Genetic background affects function and intracellular calcium regulation of mouse hearts

Abstract

Aims The genetic background is currently under close scrutiny when determining cardiovascular disease progression and response to therapy. However, this factor is rarely considered in physiological studies, where it could influence the normal behaviour and adaptive responses of the heart. We aim to test the hypothesis that genetic strain variability is associated with differences in excitation-contraction coupling mechanisms, in particular those involved in cytoplasmic Ca2+ regulation, and that they are concomitant to differences in whole-heart function and cell morphology. Methods and results We studied 8-to 10-week-old male C57BL/6, BALB/C, FVB, and SV129 mice. Echocardiography and radiotelemetry were used to assess cardiac function in vivo. FVB mice had increased left ventricular ejection fraction and fractional shortening with significantly faster heart rate (HR) and lack of diurnal variation of HR. Confocal microscopy, sarcomere length tracking, and epifluorescence were used to investigate cell volume, t-tubule density, contractility, and Ca2+ handling in isolated ventricular myocytes. Sarcomere relaxation and time-to-peak of the Ca2+ transient were prolonged in BALB/C myocytes, with more frequent Ca2+ sparks and significantly higher sarcoplasmic reticulum (SR) Ca2+ leak. There were no strain differences in the contribution of different Ca2+ extrusion mechanisms. SV129 had reduced SR Ca2+ leak with elevated SR Ca2+ content and smaller cell volume and t-tubule density compared with myocytes from other strains. Conclusion These results demonstrate that a different genetic background is associated with physiological differences in cardiac function in vivo and differences in morphology, contractility, and Ca2+ handling at the cellular level. © 2010 The Author.