Original article
Exercise training does not improve cardiac function in compensated or decompensated left ventricular hypertrophy induced by aortic stenosis

https://doi.org/10.1016/j.yjmcc.2011.01.016Get rights and content

Abstract

There is ample evidence that regular exercise exerts beneficial effects on left ventricular (LV) hypertrophy, remodeling and dysfunction produced by ischemic heart disease or systemic hypertension. In contrast, the effects of exercise on pathological LV hypertrophy and dysfunction produced by LV outflow obstruction have not been studied to date. Consequently, we evaluated the effects of 8 weeks of voluntary wheel running in mice (which mitigates post-infarct LV dysfunction) on LV hypertrophy and dysfunction produced by mild (mTAC) and severe (sTAC) transverse aortic constriction. mTAC produced ~ 40% LV hypertrophy and increased myocardial expression of hypertrophy marker genes but did not affect LV function, SERCA2a protein levels, apoptosis or capillary density. Exercise had no effect on global LV hypertrophy and function in mTAC but increased interstitial collagen, and ANP expression. sTAC produced ~ 80% LV hypertrophy and further increased ANP expression and interstitial fibrosis and, in contrast with mTAC, also produced LV dilation, systolic as well as diastolic dysfunction, pulmonary congestion, apoptosis and capillary rarefaction and decreased SERCA2a and ryanodine receptor (RyR) protein levels. LV diastolic dysfunction was likely aggravated by elevated passive isometric force and Ca2+-sensitivity of myofilaments. Exercise training failed to mitigate the sTAC-induced LV hypertrophy and capillary rarefaction or the decreases in SERCA2a and RyR. Exercise attenuated the sTAC-induced increase in passive isometric force but did not affect myofilament Ca2+-sensitivity and tended to aggravate interstitial fibrosis. In conclusion, exercise had no effect on LV function in compensated and decompensated cardiac hypertrophy produced by LV outflow obstruction, suggesting that the effect of exercise on pathologic LV hypertrophy and dysfunction depends critically on the underlying cause.

Research Highlights

► We studied the effects of exercise on cardiac function in mice with aortic stenosis. ► Mild aortic stenosis resulted in compensated cardiac hypertrophy. ► Severe aortic stenosis resulted in cardiac hypertrophy and dysfunction. ► Exercise failed to improve cardiac function in mice with mild or severe aortic stenosis.

Introduction

Myocardial hypertrophy is a compensatory mechanism by which the left ventricle (LV) adapts to an increased systolic load, which serves to restore LV wall stress to normal levels and maintain cardiac pump function [1], [2]. Clinically, chronic systolic overload of the LV most commonly results from regional loss of myocardial tissue (myocardial infarction) or elevated impedance to LV outflow (hypertension and aortic stenosis) [3], [4]. Despite the apparent appropriateness of hypertrophic remodeling in response to an increased systolic workload, LV hypertrophy has been shown to be an independent risk factor for the development of angina pectoris, congestive heart failure and sudden death [1], [5]. In contrast, hypertrophy produced by exercise training is not associated with the contractile dysfunction and perfusion abnormalities described for pressure-overload [6] or post-infarction induced hypertrophy [7] and reduces, rather than increases, the risk for developing heart failure [5].

There is ample evidence from both clinical and experimental studies that aerobic exercise training has a beneficial effect on cardiac function and remodeling in case of ischemic cardiomyopathy [8], [9], [10]. Similarly, the majority of experimental studies in genetic models of systemic hypertension [11], [12], [13] have shown a beneficial effect of regular exercise on cardiac remodeling and function, which is supported by recent clinical studies [14], [15]. In contrast, little is known about the effects of exercise on LV pressure-overload hypertrophy as a result of mechanical obstruction to outflow. This is important because there is an increasing number of patients with (congenital) aortic stenosis that are chronically exposed to LV pressure-overload and which will ultimately require surgery during their adult life [16]. The effects of regular physical exercise in such patients may well be different from that in patients with cardiac hypertrophy due to systemic hypertension. Thus the presence of an aortic stenosis results in exaggerated LV pressure responses to exercise thereby producing aggravated increases in afterload during each exercise bout [6], which contrasts with the relatively normal LV hemodynamic responses to exercise in case of systemic hypertension [17]. It is therefore possible that exercise training in case of a chronic aortic stenosis does not recapitulate the beneficial effects that are observed in ischemic heart disease or systemic hypertension.

In light of these considerations, we investigated the effects of dynamic exercise training on aortic stenosis induced LV hypertrophy and dysfunction. For this purpose, we employed 8 weeks of voluntary wheel running, an exercise protocol which we have previously shown to blunt LV dysfunction in mice with a myocardial infarction (MI) [9]. Since the effects of exercise training might depend on the severity of the aortic stenosis, we assessed the effects of exercise in mice subjected to either mild or severe aortic stenosis.

Section snippets

Methods

All experiments were performed in accordance with the “Guiding Principles in the Care and Use of Animals” as approved by the Council of the American Physiological Society and with prior approval of the Animal Care Committee of the Erasmus MC Rotterdam. A total of 134 C57Bl/6 mice (26 ± 0.4 g) of 20 weeks of age entered the study.

Exercise and survival

All mice in the exercise groups started to run on the first day after surgery with daily running distance progressively increasing over the first 2 weeks after surgery (Fig. 1). sTACEX mice ran a total distance (276 ± 38 km over 8-weeks) that was significantly less than that in SHEX (432 ± 37 km) and mTACEX (409 ± 42 km) mice. mTACSED and sTACSED were associated with mortality rates of 19% and 29%, respectively. Voluntary wheel running tended to improve survival but this failed to reach levels of

Discussion

In this study we investigated the effect of 8 weeks of voluntary wheel running on pressure-overload-induced LV hypertrophy and dysfunction produced by two degrees of TAC in mice. The main findings were that: (i) mTAC resulted in ~ 40% LV hypertrophy and elevated levels of hypertrophy marker genes and mild fibrosis, but did not result in LV dysfunction, reduced SERCA levels, or decreased capillary density; (ii) exercise had no effect on global LV dysfunction but increased interstitial fibrosis,

Acknowledgment

We gratefully acknowledge the financial support by the Netherlands Heart Foundation (2007B024 and 2005B234) and Erasmus MC (Translational Grant).

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