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Implantable cardioverter-defibrillator (ICD) therapy represents a cornerstone treatment in patients at risk for sudden cardiac death.1,2 Indications for ICD therapy have evolved considerably from survivors of sustained ventricular tachycardia or ventricular fibrillation to patients with depressed left ventricular (LV) systolic function (LV ejection fraction (LVEF) < 30-40%), regardless of prior ventricular tachyarrhythmias.3-8
The merits of ICD therapy have been demonstrated in several large randomized trials.3-8 The first Multicenter Automatic Defibrillator Implantation Trial (MADIT) was one of the first studies evaluating the effectiveness of defibrillator therapy on the reduction of arrhythmic death in patients with depressed LV systolic function.7 The prospectively designed study evaluated whether prophylactic ICD implantation showed improved survival when compared to conventional medical therapy alone. Over a 5-year course, 196 patients with a prior myocardial infarction and depressed LV systolic function (LVEF ≤ 35%) were enrolled and randomly assigned to ICD therapy (n = 95) or medical therapy alone (n = 101). During a mean follow-up of 27 months, all-cause mortality was significantly lower in patients with ICD therapy as compared to patients with conventional medication alone (16% vs 39%, P < .05). The MADIT I trial has shown that the use of prophylactic ICD therapy was associated with a significantly improved survival as compared to patients on medical therapy (HR 0.46, 95% CI 0.26-0.82, P < .01).
Even though the efficacy of ICD therapy have been demonstrated in several landmark trials,3-8 the risk of cardiac death remained considerably high in patients who underwent ICD implantation.9-11 Several randomized trials have shown that a substantial number of ICD recipients died because of progressive heart failure.9-11 The recent randomized clinical Immediate Risk Stratification Improves Survival (IRIS) trial, which was designed to evaluate the efficacy of early ICD therapy (within 40 days of myocardial infarction) in patients with depressed LV systolic function, showed that the number of ICD recipients who died because of non-sudden cardiac death was considerably high; more than 15% of the ICD recipients died over a mean follow-up of 37 months.9 Additionally, post-hoc analysis of the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) revealed that progressive heart failure contributed significantly to all-cause mortality in patients with ICD treatment.11 Progressive heart failure was identified as the mode of death in 40% of the ICD recipients who died over a mean follow-up of 45.5 months.11
Cardiac resynchronization therapy (CRT) represents an effective treatment option in patients with moderate-to-severe drug-refractory heart failure.12-15 Resynchronization therapy has been shown to improve the inherent electrical cardiac function by stimulating the ventricles in a synchronized manner.12-15 The improvement in cardiac performance, induced by synchronized pacing (which restores the intrinsic electrical conduction), has been consistently demonstrated in patients with moderate-to-severe heart failure (NYHA functional class III or IV) and ventricular conduction delay.12-15 The Comparison of Medical Therapy, Pacing and Defibrillation in Heart Failure (COMPANION) trial demonstrated that resynchronization therapy resulted in a 19% risk reduction of the primary endpoint (time to death from or hospitalization for any cause) as compared to optimal medical therapy alone in 1520 patients with NYHA functional class III or IV heart failure (HR 0.81, P = .014).14 Additionally, a recent post-hoc analysis of the COMPANION trial was published evaluating the effect of CRT on the number of hospitalizations during follow-up.15 In this study, resynchronization therapy was associated with a 44% reduction of heart failure hospital admissions and a 21% reduction of all-cause hospitalizations per patient-year of follow-up.
Recently, the hypothesis that resynchronization therapy may delay or interrupt the progressive decline in cardiac function in patients with mild heart failure, as indicated by NYHA functional class I or II, was evaluated in the Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction (REVERSE) trial.16 St. John Sutton et al16 sought to determine whether patients with NYHA I-II heart failure showed favorable effects on LV geometry and function with resynchronization therapy. In total, 610 patients with mild heart failure (NYHA functional class I-II), depressed LV systolic function (LVEF ≤ 40%), prolonged QRS interval (≥120 ms) and LV end-diastolic dimension (≥55 mm) were included. Randomization of patients was performed according to a 2:1 model; 419 patients received resynchronization therapy (on top of optimal medical treatment) and 191 patients received optimal medical therapy alone during 12 months of follow-up. Patients with CRT showed considerable reverse remodeling (as reflected by a significant decrease in LVESV and LVEDV index) as compared to patients without CRT during 12 months. Moreover, LV systolic function improved significantly in patients with resynchronization therapy (27.2% ± 6.6% vs 31.8% ± 8.8%, P < .01), whereas no significant improvement was observed in patients without resynchronization therapy. Thus, favorable effects on LV structure and function were observed in patients with mild heart failure and resynchronization therapy. Moreover, the authors postulated that the progressive deterioration of cardiac function in patients with mild heart failure may be delayed or interrupted by resynchronization therapy, and probably this may lead to a change in the natural course of the disease.
