Electrical and Mechanical Abnormalities in Heart Failure

Abnormalities of electrical function in heart failure can occur singly or in combination in either atrioventricular (AV) conduction or interventricular or intraventricular conduction. Prolongation of the A-V interval is associated with impaired atrial contribution to ventricular filling and reduced diastolic ventricular filling. Intraventricular as well as interventricular conduction delays prolong the pre-ejection time and reduce the global and regional ventricular ejection fraction (EF) because of dyssynchronous mechanical contraction and relaxation patterns. This mechanical dysfunction interferes with mitral valve function and permits mitral regurgitation.^11–14 One electrical indicator for delayed asynchronous ventricular contraction is the presence of a left bundle branch block (LBBB) pattern on the surface electrocardiogram (ECG). Ventricular conduction abnormalities, especially LBBB, may be responsible for the unequal regional distribution of ventricular work and wall stress.^15–17 At the beginning of ventricular systole, the region of earliest ventricular activation (usually the interventricular septum) contracts against minimal workload because the remaining ventricular myocardium (usually the lateral and posterolateral left ventricular regions) is still in the relaxation period or in a nonactivated phase. The regions of early ventricular activation waste contraction energy because no effective intraventricular pressure can develop. In contrast, the delayed depolarized regions, that is, the lateral and posterolateral ventricular regions, must contract against a pre-existing stiffened portion of the ventricular wall (the septum). This generates increased wall stress with increased cardiac work. These changes in regional wall stress can contribute to myocyte damage, production of fibrous tissue, and development of regional hypertrophy and may induce regional apoptosis. The mechanical contractile dysfunction caused by asynchrony or dyssynchrony can be assessed by standard echocardiographic indexes, but greater precision is obtained with tissue Doppler imaging and magnetic resonance imaging.^12,15–17

Mechanical synchrony between the atrium and the ventricle can also be disturbed when AV conduction is pathologically prolonged. A prolonged electromechanical A-V interval can be assessed by measuring the onset of the P wave of the surface ECG to the aortic valve closure. The mechanical A-V interval is always longer than the electrical A-V interval. This interval can be prolonged even in the absence of a prolonged P-R interval on the surface ECG. Prolongation of AV conduction reduces the active ventricular filling phase and shortens the passive diastolic filling, creating a ventriculoatrial (VA) gradient causing presystolic mitral regurgitation.^13,14 A prolonged mechanical A-V interval is frequently found in patients with heart failure, even with an almost normal electrical A-V interval.¹⁸

Cardiac Resynchronization Using Pacing Techniques

LBBB causes delayed electrical activation and mechanical contraction of the lateral left ventricular wall, whereas the ventricular septum itself exhibits a paradoxic movement.^19–22 Pacing electrode placement becomes a critical component of the extent of effective resynchronization achieved by CRT. For example, pre-excitation of the left lateral ventricular wall with atrio–bi-ventricular pacing in hearts with LBBB resynchronizes the ventricular contraction pattern by bypassing the conduction delay, resulting in improved ventricular contraction pattern and performance.^20–23 It is conceivable that differing patterns of intraventricular conduction delay may also produce regional wall motion abnormalities that could be addressed with CRT. Optimizing AV synchrony is a critical element in obtaining good hemodynamic outcomes in these patients.

Atrioventricular Synchrony During Physiological Pacing

Programming the AV delay appropriately is essential for the improvement of hemodynamic performance with CRT. A very long AV delay will not support ventricular resynchronization because the atrial electrical impulse will follow the same route as during sinus rhythm without pacing. A very short AV delay, in contrast, will cause early depolarization at the site of left ventricular stimulation, leaving the ventricle partially or totally refractory by the time the regularly conducted impulse reaches this region. An AV delay between these two extremes causes a collision of two activation wavefronts: one coming from the regular His-Purkinje system and the other from the pre-excited ventricular activation. The region of collision depends on individual intraventricular and interventricular conduction properties and the left ventricular pacing site (Figure 86-1). Therefore appropriate timing with respect to the AV delay, as well as the left lateral ventricular stimulus, is crucial for achieving the hemodynamic benefits of the resynchronized ventricular contraction pattern in a failing heart.^24,25 A nonphysiological short electrical A-V interval must be used with AV sequential bi-ventricular pacing to avoid AV asynchrony and to reduce presystolic mitral regurgitation. The discrepancy between electrical and mechanical AV sequences is most likely caused by a prolonged intraventricular conduction time. In patients with LBBB, the onset of the electrical depolarization of the left ventricular free wall is significantly delayed. This causes delayed mechanical onset of the left ventricular systole. Consequently, AV sequential pacing with a shortened AV delay is able to restore an adequate mechanical AV synchrony.^24,25 Maximal hemodynamic benefit is achieved when the peak of the atrial pressure curve coincides with the onset of the mechanical ventricular systole (Figure 86-2).

