(2) for at least 1 month after elective PCI and BMS implantation
(3) for at least 6 month after elective PCI and DES implantation
(4) possibly longer if high thrombotic and low bleeding risk is present
(5) in high bleeding risk or before urgent but not acute operation for 3 months after DES implantation
After that clopidogrel may be withdrawn but aspirin should be continued lifelong. Premature
discontinuation of dual antiplatelet therapy greatly increases the risk of stent thrombosis (highest in the
first weeks after intervention, and attenuated later on). Stent thrombosis causes myocardial infarction
(usually STEMI) with high mortality, and brings the patient in worse condition than before the intervention.
7.3.2. Coronary artery bypass grafting
During coronary artery bypass grafting (CABG) or aorto-coronary bypass grafting (ACBG) well perfused
grafts are attached distal to the stenoses. Venous graft, usually v. saphena magna (VSG or SVG) attached to
the ascending aorta may be used. The other solution is arterial grafts, left or right internal mammary artery
(LIMA, RIMA) with their natural origin, or radial artery graft attached to the aorta. Grafts may get stenosed
or occluded after some time, the patency of arterial grafts are better - “more important vessels” should
receive the arterial grafts. PCI of stenosed grafts is possible.
69
CABG is considered high risk operation with many possible serious complications. It involves the
opening of the chest and it means a great stress for the patient. Classical method involves establishing a
cardiopulmonary bypass (extracorporal circulation) after which the heart is stopped, and restarted after the
operation (on-pump surgery). The newer technique, off-pump surgery is performed on beating heart, with
the stabilization of the operated part, without using the heart-lung machine. With adequate skill, it has
fewer complications than on-pump surgery.
7.3.3. Choosing the method of revascularization
PCI is an easier, quicker, cheaper method of revascularization that means much smaller stress and risk
for the patient with fewer complications. It advanced to the foreground and with the development of the
technique more and more lesions can be treated transcatheterly. Some situations, however, still cannot be
solved this way, have very high risk for PCI, or have a worse outcome with PCI than with CABG; in these
cases the latter is still preferred, if the patient is otherwise suitable for the operation. When choosing
between PCI and CABG we should assess local practice, instruments and expertise, the patient’s eligibility
for operation, the clinical setup (acute/urgent/elective) as well, and sometimes consultation is required
between the non-invasive cardiologist, interventional cardiologist, heart surgeon and other partner
disciplines (e.g. anesthetist) (heart team).
PCI is contraindicated, if balloon inflation or possible periprocedural complication may cause life
threatening global ischemia (e.g. LM PCI accompanied by significant RCA stenosis). LM and proximal LAD
lesions mean higher risk. Risk for patients with severely reduced ejection fraction is greater as well.
CABG is preferred in complex anatomical situations, which is technically difficult to solve with PCI,
require many stents and has many possibilities for complication. SYNTAX score sums up the situation,
weighing the location of stenoses (LM and proximal LAD is more important than a secondary branch of Cx)
and other complicating factors (area of stenosis, presence of CTO, stenosis at bifurcation, long stenosis,
kinking stenosis, calcified stenosis).
In non-complicated cases (low SYNTAX score) LM or three vessel diseases might be treated with PCI.
In cases of multivessel disease in diabetic patients CABG might be more beneficial.
If a patient is candidate but unsuitable for CABG, PCI and if possible, at least partial (palliative)
revascularization should be considered.
70
8. Quiz
Choose at least one correct answer for each question. It is also possible that there is more than one
right answer for one question.
1.
Which of the following is a changeable risk factor of coronary artery disease?
A: age
B: genetics
C: hypertension
D: smoking
2.
Which appears the earliest in case of ischemia?
A: ST segment depression
B: myocardial necrosis
C: diastolic dysfunction
D: systolic dysfunction
3.
Which limits oxygen supply?
A: fever
B: coronary stenosis
C: anemia
D: critical bradycardia
4.
Which myocardial area is most exposed to the risk of ischemia?
A: subendocardial region
B: epicardial region
C: the whole wall
D: apex of the heart
5.
