Year: 2015
Type: editorial
Abstract: This editorial refers to ‘Association of persistent or worsened echocardiographic dyssynchrony with unfavourable clinical outcomes in heart failure patients with narrow QRS width: a subgroup analysis of the EchoCRT trial’†, by J. Gorcsan et al., on page 49. Among patients with a left ventricular ejection fraction (LVEF) <35% and a widened QRS complex, cardiac resynchronization therapy (CRT) has been shown to improve symptoms and reduce morbidity and mortality in a majority, but not all, patients receiving the therapy.1–4 A widened QRS complex is indicative of the abnormal activation pattern thought to be responsible for dyssynchronous and inefficient contraction of the LV. In virtually all of the large outcomes trials of CRT, widened QRS complex (at least >140 ms) and, more specifically, left bundle branch block have emerged as predictors of treatment benefit.5–8 Imaging-based assessments of the timing of LV regional contraction—termed intraventricular mechanical synchrony—including numerous M-mode, Doppler, tissue Doppler and strain-based measures, were developed out of a desire to better understand the physiologic underpinnings of LV dyssynchrony and to better identify patients most likely to benefit from CRT. The relationship between electrical dyssynchrony, assessed by the electrocardiogram, and mechanical dyssynchrony, assessed by cardiac imaging, has been variable. Not all patients with an LVEF <35% and QRS widening demonstrate mechanical dyssynchrony based on one of the many proposed echocardiographic indices, and single-centre studies suggested that these imaging-based indices of mechanical dyssynchrony could effectively identify those CRT candidates most likely to respond to treatment.9,10 However, when tested in the multicentre prospective PROSPECT trial, measures of mechanical dyssynchrony by echocardiography demonstrated limited reproducibility and failed to identify patients most likely to benefit from CRT.11 Exaggerated mechanical dyssynchrony had also been noted in patients with HF with reduced LVEF (HFrEF) in the absence of QRS widening, and has been associated with worse outcomes. These observations understandably led to interest in the potential for CRT to improve outcomes in HFrEF patients with mechanical dyssynchrony despite a narrow QRS. Relatively small surrogate endpoint studies have demonstrated conflicting results, but were generally disappointing.12–14 The Echocardiography-Guided Cardiac Resynchronization Therapy (EchoCRT) trial was the most definitive attempt to target mechanical dyssynchrony, in the absence of electrical dyssynchrony, in HFrEF using CRT.15 The EchoCRT trial randomized 809 patients with New York Heart Association class III or IV heart failure, LVEF ≤35%, QRS duration <130 ms and LV mechanical dyssynchrony by echocardiography to CRT implantation with CRT-on or CRT-off. LV mechanical dyssynchrony was defined by at least one of two echocardiographic criteria: tissue Doppler imaging longitudinal velocity delay ≥80 ms or speckle tracking radial strain delay ≥130 ms. Designed to demonstrate a reduction in the composite of death or HF hospitalization with CRT-on, the study was terminated prematurely for futility with a significantly higher mortality rate noted in the CRT-on arm. In this issue of the Journal, Gorcsan et al.12 report on the prognostic implications of persistent dyssynchrony at 6 months following randomization in a subgroup of 614 patients in the EchoCRT trial.16 Persistent dyssynchrony, regardless of treatment assignment, was associated with a greater risk of the composite endpoint of death or HF hospitalization and of HF hospitalization alone. Therefore this study identifies persistent mechanical dyssynchrony as a risk marker for HF hospitalization in HFrEF with narrow QRS. Whether this prognostic marker has broader clinical utility will be determined by whether it provides incremental value in identifying risk beyond established clinical and conventional echocardiographic risk factors. An equally notable finding in this study is the absence of a difference between the randomization arms in the prevalence of persistent dyssynchrony (77% in CRT-on, 76% in CRT-off). This is in contrast to the marked reduction in mechanical dyssynchrony observed after 1 year of CRT therapy in patients with a wide QRS complex in the Multicenter Automatic Defibrillator Implantation Trial–Cardiac Resynchronization Therapy (MADIT-CRT).17 This observation provides further evidence that electrical resynchronization is not an effective therapy for mechanical dyssynchrony occurring in the absence of concomitant electrical dyssynchrony. Of course, additional explanations may contribute. Just as different QRS patterns (notably left bundle branch block vs. other types of wide QRS variants) have been shown to be associated with different degrees of treatment benefit, the pattern of mechanical dyssynchrony may be important in determining treatment responsiveness in addition to the magnitude of dyssynchrony. Another, and perhaps more plausible, explanation is that isolated mechanical dyssynchrony may simply be a marker of progressive contractile dysfunction and inefficiency that is not, in itself, a targetable risk factor. The presence and prognostic relevance of isolated mechanical dyssynchrony is not specific for HFrEF and has previously been demonstrated in patients with post–myocardial infarction HF or LV systolic dysfunction18 and even in asymptomatic persons in the community.19 In addition, as noted by the authors, the mechanism by which isolated mechanical dyssynchrony improved in 23–24% of patients in both randomization arms in the EchoCRT trial is unknown. However, in at least one study of patients with acute onset non-ischaemic cardiomyopathy, marked improvement in mechanical dyssynchrony was noted in conjunction with improvements in LVEF associated with optimal medical therapy.20 These observations are particularly relevant since mechanical dyssynchrony is being assessed in clinical contexts outside of those that traditionally define candidacy for CRT. Exaggerated mechanical dyssynchrony has been described in 40–60% of patients with heart failure and preserved ejection fraction (HFpEF) despite a prevalence of QRS widening of 11–13%.21–23 Furthermore, isolated mechanical dyssynchrony is also being investigated in patients with HF risk factors such as aging, hypertension and diabetes.24,25 The findings of the EchoCRT trial, and of this subanalysis in particular, clearly demonstrate that mechanical dyssynchrony in the absence of electrical dyssynchrony is a marker of heightened risk in HFrEF that is not modifiable by CRT, and suggest more generally that isolated mechanical dyssynchrony may not be a viable treatment target. As abnormalities of these echocardiographic measures of dyssynchrony are increasingly recognized in conditions across the cardiovascular disease spectrum, EchoCRT reminds us that we must interpret the meaning of these imaging biomarkers, and their potential use as treatment targets, with caution. The work for this manuscript was also supported by the National Institutes of Health grant 1K08HL116792-01A1 (AMS) and the American Heart Association grant 14CRP20380422. Conflict of interest: none declared.
Source: European Heart Journal
Authors: Amil M. Shah, Scott D. Solomon
Institutions: Brigham and Women's Hospital, Harvard University
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2232115970