Environmental stress, particularly heat exposure, is an emerging cardiovascular risk factor, especially in vulnerable populations. This study sought to explore the molecular mechanisms by which heat stress affects vascular health in young individuals, with particular attention paid to those exposed to adverse socioeconomic, occupational, and environmental conditions. Our analysis included experimental and epidemiological studies that highlight how repeated or prolonged exposure to high temperatures triggers a cascade of physiological responses, such as oxidative stress and inflammatory signaling pathways. We also present epigenetic alterations, including DNA methylation, histone modification, and microRNA (miRNA) regulation, which contribute to long-term changes in gene expression relevant to blood pressure control. The methylation patterns of genes like IGF2 and PPARα, which are linked to endothelial dysfunction and cardio metabolic programming, as well as the modification of miR-126, are some of the primary mechanisms discussed. We further underscore the importance of acknowledging heat stress as a pertinent public health and occupational issue, especially in nations with notable socioeconomic inequality. Developing early intervention and cardiovascular disease prevention techniques for at-risk children and young people can be aided by an understanding of the molecular processes underlying heat-induced vascular alterations. Our findings emphasize how crucial it is to incorporate social and environmental factors into frameworks for assessing cardiovascular risk.

Keywords: heat stress, epigenetics, hypertension, youth, heat therapy

Once considered a disease of aging, hypertension (HYP) is now increasingly diagnosed in adolescents and young adults, suggesting a paradigm shift in its epidemiology. The World Health Organization's most recent global report on hypertension reveals the worrying rise of this condition, which now affects more than one billion people worldwide.¹ This scenario is associated with factors such as economic constraints and barriers to accessing health services.^1,2 Early-onset HYP is associated with a greater lifetime risk of cardiovascular disease and all-cause mortality.³ Lifestyle factors such as diet, physical inactivity, and psychological stress are often implicated; however, these alone do not fully explain the growing prevalence among young populations. Recent studies suggest that environmental exposures may play a pivotal role in the early emergence of hypertensive traits.⁴ Among environmental stressors, exposure to high ambient temperatures-whether through climate change or occupational conditions-has gained attention for its impact on vascular and autonomic regulation.⁵ Heat stress induces a cascade of physiological responses, including increased heart rate, vasodilation, fluid loss, and thermoregulatory strain. At the cellular level, it activates heat shock proteins (HSPs), promotes oxidative stress, and alters endothelial function, all of which are known contributors to cardiovascular dysregulation.⁶ These effects may be more pronounced in individuals with latent or developing vascular dysfunction, such as young individuals with early blood pressure alterations.⁷ A growing body of evidence indicates that epigenetic mechanisms-including DNA methylation, histone modification, and non-coding RNAs (especially microRNAs)-play a critical role in the developmental programming of HYP.⁸ Epigenetics is the field of science that investigates molecular alterations capable of controlling gene activity without modifying the genetic code itself.⁹ These changes alter the way DNA is organized within cells, directly influencing which genes become active and which remain inactive. Thus, epigenetics has a direct impact on the organism's physiological and behavioral processes.^9,10 Epigenetic marks are responsive to environmental stimuli, including heat exposure, and may mediate long-term changes in gene expression associated with vascular tone, inflammation, and sodium regulation.^8,11,12 In youth, whose epigenomic landscape is still highly plastic, such exposures can modulate gene networks that influence cardiovascular phenotype, potentially establishing trajectories toward or away from disease.^13–15