Which mechanism plays an important role in stable coronary artery disease?
A: plaque
B: thrombus
C: vasospasm
D: embolization
6.
Which is NOT true for stable coronary artery disease?
A: it is usually caused by the atherosclerotic stenosis of coronary vessels
B: thrombus formation on a ruptured plaque plays an important role
C: angina is a common symptom
D: risk of severe complication is high, thus emergency treatment is required
7.
Chronic ischemia may lead to:
A: AV block
B: reduction of pump function
C: hypertrophy of myocardium
D: dilation of left ventricle
8.
Which coronary branch supplies the anterior wall of the left ventricle?
A: RCA
B: LAD
C: Cx
D: PDA
71
9.
Which belongs to stable coronary artery disease?
A: effort angina
B: crescendo angina
C: acute myocardial infarction
D: microvascular angina
10. The patient regularly experiences squeezing chest pain after going up one floor that ceases after
resting. Which condition is suspected?
A: vasospastic angina
B: typical angina pectoris
C: crescendo angina
D: microvascular angina
11. Characteristics of stable angina pectoris:
A: always appears for the same physical exercise
B: weather changes, front may provoke it
C: emotional stress may aggravate it
D: may be provoked by hypertensive crisis
12. Characteristic of Prinzmetal angina:
A: calcium channel blockers relieve the acute attack
B: it is often accompanied by migraine or Raynaud phenomenon
C: it is caused by vasospasm
D: ST elevation is not present during the attack
13. Characteristic of unstable angina:
A: first occurance of angina pectoris should be considered unstable, and also when angina occurs at
rest or at minimal exertion
B: during chest pain ST depression can be detected on ECG but sometimes ST elevation may also occur
C: often symmetrical negative T wave develops, or pseudonormalization of T wave can be observed in
postischemic condition
D: the value of CK-MB, Troponin-T and I is always increased, but it is not as high as in the case of
myocardial infarction
14. According to the classification of the Canadian Cardiovascular Society (CCS), which class does angina
that occurs at low intensity workload and considerably limits everyday activity belong to?
A: CCS I
B: CCS II
C: CCS III
D: CCS IV
15. In case of suspected coronary artery disease, which tests should be performed by all means?
A: exercise ECG
B: 12-lead resting ECG
C: echocardiography
D: taking case history, complaints and physical examination
16. Which of the following is an anatomical imaging method?
A: exercise ECG
B: coronary angiography
C: coronary CT angiography
D: echocardiography
72
17. Which statement is incorrect?
A: in case of normal resting ECG, ischemia can be excluded
B: transthoracic echocardiography can reveal left ventricular function, segmental wall motion
disorders and diastolic dysfunction as well
C: exercise ECG is of diagnostic value in case of horizontal or downsloping ST depression ≥0.1 mV at 60
or 80 ms after J-point in one or more than one leads
D: diagnostic value of ST segment alteration in recovery is poor
18. Which test is recommended next for a patient with atrial fibrillation and left bundle branch block
who walks hard because of knee arthrosis?
A: coronary CT angiography
B: exercise ECG
C: stress myocardial perfusion scintigraphy
D: coronary angiography
19. At which pre-test probability is stress ECG recommended?
A: <15%
B: 15-65%
C: 65-85%
D: >85%
20. How can resting echocardiography help the diagnostics of coronary artery disease?
A: ejection fraction helps to assess the risk of patient
B: by visualizing the stenosis of coronary vessels
C: detecting the segments with wall motion disorder may help to identify the culprit lesion
D: to assess the viability of akinetic wall segments
21. Which medication is recommended to be temporarily stopped before exercise ECG if the test is
aimed to establish the diagnosis of coronary artery disease?
A: beta blocker
B: trimetazidine
C: ACE inhibitor
D: Ca2+ channel blocker
22. Which method is suitable to assess myocardial viability?
A: stress myocardial perfusion SPECT using 99mTc-MIBI isotope
B: gadolinium contrast cardiac MR
C: dobutamine stress echocardiography
D: coronary angiography
23. What is the next recommended examination for a patient with typical angina and reduced ejection
fraction?
