Exercise training reverses age-induced diastolic dysfunction and restores coronary microvascular function

Abstract

Key points: In a rat model of ageing that is free of atherosclerosis or hypertension, E/A, a diagnostic measure of diastolic filling, decreases, and isovolumic relaxation time increases, indicating that both active and passive ventricular relaxation are impaired with advancing age. Resting coronary blood flow and coronary functional hyperaemia are reduced with age, and endothelium-dependent vasodilatation declines with age in coronary resistance arterioles. Exercise training reverses age-induced declines in diastolic and coronary microvascular function. Thus, microvascular dysfunction and inadequate coronary perfusion are likely mechanisms of diastolic dysfunction in aged rats. Exercise training, initiated at an advanced age, reverses age-related diastolic and microvascular dysfunction; these data suggest that late-life exercise training can be implemented to improve coronary perfusion and diastolic function in the elderly.

Abstract: The risk for diastolic dysfunction increases with advancing age. Regular exercise training ameliorates age-related diastolic dysfunction; however, the underlying mechanisms have not been identified. We investigated whether (1) microvascular dysfunction contributes to the development of age-related diastolic dysfunction, and (2) initiation of late-life exercise training reverses age-related diastolic and microvascular dysfunction. Young and old rats underwent 10 weeks of exercise training or remained as sedentary, cage-controls. Isovolumic relaxation time (IVRT), early diastolic filling (E/A), myocardial performance index (MPI) and aortic stiffness (pulse wave velocity; PWV) were evaluated before and after exercise training or cage confinement. Coronary blood flow and vasodilatory responses of coronary arterioles were evaluated in all groups at the end of training. In aged sedentary rats, compared to young sedentary rats, a 42% increase in IVRT, a 64% decrease in E/A, and increased aortic stiffness (PWV: 6.36 ± 0.47 vs.4.89 ± 0.41, OSED vs. YSED, P < 0.05) was accompanied by impaired coronary blood flow at rest and during exercise. Endothelium-dependent vasodilatation was impaired in coronary arterioles from aged rats (maximal relaxation to bradykinin: 56.4 ± 5.1% vs. 75.3 ± 5.2%, OSED vs. YSED, P < 0.05). After exercise training, IVRT, a measure of active ventricular relaxation, did not differ between old and young rats. In old rats, exercise training reversed the reduction in E/A, reduced aortic stiffness, and eliminated impairment of coronary blood flow responses and endothelium-dependent vasodilatation. Thus, age-related diastolic and microvascular dysfunction are reversed by late-life exercise training. The restorative effect of exercise training on coronary microvascular function may result from improved endothelial function.

Keywords: E/A; aortic stiffness; coronary arterioles; endothelium; rat.

Figure 1. Effects of age and exercise training on E/A

A, ratio of early diastolic peak velocity to peak velocity during left atrial contraction (E/A) in young sedentary (YSED), old sedentary (OSED), young exercise trained (YET), and old exercise trained (OET) rats. B and C, E/A before (pre) and after (post) 10 weeks of cage confinement (B, n = 10) or exercise training (C, n = 18) in old rats. Values are means ± SEM; n, no. of rats. ^*Effect of age (P ≤ 0.05). ^†Effect of exercise training (P ≤ 0.05). ^§Significant difference post vs. pre (P ≤ 0.05).

Figure 2. Effects of age and exercise training on isovolumic relaxation time

A, isovolumic relaxation time (IVRT) in young sedentary (YSED), old sedentary (OSED), young exercise trained (YET), and old exercise trained (OET) rats. B and C, IVRT before (pre) and after (post) 10 weeks of cage confinement (B, n = 11) or exercise training (C, n = 20) in old rats. ^*Effect of age (P ≤ 0.05). ^†Effect of exercise training (P ≤ 0.05). ^§Significant difference post vs. pre (P ≤ 0.05).

