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Frequency-dependent changes in contribution of SR Ca2+ to Ca2+ transients in failing human myocardium assessed with
K Schlotthauer1, J Schattmann, D M Bers
1Medizinische Klinik III, Universität Freiburg, Germany.
Abstract:
We tested the influence of blocking sarcoplasmic reticulum (SR) function with ryanodine (1 microM) on stimulation rate-dependent changes of intracellular Ca2+ transients and twitch force in failing human myocardium. Isometrically contracting, electrically stimulated muscle strips from ventricles of 10 end-stage failing human hearts were used. Muscles were loaded with the intracellular Ca2+ indicator aequorin. At stimulation rates from 0.5-3 Hz, intracellular Ca2+ transients and twitch force were simultaneously recorded before and after ryanodine exposure (37 degrees C). Ryanodine significantly reduced twitch force at 1 Hz by 46 +/- 9% and aequorin light by 57 +/- 10% in failing human myocardium (P < 0.05). The blunted or inverse aequorin light- and force-frequency relation became positive after ryanodine: in failing human myocardium, twitch force and aequorin light before ryanodine did not increase with increasing frequency and force decreased significantly at 3 Hz (P < 0.05). After ryanodine, twitch force (P < 0.05) and aequorin light increased with increasing stimulation frequency and were maximum at 2 Hz. The data indicate that inhibition of SR function significantly reduces twitch force and Ca2+ transients in failing human myocardium, but converts the blunted or inverse Ca(2+)- and force-frequency relation into a positive one. We infer that Ca2+ responsible for approximately 50% of twitch force is derived from the SR and approximately 50% from sarcolemmal Ca2+ influx in failing human myocardium. This sarcolemmal component increases at higher stimulation frequencies.
Insights
Blocking sarcoplasmic reticulum (SR) function with ryanodine significantly reduced contractility in failing human hearts. However, it improved the force-frequency relationship, suggesting a crucial role for SR calcium in heart muscle function.
Area of Science:
- Cardiology
- Cellular Physiology
- Biochemistry
Background:
- Heart failure is characterized by impaired contractility and altered calcium handling.
- The force-frequency relationship describes how heart muscle force changes with stimulation rate.
Purpose of the Study:
- To investigate the role of sarcoplasmic reticulum (SR) function in regulating intracellular calcium transients and twitch force in failing human myocardium.
- To determine the impact of blocking SR function on the force-frequency relationship in heart failure.
Main Methods:
- Human ventricular muscle strips from end-stage heart failure patients were used.
- Intracellular calcium transients were measured using the aequorin luminescence.
- Twitch force and calcium transients were recorded at various stimulation rates (0.5-3 Hz) before and after ryanodine exposure.
Main Results:
- Ryanodine significantly reduced twitch force and intracellular calcium transients in failing human myocardium.
- The blunted or inverse force-frequency relationship observed in heart failure became positive after ryanodine treatment.
- Twitch force and calcium transients increased with stimulation frequency after ryanodine, peaking at 2 Hz.
Conclusions:
- Inhibition of SR function reduces contractility but normalizes the force-frequency relationship in failing human myocardium.
- Approximately 50% of the force in failing human myocardium is derived from SR calcium release, with the remainder from sarcolemmal influx.
- Sarcolemmal calcium influx plays an increasingly important role in maintaining contractility at higher stimulation frequencies in heart failure.