Original articleExercise training does not improve cardiac function in compensated or decompensated left ventricular hypertrophy induced by aortic stenosis
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).
References (46)
- et al.
Controversies in ventricular remodelling
Lancet
(2006) - et al.
A meta-analysis of the effect of exercise training on left ventricular remodeling in heart failure patients: the benefit depends on the type of training performed
J Am Coll Cardiol
(2007) - et al.
Adverse ventricular remodeling and exacerbated NOS uncoupling from pressure-overload in mice lacking the beta3-adrenoreceptor
J Mol Cell Cardiol
(2009) - et al.
Sildenafil stops progressive chamber, cellular, and molecular remodeling and improves calcium handling and function in hearts with pre-existing advanced hypertrophy caused by pressure overload
J Am Coll Cardiol
(2009) - et al.
PKC-betaII sensitizes cardiac myofilaments to Ca2+ by phosphorylating troponin I on threonine-144
J Mol Cell Cardiol
(2006) - et al.
Changes in essential myosin light chain isoform expression provide a molecular basis for isometric force regulation in the failing human heart
J Mol Cell Cardiol
(1997) - et al.
Hypertrophy of the heart: a new therapeutic target?
Circulation
(2004) - et al.
Wall stress and patterns of hypertrophy in the human left ventricle
J Clin Invest
(1975) - et al.
Regulation of cardiac hypertrophy by intracellular signalling pathways
Nat Rev Mol Cell Biol
(2006) - et al.
Differences between pathological and physiological cardiac hypertrophy: novel therapeutic strategies to treat heart failure
Clin Exp Pharmacol Physiol
(2007)
Effect of exercise on coronary pressure–flow relationship in hypertrophied left ventricle
Am J Physiol
Alterations in vasomotor control of coronary resistance vessels in remodelled myocardium of swine with a recent myocardial infarction
Med Biol Eng Comput
Mechanisms by which exercise training benefits patients with heart failure
Nat Rev Cardiol
Early exercise training normalizes myofilament function and attenuates left ventricular pump dysfunction in mice with a large myocardial infarction
Circ Res
Low-intensity exercise training delays heart failure and improves survival in female hypertensive heart failure rats
Hypertension
Improved myocardial beta-adrenergic responsiveness and signaling with exercise training in hypertension
Circulation
Exercise training alters left ventricular geometry and attenuates heart failure in dahl salt-sensitive hypertensive rats
Hypertension
Exercise and cardiovascular outcomes in hypertensive patients in relation to structure and function of left ventricular hypertrophy: the LIFE study
Eur J Cardiovasc Prev Rehabil
Regular physical activity prevents development of left ventricular hypertrophy in hypertension
Eur Heart J
Aortic stenosis at young adult age
Expert Rev Cardiovasc Ther
Influence of hypertension on the hemodynamic response to exercise
Circulation
Detrimental effect of combined exercise training and eNOS overexpression on cardiac function after myocardial infarction
Am J Physiol Heart Circ Physiol
Segregation of atrial-specific and inducible expression of an atrial natriuretic factor transgene in an in vivo murine model of cardiac hypertrophy
Proc Natl Acad Sci USA
Cited by (44)
Normal and high eNOS levels are detrimental in both mild and severe cardiac pressure-overload
2015, Journal of Molecular and Cellular CardiologyCitation Excerpt :Wt littermates were used as controls. In total, 65 eNOS-Ko, 77 Wt and 79 eNOS-Tg mice underwent mTAC (using a 25G needle), severe sTAC (using a 27G needle) or a sham operation as previously described [22]. Additionally, 30 Wt and 31 eNOS-Tg mice underwent sTAC and subsequently received the antioxidant N-acetylcysteine (NAC) (1 mg/ml in drinking water), to elucidate the effects of eNOS overexpression on ROS production in pressure-overload hypertrophy.
Myocardial proteome changes in aortic stenosis rats subjected to long-term aerobic exercise
2024, Journal of Cellular PhysiologyAerobic Exercise Training Improves Calcium Handling and Cardiac Function in Rats with Heart Failure Resulting from Aortic Stenosis
2023, International Journal of Molecular SciencesThe Dysfunctional Scenario of the Major Components Responsible for Myocardial Calcium Balance in Heart Failure Induced by Aortic Stenosis
2022, Arquivos Brasileiros de Cardiologia