Cardiac arrhythmias in congestive heart failure

Congestive heart failure (CHF) is a common clinical syndrome worldwide. Collectively, in the USA and over 50 European countries, nearly 20 million people suffer from CHF [1,2]. Although survival after the onset of CHF has improved owing to better healthcare, the incidence of heart failure has not declined during the last 20 years, as a result of an increasing aging population, and the great increment in cardiovascular diseases that has been observed in developing countries [3,4]. Cardiac arrhythmias, whether symptomatic or not, and whether benign or lethally malignant, are common in all forms of heart failure. For example, in a patient with mitral valve regurgitation, the predominant arrhythmia may be atrial fibrillation (AF), which may lead to the further progression of CHF and severity of mitral regurgitation. On the other hand, in a patient with ischemic cardiomyopathy, cardiac arrhythmia may manifest in the form of ventricular tachycardia (VT) or ventricular fibrillation (VF), potentially leading to sudden cardiac death (SCD). Furthermore, both atrial and ventricular arrhythmias are often present in the same patient.

The main arrhythmias in CHF that have drawn considerable attention are VT/VF and AF. Data from many studies indicate that in patients with CHF, the prevalence of premature ventricular beats and/or couplets is approximately 87%, and that of nonsustained VT could be as high as 45–80% [5–7]. From the EuroHeart Failure survey of AF, it is evident that not only do up to 45% of patients with CHF also present with AF [8], but in hospitalized patients with CHF new-onset AF is an independent predictor of in-hospital mortality (odds ratio: 1.53; 95% CI: 1.1–2.0) [9]. Data from the Framingham Heart Study further indicates that CHF itself increases the risk of AF 4.5-fold in men and 5.9-fold in women [10].

Regardless of the specific arrhythmia, three basic mechanisms (enhanced or suppressed automaticity, triggered activity and re-entry), are responsible for the pathogenesis of the arrhythmias. In CHF, structural changes including myocardial stretch, fibrosis and scar formation, chamber dilatation, and alteration of the cellular ionic currents, the receptors and the gap junction, provide adequate substrates for the genesis of arrhythmias. Early after depolarizarions are promoted by the reduction in repolarizing K⁺ currents such as I_to, I_Ks and I_Kr, and increases in depolarizing currents such as I_Na and I_Ca prolong action potential duration and repolarization. On the other hand, alteration of the Na⁺/Ca⁺ exchanger promotes delayed after-depolarizations. Both early after-depolarizations and delayed after-depolarizations may trigger arrhythmias [11]. A reduction in pacemaker I_f current, which is responsible for diastolic depolarization of sinuoatrial nodal cells, may lead to bradycardia, and increased expression of I_f current in nonpacemaker cells may cause enhanced automaticity-related ectopic tachycardia [11]. Anatomical or functional barriers from scars or diseased myocytes, reduced connectivity due to reduced gap junctions, nonuniform anisotropty, dispersion of refractoriness, and areas of slow conduction may all cause anatomical or functional re-entrant arrhythmia such as VT, with subsequent further wave-breaks or the occurrence of multiple wave-breaks leading to VF [12]. Recently, the role of ryanodine receptors and abnormal intracellular Ca⁺² handling by the sarcoplasmic reticulum has also been attributed to the development of myocardial contractile dysfunction and genesis of ventricular arrhythmias [13].

The role of autonomic dysfunction, especially in the genesis of malignant VT/VF leading to SCD, cannot be overemphasized. Irrespective of the etiology of heart failure, autonomic dysfunction occurs in the form of an increase in symapathetic outflow to the heart and to the peripheral vasculature, elevated plasma norepinephrine and its spill over, downregulation of myocardial β-adrenergic receptors, marked depletion of myocardial catecholamine stores and a reduction in cardiac vagal tone [14,15]. The renin–angiotensin–aldosterone system also plays an influential role in arrhythmogenesis [16].

With such complexities involved in arrhythmias and heart failure, a clinician faces a number of issues pertaining to the management of cardiac arrhythmias in patients with CHF. What are the specific arrhythmias that are more prevalent than the other? What are the prognostic implications, both on mortality and morbidities, of these arrhythmias? Are there adequate noninvasive methods that may be used for risk stratification purposes? What role do antiarrhythmic agents play? Who should be considered for nonpharmacological therapies, for example, radiofrequency ablation, and why? What role do implantable cardioverter defibrillators (ICDs) play in the treatment of VT/VF and in the prevention of SCD? Does cardiac resynchronization therapy with biventricular pacing have any impact on cardiac arrhythmias in CHF? Are pharmacological and nonpharmacological therapies of cardiac arrhythmias in patients with CHF cost effective? Some of the issues have been addressed in Expert Review of Cardiovascular Therapy[17–19], but to take on these and many more issues, the list unfortunately remains exhaustingly long.

