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Assessment of Myofilament Ca2+ Sensitivity Underlying Cardiac Excitation-contraction Coupling
Published on: August 1, 2016
Enhanced sarcolemmal Ca2+ efflux reduces sarcoplasmic reticulum Ca2+ content and systolic Ca2+ in cardiac hypertrophy
M E Díaz1, H K Graham, A W Trafford
1Unit of Cardiac Physiology, The University of Manchester, 1.523 Stopford Building, Manchester M13 9PT, UK.
Insights
In cardiac hypertrophy, reduced sarcoplasmic reticulum (SR) Ca(2+) content causes a smaller systolic Ca(2+) transient. This decrease in SR Ca(2+) load is driven by impaired Ca(2+) uptake and increased Ca(2+) efflux, potentially leading to arrhythmias.
Area of Science:
- Cardiovascular Physiology
- Cardiac Electrophysiology
- Cellular Calcium Homeostasis
Background:
- Cardiac disease states are often characterized by diminished systolic Ca(2+) transient.
- Understanding the mechanisms behind altered intracellular calcium regulation is crucial for cardiac health.
Purpose of the Study:
- To identify mechanisms responsible for impaired intracellular calcium homeostasis in cardiac myocytes.
- To determine if these changes quantitatively explain the reduced systolic Ca(2+) transient in disease.
Main Methods:
- Induction of left ventricular hypertrophy (LVH) in ferrets via aortic coarctation.
- Measurement of intracellular Ca(2+) regulation, sarcolemmal Ca(2+) fluxes, and SR function in isolated myocytes.
Main Results:
- Cardiac hypertrophy led to a 48% reduction in systolic Ca(2+) transient amplitude and a 20% decrease in SR Ca(2+) content.
- Reduced SR Ca(2+) content quantitatively explained the smaller systolic Ca(2+) transient and lower excitation-contraction coupling gain.
- Increased sarcolemmal Ca(2+) efflux was identified as the cause of reduced SR Ca(2+) content.
Conclusions:
- Decreased SR Ca(2+) content, due to impaired Ca(2+) uptake and increased efflux, is the primary cause of reduced systolic Ca(2+) transient in hypertrophy.
- Increased Na(+)-Ca(2+) exchange current in hypertrophy may contribute to arrhythmias with reduced SR Ca(2+) load.
Objective:
Recent work has identified reductions in the systolic Ca(2+) transient in cardiac disease states. The aim of the present study was to identify the mechanisms responsible for perturbations of intracellular calcium homeostasis in isolated cardiac myocytes and determine if such changes can quantitatively explain the reduced systolic Ca(2+) transient.
Methods:
Left ventricular hypertrophy (LVH) was induced by aortic coarctation in adult ferrets. Changes in intracellular Ca(2+) regulation, sarcolemmal Ca(2+) fluxes and SR function were measured in single left ventricular cardiac myocytes.
Results:
Cardiac hypertrophy was associated with a 29% increase in action potential duration (APD(90)); a 48% reduction in the amplitude of and 19% slowing in the rate of decay of the systolic Ca(2+) transient; a 20% decrease in SR Ca(2+) content and a 36% increase in inward Na(+)-Ca(2+) exchange current for a given change in [Ca(2+)](i) (all P<0.05). Peak L-type Ca(2+) current density, integrated Ca(2+) influx and SERCA2a protein levels remained unchanged in hypertrophy. By determining the relationship between SR Ca(2+) content and systolic Ca(2+), the reduction in SR Ca(2+) content quantitatively explained the smaller systolic Ca(2+) transient. The reduced SR Ca(2+) content also accounted for a smaller fractional release of Ca(2+) from the SR and lower gain of excitation contraction coupling in cardiac hypertrophy. The increased sarcolemmal-mediated Ca(2+) efflux was sufficient to explain the reduction in SR Ca(2+) content.
Conclusions:
The findings indicate that the primary mechanism underlying the smaller systolic Ca(2+) transient amplitude in cardiac hypertrophy is decreased SR Ca(2+) content occurring as a consequence of reduced SR Ca(2+)-ATPase-mediated Ca(2+) uptake and increased sarcolemmal-mediated Ca(2+) efflux from the cell. The increased Na(+)-Ca(2+) exchange-mediated current for a given change in intracellular Ca(2+) concentration provides a mechanism for the development of arrhythmias in the face of a reduced SR Ca(2+) load in cardiac hypertrophy.
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