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• W2028330111 abstract "As the population ages, the incidence of chronic heart failure will increase and remain an important health issue. Currently, almost 5 million people in the United States are affected by congestive heart failure (CHF), and the number of new patients with CHF is growing by 200,000 to 500,000 per year. 1 Despite prior major advances in pharmacologic therapies, medically refractory heart failure remains a significant source of morbidity and mortality. The presence of conduction abnormalities on the electrocardiogram (often left bundle branch block) may be present in up to 40% of individuals with moderate or severe heart failure. 2 Left bundle branch block delays left ventricular (LV) contraction and results in asynchronous right (RV) and left ventricular contraction. This interventricular asynchrony impairs cardiac performance and leads in many instances to more severe heart failure symptoms. Given that many patients with heart failure have limited exercise tolerance, further depression of cardiac function may be quite debilitating. Recently, cardiac resynchronization therapy (CRT) has become a promising new method for the treatment of these patients. By pacing the LV and RV simultaneously, the extent of interventricular asynchrony is reduced and cardiac performance improved. In large randomized trials, cardiac resynchronization has demonstrated convincing improvement in hemodynamic measures of cardiac performance. More importantly, these changes may be paralleled by significant clinical improvements in quality of life, overall exercise, and functional capacity for the patient with heart failure. This review addresses the detriments of ventricular asynchrony, the advent of CRT, and the effects of CRT on exercise performance in the patient with chronic heart failure. THE PROBLEM: THE UNTOWARD EFFECTS OF INTERVENTRICULAR ASYNCHRONY Interventricular asynchrony, evident on an electrocardiogram as prolonged electrocardiographic wave (QRS) duration (most often left bundle branch block), is common among those with depressed LV function, occurring in up to 40% of patients with heart failure. 2 Furthermore, some investigators have demonstrated a less favorable overall prognosis for these patients than for those without interventricular delay. 3,4 The hemodynamic and mechanical consequences of interventricular asynchrony can be examined by understanding the effects of left bundle branch block (LBBB), a prototypic conduction disorder in the patient with CHF. The necessity for nearly simultaneous contraction of the LV and RV to provide optimal cardiac performance is well established. 5 Mechanical ventricular asynchrony between the RV and LV can adversely affect cardiac performance. 5 In patients with LBBB, conduction delay between RV and LV develops, initially leading to ventricular septal contraction, followed by delayed contraction of the LV lateral wall. Essentially, because of this delay in LV contraction, the LV lateral wall is contracting while the septum is relaxing. As a result, the LV ejection fraction may be reduced even in those without heart disease if this inefficient systolic contraction pattern continues. 6 Limited published data suggest overall reduction in LV ejection fraction by 10% to 15% with notable depressions of mean arterial pressure, cardiac output, and the maximal rate of LV pressure increase (dP/dt) in individuals with LBBB. 6–8 In addition, delay of aortic valve closure and mitral valve opening shortens the duration of diastole (LV filling time), which can further compound an already depressed cardiac performance. 6,9 The QRS duration appears to reflect the magnitude of the interventricular mechanical asynchrony, and LBBB also may be associated with diastolic dysfunction, as noted by echocardiographic analysis. 10–12 Figure 1 summarizes the many cardiac consequences of LBBB. Because patients with chronic CHF resulting from systolic dysfunction may have severely limited cardiac function, the development of LBBB may lead to significant clinical deterioration.Figure 1.: Cardiac consequences of left bundle branch block. LV, left ventricle; RV, right ventricle; dP/dt, marker of cardiac contractility.Interestingly, prior studies confirm that single-chamber RV pacing mimics the mechanical consequences of left bundle branch block. 8,13–15 Nevertheless, investigators’ attempts to reduce CHF symptoms with synchronous dual-chamber pacing have been disappointing and essentially abandoned. 16,17 More recently, the Dual Chamber and VVI Implantable Defibrillator (DAVID) trial demonstrated that a high percentage of RV pacing in the patient with CHF may be detrimental. 18 This trial and other small retrospective observational studies have shown an association between RV pacing in those with depressed LV function and worsening clinical heart failure symptoms. A SOLUTION: THE ADVENT OF BIVENTRICULAR PACING AND CRT Biventricular pacing is achieved by strategically implanting pacing leads so that both the LV and RV may be simultaneously paced. As mentioned earlier, LV lateral wall contraction is delayed appreciably in patients with LBBB. Thus, by implanting a pacing lead in the region of the LV lateral wall (via a coronary sinus branch) and in the RV, both ventricles may be stimulated in concert without interventricular delay to provide synchronous contraction. Early attempts to achieve biventricular pacing for the restoration of ventricular synchrony consisted of epicardial LV lead implantation by a thoracotomy approach with transvenous implantation of an RV apical lead. 19–21 Obviously, a major drawback of this technique was its invasiveness and attendant complications. The recently developed percutaneous approach is favored by most clinicians. 