Cold exposure and the cardiovascular system: from physiological adaptation to pathological risk

Figures

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  FIGURE 1. From established evidence to proposed hypothesis: a homologous framework for cold adaptation in striated muscle. (Left panel, Evidence in Skeletal Muscle): The established adaptive cascade to cold in skeletal muscle involves sympathetic nervous system (SNS) activation, norepinephrine (NE) release, and the subsequent induction of futile calcium cycling (via RyR1, SERCA, and SLN) and mitochondrial remodeling (upregulated PGC-1α), culminating in heat production. (Right panel, Proposed Homology in Cardiac Muscle): Based on the evolutionary and structural similarities between striated muscle types, we propose that cardiac muscle may employ homologous adaptive pathways. Cold-induced SNS activation and NE release could similarly drive metabolic remodeling (via the SIRT1-PGC-1α axis), promote electrophysiological homeostasis (mediated by CIRP), and activate the cardiac-adipose axis (ANP/BNP release stimulating BAT thermogenesis), collectively contributing to cardioprotection and potential systemic thermoregulation.

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  FIGURE 2. Cold Exposure Signaling cascades: The mechanistic foundations of dual cardiovascular outcomes. The following schematic represents the major molecular pathways involved following cold exposure which results in either physiological adaptation (left) or pathological effects (right). Peripheral thermoreceptors (e.g., TRPM8) and central thermoregulatory centers initially receive cold stimuli and are sensed by three major response axes: (1) Sympathetic Nervous System (SNS) activation releasing norepinephrine (NE); (2) Hypothalamic-Pituitary-Thyroid (HPT) axis activation that raises thyroid hormone (TH) levels; and (3) local cellular-level stress responses such as cold-inducible RNA-binding protein (CIRP) up These major cues diverge on tissue-specific effectors: in the heart they generate protective metabolic reprogramming by SIRT1-PGC-1α, and electrophysiological stabilization by CIRP; in vasculature they regulate vasoconstriction/vasodilation; in brown adipose tissue (BAT) they induce thermogenesis by UCP1. Adaptive effects (left) are improved cardiac tolerance, metabolic optimization, and communication between cardiac-adipose axis. Nonetheless, when abnormal and/or acute, and/or…

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  FIGURE 3. Divergent Adaptive Strategies of Cardiac and Skeletal Muscle to Cold Exposure. This is a comparative figure that shows major disparities in the heart and skeletal muscle response to and adaptation during cold stress. Although they are both striated muscles that both are subjected to sympathetic stimulation, the adaptations of the two differ greatly because they have different main physiological roles. Heart competitions metabolic efficiency and contractile function (e.g., through the SIRT1-PGC-1 actions), skeletal muscle remodels to increase thermogenic capacity (e.g., by mitochondrial uncoupling and cristae biogenesis), serving as a distributed warmer to the rest of the system.

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  FIGURE 4. Biphasic Regulatory Network of Cold Exposure on the Cardiovascular System. Intermittent but moderate cold exposure (left pathway) prompts the activation of sympathetic nervous system and favorable activation of the hypothalamic-pituitary-thyroid (HPT) axis, which affect the systemic metabolism and tolerance of the cardiac system. This triggers a protective cascade including brown adipose tissue (BAT) thermogenesis, cardiac metabolic optimization (e.g., via SIRT1-PGC-1α), electrophysiological stabilization (mediated by CIRP), cardiac-adipose axis activation, and ultimately cardiovascular benefits. In contrast, exaggerated, chronic cold exposure (right pathway) induces sympathetic hyperactivation coupled with a maladaptive or excessive stimulation of the HPT axis, contributing to a pathologic cascade of acute hemodynamic overload, myocardial ischemia, electrophysiological dysfunction, inflammation, fibrosis, cell death, and ultimately increased risks of coronary artery disease (CAD), heart failure (HF), atrial fibrillation (AF), and hypertension (HTN). Key regulatory molecules in these opposing processes include CIRP, SIRT1-PGC-1α, and TMAO.