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

Michinari Hieda, Satyam Sarma, Christopher M Hearon Jr, James P MacNamara, Katrin A Dias, Mitchel Samels, Dean Palmer, Sheryl Livingston, Margot Morris, Benjamin D Levine, Michinari Hieda, Satyam Sarma, Christopher M Hearon Jr, James P MacNamara, Katrin A Dias, Mitchel Samels, Dean Palmer, Sheryl Livingston, Margot Morris, Benjamin D Levine

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.

Figures

Figure 1.. Consort Diagram in the LVH…
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…
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

Figure 3.. Effect of high-intensity exercise training…

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

The individual change…

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

Figure 4.. Effect of high-intensity exercise training…

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

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…

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

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…

Figure 5.. Starling mechanism

Change in Starling relationship. Pre, black-dash line with closed circle; Post,…

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…

Figure 5.. Starling mechanism

Change in Starling relationship. Pre, black-dash line with closed circle; Post,…

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…

Figure 6.. Preload-recruitable stroke work.

(A) control group and (B) training group. Pre, black-dash line…
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…

Figure 6.. Preload-recruitable stroke work.

(A) control group and (B) training group. Pre, black-dash line…
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.
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References
    1. Benjamin EJ, Blaha MJ, Chiuve SE, Cushman M, Das SR, Deo R, de Ferranti SD, Floyd J, Fornage M, Gillespie C, Isasi CR, et al. Heart Disease and Stroke Statistics-2017 Update: A Report From the American Heart Association. Circulation. 2017;135:e146–e603. - PMC - PubMed
    1. Zile MR, Baicu CF and Gaasch WH. Diastolic heart failure--abnormalities in active relaxation and passive stiffness of the left ventricle. The New England journal of medicine. 2004;350:1953–1959. - PubMed
    1. Kawaguchi M, Hay I, Fetics B and Kass DA. Combined ventricular systolic and arterial stiffening in patients with heart failure and preserved ejection fraction: implications for systolic and diastolic reserve limitations. Circulation. 2003;107:714–720. - PubMed
    1. Lam CS, Roger VL, Rodeheffer RJ, Bursi F, Borlaug BA, Ommen SR, Kass DA and Redfield MM. Cardiac structure and ventricular-vascular function in persons with heart failure and preserved ejection fraction from Olmsted County, Minnesota. Circulation. 2007;115:1982–1990. - PMC - PubMed
    1. Sharma K and Kass DA. Heart failure with preserved ejection fraction: mechanisms, clinical features, and therapies. Circulation research. 2014;115:79–96. - PMC - PubMed
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Figure 3.. Effect of high-intensity exercise training…
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

Figure 4.. Effect of high-intensity exercise training…

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

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…

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

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…

Figure 5.. Starling mechanism

Change in Starling relationship. Pre, black-dash line with closed circle; Post,…

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…

Figure 5.. Starling mechanism

Change in Starling relationship. Pre, black-dash line with closed circle; Post,…

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…

Figure 6.. Preload-recruitable stroke work.

(A) control group and (B) training group. Pre, black-dash line…
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…

Figure 6.. Preload-recruitable stroke work.

(A) control group and (B) training group. Pre, black-dash line…
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.
All figures (9)
Figure 4.. Effect of high-intensity exercise training…
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…
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
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
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.
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.
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.

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    1. Shibata S and Levine BD. No Improvement in Biologic Aortic Age in Healthy Seniors Aged Over 65 Years Even After One Year of Endurance Exercise Training. Am J Physiol-Heart and Circulatory Physiology. 2012; 302: 1340–1346.
    1. Reddy YN and Borlaug BA. Heart Failure With Preserved Ejection Fraction. Current problems in cardiology. 2016;41:145–188.
    1. Hill JA and Olson EN. Cardiac plasticity. The New England journal of medicine. 2008;358:1370–80.
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    1. McMullen JR, Shioi T, Zhang L, Tarnavski O, Sherwood MC, Kang PM and Izumo S. Phosphoinositide 3-kinase(p110alpha) plays a critical role for the induction of physiological, but not pathological, cardiac hypertrophy. Proceedings of the National Academy of Sciences of the United States of America. 2003;100:12355–60.
    1. Schuttler D, Clauss S, Weckbach LT and Brunner S. Molecular Mechanisms of Cardiac Remodeling and Regeneration in Physical Exercise. Cells. 2019;8:1128
    1. Chaturvedi P, Kalani A, Medina I, Familtseva A and Tyagi SC. Cardiosome mediated regulation of MMP9 in diabetic heart: role of mir29b and mir455 in exercise. Journal of cellular and molecular medicine. 2015;19:2153–2161.
    1. Soci UP, Fernandes T, Hashimoto NY, Mota GF, Amadeu MA, Rosa KT, Irigoyen MC, Phillips MI and Oliveira EM. MicroRNAs 29 are involved in the improvement of ventricular compliance promoted by aerobic exercise training in rats. Physiological genomics. 2011;43:665–673.
    1. Sallis RE. Exercise is medicine and physicians need to prescribe it! British journal of sports medicine. 2009;43:3–4.
    1. Blair SN. Physical inactivity: the biggest public health problem of the 21st century. British journal of sports medicine. 2009;43:1–2.
    1. Levine BD and Stray-Gundersen J. Dose-response of altitude training: how much altitude is enough? Adv Exp Med Biol. 2006;588:233–247.
    1. Kraus WE and Levine BD. Exercise training for diabetes: the “strength” of the evidence. Annals of internal medicine. 2007;147:423–424.
    1. Simons-Morton DG, Hogan P, Dunn AL, Pruitt L, King AC, Levine BD and Miller ST. Characteristics of inactive primary care patients: baseline data from the activity counseling trial. For the Activity Counseling Trial Research Group. Prev Med. 2000;31:513–21.
    1. Stonerock GL and Blumenthal JA. Role of Counseling to Promote Adherence in Healthy Lifestyle Medicine: Strategies to Improve Exercise Adherence and Enhance Physical Activity. Progress in cardiovascular diseases. 2017;59:455–462.

Source: PubMed

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