The Fundamental Cellular Mechanisms Underlying Cardiac Resynchronization Remain Poorly Differentiated

Dr Chung and colleagues1 present a small cohort of patients who had biventricular pacers placed between 1 and 2 months after an acute myocardial infarction (MI). They proposed to test the hypothesis that cardiac resynchronization therapy (CRT) will attenuate pathologic remodeling and improve functional status in patients with reduced left ventricular (LV) function and a history of class III heart failure (HF). Both groups received standard medical therapy. The control arm received internal cardiac defibrillators without CRT, while the active arm received both internal cardiac defibrillators and CRT. The authors report a more favorable systolic and diastolic ventricular volume profile in the patients who received CRT, but no change in functional status defined as heart class, quality of life, or 6-minute walk. This hypothesis-generating pilot trial is very interesting, but readers are cautioned to carefully balance both the merits and limitations of this small study, in which only 14 patients (6 in the control arm, 8 in the CRT arm) were included in the final data analyses. Many of the limitations of this specific study have been enumerated by the authors in the discussion section of the manuscript. However, there are additional concerns worth considering in a critical review of this innovative pilot study: There is very little discussion regarding up-titration of medications already known to favorably attenuate remodeling. There also is no mention of diuretic or aldosterone antagonist use. These medications, along with angiotensin-converting enzyme inhibitors and β-blockers, may have the potential to markedly change remodeling over the first year. Historical controls would suggest that aggressive medical therapy may produce results similar to those observed in the CRT arm.2 Although mentioned by the authors, the baseline characteristics would suggest that the CRT patients were more infirm at the beginning of the study. This would suggest that in the proposed analysis, it may be easier to demonstrate a significant difference in the CRT arm. This supposition is supported by differences in mitral regurgitation, enzyme leakage during the MI, and larger LV volumes at baseline. In addition, the echocardiographic studies could not have been blinded as suggested by the authors, because the coronary sinus lead may have been visible on the echocardiogram in some of the patients. In addition, although the authors suggest that they observed a more favorable remodeling profile with CRT, they did not comment on changes in LV end-diastolic or -systolic dimensions, nor in changes in LV mass index. Finally, although certainly not powered for analysis, it would be interesting if the authors had commented on proarrhythmic events, hospitalization, and death at the time of submission, as these data are certainly older than 12 months. If there was no functional difference, as reported, and there are no observable end-point changes, what do the differences in ventricular volumes and changes in sphericity index denote? (One contemporary issue not addressed by the manuscript or by this commentary is the economic burden for expanding CRT indications, as this concern has been raised by many authors in the recent past.3-5) In contrast to these concerns, this manuscript also has some unique features that have significant merit. I agree with the authors' main conclusion that it appears safe to implant biventricular pacers in this small cohort of patients subsequent to an MI. Interestingly, this pilot study, like the recently completed but yet-to- be-released Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction (REVERSE) trial proposes to use CRT to attenuate disease progression.6 The authors suggest that using CRT will decrease LV remodeling after an MI, and thereby may alter the progression of HF in some patients or perhaps modify post- MI mortality. One of the most important contributions of this manuscript, somewhat buried in the text, is the authors' rationale for why CRT may attenuate pathologic remodeling. This brings this author to reflect on the larger question of the mechanism of how CRT might favorably alter cardiac and myocyte function. In 2007, are we content with the publicly consumed mechanism that CRT “resynchronizes the ventricles”? Empirically, CRT can improve cardiac structure and function (eg, reduce mitral regurgitation, reverse remodeling, and LV diameter; and increase ejection fraction), as well as improve quality of life, functional status, and exercise capacity in patients with advanced disease.7, 8 Simply put, there is little debate about the efficacy of CRT, but the specific cellular mechanisms that contribute to observed clinical gains have not been identified. This limits our ability to rationally develop new therapeutic strategies that target the remodeling process, and to more effectively address reverse remodeling with progressive HF. The mechanisms that are central to this progressive process are too numerous to articulate in this commentary, but investigators are in agreement and have underscored that further progress in the field is unlikely until the major mechanisms are better clarified and understood. Part of the difficulty is the convoluted nature of the questions being asked and the heterogeneous etiology of HF. Other complicating issues revolve around how to study these unknown mechanisms. That is, human trials lend themselves to outcomes research, but may be very difficult or unethical when one considers asking specific mechanistic questions. Alternatively, transgenic mice are not human patients with HF, and in vitro studies, although potentially more mechanistic, may or may not resemble human biology.9 Hence, the difficulties can be summarized as an inability to understand the root of the disease, the lack of a sufficient model, the complexities of the signaling mechanisms, and the difficulty in assessing the complicated mechanisms under the appropriate spatial and temporal conditions. This is not to underscore the significant progress made by many superior researchers and clinicians—but we still have a long way to go. In spite of our best efforts, the significant mortality from this disease reminds us of how much work remains to be done. In their manuscript, Chung and his colleagues suggest that CRT worked in these individuals by decreasing wall stress. This hypothesis seems reasonable, but they did not assess wall strain, pressure/volume considerations, or how a change in wall stress may permanently affect cellular mechanisms. In the last decade, there have been a limited number of successful clinical HF trials. This may suggest that we need to spend more time and effort to prospectively determine the basic mechanisms that we assume will drive the results that are anticipated in a clinical trial. Simply put, we need to have basic and translational science more carefully linked to our clinical studies. After reading Dr. Chung's manuscript, one may call for a large randomized clinical trial. In the increasingly expensive and unforgiving world of health care, I would propose that we embark on a more expansive trial only after defining 1 or 2 mechanisms prospectively that may alter patient outcomes with the implantation of a CRT device subsequent to an MI. Disclosure: The author is a consultant for and has received honoraria from Medtronic.