In light of these findings, planned thermal therapy has been proposed as a non-pharmacological intervention capable of eliciting favorable cardiovascular adaptations. Interventions such as sauna bathing and passive heat exposure (e.g., hot water immersion or infrared heating) have shown promising results, including improved endothelial function, arterial compliance, and blood pressure reduction.^13,14,16 In young adults, repeated heat exposure has also been associated with beneficial changes in vascular structure and autonomic balance, with some evidence pointing toward epigenetic involvement in these adaptations.^17,18 Despite this promise, integration across mechanistic, epigenetic, and clinical domains remains limited, particularly in studies focused on young individuals at risk for HYP. A comprehensive synthesis of current knowledge is necessary to bridge this gap and identify opportunities for early preventive interventions. Therefore, the central objective of this narrative review is to map and synthesize the existing scientific evidence on the cellular and epigenetic mechanisms that link exposure to heat stress to cardiovascular alterations in young individuals vulnerable to the development of HYP, with an emphasis on the preventive potential of heat therapy, a non-pharmacological therapeutic resource. The literature search was conducted in the PubMed, Scopus, Web of Science, and SciELO databases, using the following descriptors and their combinations with Boolean operators ("AND," "OR"): heat stress, cardiovascular system, epigenetics, hypertension, young individuals, heat therapy, and heat acclimation. Articles published in English or Portuguese between 2000 and 2024 were considered. Inclusion criteria included original articles, reviews, and experimental studies addressing the interactions between heat stress, epigenetic responses, and cardiovascular alterations, as well as investigations on the therapeutic use of heat in pathophysiological contexts, especially in young populations. Articles focusing exclusively on geriatric populations, chronic non-cardiovascular diseases, or heat exposure protocols without associated cardiovascular analysis were excluded. Articles were selected by reading the title, abstract, and full text. The analysis followed a qualitative and interpretive approach, seeking to identify patterns of physiological and epigenetic responses, knowledge gaps, cellular mechanisms involved, and potential clinical applications. The discussion was structured by thematic axes, with emphasis on conceptual contributions and the possibility of translational application of the findings (Figure 1).

Figure 1 Effects of heat stress under intense heat and desired adaptations of heat therapy.

Phenotypic plasticity is the ability of an organism to modify its physical, physiological, or behavioral characteristics (phenotype) in response to environmental variations, while maintaining its genotype.¹⁹ Thermal phenotypic plasticity represents a crucial mechanism of phenotypic response to environmental stimuli, allowing organisms to express different traits based on temperature.²⁰ In this context, epigenetic changes can be defined as heritable mitotic and/or meiotic modifications that occur in DNA structure, rather than in the nucleotide sequence, resulting in changes in phenotype in the absence of changes in genotype.²¹ Recently, it has been established that environmental stimuli, such as heat stress, affect cellular functions through epigenetic mechanisms.²² In animal models, such as rats and skeletal muscle myoblast cultures, thermal interventions have been shown to influence gene expression through epigenetic modulation.²² One example of this is the increase in histone H4 acetylation and the expression of DNMTs, particularly DNMT3A, when exposed to heat. DNMTs (DNA methyltransferases) are enzymes responsible for adding methyl groups to DNA, regulating its expression. DNMT3A, specifically, is involved in de novo methylation, being crucial for epigenetic adjustments to new environmental stimuli.²³ The increase in its activity at 39°C, compared to 35°C, led to changes in cellular metabolism, including mitochondrial dysfunction, demonstrating how the thermal environment alters cellular phenotype epigenetically.²² In mice, episodes of heatstroke caused epigenetic changes, such as changes in DNA methylation patterns in ventricular cardiac muscle and bone marrow-derived monocytes and in chromatin structure,²⁴ as well as modifications in the expression of genes involved in the immune response.²⁵ These changes resulted in immunosuppression and reduced thermal responses, suggesting the formation of an epigenetic memory associated with heat stress. This type of memory promotes marked immune phenotypes, with reduced immune system response and altered production of heat shock proteins.²⁴ These examples illustrate how the environment, particularly heat, can influence the phenotype through epigenetic mechanisms. These mechanisms include DNA methylation, histone modifications, and even the activation of transposable elements, which together can regulate entire networks of gene expression. When these changes persist beyond an organism's life cycle, they constitute transgenerational plasticity, influencing descendants even without altering the genetic sequence.²⁶ Responses resulting from environmental modulation include changes in energy metabolism,^24,25 as demonstrated in various biological models. The environment acts as a dynamic modulator of genotypic expression. Thus, epigenetic thermal plasticity functions as a fundamental link between genotype and phenotype, shaping observable characteristics of organisms in response to environmental pressures that may be advantageous or not,²⁷ reversible or heritable,²⁶ depending on the intensity and frequency of exposure.²²

