Human-based modelling and simulations are becoming ubiquitous in biomedical science due to their ability to augment experimental and clinical investigations. Cardiac electrophysiology is one of the most advanced areas, with cardiac modelling and simulation being considered for virtual testing of pharmacological therapies and medical devices. Current models present inconsistencies with experimental data, which limit further progress. In this study, we present the design, development, calibration and independent validation of a human-based ventricular model (ToR-ORd) for simulations of electrophysiology and excitation-contraction coupling, from ionic to whole-organ dynamics, including the electrocardiogram. Validation based on substantial multiscale simulations supports the credibility of the ToR-ORd model under healthy and key disease conditions, as well as drug blockade. In addition, the process uncovers new theoretical insights into the biophysical properties of the L-type calcium current, which are critical for sodium and calcium dynamics. These insights enable the reformulation of L-type calcium current, as well as replacement of the hERG current model.

IntroductionHypertrophic cardiomyopathy (HCM) is a cause of sudden arrhythmic death, but the understanding of its pro-arrhythmic mechanisms and an effective pharmacological treatment are lacking. HCM electrophysiological remodelling includes both increased inward and reduced outward currents, but their role in promoting repolarisation abnormalities remains unknown. The goal of this study is to identify key ionic mechanisms driving repolarisation abnormalities in human HCM, and to evaluate anti-arrhythmic effects of single and multichannel inward current blocks.MethodsExperimental ionic current, action potential (AP) and Ca2 +-transient (CaT) recordings were used to construct populations of human non-diseased and HCM AP models (n = 9118), accounting for inter-subject variability. Simulations were conducted for several degrees of selective and combined inward current block.ResultsSimulated HCM cardiomyocytes exhibited prolonged AP and CaT, diastolic Ca2 + overload and decreased CaT amplitude, in agreement with experiments. Repolarisation abnormalities in HCM models were consistently driven by L-type Ca2 + current (ICaL) re-activation, and ICaL block was the most effective intervention to normalise repolarisation and diastolic Ca2 +, but compromised CaT amplitude. Late Na+ current (INaL) block partially abolished repolarisation abnormalities, with small impact on CaT. Na+/Ca2 + exchanger (INCX) block effectively restored repolarisation and CaT amplitude, but increased Ca2 + overload. Multichannel block increased efficacy in normalising repolarisation, AP biomarkers and CaT amplitude compared to selective block.ConclusionsExperimentally-calibrated populations of human AP models identify ICaL re-activation as the key mechanism for repolarisation abnormalities in HCM, and combined INCX, INaL and ICaL block as effective anti-arrhythmic therapies also able to partially reverse the HCM electrophysiological phenotype.

A method for deriving respiration from the pulse photoplethysmographic (PPG) signal is presented. This method is based on the pulse width variability (PWV), and it exploits the respiratory information present in the pulse wave velocity and dispersion. It allows to estimate respiration signal from only a pulse oximeter which is a cheap and comfortable sensor. Evaluation is performed over a database containing electrocardiogram (ECG), blood pressure (BP), PPG, and respiratory signals simultaneously recorded in 17 subjects during a tilt table test. Respiratory rate estimation error is computed obtaining of 1.27 ± 7.81% (0.14 ± 14.78 mHz). For comparison purposes, we have also obtained a respiratory rate estimation from other known methods which involve ECG, BP, or also PPG signals. In addition, we have also combined respiratory information derived from different methods which involve only PPG signal, obtaining a respiratory rate error of -0.17 ± 6.67% (-2.16 ± 12.69 mHz). The presented methods, PWV and combination of PPG derived respiration methods, avoid the need of ECG to derive respiration without degradation of the obtained estimates, so it is possible to have reliable respiration rate estimates from just the PPG signal.