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Contribution of abnormal sarcoplasmic reticulum ATPase activity to systolic and diastolic dysfunction in human heart
U Schmidt1, R J Hajjar, P A Helm
1Integrated Physiology Research Laboratories, Boston University School of Medicine, Department of Cardiovascular Medicine, Evans Department of Medicine, Cardiovascular Division, the Whitaker Cardiovascular Institute, Cambridge, MA 02138, USA.
Insights
In failing hearts, reduced sarcoplasmic reticulum Ca2+ ATPase activity impairs calcium handling, leading to increased diastolic calcium and impaired relaxation. This affects both systolic and diastolic function in human heart failure.
Area of Science:
- Cardiology
- Molecular Biology
- Physiology
Background:
- Failing human myocardium exhibits increased diastolic intracellular calcium ([Ca2+]i) and prolonged relaxation.
- These abnormalities worsen with higher stimulation frequencies, potentially due to altered calcium resequestration into the sarcoplasmic reticulum (SR).
Purpose of the Study:
- To investigate the force-frequency relationship and its association with intracellular calcium handling in failing and non-failing human myocardium.
- To determine the role of SR Ca2+ ATPase activity in the altered cardiac function observed in heart failure.
Main Methods:
- Force-frequency relationships were measured in multicellular human myocardial preparations (n=11 failing, n=6 non-failing).
- Intracellular calcium concentrations and SR Ca2+ ATPase activity were assessed in relation to stimulation frequency and force generation.
Main Results:
- Failing myocardium showed decreased active force at higher stimulation frequencies (>1 Hz), unlike non-failing tissue.
- Increased diastolic force and elevated diastolic [Ca2+]i were observed in failing hearts with increased stimulation frequency.
- SR Ca2+ ATPase activity was reduced in failing myocardium and inversely correlated with diastolic force.
Conclusions:
- Reduced SR Ca2+ ATPase activity is a key factor contributing to impaired systolic and diastolic function in failing human hearts.
- Altered calcium handling, particularly reduced SR Ca2+ resequestration, underlies the functional deficits in heart failure.
Abstract:
Two of the most significant characteristics of failing human myocardium are an increased diastolic [Ca2+]i and a prolonged diastolic relaxation. These abnormalities are more pronounced at higher frequencies of stimulation and may be caused by an altered Ca2+ resequestration into the sarcoplasmic reticulum (SR). The force-frequency relationship was determined in multicellular preparations obtained from non-failing (n=6) and failing human myocardium (n=11). The active force in non-failing tissue increased as a function of the frequency of stimulation. In failing myocardium, an increase in frequency of stimulation (>1 Hz) was accompanied by a decrease in active force. Changes in the frequency of stimulation and active force were also associated with changes in intracellular calcium concentrations. The diastolic force in failing myocardium was augmented following an increase in frequency of stimulation, whereas in non-failing tissue, no increase in diastolic force was observed. Associated with the increase in diastolic force was an increase in intracellular diastolic calcium concentrations. The SR Ca2+ ATPase activity was reduced in failing compared to non-failing myocardium. SR Ca2+ ATPase was positively correlated with diastolic force in non-failing myocardium. The relationship between Ca2+ ATPase activity at 1 micromol/l [Ca2+] and active force between 0.5 and 2.0 Hz was different between failing and non-failing myocardium. The diastolic force demonstrate an inverse relationship with the SR Ca2+ ATPase activity in failing myocardium. These data suggest that a reduction in SR Ca2+ ATPase activity contributes to the impairment in both systolic and diastolic function of failing human hearts.