Chapter 56 Evaluation and Management of Arrhythmias Associated with Congestive Heart Failure
Introduction
Both atrial and ventricular arrhythmias can not only lead to heart failure but can also occur as a consequence of heart failure. Arrhythmias commonly seen in heart failure include sinus tachycardia, atrial fibrillation (AF), premature ventricular contractions (PVCs), nonsustained ventricular tachycardia (NSVT), sustained ventricular tachycardia (VT), torsades de pointes (TdP), and ventricular fibrillation (VF) (Box 56-1).
Mechanisms
The mechanisms of arrhythmias in heart failure include re-entry, triggered activity, abnormal automaticity, and altered stretch (Box 56-2).
Re-entry is often seen in heart failure and may be related to conduction slowing caused by functional or anatomic barriers. The underlying mechanisms include reduced myocardial excitability and increases in resistance.1 Moreover, downregulation of the gap junction protein connexin 43 promotes cell-to-cell uncoupling, a milieu for re-entrant arrhythmia.2
Patients with heart failure often develop left ventricular hypertrophy, a compensatory mechanism for inadequate cardiac output. Left ventricular hypertrophy is associated with increased action potential duration that provides a potential for increased dispersion of repolarization leading to TdP or VF as a result of triggered activity, especially early afterdepolarization.3 Also of note, because of the downregulation of potassium (K+) currents and increased late sodium (Na+) current, the action potential duration is further prolonged, with a greater propensity for triggered activity.4 Increases in intracellular calcium (Ca2+) from enhanced sympathetic stimulation from the heart failure itself or from the use of digitalis may cause triggered arrhythmias by inducing delayed afterdepolarization.5,6
Abnormal automaticity stems from ischemia and is related to abnormal Ca2+ handling, leading to non–re-entrant arrhythmias.6
Stretch-activated channels may play an important role in arrhythmia genesis. This observation has been noted mostly in animal studies. Stretch affects both conduction and refractoriness. Any such alterations may predispose to arrhythmias in patients with heart failure. Electromechanical feedback can lead to electrical remodeling with changes in conduction and repolarization, creating heterogeneity and dispersion, with enhancement of atrial and ventricular arrhythmias.7,8
A reduction in the sinoatrial node If current (“funny” current) and its hyperpolarizing cyclic nucleotide (HCN) channel gene leads to sinus bradycardia from sinoatrial node dysfunction. In heart failure, however, increases may occur in atrial and ventricular tissue If currents that may lead to arrhythmias.9
Atrial Fibrillation
AF is quite commonly seen in patients with heart failure (30%). The tachycardia itself may predispose to heart failure but may occur as a result of heart failure. The risk of emboli is related to etiology and the CHADS 2 (Cardiac Failure, Hypertension, Age, Diabetes, Stroke [Doubled]) score. Valvular AF carries a higher risk of stroke. Compared with sinus rhythm, after adjustments for comorbidities, AF does not seem to have an independent mortality risk in heart failure.10 Mechanisms of AF in heart failure, which are complex and multi-factorial, include re-entry, triggered activity, automaticity, and activation of stretch receptors. In addition, atrial interstitial fibrosis, increased collagen synthesis, and altered connexin expression predispose to heterogeneities and electrical uncoupling and eventually AF. Of note, experimental heart failure in dogs has been shown to promote AF by causing fibrosis, interfering with local conduction, and not by altering atrial refractory period, refractoriness heterogeneity, or conduction velocity as seen with rapid atrial pacing.11
Ventricular Arrhythmias
PVCs are very common in patients with heart failure, and in those with more than 10 per hour, the incidence of NSVT is about 90%.12 In patients with prior myocardial infarction (MI), PVCs are associated with an increased risk of death, especially in those with left ventricular dysfunction. The presence of NSVT does not seem add any more risk over PVCs.13
Sustained VT and VF may account for 50% of all deaths in patients with heart failure and is often classified as sudden cardiac death (SCD). However, all SCDs may not be tachyarrhythmia related. Death from bradycardia or electromechnical dissociation is common, especially in severe heart failure.14,15 Bundle branch re-entry is a form of sustained VT that may be reproduced in the electrophysiology laboratory and is important to recognize, since this arrhythmia can be successfully treated with ablation (see below).
Evaluation
Numerous tests have been used to evaluate the excessive risks of patients with heart failure (Box 56-3). The electrocardiogram is extremely useful in determining etiologies and important prognostic factors. Sinus bradycardia in response to β-blocker therapy has been shown to be beneficial in patients with heart failure. However, sinus bradycardia may be profibrillatory in the atrium because of increased dispersion (atrial torsades) or in the ventricle, especially in the presence of class III (K+ channel blockers) antiarrhythmic drugs (see below).16 Wide QRS or bundle branch block is an independent risk factor for premature death, that is, independent of ejection fraction (EF).17,18 A fragmented QRS has been shown to be predictive of mortality and SCD in both ischemic and nonischemic cardiomyopathy. An acquired prolonged Q-T interval is also quite important and may be a harbinger of TdP, especially when associated with K+ channel blockers, bradycardia, female gender, and electrolyte imbalance.
T-wave alternans, that is, a beat-to-beat variation in T-wave morphology, although subtle, has been associated with potentially lethal arrhythmias. A more sensitive technique is microvolt T-wave alternans (MTWA). A positive test carries a poor prognosis compared with a negative test, as shown in Multicenter Automatic Defibrillator Implantation Trial II (MADIT II), in which patients with prior MI and left ventricular dysfunction were randomized to implantable cardioverter-defibrillator (ICD) or not.19 However, in the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) substudy, a positive MTWA was not predictive of excess mortality in patients with heart failure.20 Of note, a wide QRS and the use of β-blockers may affect the results. It appears that MTWA testing should not be used to make decisions on implantation of an ICD.
