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Myocardial relaxation is accelerated by fast stretch, not reduced afterload.

ABSTRACT: Fast relaxation of cross-bridge generated force in the myocardium facilitates efficient diastolic function. Recently published research studying mechanisms that modulate the relaxation rate has focused on molecular factors. Mechanical factors have received less attention since the 1980s when seminal work established the theory that reducing afterload accelerates the relaxation rate. Clinical trials using afterload reducing drugs, partially based on this theory, have thus far failed to improve outcomes for patients with diastolic dysfunction. Therefore, we reevaluated the protocols that suggest reducing afterload accelerates the relaxation rate and identified that myocardial relengthening was a potential confounding factor. We hypothesized that the speed of myocardial relengthening at end systole (end systolic strain rate), and not afterload, modulates relaxation rate and tested this hypothesis using electrically-stimulated trabeculae from mice, rats, and humans. We used load-clamp techniques to vary afterload and end systolic strain rate independently. Our data show that the rate of relaxation increases monotonically with end systolic strain rate but is not altered by afterload. Computer simulations mimic this behavior and suggest that fast relengthening quickens relaxation by accelerating the detachment of cross-bridges. The relationship between relaxation rate and strain rate is novel and upends the prevailing theory that afterload modifies relaxation. In conclusion, myocardial relaxation is mechanically modified by the rate of stretch at end systole. The rate of myocardial relengthening at end systole may be a new diagnostic indicator or target for treatment of diastolic dysfunction.

SUBMITTER: Chung CS

PROVIDER: S-EPMC5347980 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Myocardial relaxation is accelerated by fast stretch, not reduced afterload.

Chung Charles S CS Hoopes Charles W CW Campbell Kenneth S KS

Journal of molecular and cellular cardiology 20170111

Fast relaxation of cross-bridge generated force in the myocardium facilitates efficient diastolic function. Recently published research studying mechanisms that modulate the relaxation rate has focused on molecular factors. Mechanical factors have received less attention since the 1980s when seminal work established the theory that reducing afterload accelerates the relaxation rate. Clinical trials using afterload reducing drugs, partially based on this theory, have thus far failed to improve ou ...[more]

PMID: 28087265

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Project description:Humans have a lower risk of death from myocardial infarction (MI) living at low elevations (<2500 m), which are not high enough to induce hypoxia. Both chronic hypoxia pre-MI, achieved by altitude simulation >5000 m, and intermittent hypobaric hypoxia post-MI can reduce MI size in rodents, and it is believed that hypoxia is the key stimulus. To explore mechanisms beyond hypoxia we studied whether altitude simulation <2500 m would also be associated with reduced infarct size. We performed left-anterior descending artery ligation on C57BL6 mice. Control mice (n = 12) recovered at 754 mmHg (atmospheric pressure, control), and treatment group mice (n = 13) were placed in a hypobaric chamber to recover 3-hours daily at 714 mmHg for 1 week. Echocardiographic evaluation of left ventricular function was performed on Day 0, Day 1 and Day 8. Intermittent hypobaric treatment was associated with a 14.2±5.3% improvement in ejection fraction for treatment group mice (p<0.01 vs. Day 1), with no change observed in control mice. Cardiac output, stroke volume, and infarct size were also improved in treated mice, but no changes were observed in HIF-1 activation or neovascularization. Next, we studied the acute hemodynamic effects of low altitude stimulation in intact mice breathing 100% oxygen using left ventricular catheterization and recording of pressure-volume loops. Acute reductions in barometric pressure from 754 mmHg to 714 mmHg and 674 mmHg were associated with reduced systemic vascular resistance, increased stroke volume and cardiac output, and no change in blood pressure or heart rate. Ex-vivo vascular function was studied using murine mesenteric artery segments. Acute reductions in barometric pressure were associated with greater vascular distensibility. We conclude that intermittent hypobaric treatment using simulated altitudes <2500 m reduces infarct size and increases ventricular function post-MI, and that these changes are related to altered arterial function and not hypoxia-associated neovascularization.

Dataset Information

Myocardial relaxation is accelerated by fast stretch, not reduced afterload.

Publications

Myocardial relaxation is accelerated by fast stretch, not reduced afterload.

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