Saturday, September 7, 2024
9/7/2024
ABSTRACT Mechanical load is a fundamental regulator of cardiac function. The heart operates in a dynamically changing mechanical environment, and alterations in intra-cardiac pressure and/or volume preload/afterload influence cardiac performance to coordinate cardiac output with venous return and arterial blood supply. A crucial aspect of this regulation is the modulation of heart rate, which is controlled by the sinoatrial node (SAN), the primary pacemaker of the heart. The SAN anatomy and location within the heart enable it to detect fluctuations in both coronary and atrial blood pressure, establishing a structural foundation for the regulation of heart rate through SAN mechanosensitivity in response to hemodynamic changes. Although physiological stretch is an essential component of the SAN autoregulatory feedback mechanism, chronically elevated stretch results in severe myocardial remodeling and leads to SAN dysfunction (SND), also known as sick sinus syndrome. Conditions associated with mechanical overload, such as hypertension, often exhibit SND, which manifests as bradycardia, irregular atrial pauses, and sinus arrest/block. The upstream mechanisms of SND in the hypertensive heart are unexplored and contribute to lack of preventative intervention. We will address this gap in knowledge by employing a combination of several multi-level cutting-edge imaging modalities of cellular microarchitecture, Ca2+ and cAMP dynamics, electrophysiological measurements, biochemical studies, and computational modeling to demonstrate an innovative concept that proposes a tight association between mechanical loading, SAN pacemaking, and its regulation by the autonomic nervous system through a mechanosensitive caveolar pacemaker signalosome. This caveolar domain provides the spatiotemporal foundation for mechano- electrochemical signal transduction and heart rhythm regulation, which involves stretch-induced augmentation of cAMP production and cAMP/PKA-mediated phosphorylation of Ca2+ handling and sarcolemmal proteins as well as activation of caveolar mechano-sensitive ion channels. We propose that prolonged (chronic) atrial overload leads to the degradation of caveolae, causing SND and an altered response to both mechanical and autonomic stimulation, which forms the molecular basis for chronotropic incompetence. Preventing caveolae degradation or restoring caveolae structures could alleviate SND phenotype and improve the SAN ability to adequately respond to emotional or physical stressors. This research holds significant potential impact as it will provide mechanistic insights that can serve as a foundation for developing innovative therapeutic strategies aimed at preventing SND in hypertensive individuals.
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