The hemodynamic response to acute cold, typically studied using experiments such as the cold pressor test (CPT) or cold-water immersion, is defined by the sudden onset of sympatho-adrenal activity. The present evidence shows that the CPT is followed by a marked increase in heart rate, systolic and diastolic arterial pressure, and rate-pressure product (RPP) in healthy adults, unequivocal proof of increased myocardial oxygen demand (Drost et al., 2024; Bullock et al., 2023). However, this hemodynamic reactivity exhibits significant inter-individual variation. For instance, essential hypertensive subjects show blunted heart rate and diastolic blood pressure recovery and reactivity to parasympathetic activation after repeated CPT exposure in vivo, which assesses the body’s ability to adapt plastically to repeated cold stress (Bullock et al., 2023). This hemodynamic reaction, largely mediated by α1-adrenergic receptors, is markedly enhanced in postmenopausal women and is designed to emphasize the central importance of sex and age to vascular reactivity (Prodel et al., 2022). Beyond peripheral effects, such sympathetic activation produces a direct cardiac electrophysiological effect, including independent QTc interval prolongation and T-wave amplitude increase, changes only feebly correlated with systemic markers of stress like cortisol and therefore implying an alternative physiological origin (Drost et al., 2024). Furthermore, acute non-shivering cold stress also brings about deep changes in electrocardiographic parameters, including the P axis, QRS axis, and QT interval, although no direct correlation between these changes and BAT activity or plasma catecholamine levels has been reported (Raiko et al., 2021).

The autonomic nervous system also self-adjusts dynamically with exposure to cold. Following the initial sympathetic stimulation, short-term whole-body cold exposure (e.g., cryostimulation or cold-water immersion) has a seemingly paradoxical effect of increasing cardiac vagal tone. This is reflected in shifts in heart rate variability (HRV), characterized by increased high-frequency power (HF) and the root mean square of successive differences (RMSSD) and decreased low-frequency/high-frequency ratio (LF/HF) (Jdidi et al., 2024; Sun et al., 2024). Extensive inter-personal heterogeneity in thermoregulatory responses, such as “activity-thermoregulatory heat substitution”, in which certain individuals consistently exhibit lower energy expenditure during cold activity, is a feature linked with variables like body size and heart mass (Maloney and Careau, 2022). This parasympathetic stimulation in rebound can be partly explained by a “diving reflex” caused by cold and has a positive effect on cardiac autonomic regulation increased with long-term adaptive responses (e.g., repeated cold-water immersion), permitting post-exercise recovery (Malta et al., 2023). The complexity of autonomic control is also made clear by evidence that the threshold temperatures for the induction of sympathetic (via elevated mean arterial pressure) and cardiac parasympathetic (via elevated RMSSD and HF) activity are dissociable; in facial cooling models, a peak sympathetic response can be elicited at 7 °C, but a peak parasympathetic response can only be evoked by a more intense 0 °C stimulus (Gorini Pereira et al., 2024). At extreme cold temperatures (e.g., −5 °C to −15 °C), skin and blood pressure local temperature become the best indicator available to assess cold stress risk, with the initial phase of physiological stress on exposure endangering cognitive judgment and operating ability (Wu et al., 2021).

There is a long-established inverse relationship between blood pressure and environmental temperature, such that even minor decreases precipitate acute blood pressure elevations. Panel studies meticulously illustrate that in proportion to each decline in personal micro-environmental temperature by 1 °C, systolic and diastolic blood pressures in hypertensives rise by an average of 0.96 mmHg and 0.28 mmHg, respectively, within 24 h, a rise far steeper than in normotensive individuals (Xu Y. et al., 2024). Pressor effect is strongest 1–10 h after exposure and more during winter than summer (Xu Y. et al., 2024). Seasonal variation in blood pressure has a highly important effect on the epidemiology of hypertension, particularly in Asian populations, as cold-season increments may have the potential to drive increased incidence rates and complicate control (Park et al., 2020). High-population time-series research also corroborates this reverse correlation, quantifying that with each fall of 1 °C in temperature, risk of mortality and morbidity due to CVD is boosted by 1.6% and 1.2%, respectively (Fan J. F. et al., 2023). Winter disease threats’ dominance is also highlighted by research in Russian subarctic settlements, with the injurious effect of cold dominating that of heatwaves with some exceptions for subarctic settlements with extreme continental climate (Revich and Shaposhnikov, 2022). The speed and the duration of this effect are accounted for by ambulatory blood pressure monitoring, and the effect of ambient temperature on blood pressure has been found to start in the same exposure hour and last as long as 36 h (Fan P. et al., 2023). In addition to direct cardiovascular effects, the synergistic effect of cold and physical inactivity in experimental animal models results in a sharp rise in total serum cholesterol that can serve as an early indicator of systemic reprogramming of metabolism in the conditions of a cold environment (Shmakov et al., 2020).

