One-Year Committed Exercise Training Reverses Abnormal Left Ventricular Myocardial Stiffness in Patients With Stage B Heart Failure With Preserved Ejection Fraction

Abstract

Background: Individuals with left ventricular (LV) hypertrophy and elevated cardiac biomarkers in middle age are at increased risk for the development of heart failure with preserved ejection fraction. Prolonged exercise training reverses the LV stiffening associated with healthy but sedentary aging; however, whether it can also normalize LV myocardial stiffness in patients at high risk for heart failure with preserved ejection fraction is unknown. In a prospective, randomized controlled trial, we hypothesized that 1-year prolonged exercise training would reduce LV myocardial stiffness in patients with LV hypertrophy.

Methods: Forty-six patients with LV hypertrophy (LV septum >11 mm) and elevated cardiac biomarkers (N-terminal pro-B-type natriuretic peptide [>40 pg/mL] or high-sensitivity troponin T [>0.6 pg/mL]) were randomly assigned to either 1 year of high-intensity exercise training (n=30) or attention control (n=16). Right-heart catheterization and 3-dimensional echocardiography were performed while preload was manipulated using both lower body negative pressure and rapid saline infusion to define the LV end-diastolic pressure-volume relationship. A constant representing LV myocardial stiffness was calculated from the following: P=S×[Exp {a (V-V₀)}-1], where "P" is transmural pressure (pulmonary capillary wedge pressure - right atrial pressure), "S" is the pressure asymptote of the curve, "V" is the LV end-diastolic volume index, "V₀" is equilibrium volume, and "a" is the constant that characterizes LV myocardial stiffness.

Results: Thirty-one participants (exercise group [n=20]: 54±6 years, 65% male; and controls (n=11): 51±6 years, 55% male) completed the study. One year of exercise training increased max by 21% (baseline 26.0±5.3 to 1 year later 31.3±5.8 mL·min^-1·kg^-1, P<0.0001, interaction P=0.0004), whereas there was no significant change in max in controls (baseline 24.6±3.4 to 1 year later 24.2±4.1 mL·min^-1·kg^-1, P=0.986). LV myocardial stiffness was reduced (right and downward shift in the end-diastolic pressure-volume relationship; LV myocardial stiffness: baseline 0.062±0.020 to 1 year later 0.031±0.009), whereas there was no significant change in controls (baseline 0.061±0.033 to 1 year later 0.066±0.031, interaction P=0.001).

Conclusions: In patients with LV hypertrophy and elevated cardiac biomarkers (stage B heart failure with preserved ejection fraction), 1 year of exercise training reduced LV myocardial stiffness. Thus, exercise training may provide protection against the future risk of heart failure with preserved ejection fraction in such patients. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03476785.

Keywords: blood volume; heart failure; hypertrophy, left ventricular; vascular stiffness.

Figure 1.. Consort Diagram in the LVH Study.

Study enrollment, randomization, and retention of study participants randomly assigned to the exercise training or control group. LVH, left ventricular hypertrophy; ECG, electrocardiography

Figure 2.. Effect of high-intensity exercise training on peak oxygen consumption in LVH patients

The individual change and group mean response for peak oxygen uptake are shown for the control and exercise group. *P<0.05 denotes significantly different from pre.

Figure 3.. Effect of high-intensity exercise training on left ventricular end-diastolic volume

The individual change and group mean response for left ventricular end-diastolic volume are shown for the control and exercise group. *P<0.05 denotes significantly different from pre. LVEDV, left ventricular end-diastolic volume.

Figure 4.. Effect of high-intensity exercise training on left ventricular chamber. (A) and transmural stiffness (B)

The group mean left ventricular pressure-volume relationships before and after 1-year of intervention. Control group at pre, black-dash line with closed black circle; Control group at post, black line with open circle; Exercise group at pre, red-dash line with closed triangle; Exercise group at post, red line with opened circle. In the exercise group, both the LV chamber (A) and LV transmural curves (B) were shifted rightward with a flattening slope demonstrating improved LV compliance and distensibility. Those curves in the control group were unchanged. *P<0.05 denotes significantly different from pre. LVH, left ventricular hypertrophy group; PCWP, pulmonary capillary wedge pressure; LVEDV was scaled to body surface area, Transmural pressure = PCWP ─ right atrial pressure (RAP).

Figure 4.. Effect of high-intensity exercise training on left ventricular chamber. (A) and transmural stiffness (B)

The group mean left ventricular pressure-volume relationships before and after 1-year of intervention. Control group at pre, black-dash line with closed black circle; Control group at post, black line with open circle; Exercise group at pre, red-dash line with closed triangle; Exercise group at post, red line with opened circle. In the exercise group, both the LV chamber (A) and LV transmural curves (B) were shifted rightward with a flattening slope demonstrating improved LV compliance and distensibility. Those curves in the control group were unchanged. *P<0.05 denotes significantly different from pre. LVH, left ventricular hypertrophy group; PCWP, pulmonary capillary wedge pressure; LVEDV was scaled to body surface area, Transmural pressure = PCWP ─ right atrial pressure (RAP).

Figure 5.. Starling mechanism

Change in Starling relationship. Pre, black-dash line with closed circle; Post, black line with opened circle. There was no significant change in the control group (A), whereas 1-year of training improved Starling curves (B), such that an increase in stroke volume index was observed compared to baseline for a given LV filling pressure. LVH, left ventricular hypertrophy group; PCWP, pulmonary capillary wedge pressure, SV was scaled to body surface area.

Figure 5.. Starling mechanism

Change in Starling relationship. Pre, black-dash line with closed circle; Post, black line with opened circle. There was no significant change in the control group (A), whereas 1-year of training improved Starling curves (B), such that an increase in stroke volume index was observed compared to baseline for a given LV filling pressure. LVH, left ventricular hypertrophy group; PCWP, pulmonary capillary wedge pressure, SV was scaled to body surface area.

Figure 6.. Preload-recruitable stroke work.

(A) control group and (B) training group. Pre, black-dash line with closed circle; Post, black line with opened circle. There was no significant effect of exercise training or aging on preload recruitable stroke work. Interaction P value=0.150, group P value=0.940, and time P value=0.111. LVH, left ventricular hypertrophy group; LVEDV, left ventricular end-diastolic volume.

Figure 6.. Preload-recruitable stroke work.

(A) control group and (B) training group. Pre, black-dash line with closed circle; Post, black line with opened circle. There was no significant effect of exercise training or aging on preload recruitable stroke work. Interaction P value=0.150, group P value=0.940, and time P value=0.111. LVH, left ventricular hypertrophy group; LVEDV, left ventricular end-diastolic volume.