Baroreflex sensitivity (BRS), a measure of autonomic nervous system activity that is independent of β-blocker usage, has been used to identify patients at high risk, especially those with previous MI. A low BRS is associated with a poor outcome. In the Autonomic Tone and Reflexes after Myocardial Infarction (ATRAMI) trial, a depressed BRS predicted cardiac mortality after MI.21
The role of the electrophysiology study (EPS) in nonischemic cardiomyopathy has not been established, and the chance of inducing a sustained ventricular arrhythmia is quite low.22 VT caused by bundle branch re-entry is sometimes seen in patients with nonischemic cardiomyopathy, and ablation of the right bundle, if electrophysiologically induced, is curative.23 Patients with ischemic cardiomyopathy and NSVT in whom sustained VT can be provoked at EPS carry a high risk of SCD compared with those in whom the arrhythmia is not inducible. However, because of a low EF, noninducibility still carries a substantial risk.24 Thus the role of EPS is limited. Left ventricular ejection fraction is the most powerful predictor of outcome and is used frequently to guide therapy, especially nonpharmacologic therapy.
Therapy
Box 56-4 provides a brief outline of the various treatment modalities for the patient with heart failure and left ventricular dysfunction.
Pharmacologic Therapy: Antiarrhythmics
β-Blockers have been consistently shown to reduce SCD and total mortality in patients with heart failure.25–27 This effect is independent of PVC suppression.28 β-Blockers are very effective in slowing the ventricular response in AF. Not all β-blockers are created equal, and those with intrinsic sympathomimetic activity may be of limited use or harmful. Noncardioselective β-blockers may be superior to cardioselective ones; in the Carvedilol or Metoprolol European Trial (COMET), carvedilol was found to be superior to metoprolol with regard to outcome in patients with heart failure. This could be explained by the low daily cardioselective dose of 89 mg of metoprolol. Of note, the incidence of AF was lower with carvedilol.
Class III drugs such as sotalol and dofetilide can suppress both supraventricular and ventricular arrhythmias and may be considered safe, although they have no beneficial effects on mortality. However, the risk of a proarrhythmic effect is high in patients with heart failure, so extreme caution must be exercised. Amiodarone is unique and is a very complex antiarrhythmic agent with the capability of blocking Na+, Ca2+, and K+ channels. Amiodarone is also an α- and β-blocker and is very effective in suppressing atrial and ventricular arrhythmias. Proarrhythmia is not often seen with this compound. However, it has many noncardiac adverse effects, so its use may be limited. It shows no benefit on survival in patients with prior MI, those with prior MI and left ventricular dysfunction, those with heart failure, and those with AF and heart failure.12,29–31 Dronedarone has a molecular structure similar to that of amiodarone but without the iodine.
In Antiarrhythmic Trial with Dronedarone in Heart Failure (ANDROMEDA), dronedarone was associated with increased mortality caused by worsening heart failure.32 Of note, however, in the recently published Placebo-Controlled, Double-Blind, Parallel Arm Trial to Assess the Efficacy of Dronedarone 400 mg bid for the Prevention of Cardiovascular Hospitalization or Death from Any Cause in Patients with Atrial Fibrillation/Atrial Flutter (ATHENA) trial, dronedarone was effective in reducing cardiovascular hospitalization or death.33
The Ca2+ channel blockers are of no benefit and may be harmful in patients with heart failure.34,35
Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, in addition to β-blockers, are mandated in the treatment algorithm of patients with heart failure. These agents suppress both ventricular and supraventricular arrhythmias.36 They are thought to accomplish this effect by structural, functional, and electrical remodeling. Incidentally, two large prospective trials have shown that angiotensin receptor blockers have no benefit in patients with diastolic heart failure.37,38
The aldosterone receptor blockers aldactone and eplerenone have been shown to improve survival in patients with heart failure.39,40 Both drugs reduce the incidence of SCD and may be related to a decrease in the re-entrant mechanism because of a reduction of fibrosis.
Ranolazine is a very complex antianginal compound with complex antiarrhythmic activities. It can block not only the K+ and Ca2+ currents but also the late Na+ current, thereby decreasing proarrhythmia; it also has potential antiarrhythmic properties. At this time, no trials have been performed using this agent in patients with heart failure. However, ranolazine suppresses malignant ventricular arrhythmias, as shown in the Metabolic Efficiency with Ranolazine for Less Ischemia in Non–ST Segment Elevation Acute Coronary Syndrome–Thrombolysis in Myocardial Infarction (MERLIN-TIMI) trial.41
Numerous trials have shown that “statins” suppress the incidence of AF. This is especially true in the postoperative period, as shown in the Atorvastatin for Reduction of Myocardial Dysrhythmia After Cardiac Surgery (ARMYDA-3) trial, in which atorvastatin was shown to be superior to placebo.42 In retrospective analyses, statins also lower the recurrence of VT or VF in patients with ICDs.43,44
In the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico Prevenzione (GISSI) trial, n-3 polyunsaturated fatty acids (PUFAs) have been shown to reduce SCD in patients with recent MI.45 In the recently published GISSI-HF trial, PUFA reduced all-cause mortality and cardiovascular admissions.46 Of note, PUFAs attenuate heart failure–associated atrial structural remodeling and AF promotion without changing atrial refractory periods and electrical remodeling.47
In patients at high risk for AF, warfarin is the drug of choice since the risk of embolization in these patients is unacceptably high. For patients not suitable for warfarin therapy, the combination of clopidogrel and aspirin has been shown to be superior to aspirin alone, in the recent publication of the Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events (ACTIVE) trial.48
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