Its mechanisms are revealed through central stimulation of the sympathetic system and complicated local vascular reactions. The principal role of cold-induced vasoconstriction is the minimization of cutaneous heat loss. Remarkably, dilatation caused by cooling as a new counter-regulatory mechanism was discovered in cutaneous small arteries. The protective dilatation, based on SK3-mediated endothelium-derived hyperpolarization and requiring enhanced communication via myoendothelial gap junctions, is a critical regulator for preventing pathological vasoconstriction for tissue damage (Chang et al., 2023; Flavahan and Flavahan, 2020). At the sensory level, transient receptor potential channel TRPM8 is implicated directly in behavioral cold environment thermoregulation, and enhanced expression following exposure may be a protective adaptive reaction (Thapa et al., 2021a). Downregulation of cold sensors like TRPM8 with age may lead to vasomotor dysfunction and enhance cold-induced blood pressure variability and tissue hypoperfusion (Thapa et al., 2021b). In addition to hypoxia of low pressure, cold stimulation was found to evoke relative preservation of thermoregulatory and cutaneous blood flow responses, as evidenced by increases forehead temperature and pulse with no net significant change, indicating hypoxia does not influence cold-evoked thermoregulation greatly (Shin et al., 2020). In addition, cold stress produces negative hemorheological effects, such as direct and persistent increase in plasma viscosity in conditions of cold climate, offering another significant pathophysiologic connection between cold and enhanced CVD risk (Ni et al., 2022).

In addition to its pronounced effects on the cardiovascular system and brown adipose tissue, cold exposure also modulates sympathetic nervous system (SNS) activity within skeletal muscle. However, its response pattern and tissue specificity differ significantly from those of classic thermogenic organs like BAT. Dulloo et al. conducted a systemic evaluation of the influence of the cold condition and diet on the SNS activity in the various rat tissues through direct measurement of the norepinephrine (NE) turnover, which is a functional index. They discovered that the acute cold exposure (4 °C) did raise NE turnover in skeletal muscles (e.g., gastrocnemius, soleus), indicating heightened sympathetic activity, however the extent of this increase was far less than that in the heart and in interscapular brown adipose tissue (Dulloo et al., 1988). The sympathetic response in skeletal muscle was relatively low even when the cold stimulus was sustained cold exposure over 1 week. In addition, the SNS activity in skeletal muscle was not affected by the dietary manipulations like fasting or feeding the organism on sucrose, unlike the heart and iBAT that are sensitive to such changes. The results of these studies support a high level of heterogeneity of sympathetic outflow and point to the fact that skeletal muscle is not a major locus of sympathetically mediated thermogenic activities to cold and that its role is rather minimal.

Nevertheless, skeletal muscle has the molecular apparatus that can mediate the calorigenic processes of catecholamines. As reviewed by Maslow and Vychuzhanova, catecholamines have the potential to trigger a non-shivering thermogenesis in skeletal muscle, in brown and white adipose tissue, likely through stimulation of β3-adrenergic receptors (β3-AR). It is linked to the process of upregulation of uncoupling proteins (e.g., UCP3), and increased lipid mobilization (Maslov and Vychuzhanova, 2016). Therefore, despite the net reduction in sympathetic stimulation of skeletal muscle, its intrinsic adrenergic signaling in bone, its metabolic reorganising capacity indicates the possibility of a range of control in long-term cold adaptation, and places it as a more than merely passive consumer of energy.

In addition to the acute reactions that are orchestrated by the sympathetic nervous system, skeletal muscle plasticity in mitochondria that is triggered by a chronic cold treatment is core to maintaining its thermogenic potential. Research on high-altitude deer mice (a model exhibiting exceptional cold resistance) demonstrates that chronic cold exposure induces profound remodeling of mitochondrial function to enhance thermogenesis (Mahalingam et al., 2020). Key features of this remodeling include: (1) Enhanced Mitochondrial Uncoupling: This is expressed as increased leak respiration and reduced phosphorylation efficiency as well as OXPHOS coupling efficiency. A process similar to the role of UCP1 in BAT, which tries to uncouple substrate oxidation to ATP production is intended to maximize heat production; (2) Preference of Alterations in the Electron Transport Chain Complexes Preference: The reduction in the number of substrates oxidized by Complex II versus Complexes I + II indicates that the use of specific pathways to substrate oxidation may be rearranged in favor of other pathways.