FIGURE 86-1 A, Three-dimensional electroanatomic, nonfluoroscopic mapping in a patient with dilated cardiomyopathy during sinus rhythm and during biventricular stimulation. In sinus rhythm (left), the earliest ventricular activation (red) is located at the anterolateral wall of the right ventricle. After about 60 ms, the activation breaks through into the left ventricle and slowly proceeds (cell-to-cell conduction) from the septum to the lateral and posterolateral wall. The simultaneous pacing from the apex of the right ventricle and lateral wall restored a more homogeneous electrical activation of both ventricles. B, Representative functional maps showing change in various systolic and diastolic measures induced by cardiac resynchronization therapy (CRT) as a function of the left ventricular stimulation site. Top, Results for a nonfailing heart; bottom, results for a failing heart. Each set has two orientations (top, anterolateral; bottom, posterolateral) to display the optimal sites more clearly. Color coding reflects the percent change in a given hemodynamic variable referenced to the dyssynchronous baseline, with dark orange/red regions indicating most optimal CRT. The region of optimal left ventricular pacing was fairly similar among function parameters and between nonfailing and failing hearts.

C, Three-dimensional plot of relative mechanical activation time (time from QRS to peak circumferential strain) in a dyssynchronous failing heart (left bundle-branch block) and during bi-ventricular pacing. The green dot shows the left ventricular stimulation site. D, Synchrony indexed by circumferential uniformity ratio estimate (CURE) was calculated as a function of varying left ventricular pacing site and plotted on three-dimensional maps. The red region denotes the territory in the lateral wall that achieved optimal mechanical resynchronization. E, Full maps derived for ventricular stroke work and synchrony (CURE) were determined in four failing hearts, and the territories producing optimal responses (≥70% maximal) for both were calculated and are displayed in green (far right). This region was somewhat smaller and located in the midlateral (midapical) wall. F, Overlay maps generated for all four animals revealing similarly sized, shaped, and localized co-optimal regions. Dogs A and B had right ventricular free wall stimulation during bi-ventricular pacing; dogs C and D had right ventricular apical pacing during bi-ventricular pacing.

(From Helm RH, Byrne M, Helm PA, et al: Three-dimensional mapping of optimal left ventricular pacing site for cardiac resynchronization, Circulation 115[8]:953–961, 2007.)

FIGURE 86-2 Schematic representation of the hemodynamic benefit obtained when the maximum of the atrial contraction curve is coincident with the onset of the mechanical ventricular systole LV, Left ventricular.

Effect of Bundle Branch Block and Pacing Electrode Location on Efficacy of Resynchronization Therapy

In early experimental studies, Verbeek et al demonstrated that the induction of LBBB produced mechanical dyssynchrony, which could be improved by bi-ventricular pacing.²⁶ In normal or rapid pacing–induced failing canine hearts, Helms et al performed either left ventricular pacing or left bundle ablation and CRT using a fixed right ventricular pacing site and randomly selected left ventricular pacing sites covering the entire free wall (see Figure 86-1, B).²⁷ Cardiac stroke volume was measured with a conductance catheter, and mechanical synchrony was evaluated by using magnetic resonance imaging tagging. In this model, right bundle branch block (RBBB) was associated with a lesser degree of cardiac dyssynchrony compared with LBBB. Three-dimensional maps showed that optimal CRT was achieved from lateral left ventricular wall sites, which were slightly more anterior than posterior and more apical than basal (see Figure 86-1).²⁷ Left ventricular sites yielding a 70% or greater increase in dP/dT_max covered approximately 43% of the left ventricular free wall. In this model, their distribution and size were similar in both normal and failing hearts. Controversy has swirled around the benefits of left ventricular pacing alone versus bi-ventricular pacing in LBBB. In some clinical studies, the concept of tailored CRT has been advanced, but better imaging approaches such as three-dimensional echocardiography, intracardiac echocardiography, or other methods may be needed in clinical practice to prove this concept.^28–30