Intense or prolonged heat stress induces accumulation of reactive oxygen species (ROS), both from the mitochondrial respiratory chain and from enzymes such as NADPH oxidase.²⁸ This increase in ROS disrupts the redox balance and triggers oxidative stress signals in vascular and cardiac cells.²⁹ ROS activate signaling pathways, including MAPKs (such as p38, ERK, and JNK), which, coupled with NFκB, promote transcription of pro-inflammatory genes and trigger necroptosis in endothelial cells under extreme heat.^30,31 Furthermore, uncontrolled levels of ROS can drive the oxidation of DNA, lipids, carbohydrates, and proteins, promoting significant cellular damage and causing cell death by apoptosis or necrosis.³² At the same time, the TRPV1 channel appears as a thermal sensor that participates in cardiovascular inflammatory regulation.³³ TRPV1 activation, especially by capsaicin or thermal stimuli, modulates vascular inflammation via increased nitric oxide (NO) production, reducing the accumulation of cytokines such as TNFα and IL6.³⁴ In LPS-induced cardiomyocytes, TRPV1 also contributes to inflammatory activation, with possible internalization that amplifies pro-inflammatory signaling.³⁵ Exposure to passive heat, such as sauna or hot water immersion, has direct effects on vasodilation, peripheral blood flow, and vascular resistance.^7,36–38 At the endothelial level, these changes are mediated by the activation of eNOS and the release of NO, key elements in the regulation of vascular tone and the maintenance of blood pressure.^39,40 Recent studies have shown that passive heat therapy for several weeks can improve flow-mediated dilation, reduce arterial stiffness (measured by pulse wave velocity, PWV), and decrease mean arterial pressure, both systolic and diastolic, in healthy and clinical populations.^39,40 These gains are particularly relevant for individuals with HYP or compromised endothelial function.³⁹ The underlying molecular mechanisms include the induction of heat shock proteins (HSPs), which activate the Akt/eNOS pathway, increasing NO bioavailability and promoting endothelial vasodilation.^41–43 Furthermore, heat stress appears to positively modulate angiotensin,^39,44 preserving its vasodilatory capacity even in conditions of insulin resistance associated with HYP.⁴⁵

Cellular models have shown that both mild temperature elevation (≈39°C) and heat-induced circulating factors protect endothelial cells against oxidative stress and inflammation associated with hypoxia-reoxygenation, suggesting a protective effect directly on the endothelium.⁴⁶ Acute or repeated heat exposure promotes a robust increase in the expression of heat shock proteins (HSPs), especially HSP70/HSP72 and HSP90, functioning as essential cytoprotective mechanisms against heat stress.^39,40 These chaperones are typically activated through the transcription factor HSF 1, which directs the transcription of the HSPA1A/B genes in response to cellular heat.⁴⁷ HSP70/HSP72 acts to prevent protein aggregation by binding to hydrophobic regions exposed during stress, facilitating correct folding or directing damaged proteins for degradation via the proteasome or autophagy.⁴⁸ Furthermore, HSP70 directly blocks the apoptotic pathway by preventing formation of the apoptosome (procaspase 9/Apaf 1), conferring cellular resistance to thermal and oxidative stress.^40,49 In high-fat diet-induced insulin resistance models, heat restored HSP72 expression, preventing endothelial dysfunction by preserving the Ang-(1 7)/Mas/Akt/eNOS/SIRT1 axis, with consequent maintenance of NO bioavailability and vasodilation.⁴⁵ HSP90s, in turn, contribute to the fine-tuned closure of the proteome, stabilizing receptors and signaling proteins involved in the AKT/eNOS pathway and angiogenesis via VEGF. This contributes to the preservation of endothelial function and vascular tone under heat conditions.^50,51 Other isoforms, such as HSP27 and HSP22, also stand out: HSP27 regulates cytoskeletal integrity, exerts anti-inflammatory effects, and may protect against oxidative stress by increasing glutathione levels, reducing intracellular iron levels, and reducing tissue ROS concentrations;⁵² HSP22 acts in mitochondrial protection and in the activation of iNOS in cardiomyocytes under stress.^39,53,54 Evidence suggests that the induction of HSP70 and HSP90 by thermal interventions such as sauna or localized heat therapy improves heat tolerance, promotes cellular adaptation, and benefits cardiovascular function, potentially reducing the risk of HYP and related events.^39,55