Moreover, ultrastructural studies in mice further support this remodeling. Exposure to a non-thermoneutral condition, followed by even mild exposure to cold (16 °C), quickly starts a reorganization of skeletal muscle mitochondria that includes their increased abundance, morphological change to more elongated, tubular shapes and most importantly is a significant rise in cristae density. Since cristae are the main places of oxidative phosphorylation, their greater concentration literally means more energy generation and thermogenic possibilities of the mitochondria. These changes are even greater in extreme cold (4 °C). Notably, BAT and skeletal muscle coordinate mitochondrial restructuring during the cold adaptation process and indicates a possible cross-tissue communication mediator role by cytokines (e.g., FGF21 and IL-6) (Bal et al., 2017).

In addition to autonomic and regional tissue adjustments, exposure to cold has global effects, affecting metabolism and cardiovascular activity by activating the hypothalamic-pituitary-thyroid (HPT) axis as one of the endocrine links between environmental and physiological or pathological phenotypes. Cold produces an effect of thyrotropin-releasing hormone (TRH) neurons in hypothalamic nucleus including the paraventricular nucleus, increasing plasma levels of thyroid hormone (TH), increasing basal metabolic rate and thermogenic capacity, and has extensive effects on cardiac structure and function (Zhang et al., 2018; Liu et al., 2025). Adaptive changes in HPT axis hormones have been observed in Antarctic expeditioners depending on ambient temperature, photoperiod, cold exposure time period, and level of stresses (Spinelli and Werner Júnior, 2022).

Direct cardioprotective effects of the thyroid hormones occur. Signs of protective pattern in chronic conditions of administration of thyroxine, p38 MAPK and PKC potentiation of activity modulatory effect on ischemic injury of myocardial cells and post-ischemic functional recovery are observed (Pantos et al., 2002). Hyperthyroid rat models, myocardial stunning induced by ischemia-reperfusion is blocked by TH that coordinates the activity of mitochondrial sodium-calcium exchanger and potassium channels, thus, increasing cardiac energetics and calcium homeostasis (Ragone et al., 2015). In addition to this, TH increases the activity of monolysocardiolipin acyltransferase in cardiac mitochondria, thereby facilitating cardiolipin remodeling and modifying the mitochondrial membrane structure and hemodynamics in the best way possible (Mutter et al., 2000). These results indicate that the activation of the HPT axis during cold can increase cardiac tolerance to cold stress and ischemic stress indicating that cardiac tolerance to cold stress and ischemic stress works better in cold conditions.

Whole-body energy metabolic processes are also coordinated by activation of the HPT axis which has a secondary effect on cardiovascular load. Cold exposure activates TH via HPT axis, which subsequently increases brown adipose tissue and skeletal muscle mitochondrial biogenesis with uncoupling thermogenesis, regulated by β-adrenergic/cAMP/PKA/p38 MAPK/CREB signaling pathway and PGC-1 increased expression (Hohenauer et al., 2025). TH being a key signaling molecule, integrates environmental signals including nutrition, temperature, and photoperiod to coordinate seasonal metabolic, thermogenic and reproductive seasonal processes (Liu et al., 2025). In this way, the HPT axis forms an integral endocrine process of energy redistribution and increased body metabolic rate in adapting to cold.

Still, this adaptive axis is also of a two-sided nature. With prolonged or chronic cold exposure, prolonged HPT axis activation can cause excessive metabolic stimulation and elevated myocardial workload, which can put further stress on the myocardial oxygen demand and promote maladaptive remodeling, especially when pre-existing heart disease is present. Furthermore, the number and severity of thyroid disorders are also seasonal, meaning that environmental influences may affect the tendency of the HPT axis in disease pathogenesis (Liu et al., 2025).