Additionally, the value of resynchronization therapy in patients with mild heart failure and depressed LV systolic function was addressed by the Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT) trial.17 A total of 1820 patients with mild heart failure symptoms and depressed LV systolic function (LVEF ≤ 30%) were included. During a mean follow-up of 2.4 years, the primary endpoint (defined as all-cause mortality or nonfatal heart failure events) was significantly less often documented in patients receiving CRT-D when compared to patients receiving ICD treatment alone (17.2% vs 25.3%, P < .01). More specifically, a risk reduction of 34% for primary endpoint events was observed for patients receiving CRT-D (HR 0.66, 95% CI 0.52-0.84, P < .01), as compared with those in the ICD group. These positive effects of CRT-D were primarily driven by a 41% risk reduction of the risk for nonfatal heart failure events (HR 0.59, 95% CI 0.47-0.74, P < .01).
Despite its beneficial effects, the efficacy of resynchronization therapy has not been demonstrated in all patients currently indicated for CRT.18-20 It has been demonstrated that a substantial group of patients (30-40%), who were selected according to current criteria on CRT, did not show significant improvement in heart failure symptoms or LV systolic performance.21,22 LV dyssynchrony may play an important role as it has been identified as an important predictor of response to CRT.21,22 Multiple clinical studies have shown that pre-existent LV dyssynchrony predicts response to CRT in patients with symptomatic advanced heart failure despite optimal pharmacologic treatment.21,23-25 Acute hemodynamic improvement after CRT has been related to LV dyssynchrony at baseline.23,25,26 Breithardt et al26 sought to determine whether pre-existent LV dyssynchrony predicts acute response to CRT in 34 patients with heart failure. LV dyssynchrony was evaluated using echocardiographic phase analysis of LV septal and lateral wall motion and the absolute difference in septal and lateral wall motion phase angle (LS) was used as an indicator of LV dyssynchrony. Accordingly, patients were stratified into patients with or without LV dyssynchrony. In all patients, acute hemodynamic response to CRT was expressed in percentage increase in dP/dtmax. Patients with baseline LV dyssynchrony showed significantly larger increase in dP/dtmax with CRT as compared to patients without LV dyssynchrony (26% ± 14% vs 2% ± 1%, P < .05) at baseline. Accordingly, the study demonstrated that LV dyssynchrony could be used for identification of patients who showed acute response to CRT.
Additionally, the value of LV dyssynchrony has been demonstrated in studies evaluating the long-term effects of CRT.27,28 Sogaard et al27 evaluated whether baseline LV dyssynchrony could predict the long-term effects of CRT. Twenty-five consecutive patients with advanced heart failure and left-bundle branch block configuration were enrolled. The study demonstrated that the extent of baseline LV dyssynchrony (as assessed with 3D echocardiography and tissue Doppler imaging) was predictive for long-term response to CRT. Recently, the prospective study performed by Soliman et al28 sought to determine the role of LV dyssynchrony as assessed with 3D echocardiography for prediction of long-term response to CRT. The patient population consisted of 90 patients who were referred for CRT because of severe drug-resistant heart failure. All patients underwent echocardiographic evaluation before and 12 months after CRT. The standard deviation of time to minimum systolic volume of the 16 LV segments was used to define the systolic dyssynchrony index (SDI). CRT response was defined as a >15% decrease in LV end-systolic volume. A SDI >10% yielded a sensitivity of 96% and a specificity of 88% for prediction of long-term response to CRT.
Thus, LV dyssynchrony may aid to identify potential responders to resynchronization therapy. Currently, the majority of studies have focused on echocardiographic techniques to evaluate the extent of LV dyssynchrony.21,23-26 Despite its potentials, one of the major drawbacks of echocardiographic assessment of LV dyssynchrony remains its high intra- and interobserver variability; an issue that has been addressed in the Predictors of Response to Cardiac Resynchronization Therapy (PROSPECT) trial.29 As a consequence, the results of the PROSPECT trial have prompted the search for improved techniques to assess LV dyssynchrony.
