Cellular and Subcellular Mechanisms of Ventricular Mechano-Arrhythmogenicity

Abstract

The heart is an electro-mechanical pump with feedback mechanisms for responding to acute changes in its mechanical environment. This requires cellular and subcellular elements of cardiac mechano-sensitivity, including mechano-electric effectors (e.g., mechano-sensitive channels), mechano-electric transducers (e.g., the microtubule network, MTN), and mechano-electric mediators (e.g., ROS and Ca2+), which allow the heart to respond to mechanical stimuli through electrophysiological changes. While critical for tuning normal electro-mechanical function, disease-related alterations in cardiac mechano-sensitivity can contribute to arrhythmogenesis. The overall goal of my thesis was to investigate cellular and subcellular mechanisms of mechano-arrhythmogenicity in models of two specific pathologic states: acute ischaemia and hypertension.

Arrhythmogenesis in acute ischaemia involves the combination of stretch at the ischaemic border zone, and alterations in voltage-Ca2+ dynamics that create a ‘vulnerable period’ (VP) for mechano-arrhythmogenicity during which Ca2+ remains high in repolarising cells. The goal of this project was to: (i) determine if ischaemia enhances mechano-sensitive mechano-electric mediator production; (ii) isolate the role of the VP in mechano-arrhythmogenicity; and (iii) identify mechanisms underlying mechano-arrhythmogenicity during acute ischaemia. We showed that during ischaemia, mechano-arrhythmogenicity is enhanced specifically in the VP, and involves ROS, intracellular Ca2+, and the mechano-sensitive, Ca2+ permeable TRPA1 channel. Further, we showed that stretch-induced increases in ROS and Ca2+ spark production is enhanced in ischaemia, suggesting increased mechano-sensitivity, which may contribute to an arrhythmogenic substrate and/or modulate the activity of TRPA1 channels.

In hypertension, acute hemodynamic fluctuations in the presence of structural remodelling contribute to the high arrhythmic burden. Increased MTN density or stability (via detyrosination or acetylation) may increase mechano-sensitivity by enhancing mechano-transduction or mechano-effector activity (e.g., TRPA1 channels), consequentially reducing the stretch-threshold for arrhythmias. The goal of this project was to assess the role of acute changes in MTN density and stability in mechano-arrhythmogenicity. We demonstrated that increasing MTN detyrosination, rather than stiffness or acetylation, enhances mechano-arrhythmogenicity, which can be mitigated by blocking TRPA1.

Overall, the results of my thesis have given us further insight into mechanisms underlying mechanically-induced arrhythmias in acute ischaemia and hypertension, and in particular, have demonstrated the exciting potential for TRPA1 as a source of ventricular mechano-arrhythmogenicity.