A rapid mismatch between myocardial oxygen supply and demand is central to the pathogenesis of Acute Myocardial Infarction (AMI) and Acute Coronary Syndromes (ACS) and the actual failure of the myocardium in the heart underlying Acute Aortic Dissection (AAD), shares a common focus. The exposure to cold triggers this severe imbalance in a complex pathophysiology. The strong cold-induced sympathetic stimulus has a pronounced stimulating effect on the heart rate and blood pressure, changes of the myocardial contractility which results in substantially high rate-pressure product (RPP) and, as a result, in an increase in myocardial oxygen demand (Ikäheimo, 2018; Valtonen et al., 2022). This increased demand may immediately exceed a fixed or limited supply in the presence of coronary stenosis leading to ischemia or infarction. Meanwhile, cold inhibits oxygen delivery by causing coronary vasospasm and decreasing coronary blood flow (Ikäheimo, 2018), and promotes a pro-thrombotic environment by increasing blood viscosity and high plasma concentrations of fibrinogen contributes to the support of the risk of pro-occlusive coronary thrombosis (Ni et al., 2022). Moreover, the same hemodynamic factors that manifest in drastically elevated blood pressure and high ejection velocity of the left ventricle exert enormous shear stress on the aortic wall which is a major precipitant of AAD in predisposed persons (Chen et al., 2022; Yu et al., 2021; Hu et al., 2023; Sadamatsu et al., 2020). This danger is further enhanced by the high rates of change in temperature, which is believed to chronically harbor endothelial functioning and unbalances atherosclerotic plaques (Chen et al., 2022; Ma et al., 2021). The treatment problem, consequently, is to reduce this acute danger. Such potential is not in the application of acute cold but in the application of chronic and controlled cold adaptation to create a physiological condition of resistance to such stressors. Middle-range models have revealed that moderate cold acclimation has the capability of providing potent cardioprotection that mitigates myocardial infarct size and modulating catecholamine-saturates β-adrenergic receptors (Marvanova et al., 2023). This implies that, in the long-term, a well-modulated protocol of intermittent cold therapy may re-normalize the sympathetic response, and enhance vascular reactivity, so that the pathological hemodynamic effect of acute cold stressor is prevented. The best way forward would therefore be to conduct research on the best conditioning protocol of cold conditioning in high risk patients to ensure that the percentage of cold induced acute events is reduced.

A central phenomenon leading to the exacerbation and progression of chronic diseases like Heart Failure (HF) and Hypertension is a long-term mechanism of chronic hemodynamic and metabolic stress, with stress-induced by cold continually promoting a vicious cycle of pathological adaptation. Pathophysiological underpinnings of this pathway include many, which frequently interact, aspects. To begin with, cold exposure causes systemic vasoconstriction and places an excessive burden on the heart in terms of afterload; in the case of an already compromised heart already working within the confines of its compensatory reserves, this hemodynamic change easily falls into clinical decompensation and hospitalization (Miró et al., 2023; Escolar et al., 2019). More so, hypertensive people have exaggerated pressor effect of cold which is enhanced during winter (Xu Y. et al., 2024; Zhang et al., 2023); this recurring stressor has the capacity to directly ideate left ventricular hypertrophy and progressive vascular damages. A particularly vicious cycle exists between HF and cold via the Heart Failure-BAT axis. HF causes dysfunction of the BAT in turn disrupting choline metabolism causing the increase in the levels of the cardiotoxic metabolite TMAO. TMAO inhibits the mitochondrial activity of the myocardium and empties the energy resources, which additionally deteriorates the cardiac dysfunctions (Yoshida et al., 2022). This metabolic dysfunction-chronic overload loop presents a promising therapeutic target. Of particular interest is the possibility of selective BAT stimulation. As the BAT dysfunction is a symptom of the HF, the strategies aimed at the recovery of its activity (pharmacologically or by the means of controlled and mild cold exposure) might benefit the normal body metabolism and decrease the production of TMAO. In the case of hypertension, when Angiotensin-(1–7) was found to induce WAT browning and thermogenesis (Vargas-Castillo et al., 2020), it opens up a new, conceptually conceptualized cold-mimetic pathway in metabolism of blood pressure regulation. This therefore makes the clinical trials designable in order to examine whether the activation of the non-shivering thermogenesis through the safe cold exposure activities or even the use of pharmaceutical agents can enhance the metabolic conditions of patients with stable HF or hypertension and inhibit the onset of the disease.

