Elucidating the antiarrhythmic effect of targeting the cyclic guanosine monophosphate pathway

Abstract

Cardiac arrhythmias are a leading cause of mortality worldwide and often co-precipitate alongside other cardiovascular diseases (CVDs) such as heart failure (HF), post-myocardial infarction and in genetic conditions such as catecholaminergic polymorphic ventricular tachycardia (CPVT). Dysregulated calcium (Ca2+) handling within the cardiac myocytes is a key driver for cardiac arrhythmias, and recent evidence has suggested that modulation of the cyclic nucleotide, cyclic guanosine monophosphate (cGMP) provides antiarrhythmic effects through regulating cellular Ca2+ homeostasis. The present study assesses the antiarrhythmic efficacy of cGMP through utilising the drug Cinaciguat (CIN), to activate soluble guanylyl cyclase (sGC) to produce cGMP. CIN is therapeutically advantageous due to maintaining cGMP production independently of nitric oxide/sGC heme oxidation status (which can be augmented in CVDs). This study aims to assess whether modulating the cGMP pathway via CIN provides antiarrhythmic benefits at the cellular, whole heart and in vivo level in several different pro-arrhythmic models with a specific focus on Ca2+ handling alterations. In both control and pro-arrhythmic HF ovine ventricular myocytes, CIN modulated the systolic Ca2+ transient and provided antiarrhythmic effects, preventing cellular Ca2+ waves. Mechanistically, these effects were mediated through the cGMP effector protein kinase G (PKG) regulating downstream excitation contraction coupling components. Furthermore, in a pro-arrhythmic CPVT mouse model, underpinned by Ca2+ misregulation, antiarrhythmic effects were also provided when CIN reduced spontaneous Ca2+ release, whole cell Ca2+ waves and also augmented parameters of the Ca2+ transient under both baseline and catecholamine stimulation. To assess whether the cellular antiarrhythmic effect provided persisted in ex vivo perfused CPVT hearts, dual Ca2+ and voltage optical mapping was utilised. cGMP modulation reduced whole heart arrhythmias and augmented whole heart Ca2+ and voltage parameters. This antiarrhythmic effect persisted at the in vivo level whereby CIN abrogated catecholamine induced arrhythmias in CPVT mice. This study is the first to demonstrate sGC activation modulates cardiac myocyte Ca2+ handling and provides antiarrhythmic benefits at every experimental level. This study may therefore have important implications for future clinical cardiac arrhythmia management due to the recent approval of sGC modulators in HF, and the current pharmaceutical effort to identify novel 2nd generation sGC activators.

Date of Award	19 Dec 2023
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Andy Trafford (Supervisor) & Luigi Venetucci (Supervisor)