Effect of Resynchronization Therapy on Mitral Regurgitation

Patients with symptoms of heart failure and a dilated left ventricle (LV) often demonstrate moderate or even severe mitral regurgitation. This is often seen in patients with LBBB. The delay in regional ventricular activation caused by intercellular fibrosis enhances mechanical asynchrony between different ventricular regions and can involve both papillary muscles.²⁵ Geometric distortion in the dilated LV and delayed left ventricular free wall activation further decrease the timely closure of mitral leaflets along with an increased tethering of the mitral apparatus.^23,25

Pacing from the left lateral wall, especially from the proximity of the posterior papillary muscle, diminishes conduction delay and decreases mitral regurgitation. Mean capillary wedge pressure drops significantly with left ventricular free wall pacing, whereas systolic blood pressure rises. The altered ventricular geometry of the dilated failing ventricle results in incomplete closure of the mitral valve at the onset of ventricular contraction causing early systolic mitral regurgitation. Therefore, shortening of the A-V interval during AV sequential pacing, along with left ventricular pre-excitation by left ventricular pacing, diminishes or even abolishes mitral regurgitation.³¹

Short-Term Results

Acute hemodynamic testing has demonstrated that the type of intraventricular conduction block and the pacing site location are the primary determinants of hemodynamic benefits. In addition, short-term data suggest a dichotomous behavior in patients who present with a QRS duration between 120 and 150 ms.²³ Patients with a QRS duration of greater than 150 ms showed the largest hemodynamic benefit. The Pacing Therapies for Congestive Heart Failure (PATH-CHF) trial results and data from Kass and colleagues suggest that patients with LBBB and diffuse intraventricular conduction delay tend to benefit more from bi-ventricular pacing than from right ventricular pacing.^21,23 Atrial synchronous left or bi-ventricular stimulation at a nominal AV delay is significantly more beneficial than is right ventricular pacing alone. Parameters of acute systolic function significantly improved during pacing of the left ventricular free wall alone or synchronously with the right ventricle (RV) but not by pacing the right ventricular apex or septum alone. Pressure-volume loops of the LV show that in patients with LBBB, left ventricular pacing but not right ventricular pacing, increased the stroke volume while minimally affecting the end-diastolic volume. Pulmonary capillary wedge pressure dropped significantly with left ventricular pacing and bi-ventricular pacing but not with right ventricular pacing alone. Resynchronization of ventricular contraction improves mechanical performance with a net decrease in myocardial energy consumption.²² Acute benefits of resynchronization therapy depend on the A-V interval for each ventricular pacing site, with the shortest and longest AV delays being suboptimal.²³ In general, a range of AV delay around 100 ms produced the most beneficial hemodynamic effect. However, a large variability was present in the optimal AV delay during sequential right ventricular pacing, ranging from 50 to 120 ms, and during bi-ventricular stimulation, ranging from 100 to 150 ms.³²

