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Altered force-frequency relation in hypertrophic obstructive cardiomyopathy
U Schotten1, S Voss, T B Wiederin
1Dept. of Cardiology, University Hospital Aachen, Germany.
Insights
In hypertrophic obstructive cardiomyopathy (HOCM), heart muscle struggles to increase contraction force with faster rates at normal calcium levels. This impaired force-frequency relation suggests abnormal cellular calcium handling contributes to dysfunction.
Area of Science:
- Cardiology
- Physiology
- Biochemistry
Background:
- Hypertrophic obstructive cardiomyopathy (HOCM) is characterized by myocardial hypertrophy and can lead to diastolic dysfunction.
- The force-frequency relationship (FFR), describing how contraction force changes with stimulation rate, is crucial for cardiac function.
- Reduced contractile reserve in HOCM may contribute to myocardial dysfunction, but the underlying mechanisms require further investigation.
Purpose of the Study:
- To test the hypothesis that impaired frequency-dependent potentiation of contraction force contributes to myocardial dysfunction in HOCM.
- To investigate the force-frequency relationship in hypertrophied myocardium from HOCM patients compared to non-failing donor hearts.
- To explore the role of extracellular calcium concentration in modulating the force-frequency relationship in HOCM.
Main Methods:
- Myocardial tissue samples were obtained from 8 HOCM patients post-myectomy and 3 organ donors.
- Thin myocardial strips were subjected to varying stimulation frequencies (0.5-3.0 Hz) and extracellular calcium concentrations (1.8-16.2 mmol/l).
- Isometric force development and relaxation dynamics were measured to assess inotropic responses.
Main Results:
- At physiological calcium (1.8 mmol/l), HOCM myocardium showed no positive inotropic effect with increased stimulation frequency, unlike control myocardium.
- Increasing extracellular calcium concentration induced a positive FFR in HOCM, peaking at 5.4 mmol/l.
- Higher calcium levels (16.2 mmol/l) resulted in a negative FFR in HOCM, and faster rates shortened contraction and relaxation times in all groups.
Conclusions:
- Hypertrophied myocardium in HOCM patients exhibits a blunted positive force-frequency relationship at physiological calcium concentrations.
- The ability to induce a positive FFR with elevated calcium suggests abnormal cellular calcium handling is a key pathophysiological factor in HOCM.
- These findings highlight the critical role of calcium dysregulation in the contractile dysfunction observed in HOCM.
Abstract:
The present study was designed to test the hypothesis that in hypertrophied myocardium of patients with hypertrophic obstructive cardiomyopathy (HOCM) a reduced contractile reserve provided by frequency dependent potentiation of force of contraction contributes to the myocardial dysfunction. Myectomy was performed in 8 HOCM patients with normal systolic left ventricular function at rest. Nonfailing myocardium from the hearts of three multiorgan donors was investigated for comparison. In thin myocardial strips we measured the inotropic effects of different stimulation frequencies (0.5-3.0 Hz) at different extracellular Ca2+ concentrations (1.8-16.2 mmol/l). At 1.8 mmol/l extracellular Ca2+ concentration, increasing stimulation rates had no positive inotropic effect in HOCM myocardium, whereas in nonfailing myocardium force of contraction increased up to 3 Hz. Increasing extracellular Ca2+ concentrations induced a positive force-frequency relation in HOCM with a maximum at 5.4 mmol/l Ca2+. A further increase to 16.2 mmol/l Ca2+ resulted in a negative force-frequency relation in these specimens. The time to peak tension and the time to relaxation decreased at increasing stimulation frequencies at all Ca2+ concentrations investigated. In conclusion, in hypertrophied myocardium of HOCM patients increasing stimulation frequencies failed to have a positive inotropic effect at physiological extracellular Ca2+ concentrations. The induction of a positive force-frequency relation by higher Ca2+ concentrations suggests that an abnormal cellular Ca2+ handling may play an important pathophysiological role.