Acute mechanical stretch enhances β‐adrenergic–protein kinase A signalling and increases susceptibility to ventricular arrhythmias

Mechanical stretch can increase ventricular arrhythmia susceptibility during sympathetic activation, but the mechanisms linking stretch to altered β‐adrenergic receptor (βAR) signalling, Ca 2 + handling and electrical instability remain unclear. We tested whether left ventricular (LV) stretch alters Cav3‐associated membrane organisation and enhances βAR–protein kinase A (PKA)‐dependent arrhythmogenic signalling. Langendorff‐perfused male rat hearts were studied using a fluid‐filled LV balloon, with sham hearts fitted with an unstretched balloon. Optical mapping during S1–S2 programmed stimulation showed that LV stretch had limited effects at baseline but altered the response to βAR stimulation, increasing ventricular arrhythmia severity, prolonging APD50, reducing local conduction velocity and steepening APD80 restitution. H89 markedly reduced βAR stimulation‐induced arrhythmia severity in stretched hearts, whereas KN93 did not provide comparable protection. LV stretch also increased cardiomyocyte length and altered Cav3 organisation at wheat germ agglutinin (WGA)‐defined membrane regions. In isolated LV cardiomyocytes, hypoosmotic membrane deformation did not alter basal caffeine‐induced Ca 2 + release but enhanced isoprenaline‐induced irregular activity and Ca 2 + ‐transient amplitude, both of which were attenuated by PKA inhibition. Hypoosmotic membrane deformation also amplified isoprenaline‐evoked PKA activity and increased RyR2 Ser2030 phosphorylation. These findings indicate that LV mechanical stretch alters the ventricular βAR response in association with altered Cav3‐associated membrane organisation and enhanced βAR–PKA‐dependent Ca 2 + instability. image Key points Left ventricular (LV) balloon stretch has limited baseline electrophysiological effects but increases arrhythmia severity, slows conduction and steepens APD80 restitution during β‐adrenergic stimulation. LV balloon stretch is associated with cardiomyocyte elongation and altered Cav3 enrichment at wheat germ agglutinin (WGA)‐defined membrane regions. Hypoosmotic membrane deformation enhances isoprenaline‐induced irregular activity and Ca 2 + ‐transient amplitude without increasing basal caffeine‐induced Ca 2 + release. PKA inhibition reduces stretch‐enhanced irregular activity in isolated ventricular myocytes and β‐adrenergic receptor (βAR)‐induced arrhythmia severity in stretched hearts. Hypoosmotic membrane deformation enhances isoprenaline‐evoked PKA activity and increases RyR2 Ser2030 phosphorylation.