22 Since its introduction, the use of cardiac resynchronization devices for patients with depressed LV function and interventricular asynchrony has increased. The common transvenous technique involves implantation of the LV pacing lead in a lateral or posterolateral tributary of the distal coronary sinus or middle cardiac vein. The RV and right atrial leads are implanted using the usual established techniques. The impetus behind CRT was the vision to develop a technique by which cardiac synchrony could be restored, which then would lead to improved cardiac performance. Using CRT, investigators demonstrated significant increases in systolic blood pressure, dP/dt, and cardiac index with reduction of left atrial pressures, mitral regurgitation, and systemic vascular resistance. 21,23,24 In addition, limited invasive hemodynamic studies show a short-term improvement in LV ejection fraction by 35%. 10 Interestingly, initial studies demonstrated similar improvement in cardiac function with both LV pacing and biventricular pacing. 23,24 Investigators concluded that the hemodynamic benefit of LV or biventricular pacing is derived from the early activation of the region of the LV that usually exhibits delayed activation in the setting of LBBB. In all these studies, mechanical resynchronization appeared to be the driving force for improved cardiac function. Furthermore, the magnitude of baseline asynchrony, as determined by the QRS duration, appears to predict pacing response. Those with greater asynchrony (wider QRS complex) have greater hemodynamic benefit. 19,21 However, the change in QRS duration with biventricular pacing is less likely to predict efficacy. 25,26 Soon, the use of CRT was evaluated in patients with CHF. Initially, small studies involving patients with severe heart failure appeared promising. 10,21,23,27–29 Blanc et al 23 introduced LV or biventricular pacing in patients with end-stage heart failure (NYHA class III/IV, mean LV ejection fraction of 27%), demonstrating a 7% increase in systolic blood pressure and a 22% depression of pulmonary capillary wedge pressure, both of which were statistically significant. Other parameters of cardiac performance also improved, as noted by Kass et al, 21 who reported a 24% increase in dP/dt in patients with LBBB and a mean LV ejection fraction of 19%. Leclercq et al 28 showed a cardiac index increase of 35% in an equally ill group of patients (mean LV ejection fraction of 19%). Most of these investigators evaluated only patients who had QRS durations longer than 120 msec with LBBB, arguing that these patients (from early pilot studies) benefit the greatest because of their greater degree of ventricular asynchrony. More recently, large prospective clinical trials of biventricular pacing have suggested that CRT also confers clinical improvement (better quality of life) for patients with heart failure as well as the previously reported hemodynamic benefit. 30,31 Moreover, these prospective trials have clearly demonstrated that many patients experience dramatic improvements in exercise tolerance, allowing them to participate in activities previously untenable. The remainder of this review describes the effects of CRT on the functional capacity of the patient with CHF and the potential mechanisms by which it improves. EXERCISE CAPACITY OF THE PATIENT WITH CHRONIC HEART FAILURE The patient with chronic CHF often experiences profound limitations in activity as a result of reduced exercise tolerance, which may be accompanied by a poor quality of life. The mechanisms by which these limitations occur are complex, and many currently are inadequately understood. Interestingly, reduced exercise capacity does not appear to correlate with cardiac performance as measured by central hemodynamic parameters. 32,33 As an example, patients with heart failure often have LV ejection fractions of less than 25%, but many may nevertheless function with minimal symptoms of dyspnea and fatigue. Figure 2 lists some of the factors that may contribute to poor exercise capacity in patients with CHF. Because of low cardiac outputs, muscle function is depressed by demand perfusion mismatch, leading to fatigue as metabolic products increase in muscle tissue. In fact, patients with heart failure appear to distribute only 50% to 60% of cardiac output to active muscles, as opposed to 90% distribution noted in healthy individuals. 34 In addition, data suggest that patients with CHF have an alteration in skeletal muscle metabolism, which leads to further inefficient muscle performance and fatigue. 35 The inability to elevate heart rate appropriately during exercise (chronotropic incompetence) may be another mechanism by which patients with CHF experience limited exercise capacity. 