Proarrhythmic effects of carbon monoxide in human ventricular tissue: Insights from computational modeling

Etiology-Specific Remodeling in Ventricular Tissue of Heart Failure Patients and Its Implications for Computational Modeling of Electrical Conduction

Frontiers in Physiology ◽

10.3389/fphys.2021.730933 ◽

2021 ◽

Vol 12 ◽

Author(s):

Aparna C. Sankarankutty ◽

Joachim Greiner ◽

Jean Bragard ◽

Joseph R. Visker ◽

Thirupura S. Shankar ◽

...

Keyword(s):

Heart Failure ◽

Risk Stratification ◽

Computational Modeling ◽

Volume Fraction ◽

Left Ventricular ◽

Patient Specific ◽

Cardiac Tissues ◽

Ventricular Tissue ◽

Specific Modeling ◽

Anisotropic Conduction

With an estimated 64.3 million cases worldwide, heart failure (HF) imposes an enormous burden on healthcare systems. Sudden death from arrhythmia is the major cause of mortality in HF patients. Computational modeling of the failing heart provides insights into mechanisms of arrhythmogenesis, risk stratification of patients, and clinical treatment. However, the lack of a clinically informed approach to model cardiac tissues in HF hinders progress in developing patient-specific strategies. Here, we provide a microscopy-based foundation for modeling conduction in HF tissues. We acquired 2D images of left ventricular tissues from HF patients (n = 16) and donors (n = 5). The composition and heterogeneity of fibrosis were quantified at a sub-micrometer resolution over an area of 1 mm2. From the images, we constructed computational bidomain models of tissue electrophysiology. We computed local upstroke velocities of the membrane voltage and anisotropic conduction velocities (CV). The non-myocyte volume fraction was higher in HF than donors (39.68 ± 14.23 vs. 22.09 ± 2.72%, p < 0.01), and higher in ischemic (IC) than nonischemic (NIC) cardiomyopathy (47.2 ± 16.18 vs. 32.16 ± 6.55%, p < 0.05). The heterogeneity of fibrosis within each subject was highest for IC (27.1 ± 6.03%) and lowest for donors (7.47 ± 1.37%) with NIC (15.69 ± 5.76%) in between. K-means clustering of this heterogeneity discriminated IC and NIC with an accuracy of 81.25%. The heterogeneity in CV increased from donor to NIC to IC tissues. CV decreased with increasing fibrosis for longitudinal (R2 = 0.28, p < 0.05) and transverse conduction (R2 = 0.46, p < 0.01). The tilt angle of the CV vectors increased 2.1° for longitudinal and 0.91° for transverse conduction per 1% increase in fibrosis. Our study suggests that conduction fundamentally differs in the two etiologies due to the characteristics of fibrosis. Our study highlights the importance of the etiology-specific modeling of HF tissues and integration of medical history into electrophysiology models for personalized risk stratification and treatment planning.

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Deterministic and Stochastic Cellular Mechanisms Contributing to Carbon Monoxide Induced Ventricular Arrhythmias

Frontiers in Pharmacology ◽

10.3389/fphar.2021.651050 ◽

2021 ◽

Vol 12 ◽

Author(s):

Moza M. Al-Owais ◽

Derek S. Steele ◽

Arun V. Holden ◽

Alan P. Benson

Keyword(s):

Carbon Monoxide ◽

Guinea Pig ◽

Ventricular Myocytes ◽

Delayed Rectifier ◽

Cellular Mechanisms ◽

Maximal Conductance ◽

Ventricular Cell ◽

Ventricular Tissue ◽

Increased Risk ◽

Induced Changes

Chronic exposure to low levels of Carbon Monoxide is associated with an increased risk of cardiac arrhythmia. Microelectrode recordings from rat and guinea pig single isolated ventricular myocytes exposed to CO releasing molecule CORM-2 and excited at 0.2/s show repolarisation changes that develop over hundreds of seconds: action potential prolongation by delayed repolarisation, EADs, multiple EADs and oscillations around the plateau, leading to irreversible repolarisation failure. The measured direct effects of CO on currents in these cells, and ion channels expressed in mammalian systems showed an increase in prolonged late Na+, and a decrease in the maximal T- and L-type Ca++. peak and late Na+, ultra-rapid delayed, delayed rectifier, and the inward rectifier K+ currents. Incorporation of these CO induced changes in maximal currents in ventricular cell models; (Gattoni et al., J. Physiol., 2016, 594, 4193–4224) (rat) and (Luo and Rudy, Circ. Res., 1994, 74, 1071–1096) (guinea-pig) and human endo-, mid-myo- and epi-cardial (O’Hara et al., PLoS Comput. Biol., 2011, 7, e1002061) models, by changes in maximal ionic conductance reproduces these repolarisation abnormalities. Simulations of cell populations with Gaussian distributions of maximal conductance parameters predict a CO induced increase in APD and its variability. Incorporation of these predicted CO induced conductance changes in human ventricular cell electrophysiology into ventricular tissue and wall models give changes in indices for the probability of the initiation of re-entrant arrhythmia.

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