Figure 3. Effects of age and exercise training on myocardial performance index

A, myocardial performance index (MPI) in young sedentary (YSED), old sedentary (OSED), young exercise trained (YET), and old exercise trained (OET) rats. B and C, values for MPI before (pre) and after (post) 10 weeks of cage confinement (B, n = 11) or exercise training (C, n = 18) in old rats. Values are means ± SEM; n, no. of rats. ^*Effect of age (P ≤ 0.05). ^†Effect of exercise training (P ≤ 0.05). ^§Significant difference post vs. pre (P ≤ 0.05).

Figure 4. Effects of age and exercise training on aortic stiffness

A, pulse wave velocity (PWV) in young sedentary (YSED), old sedentary (OSED), young exercise trained (YET), and old exercise trained (OET) rats. B and C, values for PWV before (pre) and after (post) 10 weeks of cage confinement (B, n = 11) or exercise training (C, n = 21) in old rats. ^*Effect of age (P ≤ 0.05). ^†Effect of exercise training (P ≤ 0.05). ^§Significant difference post vs. pre (P ≤ 0.05).

Figure 5. Right ventricular blood flow

A and B, blood flow to the right ventricular free wall at rest (A) and during treadmill exercise (B) in young sedentary (YSED), old sedentary (OSED), young exercise trained (YET), and old exercise trained (OET) rats. Values are means ± SEM; n, no. of rats. ^*Effect of age (P ≤ 0.05). ^†Effect of exercise training (P ≤ 0.05).

Figure 6. Endocardial and epicardial blood flow in the left ventricle

Blood flow to the endocardium (A and B) and epicardium (C and D) of the left ventricular free wall at rest (A and C) and during treadmill exercise (B and D) in young sedentary (YSED), old sedentary (OSED), young exercise trained (YET), and old exercise trained (OET) rats. Values are means ± SEM; n, no. of rats. ^*Effect of age (P ≤ 0.05). ^†Effect of exercise training (P ≤ 0.05).

Figure 7. Blood flow to septum and papillary muscle

Blood flow to the ventricular septum (A and B) and papillary muscle (C and D) at rest (A and C) and during treadmill exercise (B and D) in young sedentary (YSED), old sedentary (OSED), young exercise trained (YET), and old exercise trained (OET) rats. Values are means ± SEM; n, no. of rats. ^*Effect of age (P ≤ 0.05). ^†Effect of exercise training (P ≤ 0.05).

Figure 8. Effects of age and exercise training on endothelium‐dependent vasodilation

A and B, effect of age on vasodilatation to bradykinin in coronary arterioles from sedentary (young sedentary, YSED; old sedentary, OSED) rats (A), and in coronary arterioles from exercise trained (young exercise trained, YET; old exercise trained, OET) rats (B). C and D, effects of exercise training on vasodilatation in respose to bradykinin in coronary arterioles from young (C) and old (D) rats. Values are means ± SEM; n, no. of rats. ^*Effect of age (P ≤ 0.05), ^†Effect of exercise training (P ≤ 0.05) on overall relaxation. ^||Effect of age (P ≤ 0.05), ^#Effect of exercise training (P ≤ 0.05) on EC₅₀.

Figure 9. Effects of age and exercise training on SOD protein levels in coronary arterioles

Summary (A) and representative images (B) of immunohistochemical staining for superoxide dismutase‐1 (SOD‐1) protein in coronary arterioles from young sedentary (YSED), old sedentary (OSED), young exercise trained (YET), and old exercise trained (OET) rats. ^*Effect of age (P ≤ 0.05).

Figure 10. Relationships between ventricular relaxation and microvascular function in old and young, sedentary and exercise trained rats

Relationship between isovolumic relaxation time (IVRT) and microvascular function in the left ventricle of old and young, sedentary and exercise trained rats. A, relationship between IVRT and resting left ventricular blood flow (n = 21). B, relationship between IVRT and ventricular blood flow during treadmill exercise (n = 20). C, relationship between IVRT and bradykinin‐induced relaxation in resistance arterioles from the left ventricular free wall (n = 27).