Dataset Information

Detection of genetic cardiac diseases by Ca²⁺ transient profiles using machine learning methods.

ABSTRACT: Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have revolutionized cardiovascular research. Abnormalities in Ca²⁺ transients have been evident in many cardiac disease models. We have shown earlier that, by exploiting computational machine learning methods, normal Ca²⁺ transients corresponding to healthy CMs can be distinguished from diseased CMs with abnormal transients. Here our aim was to study whether it is possible to separate different genetic cardiac diseases (CPVT, LQT, HCM) on the basis of Ca²⁺ transients using machine learning methods. Classification accuracies of up to 87% were obtained for these three diseases, indicating that Ca²⁺ transients are disease-specific. By including healthy controls in the classifications, the best classification accuracy obtained was still high: approximately 79%. In conclusion, we demonstrate as the proof of principle that the computational machine learning methodology appears to be a powerful means to accurately categorize iPSC-CMs and could provide effective methods for diagnostic purposes in the future.

SUBMITTER: Juhola M

PROVIDER: S-EPMC6008430 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Detection of genetic cardiac diseases by Ca2+ transient profiles using machine learning methods.

Juhola Martti M Joutsijoki Henry H Penttinen Kirsi K Aalto-Setälä Katriina K

Scientific reports 20180619 1

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have revolutionized cardiovascular research. Abnormalities in Ca2+ transients have been evident in many cardiac disease models. We have shown earlier that, by exploiting computational machine learning methods, normal Ca2+ transients corresponding to healthy CMs can be distinguished from diseased CMs with abnormal transients. Here our aim was to study whether it is possible to separate different genetic c ...[more]

PMID: 29921843

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Project description:Mitochondrial Ca2+ handling is accomplished by balancing Ca2+ uptake, primarily via the Ru360-sensitive mitochondrial calcium uniporter (MCU), Ca2+ buffering in the matrix and Ca2+ efflux mainly via Ca2+ ion exchangers, such as the Na+/Ca2+ exchanger (NCLX) and the Ca2+/H+ exchanger (CHE). The mechanism of CHE in cardiac mitochondria is not well-understood and its contribution to matrix Ca2+ regulation is thought to be negligible, despite higher expression of the putative CHE protein, LETM1, compared to hepatic mitochondria. In this study, Ca2+ efflux via the CHE was investigated in isolated rat cardiac mitochondria and permeabilized H9c2 cells. Mitochondria were exposed to (a) increasing matrix Ca2+ load via repetitive application of a finite CaCl2 bolus to the external medium and (b) change in the pH gradient across the inner mitochondrial membrane (IMM). Ca2+ efflux at different matrix Ca2+ loads was revealed by inhibiting Ca2+ uptake or reuptake with Ru360 after increasing number of CaCl2 boluses. In Na+-free experimental buffer and with Ca2+ uptake inhibited, the rate of Ca2+ efflux and steady-state free matrix Ca2+ [mCa2+]ss increased as the number of administered CaCl2 boluses increased. ADP and cyclosporine A (CsA), which are known to increase Ca2+ buffering while maintaining a constant [mCa2+]ss, decreased the rate of Ca2+ efflux via the CHE, with a significantly greater decrease in the presence of ADP. ADP also increased Ca2+ buffering rate and decreased [mCa2+]ss. A change in the pH of the external medium to a more acidic value from 7.15 to 6.8∼6.9 caused a twofold increase in the Ca2+ efflux rate, while an alkaline change in pH from 7.15 to 7.4∼7.5 did not change the Ca2+ efflux rate. In addition, CHE activation was associated with membrane depolarization. Targeted transient knockdown of LETM1 in permeabilized H9c2 cells modulated Ca2+ efflux. The results indicate that Ca2+ efflux via the CHE in cardiac mitochondria is modulated by acidic buffer pH and by total matrix Ca2+. A mechanism is proposed whereby activation of CHE is sensitive to changes in both the matrix Ca2+ buffering system and the matrix free Ca2+ concentration.

Dataset Information

Detection of genetic cardiac diseases by Ca²⁺ transient profiles using machine learning methods.

Publications

Detection of genetic cardiac diseases by Ca<sup>2+</sup> transient profiles using machine learning methods.

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