A: exercise ECG
B: coronary angiography
C: stress myocardial perfusion scintigraphy
D: coronary CT angiography
24. For which patient is coronary angiography recommended?
A: young female with stabbing chest pain at rest lasting for seconds
B: middle aged male with hypertension, diabetes, without left ventricle wall motion disorder on resting
echocardiography but with extensive transient perfusion defect of the anterior wall on scintigraphy
C: cachectic patient with metastasizing colon tumor and NSTEMI
D: 65-year-old patient with typical angina and ejection fraction of 40%
73
25. The correct answer:
A: complete physical inactivity is recommended for patients with previous myocardial infarction, PCI or
CABG
B: decrease in the daily salt consumption (<5 gr) is advised for patients with coronary artery disease
C: the BMI goal is 20-25 kg/m2, where total mortality is the lowest
D: hormone replacement therapy (oestrogen) is recommended in women over 60 years for primary or
secondary prevention of coronary artery disease
26. The goal for serum LDL cholesterol in high risk cardiovascular patients:
A: less than 3.5 mmol/l
B: less than 2.5 mmol/l
C: less than 1.8 mmol/l
D: 3 mmol/l is acceptable in case of low dose statin therapy
27. Recommended blood pressure in coronary artery disease:
A: systolic value 140 mmHg, diastolic value 90 mmHg
B: systolic value 150 mmHg, diastolic value 90 mmHg
C: in diabetic population below 140/85 mmHg
D: in diabetic population below 135/80 mmHg
28. Which drugs have both antianginal effect and improve survival?
A: statins
B: beta blockers
C: nitrates
D: Ca channel blockers
29. Which drugs are recommended in first line treatment of stable angina?
A: aspirin
B: trimetazidine
C: statins
D: short acting nitrates used on demand
30. Which statement is correct?
A: target heart rate in stable coronary artery disease is around 55-60 beats per minute
B: target heart rate in stable coronary artery disease is around 65-75 beats per minute
C: ivabradine can be used in stable coronary artery disease, if patient has sinus rhythm and target
heart rate cannot be reached with beta blocker
D: ivabradine can be used in stable coronary artery disease, if patient has atrial fibrillation and target
heart rate cannot be reached with beta blocker
31. Which medication is recommended for angina of mainly vasospastic origin?
A: metoprolol (beta blocker)
B: amlodipine (Ca channel blocker)
C: rosuvastatin (statin)
D: nitroglycerin spray (short acting nitrate)
32. Which statement is correct?
A: single antiplatelet therapy is sufficient after BMS stent implantation
B: lifelong dual antiplatelet therapy is required after DES stent implantation
C: dual antiplatelet therapy is necessary for 12 months after acute coronary syndrome, even if no stent
was implanted
D: no antiplatelet therapy is needed 2 years after stent implantation
74
33. Which statement is correct?
A: routine measurement of platelet aggregation is essential to assess the effectiveness of antiplatelet
therapy
B: dual altiplatelet therapy (aspirin+clopidogrel) is required after stent implantation
C: riclopidine is not recommended in cease of neutropenia or thrombocytopenia
D: aspirin reversibly inhibits thromboxane A2 synthesis
34. Which revascularization method may lead to stent thrombosis?
A: POBA
B: BMS
C: DES
D: CABG
35. In which case is CABG the preferred method of revascularization?
A: severely calcified stenosis of the left main
B: significant three vessel disease
C: significant isolated Cx stenosis
D: spastic coronary vessels without organic stenosis
75
9. Right answers
1. C,D
2. C
3. B,C,D
4. A
5. A,C
6. B,D
7. A,B,D
8. B
9. A,D
10. B
11. A,B,C,D
12. B,C
13. A,B,C
14. C
15. B,C,D
16. B,C
17. A,D
18. C
19. B
20. A,C
21. A,B,D
22. B,C
23. B
24. B,D
25. B,C
26. C
27. A,C
28. B
29. A,C,D
30. A,C
31. B,D
32. C
33. B,C
34. B,C
35. A,B
76
10. References
[1]
[2]
[3]
[4]
[5]
[6]
[7]
[8]
[9]
[10]
[11]
[12]
[13]
[14]
[15]
[16]
[17]
[18]
[19]
[20]
[21]
[22]
[23]
[24]
[25]
Carter C, McGee D, Reed D, Yano K, et al. Hematocrit and the risk of coronary heart disease: The Honolulu heart
program. Am Heart J 1983; 105: 674-679.