Recent evidence suggests that susceptibility to HYP in young people may result from epigenetic alterations acquired early in life. Epigenetics, understood as the set of stable and heritable modifications of gene expression that do not involve alterations in the DNA sequence, provides a mechanistic basis for understanding the plasticity of the hypertensive phenotype in the face of early environmental influences. Among the main epigenetic mechanisms involved are DNA methylation, histone modification, and regulation by microRNAs (miRNAs), all implicated in vascular regulation and the development of HYP in young populations.^56,57 DNA methylation is one of the main epigenetic mechanisms and occurs predominantly at the 5' cytosine position in CpG islands, generally promoting gene silencing. Alterations in the methylation patterns of key vasoregulatory genes have been observed in individuals predisposed to HYP.^58,59 Genes such as eNOS (NOS3), which encodes the endothelial synthase enzyme responsible for NO production, have been frequently targeted in these studies. Hypermethylation of the NOS3 gene promoter has been associated with reduced eNOS expression, resulting in reduced NO bioavailability and, consequently, endothelial dysfunction and increased peripheral vascular resistance.^39,40 Furthermore, the ACE gene, which encodes the angiotensin-converting enzyme, was shown to be hypomethylated in experimental models of juvenile HYP, which leads to increased expression and greater activation of the renin-angiotensin-aldosterone system (RAAS), contributing to vasoconstriction and sodium retention.^59,60 These findings support the idea that the methylation pattern of genes involved in vascular homeostasis may be modulated by early environmental factors such as maternal nutrition, perinatal stress, and environmental pollution, and contribute to the development of the hypertensive phenotype in youth. MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate gene expression post-transcriptionally, promoting mRNA degradation or translation inhibition. Several miRNAs have been identified as regulators of vascular hypertrophy, arterial remodeling, and endothelial dysfunction, all central processes in the genesis of HYP.

miR-155 is involved in controlling the expression of Angiotensin II Type 1 Receptor (AT1R). In experimental models of HYP, its downregulation leads to increased AT1R expression and intensifies the vasoconstrictor effects of angiotensin II.⁶¹ Another example is miR-21, frequently overexpressed under conditions of hemodynamic stress and vascular inflammation, promoting vascular smooth muscle cell hypertrophy and fibrosis.⁶² MiR-126, one of the main endothelial miRNAs, is crucial for vascular integrity and signaling of growth factors such as VEGF. Its reduced expression was observed in young individuals with early endothelial dysfunction and high blood pressure, suggesting a protective role against the development of HYP.^59,60 These data reinforce the relevance of miRNAs as emerging therapeutic targets, particularly in the subclinical phase of HYP. One of the most intriguing contributions of epigenetics to the pathophysiology of HYP is related to Barker's concept of the fetal origin of adult diseases. Epidemiological and experimental studies demonstrate that stressors during pregnancy-such as malnutrition, maternal HYP, exposure to tobacco, or extreme heat-induce lasting epigenetic changes in the fetus, permanently modifying the expression of genes involved in cardiovascular regulation.^63,64 A classic example is the study of children of mothers exposed to famine during the “Dutch Hunger Winter”, in which hypermethylation of the IGF2 gene and a higher prevalence of cardio metabolic diseases in adulthood were observed.⁶⁵ In animal models, pregnant rats subjected to protein restriction gave birth to offspring with hypermethylation of the PPARα gene, involved in lipid metabolism, and increased blood pressure throughout life.⁶⁶ More recently, the concept of transgenerational epigenetic inheritance has gained relevance. Studies in rodents have shown that epigenetic alterations acquired through exposure to heat or dietary stress can be transmitted to future generations, even in the absence of direct exposure, perpetuating cardiovascular risk.⁶⁷ This evidence challenges the classical view of genetic inheritance and points to a model in which environmental factors can functionally “imprint” the genome, influencing the cardiovascular health of descendants.