Could we use antiarrhythmic agents to treat arrhythmias? With changes in pharmacokinetics from depleted volume of distribution and delayed clearance and elimination half-life, and changes in the pharmcodynamics, in CHF all antiarrhythmic drugs may potentially cause negative inotropy and proarrhythmias. The risk is profoundly high for Class I antiarrhythmic agents. With the exception of dofetilide [20], if used cautiously with vigorous monitoring, and amiodarone [21,22], most antiarrhythmic drugs should be considered harmful in patients with CHF. Although, amiodarone reduces the frequency of arrhythmias, it has not shown to reduce mortality in the presence of CHF. In the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT), amiodarone was not only inferior to ICD, but was comparable to a placebo for the prevention of SCD [23]. A derivative of amiodarone, dronedarone, has been clearly shown to increase early mortality in patients with severe heart failure [24]. The US FDA approval of MULTAQ^® (dronedarone, Sanofi-Aventis, Surrey, UK) has thus been contingent on a black-box warning clearly stating that the drug is contraindicated in patients with New York Heart Association (NYHA) Class IV heart failure, or NYHA Class II–III heart failure with a recent decompensation requiring hospitalization or referral to a specialized heart failure clinic.

For patients with CHF and AF, should we aggressively follow rhythm control, be it with antiarrhythmic agents or by nonpharmacological means, typically with left atrial ablation of pulmonary vein isolation, or should we follow a rate control approach either pharmacologically or by ablation of the atrioventricular node? The Atrial Fibrillation and Congestive Heart Failure trial, a large multicenter study, showed identical end points of mortality from cardiovascular causes in two groups of patients, with rhythm and rate control strategies of 27 and 25%, respectively (hazard ratio: 1.06; 95% CI: 0.86–1.30) [25]. However, it is worth noting that although most patients in the rhythm control group were free of AF at repeated assessments, not all patients were in sinus rhythm at all times. In addition, some patients in the rate control group were free of AF during follow-up. Other studies of rhythm versus rate control may be criticized similarly. Furthermore, the mere rate control regimen may not be appropriate for highly symptomatic and young patients, and even rate control may not be an easy task in spite of using multiple drugs in some patients. Emerging data on pulmonary vein isolation for AF in patients with CHF are encouraging. In a prospective multicenter, randomized trial, Pulmonary Vein Antrum Isolation versus AV Node Ablation with Bi-Ventricular Pacing for Treatment for Atrial Fibrillation in Patients with Congestive Heart Failure (PABA-CHF), there were significant improvements in each component (ejection fraction, 6-min walk distance and assessment of quality of life) of primary end points accomplished by pulmonary vein isolation compared with atrioventricular nodal ablation and biventricular pacing [26].

How effective are ICDs for the prevention of SCD in patients with CHF? The ICD trials, Multicenter Automatic Defibrillator Implantation Trial (MADIT) [27], Multicenter Unsustained Tachycardia Trial (MUSTT) [28], MADIT-II [29] and the SCD-HeFT trial [23] demonstrated a reduction in mortality with ICDs by 19% over 2 years, 31% over 5 years, 6% over 2 years and 7% over 5 years, respectively. When SCD-HeFT data were further analyzed, microvolt T-wave alternans also failed as a potentially useful noninvasive method to predict the future incidence of SCD and for risk-stratification in patients with CHF [30]. Among the patients with severe CHF requiring cardiac resynchronization therapy, the Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure Trial (COMPANION) showed lower (36%) relative reduction in all-cause mortality with cardiac resynchronization therapy when compared with optimized medical therapy [31]. Even in the presence of CHF, ICDs are cost effective [32].

In conclusion, cardiac arrhythmias are not only very common in the setting of CHF, but also have prognostic implications. Treatment of cardiac arrhythmias, particularly in patients with CHF, poses multiple challenges. It appears that pharmacotherapy with currently available antiarrhythmic agents imparts more risks than benefits, especially for AF and VT/VF, and the nonpharmacological therapies, including ablation and devices, although effective, are not readily available to many patients who require them. It is my viewpoint that a much stronger cohesive and multidisciplinary approach by, for example, specialists in cardiac arrhythmias, heart failure, pharmacology, epidemiology, biomedical engineering and chemistry, is needed not just to deliver the best treatment but also to develop the preventative strategies required to tackle the complexities of cardiac arrhythmias and heart failure.

Financial & competing interests disclosure

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.