Cold stress has a direct pathogenic relationship with the myocardial electrophysiological system, and it shocks the mechanism of electrical homeostasis, creating a substrate of arrhythmias and a high risk of Sudden Cardiac Death (SCD). Several mechanisms underlie this pathological pathway. Firstly, cold pressor test results in the long-term repolarization, which is reflected by the prolongation of QTc interval and higher T-wave amplitude, which suggests the increased dispersion of ventricular repolarization and the formation of a substrate depolarization re-entrant arrhythmia (ventricular tachycardia and ventricular fibrillation) (Drost et al., 2024). Secondly, during individuals who are susceptible and with underlying channelopathies such as long QT Syndrome (LQTS), cold exposure can elicit an unusually steep QT/heart rate relationship, which puts them at an amazing risk of life-threatening events at low heart rates (Takahashi et al., 2020). Thirdly, the dysregulation of protective molecular stabilizers is also crucial; particularly, deficiency of the cold-inducible RNA-binding protein (CIRP) as an important physiological stabilizer that causes a pro-arrhythmic condition by activating potassium channels, quickening repolarization, shortening the action potential duration, and consequently predisposing to arrhythmia like atrial fibrillation (Xie et al., 2020a; Xie et al., 2020b). Consequently, prevention and stabilization is cautioned as the therapeutic emphasis of this pathway instead of the use of cold as an intervention. The importance of CIRP as the key new target of anti-arrhythmic therapy is highlighted by the fact that the approach to preserving or optimizing its activity may help prevent electrophysiological destabilization of the body under cold stress. Beyond, it is possible that additional processes by which intrinsic electrical resilience occurs can identify new processes by investigating the possibility that long-term adaptation to cold (such as in experienced cold-water swimmers) can increase the process of endogenous CIRP and other stabilizing proteins. For clinical practice, these observations demonstrate how important patient education and strict protection, indicating that individuals with known arrhythmogenic conditions should avoid experiencing acute cold strictly.

The pathophysiological pathways outlined above, acute hemodynamic stress, chronic maladaptive remodeling, and electrophysiological instability, have a unified mechanistic explanation of how cold exposure poses a direct challenge to the cardiovascular system. Nevertheless, the severe winter spike of CVD morbidity and mortality witnessed in epidemiology studies demonstrates that in nature the risk environment is never typically determined solely by a single climatic influence (Wang et al., 2020). Cold stress typically occurs within a complex seasonal environment in which several confounding factors come together and may act synergistically with the direct impacts of low temperature (Pettersson et al., 2020). As the epidemiological and pathophysiological data indicate that cold exposure is a direct cause of the acute CVD event (Borchert et al., 2023; Saucy et al., 2021) it is important to note that cold stress can regularly take place in a very complicated seasonal context, which is riddled with a range of confounding factors. These aspects may either act alone, or interact with each other in a synergistic manner with the cardiovascular burden of cold. To start with, there is an increase in respiratory infections (e.g., influenza) in the winter that may trigger an acute cardiovascular event due to systemic inflammation, augmented metabolic rate, and pro-thrombotic actions (Achebak et al., 2024). Second, seasonal air pollution, especially in areas that use fossil fuel to heat buildings, may further increase endothelial dysfunction and oxidative stress which may combine with cold to increase risk to the heart (Rivera-Caravaca et al., 2020). In addition, cold-month changes like decreased physical activity and changes to lower-energy food intake may result into gaining weight and unhealthy changes in blood pressure, and thus a change in baseline risk profile of an individual (Wang M. et al., 2021). Finally, pharmacological factors should be taken into account as, e.g., β-blockers can attenuate the tachycardic response to cold that might lead to a lack of efficient thermoregulation and one of the physiological compensation systems may be concealed (Tang et al., 2023). Therefore, the CVD morbidity and mortality winter peak observed probably represents only an interaction between the direct effect of the cold environment and these concomitant seasonal difficulties, and thus highlights the necessity of combined public health action to handle this syndemic of environmental and behavioral hazards.

As a high energy requiring organ, the heart is subjected to changes in its metabolic program following cold exposure. The short term would seem to be adaptive to cold stress by upregulating the signaling pathway SIRT1-PGC-1α, which promotes mitochondrial biogenesis and function, and increases the capacity for fatty acid oxidation, thereby enhancing cardiac cold tolerance (Mohan et al., 2023a; Mohan et al., 2023b). This adaptive response was recently extended to include intermittent cold stress upregulating cardiac SIRT3, reducing mitochondrial protein acetylation, and enhancing antioxidant defenses via MnSOD, collectively improving mitochondrial metabolic function (Mohan et al., 2023a). Mitochondrial physiological changes with regards to hypothermia are complex; they extend the mitochondria and they inhibit oxygen consumption by inhibiting Drp1, a process because of the inactivation of TRPV1 channels (Taylor et al., 2021). Notably, a metabolic defense of decoupling reactive oxygen species production, respiration, and Ca²⁺ dynamics in mitochondria in heart occurs under hypothermic conditions. The protective effects associated with mild degrees of hypothermia are partly due to blockage of reverse electron transfer as well as blockage of MCU facilitated Ca²⁺ uptake (Stevic et al., 2022).