CVDs, commonly associated with aging, are increasingly occurring at an earlier age, requiring special attention in young populations. The concept of "vulnerable youth" goes beyond chronological age and encompasses individual, social, and environmental factors that contribute to the early onset of cardio metabolic conditions, such as pre-HYP.⁶⁸ The concept of "vulnerable youth" goes beyond chronological age and encompasses individual, social, and environmental factors that contribute to the early onset of cardio metabolic conditions, such as pre-HYP.⁶⁸ This often overlooked intermediate condition between normal blood pressure levels and established HYP is an early marker of future cardiovascular risk and, in many cases, remains underdiagnosed in youth.⁶⁹ In recent years, evidence has shown that the modern environment favors the adoption of sedentary behaviors, high-calorie food consumption, and low adherence to regular physical activity.⁷⁰ The increase in youth obesity is a direct consequence of this scenario.⁷¹ Visceral obesity, associated with the accumulation of inflammatory adipose tissue, is directly linked to early endothelial dysfunction and the development of insulin resistance, contributing to elevated blood pressure levels even in the absence of clinical hypertensive disorders.⁷² Longitudinal studies show that childhood overweight is associated with a higher risk of hypertensive disorders and cardiovascular events in adulthood, regardless of adult body weight.⁷³

A sedentary lifestyle is another widely recognized factor. The World Health Organization (WHO) recommends at least 60 minutes of moderate to vigorous physical activity per day for children and adolescents, but data reveal that more than 80% of adolescents globally do not achieve this goal.⁷⁴ Low physical activity compromises cardiovascular function, autonomic control, and lipid metabolism, in addition to being associated with low-grade chronic inflammatory changes. Another less discussed but highly relevant risk factor is early occupational exposure to unhealthy environments. In economically disadvantaged populations, early entry into the informal labor market often exposes young people to excessive heat, toxic substances, and intense physical exertion. Such exposures, in addition to causing physical exhaustion, contribute to changes in blood pressure and the cardiovascular system as a whole, increasing the risk of early illness.^75,76 Furthermore, environmental factors such as air pollution, exposure to densely populated urban environments, and a lack of green spaces have also been implicated in adverse effects on cardiovascular health from childhood onward. Chronic exposure to fine particulate matter (PM2.5) and other pollutants can induce systemic inflammation and oxidative stress, central mechanisms in the pathophysiology of HYP and endothelial dysfunction.⁷⁷ Social inequalities pose significant barriers to promoting cardiovascular health in young people. Parental education, family income, and limited access to health services and healthy eating are social determinants strongly associated with early cardiovascular risk. Children and adolescents living in peripheral areas, for example, often have less access to safe spaces for sports, quality food, and adequate clinical monitoring.^78,79 Structural racism, urban violence, and food insecurity are additional factors that intensify chronic stress in vulnerable young populations. Toxic stress, defined as prolonged activation of the stress response system without adequate support, has been linked to a higher incidence of HYP in young adults and adolescents.^80,81 Pre-HYP, defined in adults by blood pressure levels between 120-139 mmHg (systolic) or 80-89 mmHg (diastolic), and adapted to specific percentiles in children and adolescents, is a condition frequently overlooked in clinical practice. The absence of symptoms, combined with the lack of systematic blood pressure screening in pediatric consultations, contributes to under diagnosis.^82,83 Another relevant point is the scarcity of guidelines for blood pressure screening in young populations outside of a clinical setting. Most of the available data comes from school studies, making it difficult to implement effective public prevention policies (Table 1).

