Killing Many Birds With Two Stones: Hypoxia and Fibrosis Can Generate Ectopic Beats in a Human Ventricular Model

Abstract

During cardiac diseases many types of anatomical and functional remodeling of cardiac tissue can occur. In this work, we focus on two conditions: hypoxia and fibrosis, which are part of complex pathological modifications that take place in many cardiac diseases (hypertrophic cardiomyopathy, hypertensive heart disease, and recurrent myocardial infarction) and respiratory diseases (obstructive pulmonary disease, obstructive sleep apnea, and cystic fibrosis). Using computational models of cardiac electrophysiology, we evaluate if the interplay between hypoxia and fibrosis is sufficient to trigger cardiac arrhythmia. We study the mechanisms behind the generation of ectopic beats, an arrhythmic trigger also known as premature ventricular contractions (PVCs), in regions with high hypoxia and fibrosis. First, we modify an electrophysiological model of myocytes of the human left ventricle to include the effects of hypoxia. Second, diffuse fibrosis is modeled by randomly replacing cardiac myocytes by non-excitable and non-conducting cells. The Monte Carlo method is used to evaluate the probability of a region to generate ectopic beats with respect to different levels of hypoxia and fibrosis. In addition, we evaluate the minimum size of three-dimensional slabs needed to sustain reentries for different stimulation protocols. The observed mechanism behind the initiation of ectopic beats is unidirectional block, giving rise to sustained micro-reentries inside the region with diffuse fibrosis and hypoxia. In summary, our results suggest that hypoxia and fibrosis are sufficient for the creation of a focal region in the heart that generates PVCs.

Acute effects of alcohol on cardiac electrophysiology and arrhythmogenesis: Insights from multiscale in silico analyses

“…We initially simulated a mild degree of fibrosis (4-5% fibrosis) for all three fibrosis types. However, as previously reported [37], the 4% diffuse fibrosis significantly impaired wave propagation. Therefore, we had to reduce the amount of fibrosis to 1.2% to maintain wave propagation throughout the tissue.…”

Burden of premature ventricular contractions beyond nonsustained ventricular tachycardia is related to the myocardial extracellular space expansion in patients with hypertrophic‐cardiomyopathy

“…hypoxia, as a trigger ectopic beat or fatal ventricular arrhythmia, contribute to high arrhythmic propensity in HCM. 4 Consistent with previous studies, higher myocardial fibrotic burden was seen in the NSVT group. Furthermore, higher LGE% and ECV and lower post-T1 value were seen in the higher PVC burden group compared with the lower PVC burden group even in the patients without NSVT in our study.…”

“…In HCM, myocyte disarray and myocardial fibrosis play a critical role in the arrhythmogenesis by promoting dispersion of electrical depolarization and repolarization, which results in the unidirectional conduction block and re‐entry. Both fibrosis, as an abnormal substrate, and ischemia or hypoxia, as a trigger ectopic beat or fatal ventricular arrhythmia, contribute to high arrhythmic propensity in HCM 4 . Consistent with previous studies, higher myocardial fibrotic burden was seen in the NSVT group.…”

“…A fibrotic myocardium could trigger and act as a substrate for both premature ventricular contraction (PVC) and NSVT. 4 High-PVC burden may reflect myocardial fibrosis even in the absence of NSVT. Moreover, sarcomere-associated gene mutations have been associated with ventricular arrhythmia.…”

“…However, there are some cases that NSVT is not detected in a 24 to 48 hour Holter monitoring, a recommendation of the current guidelines. A fibrotic myocardium could trigger and act as a substrate for both premature ventricular contraction (PVC) and NSVT 4 . High‐PVC burden may reflect myocardial fibrosis even in the absence of NSVT.…”