A distinction between adaptation and pathology is narrow though. The chronic exposure to cold may force the heart into maladaptive remodeling phenotype. Such exposure induces cardiomyocyte enlargement, ANP/BNP hypertrophy marker gene expression and downregulation of fatty acid oxidation genes, which is phenotypically similar to pathologic hypertrophy (Ruperez et al., 2022; Kolleritsch et al., 2023). The process is plastic and reversible. Cardiac hypertrophy caused by cold reverts with re-establishment of thermoneutrality by the induction of autophagy (Ruperez et al., 2022). Another factor has been indicated to be autophagy which plays a critical role in cardiac structural remodeling (Ruperez et al., 2022).

The ultimate solution is: The therapeutic benefit of this route is restated in ischemia-reperfusion conditions where intensive cardioprotection with hypothermia is brought about by augmented autophagic level and mite-related quality (Marek-Iannucci et al., 2019). The path of cardiac energy substrate is also complex to control. May be phosphorylated by PKA: In basal conditions, the lipid droplet-bound protein Perilipin 5 (Plin5) acts as a context-specific rheostat: the CGI-58 sequestration protein Plin5 inhibits ATGL under normal conditions and lipolysis (Zhang et al., 2022). However, when exposed to cold stimuli, Plin5 is phosphorylated by PKA, which removes the inhibition on ATGL to increase the mobilization of fatty acids to cardiac oxidation to support the energy homeostasis in the body Such responses can even be preprogrammed in advance, e.g., the exposure of maternal cold triggers the offspring hypertension by the dysfunctioning of hypothalamus and hyperactivation of sympathetic bisynaptic responses (Chen et al., 2019).

Comparative Insight with Skeletal Muscle: The primary point of divergence is evident on the basis of the detailed above processes (Sections 2.4, 4.1). Although cold stress and catecholaminergic drive are commonly applied, heart and skeletal muscle are characterized by strongly different mitochondrial related adaptation strategies as their physiological functions are different. As a distributed thermogenic organ, skeletal muscle shows adaptations that favour thermogenic performance. This is defined by a high uncoupling propensity alongside systemic augmentation in cristae density both of which contribute to systemic non-shivering thermogenesis. On the other hand, the heart as a constantly operating pump focuses its mitochondrial adaptation on the preservation or regulation of the efficiency of the metabolism. This maintains a permanent ATP production to maintain the contractile ability during hemodynamic stress caused by coldness. Upregulation of mitochondrial biogenesis and fatty acids oxidizing potential through the SIRT1-PGC-1α pathway in the heart is, most importantly, a metabolic, but not active, uncoupling thermogenesis. It is through this functional specialization that the systemic division of labor is effectively captured, skeletal muscle as distributed heaters and the heart as a high-efficiency perpetual motion machine where harmonic function is confined to supporting its own functionality, and has no role to play in thermogenesis. It is this inherent weakness that, in part, could position why the heart would be readily susceptible of cold-induced injuries even though it is well set to withstand plastic reactions. The comparing systematic approach on cold adaptation of cardiac and skeletal muscle tissues is summarized by Figure 3 by showing the divergent sympathetic response and the divergent mitochondrial response based on the different physiological priorities.

