Key result
Pathological stretch triggers pulmonary vein arrhythmogenesis by activating caveolae-associated mechanosensitive chloride channels.
Why the study?
Mechanoelectric feedback in atrial dilation is linked to ectopic beats triggering paroxysmal AF from pulmonary veins, but the precise mechanisms remain poorly understood.
Does caveolae-mediated activation of mechanosensitive chloride channels trigger atrial arrhythmogenesis in stretched pulmonary veins?
Does caveolae-mediated activation of mechanosensitive chloride channels trigger atrial arrhythmogenesis in stretched pulmonary veins?
This study identifies caveolae-mediated activation of mechanosensitive chloride channels as a novel mechanistic trigger for atrial fibrillation, particularly in the context of elevated blood pressure and atrial dilation.
Answers are grounded in this paper and cite their sources.
May support ICl,swell as AF trigger in hypertension; hypothesis-generating, requires human validation before practice change.
Background Atrial fibrillation often occurs in the setting of hypertension and associated atrial dilation with pathologically increased cardiomyocyte stretch. In the setting of atrial dilation, mechanoelectric feedback has been linked to the development of ectopic beats that trigger paroxysmal atrial fibrillation mainly originating from pulmonary veins ( PVs ). However, the precise mechanisms remain poorly understood. Methods and Results We identify mechanosensitive, swelling‐activated chloride ion channels ( I C l,swell ) as a crucial component of the caveolar mechanosensitive complex in rat and human cardiomyocytes. In vitro optical mapping of rat PV , single rat PV , and human cardiomyocyte patch clamp studies showed that stretch‐induced activation of I Cl,swell leads to membrane depolarization and decreased action potential amplitude, which trigger conduction discontinuities and both ectopic and reentrant activities within the PV . Reverse transcription quantitative polymerase chain reaction, immunofluorescence, and coimmunoprecipitation studies showed that I Cl,swell likely consists of at least 2 components produced by mechanosensitive ClC‐3 (chloride channel‐3) and SWELL 1 (also known as LRRC8A [leucine rich repeat containing protein 8A]) chloride channels, which form a macromolecular complex with caveolar scaffolding protein Cav3 (caveolin 3). Downregulation of Cav3 protein expression and disruption of caveolae structures during chronic hypertension in spontaneously hypertensive rats facilitates activation of I Cl,swell and increases PV sensitivity to stretch 10‐ to 50‐fold, promoting the development of atrial fibrillation. Conclusions Our findings identify caveolae‐mediated activation of mechanosensitive I Cl,swell as a critical cause of PV ectopic beats that can initiate atrial arrhythmias including atrial fibrillation. This mechanism is exacerbated in the setting of chronically elevated blood pressures.
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Egorov et al. (2019) studied Atrial arrhythmogenesis / Pulmonary vein ectopic beats (n=79). Pathological mechanical stretch / hypotonic swelling vs. Unstretched baseline / isotonic conditions was evaluated on Membrane depolarization, action potential amplitude suppression, and intra-PV conduction block. Pathological stretch activates caveolae-associated mechanosensitive chloride channels (ICl,swell), leading to membrane depolarization and intra-pulmonary vein conduction discontinuities that trigger ectopic and reentrant activities.
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