Intermediate-Term Results

In the short term, hemodynamic results of bi-ventricular or left ventricular pacing alone clearly demonstrate hemodynamic improvement, but it is necessary to show that this translates into symptomatic improvement and eventually survival benefit.^33–40 Data from several prospective randomized studies on CRT pacing (CRT-P) and on CRT with defibrillator therapy (CRT-D) (Table 86-1) and large patient registries have been very encouraging in the intermediate term. The majority of patients enrolled in these randomized studies had severely impaired functional capacity (New York Heart Association [NYHA] heart failure classes III to IV), left ventricular systolic dysfunction (EF <35%), a wide QRS complex (>120 ms) and, in most cases, LBBB. None of the patients had conventional indications for pacing therapy. The Multi-site Stimulation in Cardiomyopathy (MUSTIC) study, the Contak-CD trial, and the Multicenter InSync Randomized Chronic Evaluation (MIRACLE) study exclusively assessed the role of bi-ventricular stimulation in patients with heart failure. The PATH-CHF I study was performed to address the question of whether acutely optimized atrial-synchronous ventricular stimulation (right ventricular, left ventricular, or bi-ventricular stimulation based on acute hemodynamic evaluation) reduces heart failure in patients with intraventricular conduction defects. In these studies, CRT increased exercise tolerance, improved quality of life, and reduced hospitalization (Table 86-2).^{23,25,33–35} Oxygen consumption at maximal exercise capacity increased, on average, from 11 to 12 mL/kg/min before pacing to 15 to 16 mL/kg/min after 3 to 6 months of pacing (see Table 86-2). The 6-minute walk test, a generally accepted parameter of physical exercise capacity, increased on average by 10% to 15%, and patients showed a positive improvement in quality of life. Nearly two thirds of patients who underwent bi-ventricular therapy improved to NYHA class I or II from class III or IV. Patients in whom the CRT device was turned on were hospitalized less frequently and needed fewer days in the hospital for worsening of heart failure.

Objective assessment of autonomic and neurohormonal systems has shown the beneficial effects of CRT. Changes in heart rate variability (HRV) and resting heart rate reflect changes of the autonomic nervous system. The PATH-CHF I study showed that resting heart rate was significantly reduced after 3 months of pacing. HRV increased during CRT, whereas during the CRT-off phase, an almost complete reversion to baseline values was observed. In the Vigor in Congestive Heart Failure (VIGOR-CHF) study, a significant reduction of the norepinephrine plasma level after 16 weeks of continuous bi-ventricular stimulation was seen, which also confirmed the positive effect of CRT on neurohumoral activation.³⁶

The Contak-CD study, which is considered one of the first-generation CRT-D studies, differed from many other studies of CRT by including patients with NYHA class I indication for an implantable cardioverte-defibrillator (ICD).³⁴ A reduction of 21% occurred in the overall combined endpoint in Contak-CD, which was not statistically significant (P = .17). This may be attributed to the fact that the relatively large proportion of patients in NYHA class II enrolled in Contak-CD did not show a mortality benefit from CRT-D. Nevertheless, CRT-D in the Contak-CD trial was associated with fewer deaths (23% relative risk [RR] reduction), a lower hospitalization rate (13% RR reduction), and a smaller proportion of patients with worsening heart failure (26% RR reduction). Ventricular tachyarrhythmias were only modestly reduced in some studies of patients receiving CRT.^34,40 All patients showed a significant increase in peak oxygen consumption. Patients in an advanced functional class (NYHA class III or IV) showed double the average increase of oxygen consumption. Longer term outcomes of CRT in the ICD subpopulations are available from the recently completed Multicenter Automatic Defibrillator Implantation Trial (MADIT)-CRT and Resynchronization/Defibrillation for Ambulatory Heart Failure Trial (RAFT) studies (discussed later).^37,38

Although the effect of CRT on the diseased myocardial structure is still not completely understood, it is now well accepted that CRT can lead to reverse remodeling with a significant reduction of left ventricular diameters within 6 to 12 months. CRT is able to reduce abnormal myocardial strain distribution and induce reverse remodeling with a significant decrease of left ventricular volume within the first 6 months after initiation of CRT.³⁹ These effects may be attributed to a direct reduction of regional wall stress or a reduction of increased oxygen demand of the asynchronously contracting ventricles. It is possible, however, that at a critical size of the left ventricular end-diastolic or end-systolic volume, reverse remodeling cannot be achieved. A beneficial effect is also achieved with a decrease in mitral regurgitation.

Many patients with heart failure are not candidates for CRT; the current indications for CRT are limited to patients who fulfill the disease and selection criteria outlined in the practice guidelines, which are largely based on clinical trials. The type of conduction delays, typically RBBB or LBBB or nonspecific intraventricular conduction delays, may play an important role in predicting a beneficial effect of pacing. Although morphologic ECG features may be similar in patients with either RBBB or LBBB, left ventricular electrical activation sequences may differ. The precise spread of activation may only be assessed with detailed high resolution invasive electroanatomic mapping.⁴¹ This, however, is difficult to perform in daily practice. In some cases, it may, indeed, help to select the optimal left ventricular pacing site by accurately detecting the region(s) of delayed left ventricular activation that may be optimal left ventricular pacing sites for CRT. Another approach that has been recently proposed uses intracardiac echocardiography intraoperatively to guide left ventricular pacing to maximize acute improvement in left ventricular EF (LVEF) with varying left ventricular lead position and AV interval programming. Reduction in nonresponder rates has been suggested with this approach, but a large clinical trial is awaited.³⁰

