Reversing the Cardiac Effects of Sedentary Aging in Middle Age-A Randomized Controlled Trial: Implications For Heart Failure Prevention

Abstract

Background: Poor fitness in middle age is a risk factor for heart failure, particularly heart failure with a preserved ejection fraction. The development of heart failure with a preserved ejection fraction is likely mediated through increased left ventricular (LV) stiffness, a consequence of sedentary aging. In a prospective, parallel group, randomized controlled trial, we examined the effect of 2 years of supervised high-intensity exercise training on LV stiffness.

Methods: Sixty-one (48% male) healthy, sedentary, middle-aged participants (53±5 years) were randomly assigned to either 2 years of exercise training (n=34) or attention control (control; n=27). Right heart catheterization and 3-dimensional echocardiography were performed with preload manipulations to define LV end-diastolic pressure-volume relationships and Frank-Starling curves. LV stiffness was calculated by curve fit of the diastolic pressure-volume curve. Maximal oxygen uptake (Vo₂max) was measured to quantify changes in fitness.

Results: Fifty-three participants completed the study. Adherence to prescribed exercise sessions was 88±11%. Vo₂max increased by 18% (exercise training: pre 29.0±4.8 to post 34.4±6.4; control: pre 29.5±5.3 to post 28.7±5.4, group×time P<0.001) and LV stiffness was reduced (right/downward shift in the end-diastolic pressure-volume relationships; preexercise training stiffness constant 0.072±0.037 to postexercise training 0.051±0.0268, P=0.0018), whereas there was no change in controls (group×time P<0.001; pre stiffness constant 0.0635±0.026 to post 0.062±0.031, P=0.83). Exercise increased LV end-diastolic volume (group×time P<0.001), whereas pulmonary capillary wedge pressure was unchanged, providing greater stroke volume for any given filling pressure (loading×group×time P=0.007).

Conclusions: In previously sedentary healthy middle-aged adults, 2 years of exercise training improved maximal oxygen uptake and decreased cardiac stiffness. Regular exercise training may provide protection against the future risk of heart failure with a preserved ejection fraction by preventing the increase in cardiac stiffness attributable to sedentary aging.

Clinical trial registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02039154.

Keywords: catheterization; diastole; exercise; humans; monitoring, physiological; prevention & control; ventricular function; ventricular remodeling.

Figure 1

Enrollment, randomization and retention of study participants randomized to the Exercise Training or Control group.

Figure 2

A–D. Effect of intervention on maximal exercise capacity. The individual change and group mean response for maximal oxygen uptake are shown in Figure 2A and B for Control and Exercise Group. As expected, with sedentary aging there was small decrease in maximal oxygen uptake in the control group over the 2 years, while in the ExT group, VO₂max increased from pre to testing at 10 months, before remaining unchanged for the remaining 14 months of the study. * P<0.05 denotes significantly different from pre

Figure 3

A–B. Effect of intervention on LV end-diastolic volume index. The group mean response for LV end-diastolic volume are shown in Figure 3A and B for Control and Exercise Group, respectively. The progressive exercise training from pre to testing at 10 months resulted in a 17% increase in LV end-diastolic volume, without further increase when training intensity maintained. * P<0.05 denotes significantly different from pre, # P<0.05 denotes significantly different from mid.

Figure 4

A–D. Effect of intervention on diastolic function. Figures 4A–B represent change in individual stiffness constants from the diastolic portion of the LV diastolic pressure-volume relationships and LV diastolic transmural pressure-volume relationship, respectively. Modeling was performed for each individual participant, at baseline and repeated after 2 years. Figures 2C–D, represent the group mean LV diastolic pressure-volume and LV diastolic transmural pressure-volume relationships before and after 2 years of intervention. In the ExT group, both the LV pressure-volume and transmural curves were shifted rightwards with a flattening slope demonstrating improved LV compliance and distensibility. The Control group was unchanged. * P<0.05 denotes significantly different from pre

Figure 5. A–D. Frank Starling Relationship and Preload-recruitable stroke work

Fig. 5A–B represent change in Frank starling relationship. There was no change in the control group (Fig. 5A), while two years of training improved Frank starling curves (Fig. 5B), such that a statistically significant increase in stroke volume index was observed compared to baseline for a given filling pressure. In contrast there was no significant effect of exercise training or aging on preload recruitable stroke work (Fig. 5C–D represent the pre/post changes in the control and ExT group respectively).