Clinical neurocardiology: defining the value of neuroscience‐based cardiovascular therapeutics – 2024 update

The Journal of Physiology, Год журнала: 2025, Номер unknown

Опубликована: Март 8, 2025

The intricate role of the autonomic nervous system (ANS) in regulating cardiac physiology has long been recognized. Aberrant function ANS is central to pathophysiology cardiovascular diseases. It stands reason, therefore, that neuroscience-based therapeutics hold great promise treatment diseases humans. A decade after inaugural edition, this White Paper reviews current state understanding human neuroanatomy, neurophysiology and specific disease conditions, testing, risk stratification, neuromodulatory strategies mitigate progression

Язык: Английский

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Pacemaker Channels and the Chronotropic Response in Health and Disease

Circulation Research, Год журнала: 2024, Номер 134(10), С. 1348 - 1378

Опубликована: Май 9, 2024

Loss or dysregulation of the normally precise control heart rate via autonomic nervous system plays a critical role during development and progression cardiovascular disease-including ischemic disease, failure, arrhythmias. While clinical significance regulating changes in rate, known as chronotropic effect, is undeniable, mechanisms controlling these remain not fully understood. Heart acceleration deceleration are mediated by increasing decreasing spontaneous firing pacemaker cells sinoatrial node. During transition from rest to activity, sympathetic neurons stimulate activating β-adrenergic receptors intracellular cyclic adenosine monophosphate. The same signal transduction pathway targeted positive drugs such norepinephrine dobutamine, which used treatment cardiogenic shock severe failure. monophosphate-sensitive hyperpolarization-activated current (I

Язык: Английский

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Revisiting Cardiac Biology in the Era of Single Cell and Spatial Omics

Circulation Research, Год журнала: 2024, Номер 134(12), С. 1681 - 1702

Опубликована: Июнь 6, 2024

Throughout our lifetime, each beat of the heart requires coordinated action multiple cardiac cell types. Understanding biology, its intricate microenvironments, and mechanisms that govern their function in health disease are crucial to designing novel therapeutical behavioral interventions. Recent advances single-cell spatial omics technologies have significantly propelled this understanding, offering insights into cellular diversity complex interactions tissue. This review provides a comprehensive overview landscape heart, bridging gap between suspension-based emerging situ approaches, focusing on experimental computational challenges, comparative analyses mouse human systems, rising contextualization cells within niches. As we explore at unprecedented resolution, integrating from both studies will pave way for diagnostic tools therapeutic interventions, ultimately improving outcomes patients with cardiovascular diseases.

Язык: Английский

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Are physiological oscillationsphysiological?

The Journal of Physiology, Год журнала: 2023, Номер unknown

Опубликована: Авг. 25, 2023

Abstract Despite widespread and striking examples of physiological oscillations, their functional role is often unclear. Even glycolysis, the paradigm example oscillatory biochemistry, has seen questions about its function. Here, we take a systems approach to argue that oscillations play critical roles, such as enabling avoid desensitization, chronically high therefore toxic levels chemicals, become more resistant noise. Oscillation also enables complex reconcile incompatible conditions oxidation reduction, by cycling between them, synchronize many small units into one large effect. In pancreatic β‐cells, glycolytic with calcium mitochondrial drive pulsatile insulin release, for liver regulation glucose. addition, oscillation can keep biological time, essential embryonic development in promoting cell diversity pattern formation. The importance processes requires re‐thinking traditional doctrine homeostasis, holding quantities are maintained at constant equilibrium values, view largely failed clinic. A dynamic will initiate shift our health disease. deeper look mechanisms create, sustain abolish language nonlinear dynamics, well beyond linearization techniques control theory. Nonlinear dynamics us identify (‘pacemaking’) cellular, tissue system levels. image

Язык: Английский

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Cardiac arrhythmogenesis: roles of ion channels and their functional modification

Frontiers in Physiology, Год журнала: 2024, Номер 15

Опубликована: Март 4, 2024

Cardiac arrhythmias cause significant morbidity and mortality pose a major public health problem. They arise from disruptions in the normally orderly propagation of cardiac electrophysiological activation recovery through successive cardiomyocytes heart. reflect abnormalities automaticity, initiation, conduction, or cardiomyocyte excitation. The latter properties are dependent on surface membrane mechanisms underlying action potential. Their disruption results spatial temporal instabilities heterogeneities generation cellular These abnormal function their membrane, ion channels, transporters, as well interactions between them. latter, turn, form common regulatory targets for hierarchical network diverse signaling reviewed here. In addition to direct molecular-level pharmacological physiological actions these biomolecules, accessory, adhesion, signal transduction, cytoskeletal anchoring proteins modify both localization. At level excitation–contraction coupling processes, Ca 2+ homeostatic phosphorylation processes affect channel activity excitability directly intermediate signaling. Systems -level autonomic exerts acute longer-term expression. Further upstream intermediaries metabolic changes modulate channels themselves modifying homeostasis. Finally, organ inflammatory structural changes, such fibrotic hypertrophic remodeling, similarly can influence all with potential pro-arrhythmic consequences. normal may target either individual groups ionic species alter particular pathological conditions. also potentially alterable by action, effects protein cofactor structure, expression, participating specific often clarified experimental genetically modified models, thus constitute therapeutic targets. insights framework outlined here provide basis recent modernized drug classification. Together, they offer translational current understanding. This would facilitate future mechanistically directed advances, which number examples considered useful treating cardiac, arrhythmic, disease.