Long-Term Clinical Outcomes of Cardiac Resynchronization Therapy

Second-generation prospective, randomized, controlled studies have examined the effect of CRT and CRT-D on clinical outcomes, morbidity, and disease progression.^42–45 Several have examined the effect of CRT-P (exclusively bi-ventricular pacing) and CRT-D (bi-ventricular pacing with ICD) therapy on outcome and morbidity. The Comparison of Medical Therapy, Pacing and Defibrillation in Chronic Heart Failure (COMPANION) trial was a multi-center trial evaluating the effect of CRT on mortality, morbidity, and exercise performance in symptomatic heart failure patients without ICD indications.⁴³ The study randomized patients in NYHA class III or IV with an LVEF of less than 35% and a prolonged QRS duration (>120 ms) and left ventricular dilation (left ventricular end-diastolic diameter >60 mm). This trial showed that CRT reduced the composite endpoint of death or hospitalization for major cardiovascular event by 12%. However, significant mortality reduction was achieved only in the CRT-ICD arm. Similarly, Cardiac Resynchronization in Heart Failure (CARE-HF) was a mortality and morbidity trial that included patients with NYHA class III or IV heart failure, an LVEF of less than 35%, and a prolonged QRS duration (>150 ms or >120 ms with echocardiographic criteria of dyssynchrony on optimal medical therapy).⁴³ CRT plus optimal pharmacologic treatment was compared with pharmacologic treatment alone. Over a mean follow-up of 29 months, the CARE-HF study showed significant reduction of 37% for the composite endpoint of death or hospitalization for a major cardiovascular event, and a 46% reduction in SCD. CRT-P also reduced mortality rate from 30% in the medical therapy group to 20% in the CRT-P group (hazard ratio [HR], 0.64; P < .002). Reductions in mortality rate from heart failure (HR, 0.55; P = .003) and SCD (HR, 0.54; P < .006) were seen compared with medical therapy. Compared with the control group, the CRT group showed significant improvements in indexes of left ventricular function, symptoms, and quality of life. Longer term follow-up in this study has confirmed long-term benefits in both mortality and morbidity.⁴⁴

The impact of CRT on ventricular remodeling and function was assessed in the Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction (REVERSE) study.^39,45 At 12 months, the clinical composite response endpoint, which measured disease progression, rose by 16% with CRT-on compared with 21% in CRT-off (P = .10). However, the patients assigned to CRT-on experienced a greater improvement in left ventricular end-systolic volume index (−18.4 + 29.5 mL/m² vs. −1.3 + 23.4 mL/m²; P < .0001) and other measures of left ventricular remodeling. Time to first heart failure hospitalization was significantly delayed in CRT-on (HR, 0.47; P = .03).

The MADIT-CRT study evaluated the additional beneficial effect of CRT on the occurrence of heart failure or death in patients with moderate to severe left ventricular systolic dysfunction, with minimal or no symptoms of heart failure and a QRS width of 130 ms (Table 86-3).³⁷ Patients with CRT-D were compared with those receiving ICD-only therapy. CRT provided an additional 34% risk reduction in the primary endpoint after a mean follow-up of 2.4 years. The benefit of CRT was mainly attributable to a 41% reduction of heart failure. Patients with LBBB and women showed the most benefit, whereas patients with RBBB and intraventricular conduction delay demonstrated no benefit. Patients with ischemic and nonischemic cardiomyopathy derived similar benefits. Evidence of left ventricular reverse remodeling was evident as marked reduction in left ventricular volumes and an increase in LVEF with CRT-D. Overall mortality rate was not significantly reduced, which may be a result of follow-up duration. Similar findings were observed in RAFT. (see Table 86-3).³⁸ This trial had a longer follow-up of the enrolled patients and reported a reduction of overall mortality rate. These trials suggest a potential for an early role of CRT in the prevention of progression of heart failure.