Kannel WB, D’Agostino RB, Belanger AJ. Fibrinogen, cigarette smoking, and risk of cardiovascular disease: insights from
the Framingham study. Am Heart J 1987; 113: 1006-1010.
Baigent C, Sudlow C, Collins R, et al. Collaborative meta-analysis of randomised trials of antiplatelet therapy for
prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002; 324: 71-86.
Bhatt DL, Fox KA, HackeW, et al; CHARISMA Investigators. Clopidogrel and aspirin versus aspirin alone for the
prevention of atherothrombotic events. N Eng J Med 2006; 354: 1706-1717.
Gent M, Beaumont D, Blanchard J, et al; CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus
aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996; 348: 1329-1339.
Cholesterol Treatment Trialists’ (CTT) Collaboration, Baigent C, Blackwell L, et al. Efficacy and safety of more intensive
lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet 2010;
376: 1670-1681.
Ballantyne C. Low-density lipoproteins and risk for coronary artery disease. Am J Cardiol 1998; 82: 3Q-12Q.
Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin
in 20,536 high risk individuals: a randomised placebo-controlled trial. Lancet 2002; 360: 7-22.
Management of stable angina pectoris. Recommendations of the Task Force of the European Society of Cardiology. Eur
Heart J 2006; 27: 1341-1381.
J Leal Luengo-Fernández R, Gray A, Petersen S, et al. Economic burden of cardiovascular diseases in the enlarged
European Union. Eur Heart J 2006; 27: 1610-1619.
Sever PS, Dahlöf B, Poulter NR, et al; ASCOT investigators. Prevention of coronary and stroke events with atorvastatin
in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the AngloScandinavian Cardiac Outcomes Trial - Lipid Lowering Arm: a multicentre randomised controlled trial. Lancet 2003;
361: 1149-1158.
Henderson RA, O’Flynn N. Management of stable angina: summary of NICE guidance. Heart 2012; 98: 500-507.
IONA Study Group. Effect of nicorandil on coronary events in patients with stable angina: the Impact Of Nicorandil in
Angina (IONA) randomised trial. Lancet 2002; 359: 1269-1275.
Juul-Möller S, Edvardsson N, Jahnmatz B, et al. Double blind trial of aspirin in primary prevention of myocardial
infarction in patients with stable chronic angina pectoris. The Swedish Angina Pectoris Aspirin Trial (SAPAT) Group.
Lancet 1992; 340: 1421-1425.
Kosiborod M, Arnold SV, Spertus JA, et al. Evaluation of Ranolazine in Patients with Type 2 Diabetes Mellitus and
Chronic Stable Angina. Results from the TERISA randomized clinical trial. J Am Coll Cardiol 2013; 61: 2038-45.
Morrow DA, Scirica BM, Chaitman BR, et al; MERLIN-TIMI 36 Investigators. Evaluation of the glycometabolic effects of
ranolazine in patients with and without diabetes mellitus in the MERLIN-TIMI 36 randomized controlled trial.
Circulation 2009; 119: 2032-2039.
European Association for Cardiovascular Prevention & Rehabilitation, Reiner Z, Catapano AL, et al; ESC Committee for
Practice Guidelines (CPG) 2008-2010 and 2010-2012 Committees. The Task Force for the management of
dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS): ESC/EAS
Guidelines for the management of dyslipidaemias. Eur Heart J 2011; 32: 1769-1818.
