Elsevier

Life Sciences

Volume 81, Issue 14, 15 September 2007, Pages 1152-1159
Life Sciences

Chronic cardiac resynchronization therapy and reverse ventricular remodeling in a model of nonischemic cardiomyopathy

https://doi.org/10.1016/j.lfs.2007.08.022Get rights and content

Abstract

While cardiac resynchronization therapy (CRT) has been shown to reduce morbidity and mortality in heart failure (HF) patients, the fundamental mechanisms for the efficacy of CRT are poorly understood. The lack of understanding of these basic mechanisms represents a significant barrier to our understanding of the pathogenesis of HF and potential recovery mechanisms. Our purpose was to determine cellular mechanisms for the observed improvement in chronic HF after CRT. We used a canine model of chronic nonischemic cardiomyopathy. After 15 months, dogs were randomized to continued RV tachypacing (untreated HF) or CRT for an additional 9 months. Six minute walk tests, echocardiograms, and electrocardiograms were done to assess the functional response to therapy. Left ventricular (LV) midmyocardial myocytes were isolated to study electrophysiology and intracellular calcium regulation. Compared to untreated HF, CRT improved HF-induced increases in LV volumes, diameters and mass (p < 0.05). CRT reversed HF-induced prolongations in LV myocyte repolarization (p < 0.05) and normalized HF-induced depolarization (p < 0.03) of the resting membrane potential. CRT improved HF-induced reductions in calcium (p < 0.05). CRT did not attenuate the HF-induced increases in LV interstitial fibrosis. Using a translational approach in a chronic HF model, CRT significantly improved LV structure; this was accompanied by improved LV myocyte electrophysiology and calcium regulation. The beneficial effects of CRT may be attributable, in part, to improved LV myocyte function.

Introduction

Heart Failure (HF) is defined as an inability of the heart to support the metabolic and physiologic needs of the body (Ventura-Clapier et al., 2004). This syndrome is often a progressive disease, which includes changes in physiology, cellular biology and neurohormonal regulation irrespective of the initial etiology (Francis, 2001). Newly diagnosed HF patients have a mortality rate of 10% a year, and if hospital admission is warranted, the one year mortality rate may be close to 30% (Patterson and Adams, 1993). Although there have been many significant advances in HF medical therapy, this disease state is a major concern and its incidence continues to rise in the US while most other forms of heart disease are in decline. There is clearly a need to better define the key mechanisms of HF progression in order to develop improved therapeutic strategies.

A hallmark feature of chronic HF progression in humans and animal models is the time-dependent adaptation of myocardium, leading to changes in cardiac myocyte performance or survival, and changes in myocardial tissue composition. Specifically, ventricular chamber dilation, and myocyte hypertrophy are all well recognized features of cardiac adaptations in HF (Dhalla et al., 2006), and can be considered favorable adaptations for acute increases in cardiac demand, but are also likely contributors to progressive pump failure which may be deleterious over the long term. Long-term or chronic-progressive HF (CPHF) has been less extensively studied in controlled large animal studies. Cumulative evidence, now suggests that spatial as well as temporal signaling will have a significant impact on long-term patient outcomes, but chronic large animal studies remain difficult and often cost-prohibitive. The scarcity of such information represents a fundamental gap in our knowledge base, precluding our scientific understanding of cellular mechanisms in HF patients.

Therapies shown to provide long term efficacy in CPHF typically reduce or reverse one or more cardiac remodeling features (e.g., decreased chamber dimension, reduction in hypertrophy), and it is clear that cardiac tissue characteristics, rather than hemodynamic endpoints, are better predictors of long term therapeutic value for chronic HF (Frigerio and Roubina, 2005). Recent evidence suggests that cardiac resynchronization therapy (CRT) with bi-ventricular pacing results in improved left ventricular ejection fraction, New York Heart Association class, exercise capacity, and quality of life (Berger et al., 2005, Rao et al., 2007). Findings of the COMPANION and CARE HF trials indicate that CRT reduces all-cause mortality and hospitalization in HF patients (Epstein, 2005, Leclercq and Daubert, 2003). CRT can also improve cardiac structure and function (e.g., decreased LV diameter, and increased ejection fraction), suggesting that it elicits favorable effects on remodeling mechanisms contributing to HF progression (Bristow et al., 2004, Cleland et al., 2005, Rivera and Bristow, 2005). This phenomenon of ‘reverse remodeling’ elicited in many patients receiving CRT therapy is now well-documented, but the specific cellular mechanisms that contribute to the observed clinical gains have not been identified.

We have recently established a dog model of nonischemic dilated cardiomyopathy which involves chronic RV tachypacing for over one year, leading to sustained reductions in LV contractility, ventricular dilation and hypertrophy, and ventricular dyssynchrony. Prolongation of in vivo repolarization and impaired exercise capacity were also observed (Nishijima et al., 2005). Currently, no previous reports have described an animal preparation for mechanistic studies of CRT in vivo. Since this large animal model of HF mimics the patient population most appropriate to receive CRT (decreased ejection fraction with an intraventricular conduction delay), we postulated that it would be appropriate for CRT investigations. Here we tested the hypothesis that this established canine model of CPHF would be useful for the study of CRT-induced reverse remodeling effects. We investigated potential mechanisms of CRT effects in vivo and ex vivo, with a specific focus on mechanisms known to be altered in HF patients (LV performance, chamber dilation, hypertrophy, and fibrosis). In addition to tissue-level adaptations during HF, numerous studies have documented alterations within myocytes, particularly with respect to cellular electrophysiology and intracellular calcium handling. We therefore examined the effects of chronic CRT on these aspects of myocyte function to test the hypothesis that CRT elicits favorable effects on myocyte action potentials and calcium handling.

Section snippets

Animal model and study design

All animal procedures were approved by the Ohio State University Institutional Laboratory Animal Care and Use Committee and conform to the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85-23, revised 1996). A total of 11 dogs were investigated in this study (ages 1.5–3 years; weights 20–33 kg), using methods we have previously described (Nishijima et al., 2005). All dogs were initially verified to have normal cardiac

Results

Shown in Table 1 are physiological changes induced by 15 months of continuous RV tachypacing in dogs, leading to stable and reproducible HF. Similar to previous reports the tachypacing protocol produced significant reductions in LV contractility, and evidence of chamber dilation and hypertrophy, and dyssynchrony at the mid-ventricular level. There were no elevations in Troponin C, Troponin I, or C-reactive protein (data not shown).

After establishing HF via RV tachypacing for 15 months, dogs

Discussion

Of the five million Americans with CPHF, it is estimated that greater than 25% may qualify for CRT, with an average procedural cost of $40,000. These resources will be expended without the mechanism(s) of reverse-remodeling of CRT having been clearly elucidated. Additionally, for unknown reasons, some patients respond remarkably well with CRT, while others have only modest or no improvement. To address these issues, we have established an animal model of chronic HF that mimics key features of

Conclusion

These studies show that that the dog model of HF is appropriate for mechanistic investigations of CRT and recapitulates the phenomenon of reverse remodeling described in heart failure patients. Our observations suggest that in vivo function and myocyte calcium regulation are linked, not only during the development of heart failure, but also during reverse remodeling, and that CRT may directly modulate myocyte excitation-contraction coupling. In the future it may be possible to further elucidate

Acknowledgements

Disclosures: Abraham: Medtronic: consultant and research grants

Feldman: Medtronic: consultant and research support

Supported in part by grants from the NIH: HL084498 (D.S.F.), HL074045 and HL063043 (S.G.)

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