Cardiac Resynchronization Therapy with Defibrillator Therapy

Controversy has swirled on the need for defibrillation therapy in patients receiving CRT therapy. Death in patients with heart failure can result from a variety of causes other than mechanical pump failure. SCD in heart failure is a catastrophic event. The incidence increases from 2% to 6% per year in patients with NYHA class II symptoms and up to 24% per year for patients with class III or IV symptoms.⁴⁶ Mechanisms of SCD can include ventricular tachycardia,ventricular fibrillation, bradycardia- or tachycardia-dependent polymorphic ventricular tachycardia, primary bradyarrhythmias, and conduction disturbances resulting in asystolic cardiac arrest and electrical mechanical dissociation or pulseless electrical activity. Early ICD trials did not systematically select patients with advanced heart failure despite observational data and clinical trial subgroup analyses that suggested major benefits accruing with appropriate ICD use in patients with severe left ventricular dysfunction.^47–52 In the Antiarrhythmics Versus Implantable Defibrillators (AVID) study, ICD survival benefit was restricted to patients with an EF below 35%.⁵⁰ The survival benefit in the MADIT I study was almost entirely confined to the ICD group with an EF below 26%.⁵¹ The Canadian Implantable Defibrillator Study (CIDS) showed the greatest benefit was derived by patients in the highest risk quartiles, that is, those with a low EF and a poorer NYHA functional classification.⁵²

In early CRT studies, SCD rates ranged from 33% to 47%. In examining modes of death in the CRT-only group in the CARE-HF study, SCD was observed in 32 of 101 deaths during the extended follow-up, and a certain proportion of these deaths would be deemed preventable by ICD therapy.^43,44 The Multicenter Longitudinal Observational Study (MILOS) group reported their analysis of the long-term outcomes of 1303 patients treated with CRT alone, CRT-P, or CRT-D.⁵³ The cumulative event-free survival rates were 92% and 56% at 1 and 5 years, respectively; and the cumulative incidence rates of death from heart failure and SCD were 25.1% and 9.5%, respectively. CRT-D was associated with a 20% decrease in mortality rate, and its protective effect against SCD was highly significant (P < .002).

Dual-chamber ICD devices have traditionally been used in these patients, but some pacing features may be deleterious. Data from the Dual Chamber and VVI Implantable Defibrillator (DAVID) study suggest that adverse physiological effects and outcomes result from chronic right ventricular apical pacing.⁵⁴ CRT can be considered when intraventricular conduction disturbances, as previously discussed, are present. However, the use of CRT in ICD devices is primarily based on the assumption that prevention of SCD in heart failure populations will provide survival benefits not seen with pacing alone. Table 86-3 summarizes the experience with CRT-D therapy in multi-center clinical trials in this population. Initial experience with an ICD incorporating ventricular resynchronization therapy was assessed in a prospective study using the InSync model 7272 ICD (Medtronic Inc., Minneapolis, MN).⁵⁵ Significant improvement of heart failure symptoms and left ventricular dimensions were seen in these patients, particularly those in NYHA classes III and IV. Patients showed improvement in the 6-minute walk test at 3 and 6 months. All ventricular tachyarrhythmias were correctly identified, and double counting of sensed QRS events did not occur. In the Contak-CD trial, patients with class I indication for ICD therapy and NYHA class II or more heart failure had a 21% reduction of overall mortality rate (nonsignificant).

Table 86-3 summarizes the long-term outcomes of major CRT trials. In the COMPANION study, CRT alone improved NYHA class and quality of life and reduced hospitalizations for heart failure. However, significant mortality rate reduction was achieved only in the CRT-ICD arm. These data are consistent with the original pacing trials in this population, which suggested that SCD can limit the benefits achieved with CRT and challenges the notion that CRT, per se, reduced SCD. However, the delayed separation (after 9 months) of mortality curves (P = .12) between the pacing and medical therapy arms in this study raises the possibility of ventricular remodeling trending to improving survival. This is supported by long-term follow-up in CARE-HF. Over a mean follow-up of 29 months, CRT reduced mortality rates from 30% in the medical therapy group to 20% in the CRT group (HR, 0.64; P < .002), with a reduction in SCD rates (HR, 0.54; P = .005).⁴⁴