Biventricular Pacing in Congestive Heart Failure
William T. Abraham
Electrophysiological disturbances, including arrhythmias and conduction disorders, are common in the setting of congestive heart failure. For example, approximately 30% to 40% of unselected heart failure patients with reduced or preserved left ventricular (LV) systolic function exhibit atrial fibrillation (1,2,3). Nearly one-half of total mortality in heart failure patients with reduced LV ejection fractions may be attributable to ventricular tachyarrhythmias (4,5). About one-third of patients with systolic heart failure have a delay in ventricular conduction when defined as a QRS duration greater than 120 milliseconds (6,7). In this latter instance, the abnormality in ventricular conduction may result in an irregular or dysynchronous pattern of LV contraction, which may further impair the pumping ability of the already failing heart (8,9,10,11). Specifically, LV dysynchrony may cause suboptimal ventricular filling, prolonged duration of mitral regurgitation, and a reduction in LV dP/dt. Ventricular dysynchrony has also been associated with increased morbidity and mortality in heart failure patients (12,13,14,15).
Over the past 10 years, techniques have been developed to correct the mechanical and clinical manifestations of ventricular dysynchrony through the use of atrial-synchronized biventricular pacing, now known as cardiac resynchronization therapy. This technique involves simultaneous pacing of both the right and left ventricles with the goal of improving the ventricular contraction pattern and, ultimately, patient outcomes. Substantial evidence supports the routine use of cardiac resynchronization therapy in congestive heart failure patients with ventricular dysynchrony. More than 4,000 patients have been evaluated in randomized, controlled trials of cardiac resynchronization and several thousand additional patients have been assessed in observational studies and in registries. Results of these studies have consistently demonstrated the safety and efficacy of biventricular pacing in New York Heart Association (NYHA) Class III and IV heart failure patients. In such patients, cardiac resynchronization therapy has been shown to significantly improve LV structure and function, NYHA functional class, exercise tolerance, quality of life, and morbidity and mortality. Given the benefits of biventricular pacing, recent evidence-based guidelines and consensus statements strongly support the use of this therapy in all eligible heart failure patients (16,17). This chapter reviews the history, proposed mechanisms of action, clinical trials evidence, guidelines recommendations, and limitations of cardiac resynchronization therapy, and concludes with a look at future directions for biventricular pacing.
History of Biventricular Pacing for Congestive Heart Failure
Cardiac resynchronization therapy was not the first pacing approach evaluated as a treatment for heart failure. Standard right-sided, dual-chamber (DDD) pacing, right ventricular outflow tract/His bundle pacing, and multisite right ventricular pacing were studied and produced inconsistent results on clinical outcomes in heart failure patients (18,19,20,21,22,23). Hochleitner et al. (18,19) were the first to suggest that right-sided DDD pacing might help correct the conduction disturbances seen in advanced heart failure and improve cardiac function. Expanding on this work, Brecker et al. (20) evaluated the effects of changing the atrial-ventricular (AV) interval during acute DDD pacing in patients with dilated cardiomyopathy and short ventricular filling times due to
mitral and/or tricuspid regurgitation. While initially encouraging, the results of these early studies were not confirmed by later studies conducted by other investigators (21,22,23). Similarly, studies of multisite right ventricular pacing produced generally disappointing results. Considering this limited potential for right-sided pacing in systolic heart failure, attention turned to studies of biventricular pacing.
mitral and/or tricuspid regurgitation. While initially encouraging, the results of these early studies were not confirmed by later studies conducted by other investigators (21,22,23). Similarly, studies of multisite right ventricular pacing produced generally disappointing results. Considering this limited potential for right-sided pacing in systolic heart failure, attention turned to studies of biventricular pacing.
The evolution of biventricular pacing for the management of heart failure progressed rapidly following the first reported case in 1994 (24). Cazeau et al. (24) applied four-chamber pacing in a 54-year-old man with NYHA Class IV heart failure and several conduction abnormalities, including a QRS duration of 200 milliseconds, a PR interval of 200 milliseconds, and an interatrial conduction time of 90 milliseconds. Standard transvenous pacing leads were placed in the right atrium and right ventricle (RV), the left atrium was paced by a lead placed in the coronary sinus, and the LV was paced by an epicardial lead located on the LV free wall. After 6 weeks of pacing, the patient’s clinical status markedly improved to NYHA Class II. Thus, with this single-case experience, the era of biventricular pacing for congestive heart failure was born.