36Figure 2.: Factors that may contribute to the limited exercise capacity in many chronic congestive heart failure patients.The use of cardiopulmonary exercise testing (CPET) in patients with heart failure has provided an effective means for acquiring more information regarding the factors that may contribute to the poor functional status in these patients. 37,38 In addition, CPET allows clinicians to assess their patients after interventions aimed at improving exercise capacity. 39,40 With CPET, the measurement of peak oxygen uptake (VO2) during exercise is used traditionally as an index for assessing functional impairment. 41 Patients with chronic CHF often have a VO2 less than 10 to 14 mL/kg per minute, which is a reflection of many factors including depression of cardiac output, abnormal skeletal muscle metabolism, impaired chronotropic response, and abnormal ventilatory drive. 33,34–36,41 Furthermore, the level of VO2 above which aerobic energy production is augmented by anaerobic mechanisms (ie, the anaerobic threshold) is markedly depressed in these patients. 42 Careful CPET analysis also has demonstrated that the ratio of peak VO2 to the VO2 at the anaerobic threshold is elevated. Essentially, patients with chronic heart failure, already limited by a markedly depressed peak VO2, may experience anaerobic metabolism earlier in their exercise than individuals without heart disease, which contributes to fatigue and cessation of activity. The peak VO2 among patients with heart failure appears to be a more robust indicator of functional capacity than central hemodynamic measurements, and may provide a means to assess prognosis. The slope of minute ventilation (VE) per unit of ventilated carbon dioxide (VCO2), a measure of ventilatory drive, also is a powerful index of prognosis for patients with CHF. 41 Patients with heart failure often have a steep VE/VCO2 slope that portends a worse prognosis. 43 Therapeutic maneuvers for patients with CHF to improve CPET parameters may result in therapy that improves exercise capacity and subsequently improves quality of life. THE EFFECTS OF CRT ON EXERCISE CAPACITY Early studies of CRT were designed primarily to evaluate the central cardiac hemodynamic response of patients with severe systolic heart failure. End points included variables such as change in LV ejection fraction, pulmonary capillary wedge pressure, dP/dt, and myocardial oxygen consumption, all of which appeared to be favorable. 21,23,27–29 In most cases, these small observational studies consisted of patients with severe dilated cardiomyopathy regardless of etiology. Furthermore, they rarely addressed the clinical status of the patient throughout the protocol. Some of these investigations have been discussed previously. Since the recent introduction of the less invasive transvenous approach to achieve CRT, a number of large prospective trials have been completed, each with varying end points (Table 1). These studies investigated patients with similar clinical characteristics: LV ejection fraction less than 35%, QRS duration longer than 130 msec, and NYHA class III and IV heart failure with optimal medical therapy. Notably, these general inclusion criteria were those adopted by the Food and Drug Administration when approving the use of CRT for patients with medically refractory severe CHF. These studies were designed specifically to determine whether the hemodynamic improvement in cardiac function predicted clinical improvement. The factors addressed included assessment of quality of life and exercise capacity with and without CRT. 30,31,50,52Table 1: MAJOR CARDIAC RESYNCHRONIZATION THERAPY PROSPECTIVE RANDOMIZED TRIALS, THEIR INCLUSION CRITERIA, AND ENDPOINTS IN EXERCISE CAPACITYOne of the first prospective clinical trials examining the effects of CRT on exercise capacity was the Multicenter Stimulation in Cardiomyopathies study (MUSTIC) that included patients with NYHA class III and IV heart failure, QRS duration exceeding 150 msec (primarily LBBB), and LV ejection fractions less than 35%. 30,44,45 In these trials, the patient received a biventricular pacemaker programmed to either biventricular pacing (CRT) or no pacing (ventricular backup pacing at 40 beats per minute). After 3 months, the patients crossed over to the opposite arm, in which they acted as their own controls. After another 3 months, devices were programmed to patient preference. In this trial, the exercise variables studied at the crossover intervals included peak VO2, as determined by CPET, and the distance attained during a 6-minute walk test. The data showed that the actively paced patients (CRT group) demonstrated an improvement in the peak VO2 attained (8%; P < .03) and the distance walked in 6-minutes (23%; P < .001). The absolute changes are presented in Figures 3 and 4. Patients in MUSTIC also experienced a substantial increase in their anaerobic threshold with CRT after 3 months (9.5 mL/kg/minute with no pacing; 11.2 mL/kg/minute with CRT; P = .014). Changes in ventilatory drive (VE/VCO2) also were favorable (36 with no pacing; 32 with CRT; P = .03). Overall, the impressive improvements in the functional capacity of the MUSTIC patients remained when they were evaluated after 12 months, suggesting long-term benefit of CRT.Figure 3.: Long-term improvement in peak oxygen consumption (VO2) after cardiac resynchronization therapy (CRT) in the MUSTIC study (P = .02) and the PATH-CHF trial (P < .001). White bars = no pacing. Black bars = CRT.Figure 4.: Improvement in 6-minute walking distance with cardiac resynchronization therapy (CRT) in the MUSTIC study (P = .001) and the PATH-CHF trial (P < .001). White bars = no pacing. Black bars = CRT.The Multicenter InSync Randomized Clinical Evaluation (MIRACLE) study is one of the largest prospective CRT trials published to date. 31,46–48 This trial enrolled 453 patients divided into a CRT arm and a no-pacing arm, a design similar to that of MUSTIC. The patients exhibited NYHA class III and IV heart failure, LV ejection fractions less than 35%, and QRS durations exceeding 130 msec (again, primarily LBBB). The patients were randomized to CRT or no pacing for 6 months and crossover to the opposite arm after 6 months. The 6-month data demonstrated a median increase in VO2 by 1.1 mL/kg/minute (P = .009) and the distance walked in 6 minutes by 39 m (P = .005). In addition, these patients experienced clinical improvement, with fewer hospitalizations for CHF and improved quality of life scores by standardized inventory. Again, similar to the MUSTIC findings, the MIRACLE benefits are sustained after 1 year. 47 The MIRACLE ICD trial was similar in design to MIRACLE, but biventricular internal cardioverter defibrillators were used rather than biventricular pacemakers. 49 The mechanism of resynchronization with both devices is the same. The MIRACLE ICD trial yielded results similar to those of the MIRACLE trial (Table 1). More recently, the investigators of the Pacing Therapies in Congestive Heart Failure (PATH-CHF) trial published their long-term results. 50,51 The PATH-CHF study enrolled patients with severe cardiomyopathy (mean LV ejection fraction of 21%), NYHA class III or IV heart failure symptoms, and QRS durations exceeding120 msec. Similar to the previously discussed trials, PATH-CHF used a crossover design with 41 patients. The patients were randomized to 4 weeks of CRT or no pacing (first treatment), 4 weeks of no treatment, and 4 weeks of treatment in the opposite arm (2nd treatment). After this protocol, long-term data were ascertained after 9 months of CRT for both groups. Initial data from the PATH-CHF investigation showed favorable outcomes in terms of hemodynamic parameters. After 12 months, the patients receiving CRT showed a 20% improvement in peak VO2 (P < .001) and a mean increase of 89 m in the distance walked in 6 minutes (P < .001) (Figures 3 and 4). Furthermore, similar to the MUSTIC data, the PATH-CHF data showed an improvement in anaerobic threshold after CRT (9.9 mL/kg/minute with no pacing; 11.5 mL/kg/minute with CRT; P < .037). The changes in exercise parameters were paralleled by impressive improvements in NYHA classification and quality-of-life scores. The PATH-CHF data also demonstrated improved ventilatory efficiency (shallower VE/VO2 slope) with CRT (37.9 with no pacing; 33.2 with CRT; P < .05). Interestingly, a retrospective analysis of PATH-CHF suggested that the greatest improvement in peak VO2 and VO2 at the anaerobic threshold is most apparent in the patients with the lowest pretreatment peak VO2 (<10.9 mL/kg/minute). Among patients with a pretreatment VO2 that exceeds 16.3 mL/kg/minute, the changes in peak VO2 and anaerobic threshold with CRT were nonsignificant. The consistency among the largest of the published trials on CRT suggests that a significant subset of patients with CHF will derive a clear clinical benefit by an improvement in functional capacity. The mechanisms by which these improvements occur are less clear. The short-term encouraging hemodynamic responses with CRT likely explain many of the changes in exercise capacity. However, other factors have become of interest to investigators recently. These factors include more efficient regulation of vascular beds, enhanced skeletal muscle metabolism, reverse remodeling of the LV to reduce its size, and promotion of a more physiologic chronotropic response to exercise. CONCLUSIONS Congestive heart failure remains an important cause of morbidity and mortality despite major advances in pharmacologic therapies. Significant ventricular conduction disease develops in many patients with CHF over their lifetime, which becomes detrimental to the performance of their failing heart. In addition, even with optimal medical therapy, these patients may experience severely limited exercise capacity that prevents them from performing everyday activities. Biventricular pacing therapy (CRT) has become an established method for improving cardiac function by producing synchronous ventricular contraction and thus achieving cardiac resynchronization. Small and large prospective trials have showed that patients experience impressive improvements in exercise capacity with elevations of peak exercise VO2, anaerobic threshold, and distance during 6-minute walk tests. More importantly, CRT improves the quality of life for patients with heart failure, and may allow these patients to lead a more independent and active life." @default.
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• W2028330111 title "Cardiac Resynchronization Therapy" @default.
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