Язык: Английский

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What makes the sinoatrial node tick? A question not for the faint of heart

Philosophical Transactions of the Royal Society B Biological Sciences, Год журнала: 2023, Номер 378(1879)

Опубликована: Май 1, 2023

Even before the sinoatrial node (SAN) was discovered, cardiovascular science engaged in an active investigation of when and why heart would beat. After electrochemical theory bioelectric membrane potentials formulated first action were measured contracting muscle cells, field became divided: some investigators studied electrophysiology ion channels, others contraction. It later known that changes intracellular Ca 2+ cause The pacemaking reunited by coupled-clock pacemaker cell function, which integrated cycling transmembrane voltage into one rhythmogenic system. In this review, we will discuss recent discoveries contextualize system, described isolated SAN complex world tissue: heterogeneous local releases, generated within cells regulated other types cytoarchitecture, variably co-localize synchronize to give rise relatively rhythmic impulses emanate from excite heart. We ultimately conceptualize as a brain-like structure, composed intercommunicating meshworks multiple interstitial intertwined networks nerves glial more. This article is part theme issue ‘The heartbeat: its molecular basis physiological mechanisms’.

Язык: Английский

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Cardiomyocyte electrophysiology and its modulation: current views and future prospects

Philosophical Transactions of the Royal Society B Biological Sciences, Год журнала: 2023, Номер 378(1879)

Опубликована: Май 1, 2023

Normal and abnormal cardiac rhythms are of key physiological clinical interest. This introductory article begins from Sylvio Weidmann's historic 1950s microelectrode measurements electrophysiological activity Singh & Vaughan Williams's classification cardiotropic targets. It then proceeds to introduce the insights into cardiomyocyte function its regulation that subsequently emerged their therapeutic implications. We recapitulate resulting view surface membrane events underlying excitation initiation, conduction recovery constitute final common path for cellular mechanisms impinge upon this normal or activity. consider progress in more recently characterized successive regulatory hierarchies involving Ca

Язык: Английский

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Heart Rhythm Harmony Becomes Discordant as We Age

Heart Lung and Circulation, Год журнала: 2025, Номер unknown

Опубликована: Май 1, 2025

Heartbeats are initiated by pacemaker cells within the sinoatrial node (SAN) that generate spontaneous impulses at intervals resonate around a preferred mean frequency. A coupled-clock system (CCS) intrinsic to individual cells, is modulated autonomic input, drives SAN normal automaticity. Subcellular and cell-wide mechanisms CCS in "dynamic equilibrium," never achieve true steady state. Nanoscale electromagnetic "vibrations" caused their modulation create heartbeat rhythm, ("heartbeat music"). "Heart-Brain Grand Symphony" (HBGS), emerges from this "beautiful noise" as heart beats, broadcast body surface, its numerous motifs symphony can be experienced tuning into electrocardiogram (EKG) RR-interval variability rhythms. As age increases, one or more of components physiologic coupling neuroautonomic regulatory sinus atrial networks begins deteriorate, cacophony HBGS, manifested reductions rate rhythm which fires action potentials. These subclinical changes structure function advances become "partners" with pathophysiology defines clinical other cardiac tissue diseases, e.g., Sick Sinus Syndrome fibrillation, such age-associated co-morbidities these diseases. In terms advances, sub-clinical function, per se, major shareholders disease enterprises.

Язык: Английский

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Cardiovascular System, Its Functions and Disorders

Опубликована: Янв. 1, 2024

Язык: Английский

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Electrophysiological and sick sinus syndrome effects of Remdesivir challenge in guinea-pig hearts

Frontiers in Physiology, Год журнала: 2024, Номер 15

Опубликована: Авг. 13, 2024

Remdesivir (RDV) is the first drug approved by FDA for clinical treatment of hospitalized patients infected with COVID-19 because it has been shown to have good antiviral activity against a variety viruses, including Arenaviridae and Coronaviridae viral families. However, reported that its leads symptoms sick sinus syndrome such as bradycardia, conduction block, arrest, but electrophysiological mechanism specific cardiac adverse events still unclear. We report complementary, experimental, studies effects. In wireless telemetry experiments in vivo electrocardiographic ex preparations, RDV significantly caused atrial prolongation QT interval guinea pigs. Dose-dependent effects on electrical activities sinoatrial node (SA node) preparations pigs were characterised multielectrode, optical RH237 voltage mapping. These revealed reversibly reduced time (SACT), increased AP durations (APDs), decreased pacemaking rate SA node. Patch-clamp showed inhibited I f current HCN4 channels, resulting significant decrease spontaneous firing cells, which may underlie development syndrome. addition, inhibits Kr currents hERG leading playing role bradycardia. Therefore, these findings provide insights into understanding bradycardia effect RDV, be used basic theoretical guidance intervention events, prompt safety investigations RDV’s future.

Язык: Английский

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