Cold exposure has a direct negative effect on the electrophysiological integrity of the heart, promoting arrhythmogenesis. Cold-inducible RNA-binding protein (CIRP) is one of the electrical stability proteins. It has a protective effect, localizing and stabilizing phosphodiesterases PDE4B and PDE4D mRNA and consequently modulates cAMP levels in the sinoatrial node cells and sustaining the guard against an excessive increase in heart rate in case of being burdened with the conditions of the β-adrenergic stimulation (Xie et al., 2020a). CIRP itself is controlled in a complex fashion, with hypothermia in non-hibernating mice altering the splicing of CIRBP transcripts to favor shorter forms that encode functional protein, demonstrating that splicing control is a conserved regulatory mechanism (Horii et al., 2019). Conversely, lack of CIRP fosters a pro-arrhythmic state, upregulating potassium channels (Kv1.5 and Kv4.2/4.3, for example) to accelerate repolarization, shorten the action potential duration, and enhance vulnerability to atrial fibrillation (Xie et al., 2020b). Besides myocyte-autonomous mechanisms, voltage-gated potassium channel KCNQ1 is also a sexually dimorphic sensor of moderate cold, coordinating with TRPM8 to control cold avoidance behaviors in male mice (Kiper et al., 2024). Additionally, the gap junction protein Connexin 43 (Cx43), which is essential for intercellular electrical coupling, is also remodeling in cold adaptation. Cold acclimation in spontaneously hypertensive rats improves Cx43 and its phosphorylated isoform (p-Cx43Ser368) expression, improves its distribution, and suppresses the TGF-β1/SMAD pro-fibrotic pathway in the meantime, revealing a mechanism of cold-induced electrophysiological protection (Andelova et al., 2022).

Chronic exposure to cold establishes a pro-inflammatory and pro-fibrotic environment, predisposing to pathological remodeling. In a rat model of combined high-altitude and cold (HAC) exposure and hemorrhagic shock, cold exacerbated cardiac fibrosis, which was associated with upregulation of inflammatory cytokines (TNF-α, IFN-γ) and downregulation of anti-apoptotic protein Mcl-1 (Xu J. et al., 2024). This is in part orchestrated by the TGF-β/SMAD signaling pathway, inhibition of which is for instance, by 2,5-Dimethylcelecoxib (DM-C) via activation of GSK-3 and subsequent inhibition of Smad2/3 phosphorylation, effectively decreases cardiac fibrosis following injury (Ikushima et al., 2022). The translational promise of cold-induced inflammation is seen in findings that elevated serum levels of extracellular CIRP (eCIRP) in patients post-cardiac arrest are linked with higher systemic inflammation, disease severity, and are predictive of adverse 28-day outcomes (Wang L. et al., 2021). Extracellular matrix (ECM) integrity is not only critical in the heart but also in fat tissue, where defective ECM remodeling in BAT is linked to fibrotic inflammation and defective diet-induced thermogenesis (Pellegrinelli et al., 2023).

In addition to classical mechanisms, novel cell death forms contribute to cold-induced damage. Evidence is provided for the role of ferroptosis, which is a cell death induced by lipid peroxidation, in cold-stressed hearts. Remarkably, Beclin1 haploinsufficiency significantly improves cold-induced cardiac dysfunction and metabolic perturbations by inhibiting ferroptosis and mitochondrial injury (Yin et al., 2020). Metabolic disorder in cold stress is uncovered in plasma dynamic profiles and TAG profiles, in which the early reduction of unsaturated TAGs to provide thermogenesis is followed by the rise of liver-derived, polyunsaturated-enriched TAGs accompanying concurrent adipose tissue lipolysis, a process ATGL-dependent (Straat et al., 2022). Dietary treatment, for example, full-fat rice bran supplement, has been demonstrated to have the potential to circumvent this damage by augmenting cardiac antioxidant defense mechanisms (e.g., via Nrf2/HO-1 induction) and simultaneously inhibiting mitophagy, ferroptosis, and pyroptosis (Sun et al., 2023).

The “Cardiac-Adipose Axis” new paradigm foresees an intrinsic, bidirectional cross-talk between the heart and adipose tissues, and in particular BAT, whose functional activity dictates on a large scale systemic metabolic and cardiovascular homeostasis (Tang et al., 2023; Lu et al., 2023). BAT activation is the substrate of non-shivering thermogenesis. On cold exposure, BAT β3-adrenergic receptors are stimulated by sympathetic release of norepinephrine, and this results in UCP1-mediated heat production along with co-uptake of fatty acids and glucose with beneficial effects on total-body metabolism (Challa et al., 2024; Christen et al., 2022; McNeill et al., 2020). Advanced multilayered regulation of this activation is also underway such as with the presence of intrinsic brakes such as a cold-activated truncated version of adenylate cyclase 3 (AC3-AT) that suppresses the formation of cAMP to prevent over-activation of BAT and exhaustion of energy (Khani et al., 2024). Regulation is also observed in mitochondrial dynamics, as the PACT RNA-binding protein inhibits mitochondrial biogenesis by activating miR-181c maturation (Dogan et al., 2022), and in inter-organelle contact, wherein the lipid droplet protein PLIN5 recruits mitochondrial FATP4 to augment fatty acid transport and oxidation during stress (Miner et al., 2023). Other layers include PEMT regulation of UCP1 splicing in a non-cell-autonomous fashion (Johnson et al., 2020) and the unexpected function of myoglobin (MB) in BAT, whose lipid-binding activity induces lipolysis and mitochondrial respiration after adrenergic stimulation (Christen et al., 2022). Some others, like the cold-regulated ubiquilins, are not required for BAT protein homeostasis and thermogenesis (Muley et al., 2021).

