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Calcium content of the sarcoplasmic reticulum in isolated ventricular myocytes from patients with terminal heart
M Lindner1, E Erdmann, D J Beuckelmann
1Department of Medicine III, University of Cologne, Germany.
Insights
Heart failure patients show reduced intracellular calcium transients in heart cells. This is likely due to lower calcium stores in the sarcoplasmic reticulum (SR), not impaired calcium release.
Area of Science:
- Cardiology
- Cellular Physiology
- Biochemistry
Background:
- Systolic intracellular calcium ([Ca2+]i) transients are depressed in heart failure.
- The underlying cause of this reduction is not fully understood.
Purpose of the Study:
- To investigate if reduced sarcoplasmic reticulum (SR) Ca(2+) content contributes to depressed systolic [Ca2+]i-transients in heart failure.
- To compare SR Ca(2+) content in human ventricular myocytes from heart failure patients and healthy controls.
Main Methods:
- Isolated human ventricular myocytes from heart failure patients and controls were used.
- Intracellular calcium ([Ca2+]i) transients were measured using fura-2 under voltage clamp.
- SR Ca(2+) content was assessed by measuring caffeine-induced [Ca2+]i transients.
Main Results:
- Systolic [Ca2+]i-transients were significantly smaller in heart failure myocytes compared to controls.
- Caffeine-induced [Ca2+]i-transients, reflecting SR Ca(2+) content, were significantly lower in heart failure cells.
- A positive correlation was observed between left ventricular ejection fraction and caffeine-induced [Ca2+]i-transients.
Conclusions:
- Depressed systolic [Ca2+]i-transients in heart failure are likely caused by decreased SR Ca(2+) content.
- Altered Ca(2+)-ATPase activity may contribute to reduced SR Ca(2+) content.
- No additional defect in SR Ca(2+) release function is needed to explain these findings.
Abstract:
Systolic [Ca2+]i-transients have been shown to be depressed in isolated ventricular myocytes from patients with terminal heart failure compared to controls. Experiments were performed in human ventricular cells to investigate whether this reduced systolic [Ca2+]i-transient may be due to a decreased Ca(2+)-content of the sarcoplasmic reticulum (SR). Single myocytes were isolated from left ventricular myocardium of patients with terminal heart failure undergoing cardiac transplantation. These results were compared to those obtained from cells of healthy donor hearts that were not suitable for transplantation for technical reasons. [Ca2+]i-transients were recorded from isolated cells under voltage clamp perfused internally with the Ca(2+)-indicator fura-2. The Ca(2+)-content of the SR was estimated by rapid extracellular application of caffeine (10 mM) to open the Ca(2+)-release channel of the SR and comparison of the caffeine-induced [Ca2+]i-transients in cells from patients with heart failure and from controls without heart failure. Upon steady-state depolarizations to +10 mV (maximum of the Ca(2+)-current), [Ca2+]i-transients in cells from patients with heart failure were significantly smaller than in myocytes from undiseased hearts (333 +/- 26 v 596 +/- 80 nM, P < 0.05). Application of caffeine caused a [Ca2+]i-transient that was always larger than during depolarization. Caffeine-induced [Ca2+]i-transients were significantly smaller in cells from diseased hearts compared with controls (970 +/- 129 v 2586 +/- 288 nM, P < 0.01). A positive correlation was found between left ventricular ejection fraction and caffeine-induced [Ca2+]i-transients in these cells. It is concluded, that depressed [Ca2+]i-transients in myocytes from patients with heart failure may be caused by a decreased Ca(2+)-content of the SR possibly due to an altered Ca(2+)-ATPase activity in these hearts. It is not necessary to postulate an additional defect of the Ca(2+)-release function of the SR to account for the alterations of intracellular (Ca2+]i-handling.