Of course, it took many additional studies and several years to confirm the benefits of biventricular pacing before it could be recommended as a routine therapy for heart failure (16,17). Following Cazeau’s initial report, other mechanistic and observational studies provided additional proof of concept supporting the benefits of biventricular pacing in heart failure (10,25,26,27,28,29,30,31,32). The first randomized, controlled trials designed to evaluate the effects of resyn-chronization therapy on quality of life, functional status, exercise capacity, pathological ventricular remodeling, and morbidity were then begun in the late 1990s. These studies affirmed that biventricular pacing, delivered using a wholly transvenous approach for right atrial, RV, and LV lead placement, was safe and confirmed the benefits seen in earlier uncontrolled experiences (33,34,35,36,37,38,39,40). Finally, randomized, controlled trials to assess the effects of biventricular pacing on morbidity and mortality were initiated. These trials demonstrated unequivocally the effects of cardiac resynchronization therapy, with or without an implantable cardioverter-defibrillator, to reduce morbidity and mortality in patients with moderate to severe heart failure (41,42,43,44).
Proposed Mechanisms of Action of Cardiac Resynchronization Therapy
The mechanism of benefit of biventricular pacing remains incompletely understood. In this regard, it is important to note that the underlying target of therapy—ventricular dysynchrony—occurs at three levels within the heart (45). Interventricular dysynchrony describes a mismatch in timing between RV and LV contraction, usually measured as a difference in the onsets of pulmonary and aortic flow. Intraventricular dysynchrony is seen as a loss in the normal contraction pattern of the LV, generally associated with normal (early) activation of the septum and delayed (late) activation of the LV free wall, particularly in the setting of left bundle branch block. The hallmark of LV dysynchrony is paradoxical septal wall motion, where the septum moves away from the LV free wall during systole. Because of the abnormal septal motion, LV end-systolic diameter is increased and regional septal ejection fraction (EF) is decreased. Finally, intramural dysynchrony may affect both the mechanics and biology of the heart.
Early studies of biventricular pacing provided important insight into the potential mechanisms of action of cardiac resynchronization. The hemodynamic improvement seen with atrial-synchronized, biventricular pacing appears related to its ability to increase LV filling time, decrease septal dyskinesis, and reduce mitral regurgitation in the failing heart. Over time, these effects of resynchronization therapy result in improvements in ventricular geometry and function, compatible with reverse remodeling of the heart.
Acutely and chronically, cardiac resynchronization therapy increases LV filling time. In the presence of a long AV delay and/or an interventricular conduction delay (IVCD), LV activation is delayed but atrial activation is not. Thus, both early passive LV filling and the so-called atrial kick may occur simultaneously, resulting in decreased total transmitral blood flow and diminished preloading of the LV (46). These events are often seen as a fusion of the E and A waves on Doppler echocardiogram of transmitral blood flow. With atrial-synchronized biventricular pacing, both ventricles are activated simultaneously; thus, the LV is able to complete contraction and begin relaxation earlier, which increases filling time. The effect of resynchronization therapy can be seen by the return of normal E and A wave separation on Doppler echocardiogram of transmitral blood flow (Fig. 36-1).
Biventricular pacing also decreases septal dyskinesis, resulting in an improved contraction pattern and thus stroke volume. While LV activation and contraction are delayed in the presence of an IVCD, septal activation and contraction are not. This timing mismatch results in septal dyskinesis or paradoxical septal wall motion, in that the septum moves away from the LV free wall during systole. This paradoxical septal wall motion impairs mitral valve function by increasing mitral regurgitation and reduces the septum’s contribution to LV stroke volume (47). With biventricular pacing, the ventricles are activated simultaneously, allowing ventricular ejection to occur prior to relaxation of the septum, resulting in decreased mitral regurgitation and increased LV stroke volume (34).
In addition, in the presence of a long PR interval and/or an IVCD, mitral valve closure may not be complete, since atrial contraction is not followed by a properly timed ventricular systole. If the time lag is long enough, a ventricularatrial pressure gradient may develop and cause diastolic mitral regurgitation (48). By resynchronizing AV activation and contraction, normal mitral valve timing is restored and regurgitation is potentially reduced or eliminated. Serial evaluations in large numbers of heart failure patients with ventricular dysynchrony have confirmed a marked reduction in mitral regurgitant flow following the application of cardiac resynchronization therapy (38).
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