Phase analysis on gated myocardial perfusion single photon emission computed tomography (SPECT) has emerged as an interesting technique that provides information on cardiac wall motion in addition to the evaluation of myocardial infarction and ischemia.30,31 Currently, several nuclear studies using phase analysis on gated myocardial perfusion SPECT have demonstrated that LV dyssynchrony provides useful information in patients with CRT.32,33 Henneman et al33 evaluated whether phase analysis on gated myocardial perfusion SPECT was able to predict response to CRT at 6 months in 42 patients with advanced heart failure. An improvement of ≥1 New York Heart Association (NYHA) functional class was used as a criterion for CRT response. The extent of LV dyssynchrony was significantly larger in responders as compared to non-responders to CRT, as reflected by higher values of histogram bandwidth (175 ± 63° vs 117 ± 51°, P < .01) and phase standard deviation (56.3 ± 19.9° vs 37 ± 14.4°, P < .01) in responders to CRT. Furthermore, ROC curve analysis was performed to identify the optimal point for prediction of response to CRT. A cutoff point of 135° for histogram bandwidth yielded a sensitivity and specificity of 70% for prediction of response to CRT. For phase standard deviation, a cutoff point of 43° yielded a sensitivity and specificity of 74% for prediction of CRT response. As a result, this study demonstrated that LV dyssynchrony derived from phase analysis on gated myocardial perfusion SPECT could be used to identify responders to CRT.
Accordingly, the question comes up whether LV dyssynchrony can also be used to identify patients with ICD therapy who will show additional benefit from receiving combined resynchronization-defibrillator therapy. Even though this was not tested in the study by Aijaroudi et al,34 the study clearly demonstrated that LV dyssynchrony was associated with increased risk of adverse cardiovascular events in ICD recipients. The retrospective study by Aijaroudi et al34 was based on 70 patients with depressed LV systolic function (LVEF < 40%) and ICD therapy. For comparison reasons, 157 control patients with normal LV systolic function were enrolled. Stress-rest gated myocardial perfusion SPECT imaging was performed in all patients within 6 weeks prior to ICD implantation. Automated phase analysis was applied to the conventional gated SPECT data sets to evaluate the extent of baseline LV dyssynchrony, as reflected by the histogram bandwidth and phase standard deviation. Furthermore, all-cause mortality and appropriate ICD shocks (both were used as the primary endpoint) were identified in all patients during clinical follow-up. All-cause mortality or appropriate ICD shock was identified in 8 (11%) patients at 1-year follow-up. ICD patients showed significantly more LV dyssynchrony as compared to the healthy control patients. In addition, phase standard deviation (60° ± 5° vs 50° ± 21°, P < .01) was significantly higher in patients with an event as compared to patients without an event during follow-up, and the histogram bandwidth (185° ± 37° vs 154° ± 75°, P = .07) tended to be higher in patients with an event as compared to patients without an event. Moreover, a phase standard deviation of <50° was associated with no events during follow-up. Importantly, the study suggests that patients with extensive LV dyssynchrony have an increased risk for cardiac death partially due to progressive heart failure.
Although the current study provides important information for prognostication of ICD patients, some limitations need to be considered. The association between baseline LV dyssynchrony and cardiovascular events was evaluated in a small subset of patients using a retrospective approach. A prospective analysis would have been preferred when evaluating the predictive value of LV dyssynchrony in ICD patients. Furthermore, the current findings are based on a small number of adverse events. In total, only 8 patients (3 patients died and 5 patients received appropriate ICD shock) showed an event at 1-year follow-up. Moreover, a combined endpoint (consisting of all-cause mortality and appropriate ICD shocks) was used to evaluate the predictive value of baseline LV dyssynchrony in ICD recipients. However, a single endpoint (cardiac death due to progressive heart failure) would have been preferred to assess the predictive value of baseline LV dyssynchrony in ICD patients.
Additional prospective studies are needed that evaluate whether LV dyssynchrony can be used to select patients who should receive combined resynchronization-defibrillator therapy or defibrillator therapy alone. These prospective studies should stratify patients, who are currently indicated for ICD therapy, according to the presence of baseline LV dyssynchrony into patients with or without LV dyssynchrony; patients with baseline LV dyssynchrony should receive combined resynchronization-defibrillator therapy, whereas patients without baseline LV dyssynchrony should receive defibrillator therapy alone. These prospectively designed studies will establish the actual role of LV dyssynchrony in patients currently indicated for ICD therapy.
Mark J. Boogers is supported by the Dutch Heart Foundation grant number 2006T102. Martin J. Schalij received research grants from Boston Scientific, Medtronic and Biotronik. Jeroen J. Bax received research grants from Medtronic, Boston Scientific, Biotronik, Edwards Lifesciences, BMS medical imaging, St. Jude Medical and GE Healthcare.
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See related article on doi:10.1007/s12350-009-9169-7
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