Altered diastolic [Ca2+]i handling in human ventricular myocytes from patients with terminal heart failure

Area of Science:

• Cardiology
• Cell Physiology
• Biochemistry

Background:

• Diastolic dysfunction in heart failure is linked to altered intracellular calcium (Ca2+) handling.
• The roles of sarcoplasmic reticulum Ca2+ ATPase and sarcolemmal Ca2+ ATPase in this dysfunction are not fully understood.

Purpose of the Study:

• To determine if impaired Ca2+ adenosine triphosphatase (ATPase) function of the sarcoplasmic reticulum or sarcolemma contributes to slow diastolic Ca2+ decay in heart failure.
• To investigate the specific contributions of sarcoplasmic reticulum and sarcolemmal Ca2+ removal mechanisms.

Main Methods:

• Ventricular myocytes were isolated from human hearts with terminal heart failure and from healthy donors.
• Intracellular Ca2+ ([Ca2+]i) transients were measured using voltage-clamp techniques.
• To isolate sarcoplasmic reticulum Ca2+ reuptake, Na+/Ca2+ exchange was inhibited, and sarcoplasmic reticulum was loaded with Ca2+ via voltage-clamp pulses.

Main Results:

• Diastolic [Ca2+]i decay was significantly slower in myocytes from heart failure patients (538 msec) compared to controls (305 msec).
• Caffeine application, which inhibits sarcoplasmic reticulum Ca2+ reuptake, abolished significant [Ca2+]i decay in both groups, indicating sarcoplasmic reticulum involvement.
• Sarcolemmal Ca2+ ATPase activity did not significantly impact [Ca2+]i removal during individual heartbeats.

Conclusions:

• Decreased Ca2+ reuptake by the sarcoplasmic reticulum is a significant factor contributing to the slow diastolic [Ca2+]i decay observed in heart failure.
• Sarcolemmal Ca2+ ATPase is not a major contributor to cytoplasmic [Ca2+]i removal during the cardiac cycle in the context of heart failure.