The “axis” is extremely bidirectional. Cardiac-secreted hormones ANP and BNP exert direct actions to activate BAT and browning of white adipose tissue, enhancing total energy expenditure (Lu et al., 2023; Kashiwagi et al., 2020). Conversely, BAT dysregulation in heart failure models leads to diminished thermogenesis and, through disrupted choline metabolism, elevates the cardiotoxic metabolite TMAO, which inhibits cardiac mitochondrial function and exacerbates dysfunction (Yoshida et al., 2022). This multiplicity is further attested by sex-differential behavior; diet-induced obese female mice cardiac-specific overexpression of βARKct increased insulin sensitivity but paradoxically caused deleterious cardiac remodeling and suppressed BAT thermogenesis (Manaserh et al., 2023). Smad4-mediated endothelial cell angiogenesis also promotes white adipose tissue through the proliferation of beige adipocyte progenitors (Wang et al., 2023). The delicate balance of nitroso-redox homeostasis in BAT, regulated by ADH5-catalyzed S-denitrosylation of proteins (conserved in HSF1) is required for UCP1-dependent thermogenesis and a potential target (Sebag et al., 2021). Together, these lines of investigation place BAT on the pedestal from coarse heater to an important regulatory center for cardiovascular health.

The process of hormesis, where enhanced tolerance to a greater stressor is elicited by a smaller stressor, is graphically demonstrated by repeated chilling. There is now compelling evidence in animal models that acute MCA of short duration provide robust cardioprotection, reducing myocardial infarct size significantly and potentiating mitochondrial resistance to calcium overloading (Marvanova et al., 2023). The mechanisms are sophisticated and include protective desensitization of β1/β2-adrenergic receptors to catecholamine-induced cardiac load while inducing the simultaneous stimulation of the pro-survival β3-AR/PKG/AMPK pathway and a healthy serum immunomodulatory cytokine profile (Marvanova et al., 2023). Moreover, this therapeutic approach is not associated with adverse effects such as hypertension or cardiac hypertrophy (Marvanova et al., 2023).

This adaptive response is found to exhibit cross-talk with other stress signals, such as exercise- and hypoxia-induced signals. Alternating cold exposure, for instance, activates the principal regulators of mitochondrial biogenesis and function (e.g., PGC-1α, NRF-1) via PKA and SIRT3 signaling, thereby augmenting the metabolic and antioxidant reserve of the heart as well as its overall stress resistance (Mohan et al., 2023a). In keeping with the concept of common adaptive pathways, mouse models illustrate that cold exposure modifies thermoregulatory parameters (e.g., lowered skin, elevated core temperature), yet induces a gene expression pattern of mitochondrial biogenesis and mitophagy that is remarkably similar to exercise in room temperature (Opichka et al., 2019). Similarly, combined intermittent hypobaric hypoxia plus cold exposure can produce adaptive physiological adaptations like skeletal muscle angiogenesis (Santocildes et al., 2021). However, as the recent review indicates, coordinated thermoregulatory and cardiovascular control of humans with combined hypoxia and cold remains a major and as-yet-unresolved frontier (Mugele et al., 2021). Considered collectively, this work implies that controlled exposure to mild stress can be used as a non-pharmacologic intervention for improving cardiovascular health more broadly.

Building on the concept of cold adaptation, a number of voluntary cold exposure modalities have been investigated for their cardiometabolic protective benefits and adverse dangers. As systematically compared in Table 1, the exposures of Cold Pressor Test (CPT), Cold-Water Immersion (CWI), Whole-Body Cryostimulation (WBC), and controlled ambient cold exposure each induce distinct physiological responses and have specific uses and limitations. This comparative framework is of value in selecting appropriate interventions on an individual’s health status and desired outcomes, to be elaborated in greater detail in the presentation of behavioral and pharmacological interventions.