Task Force Members, Montalescot G, Sechtem U, et al. The Task Force on the management of stable coronary artery
disease of the European Society of Cardiology: 2013 ESC guidelines on the management of stable coronary artery
disease. Eur Heart J 2013; 34: 2949-3003.
Authors/Task Force members, Windecker S, Kolh P, et al. The Task Force on Myocardial Revascularization of the
European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS): 2014
ESC/EACTS Guidelines on myocardial revascularization. Eur Heart J 2014; 35: 2541-2619.
Zheng W, McLerran DF, Rolland B, et al. Association between body-mass index and risk of death in more than 1 million
Asians. N Engl J Med 2011; 364: 719-729.
Nordestgaard BG, Benn M, Schnohr P, et al. Nonfasting triglycerides and risk of myocardial infarction, ischemic heart
disease, and death in men and women. JAMA 2007; 298: 299-308.
Wood DA, Kotseva K, Connolly S, et al; EUROACTION Study Group. Nurse-coordinated multidisciplinary, family-based
cardiovascular disease prevention programme (EUROACTION) for patients with coronary heart disease and
asymptomatic individuals at high risk of cardiovascular disease: a paired, cluster-randomised controlled trial. Lancet
2008; 371: 1999-2012.
Giannuzzi P, Temporelli PL, Marchioli R, et al; GOSPEL Investigators. Global secondary prevention strategies to limit
event recurrence after myocardial infarction: results of the GOSPEL study, a multicenter, randomized controlled trial
from the Italian Cardiac Rehabilitation Network. Arch Intern Med 2008; 168: 2194-2204.
Lowe GDO, Smith WCS, Tunstall-Pedoe HD, et al. Cardiovascular risk and haemorheology - results from the Scottish
heart health study and the MONICA project, Glasgow. Clin Hemorheol 1988; 8, 517-524.
Perk J, De Backer G, Gohlke H, et al; European Association for Cardiovascular Prevention & Rehabilitation (EACPR).
European Guidelines on cardiovascular disease prevention in clinical practice (version 2012). Eur Heart J 2012; 33:
1635-1701.
77
[26] Jneid H, Anderson JL, Wright RS, et al; 2012 Writing Comittee Members; American College of Cardiology Foundation;
American Heart Association Task Force on Practice Guidelines. 2012 ACCF/AHA focused update of the guideline for the
management of patient with unstable angina/Non-ST-elevation myocardial infarction (updating the 2007 guideline and
replacing the 2011 focused update). Circulation 2012; 126: 875-910.
[27] Hamm CW, Bassand JP, Agewall S, et al; ESC Committee for Practice Guidelines. ESC Guidelines for the management of
acute coronary syndromes in patients with presenting without persistent ST-segment elevation: The Task Force for the
management of acute coronary syndromes (ACS) in patients presenting without persistent ST-segment elevation of the
European Society of Cardiology (ESC). Eur Heart J 2011; 32: 2999-3054.
[28] Smith SC Jr, Benjamin EJ, Bonow RO et al; AHA/ACCF secondary prevention and risk reduction therapy for patients with
coronary and other atherosclerotic vascular disease: 2011 update: a guideline from the American Heart Association
and American College of Cardiology Foundation endorsed by the World Heart Federation and the Preventive
Cardiovascular Nurses Association. J Am Coll Cardiol 2011; 58: 2432-46.
[29] Levine GN, Bates ER, Blankenship JC et al; American College of Cardiology Foundation; American Heart Association Task
Force on Practice Guidelines; Society for Cardiovascular Angiography and Interventions 2011 ACCF/AHA/SCAI Guideline
for Percutaneous Coronary Intervention. A report of the American College of Cardiology Foundation/American Heart
Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. J Am
Coll Cardiol 2011; 58: e44-122.
[30] Hillis LD, Smith PK, Anderson JL, et al; 2011 ACCF/AHA Guideline for Coronary Artery Bypass Graft Surgery. A report of
the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.
Developed in collaboration with the American Association for Thoracic Surgery, Society of Cardiovascular
Anesthesiologists, and Society of Thoracic Surgeons. J Am Coll Cardiol 2011; 58: e123-210.
78