Striking correlations are found between cardiac contractility and Ca2+ binding to isolated cardiac sarcolemma in rabbit, neonatal rat, and frog ventricular tissue. Deviations from this correlation are seen in the adult rat ventricle and rabbit atrium. The observation of this correlation in the three former tissues and under various ionic conditions suggests that this correlation is not coincidental and that Ca2+ bound to the cardiac sarcolemma is of major importance in the control of myocardial contractility. The data are consistent with a functional Ca2+-induced Ca2+ release system in the sarcoplasmic reticulum (SR) of all the tissues (which is controlled by Ca2+ entry from sarcolemmal sites), with the adult rat ventricular and rabbit atrial SR Ca2+ release being much more sensitive to CA2+. It is suggested that the frog, neonatal rat, and rabbit ventricles depend more directly on the entry of Ca2+ from sarcolemmal sites for the control of tension development, whereas the adult rat ventricle and rabbit atrium depend to a greater extent on CA2+ released from the SR.

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Because of a typographical error, the maximal conductances of the slow and fast components of the transient outward K þ current I to , G to,s , and G to,f were erroneously set to 0.02 and 0.06 mS/mF, respectively. These values should be reversed. The model should be adjusted to correctly describe the ratio between slow and fast components in rabbit ventricular myocytes by setting G to,s and G to,f to 0.06 and 0.02 mS/mF, respectively, as shown by Grandi et al. (1).

Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): BioTechMed-Graz Mitochondrial dysfunction in cardiomyocytes is a hallmark of heart failure (HF) development. Although initial studies recognized the importance of different mitochondrial subpopulations, there is a striking lack of direct comparison of intrafibrillar (IF) vs. perinuclear (PN) mitochondria during the development of HF. Here, we use multiple approaches to examine the morphology and functional properties of IF vs. PN mitochondria in pressure overload-induced cardiac remodeling in mice, and in non-failing and failing human cardiomyocytes. We could demonstrate that PN mitochondria from failing cardiomyocytes are more susceptible to changes in mitochondrial membrane potential (ΔΨm), ROS generation and impairment in Ca2+ uptake compared to IF mitochondria at baseline and under physiological stress protocol. We also demonstrated, for the first time, that under normal conditions PN mitochondrial Ca2+ uptake shapes nucleoplasmic Ca2+ transients (CaTs) and prevents nucleoplasmic Ca2+ overload. Loss of PN mitochondria Ca2+ buffering capacity translates into increased nucleoplasmic CaTs and may explain disproportionate rise in nucleoplasmic [Ca2+] in failing cardiomyocytes at increased stimulation frequencies. Therefore, a previously unidentified benefit of restoring the mitochondrial Ca2+ uptake may be normalization of nuclear Ca2+ signaling and alleviation of altered excitation-transcription, which could be an important therapeutic approach to prevent adverse cardiac remodeling.

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