Sympathetic Nervous Regulation of Calcium and Action Potential Alternans in the Intact Heart

Abstract

Rationale: Arrhythmogenic cardiac alternans are thought to be an important determinant for the initiation of ventricular fibrillation. There is limited information on the effects of sympathetic nerve stimulation (SNS) on alternans in the intact heart and the conclusions of existing studies, focused on investigating electrical alternans, are conflicted. Meanwhile, several lines of evidence implicate instabilities in Ca handling, not electrical restitution, as the primary mechanism underpinning alternans. Despite this, there have been no studies on Ca alternans and SNS in the intact heart. The present study sought to address this, by application of voltage and Ca optical mapping for the simultaneous study of APD and Ca alternans in the intact guinea pig heart during direct SNS.Objective: To determine the effects of SNS on APD and Ca alternans in the intact guinea pig heart and to examine the mechanism(s) by which the effects of SNS are mediated.Methods and Results: Studies utilized simultaneous voltage and Ca optical mapping in isolated guinea pig hearts with intact innervation. Alternans were induced using a rapid dynamic pacing protocol. SNS was associated with rate-independent shortening of action potential duration (APD) and the suppression of APD and Ca alternans, as indicated by a shift in the alternans threshold to faster pacing rates. Qualitatively similar results were observed with exogenous noradrenaline perfusion. In contrast with previous reports, both SNS and noradrenaline acted to flatten the slope of the electrical restitution curve. Pharmacological block of the slow delayed rectifying potassium current (IKs), sufficient to abolish IKs-mediated APD-adaptation, partially reversed the effects of SNS on pacing-induced alternans. Treatment with cyclopiazonic acid, an inhibitor of the sarco(endo)plasmic reticulum ATPase, had opposite effects to that of SNS, acting to increase susceptibility to alternans, and suggesting that accelerated Ca reuptake into the sarcoplasmic reticulum is a major mechanism by which SNS suppresses alternans in the guinea pig heart.Conclusions: SNS suppresses calcium and action potential alternans in the intact guinea pig heart by an action mediated through accelerated Ca handling and via increased IKs.

Age‐related changes in cardiac electrophysiology and calcium handling in response to sympathetic nerve stimulation

“…; Winter et al . ). Although these differences may be species‐dependent, our data indicate that age may also play an important role in how SNS impacts alternans severity.…”

“…; Winter et al . ). Following mid‐sternal incision, the thoracic cavity was isolated with the intact spinal column (T1‐T12 vertebrae).…”

ElectroMap: High-throughput open-source software for analysis and mapping of cardiac electrophysiology

“…Pacing was performed via bipolar platinum electrode, and fluorescence captured using ORCA flash 4.0 camera (1 kHz sampling rate, maximum field of view: 200 × 2048 pixels, 71 µm/pixel, Hamamatsu Electronics, Japan). Isolated guinea pig hearts 8 were loaded with voltage dye Di-8-ANEPPS, paced via silver bipolar electrodes and imaged using Evolve Delta 512 × 512 pixel EMCCD cameras (500 Hz sampling rate, 64 × 64 pixels, 320 µm/pixel, Photometrics, USA) mounted on a Olympus MVX10 stereomicroscope.…”

“…Optically imaging intact tissue using voltage or calcium sensitive fluorescent dyes has advantages over surface electrodes but the requirement for contraction uncouplers and inability to perform in vivo experiments limits clinical utility of optical mapping 4 . Nevertheless, insights from optical mapping experiments have informed our understanding of complex arrhythmias and electrophysiological remodelling in heart disease 5–8 . Electrode mapping has equally provided vital knowledge 9,10 , demonstrating that re-entry drives ventricular tachycardia 11 , actively guiding current clinical ablation strategies.…”

Disruption of STAT6 Signal Promotes Cardiac Fibrosis Through the Mobilization and Transformation of CD11b+ Immature Myeloid Cells

“…The sympathetic-catecholamine system is involved in the regulation of multiple cardiovascular physiological activities through adrenergic receptor (Winter et al, 2018;Schinner et al, 2017). β-AR is a member of the superfamily of G protein-coupled receptors, which are also called seven-transmembrane receptors (Vassilatis et al, 2003).…”