Currently, drug therapies lead the control of HYP, non-pharmacological alternatives emerge with a supporting role in more severe cases and with treatment potential in milder clinical cases.⁸⁴ Given the current scenario where drug therapies are the leading treatment for HYP, non-pharmacological alternatives are emerging as a supporting role in more severe cases and potentially as a treatment for milder clinical cases. Heat therapy, also known as thermotherapy, involves transferring heat to the body to increase blood flow and promote healing.⁸⁵ The application of heat can induce vasodilation, facilitating the removal of toxic metabolites and enhancing oxygen flow in affected tissues.⁸⁶ Different methods have been developed to study the effects and mechanisms involved in heat therapy, where the selection of a suitable heating method depends on the research question, clinical setting, and complexity required.⁸⁷ Lower and higher temperatures than the normal body temperature of 37°C can elicit positive or negative effects, which several minimally invasive therapies exploit to manipulate perfusion, facilitate cell destruction, or remove tissue.⁸⁸ Advances in technologies such as lasers and microwave have propelled the development of thermal treatments, and targeted temperature management is gaining recognition for its importance in patient outcomes in various clinical scenarios. Traditionally used in musculoskeletal rehabilitation, thermotherapy has expanded its use to control cardiovascular, metabolic, and neurological conditions, driven by technological advances and the elucidation of its cellular mechanisms.⁸⁹ Several heat application modalities have been developed, varying in thermal penetration depth, exposure time, and tissue target specificity. Table 1 describes the available methods, as well as the relative depth of each (Table 2).

Despite recent advances in understanding the cellular and epigenetic mechanisms involved in the cardiovascular response to heat stress, several knowledge gaps persist and limit the translational application of heat therapy for the prevention of hypertension (HYP) in young populations. Most available evidence comes from cross-sectional studies or acute experimental models. Longitudinal studies evaluating epigenetic modifications associated with planned heat exposure and their persistence over time are scarce. Cohort studies with repeated measurements of DNA methylation, histone modifications, and miRNA expression are essential to clarify the stability of these markers and their causal relationship with the hypertensive trajectory.

Although the effects of heat therapy are promising in adults and clinical populations, there is also a critical lack of randomized clinical trials testing the efficacy, safety, and feasibility of the intervention in young people with pre-HYP or increased risk. Investigations in this age group are essential, given the potential for phenotypic reversibility before the onset of irreversible structural damage to the cardiovascular system. There is still no consensus on the ideal parameters for time, temperature, and frequency of heat exposure. Data on the dose-response curve are limited, especially in the context of long-term interventions in healthy or subclinical individuals. Comparative trials between different heat therapy modalities are needed to optimize protocols based on efficacy and adherence. Progress on these fronts could consolidate heat therapy as a validated preventive strategy for vulnerable young people, with potential impact on epigenetic modulation and early blood pressure control.

The evidence gathered in this study highlights that heat stress has direct effects on cardiovascular homeostasis, especially in vulnerable young populations. Chronic exposure to intense heat, common in precarious occupational environments and climate change scenarios, triggers a cascade of molecular alterations that compromise endothelial function and favor the early development of cardiovascular diseases. Among the main mechanisms involved are increased production of reactive oxygen species, induction of heat shock proteins, and epigenetic modulation of blood pressure-regulating genes. Reduced expression of protective miRNAs, such as miR-126, and changes in the methylation of genes such as PPARα and IGF2, reinforce the idea that environmental exposures can permanently reprogram the cardiovascular physiology of young individuals. Heat stress triggers a complex cellular response in the cardiovascular system, ranging from increased expression of heat shock proteins (HSPs), such as HSP70, to the activation of signaling pathways that regulate endothelial function, vascular tone, and cardiac remodeling. These effects on cells are partially mediated by epigenetic processes, which involve changes in DNA methylation, histone modification, and microRNA regulation. These mechanisms affect gene expression related to inflammation, oxidative stress, and cardiac hypertrophy. In young individuals, these epigenetic changes may constitute a critical period for cardiovascular phenotypic programming, affecting both the prevention and worsening of early-onset hypertension. Continuous and controlled heat exposure, similar to planned heat therapy, has demonstrated the potential to induce protective cellular adaptations, which positively modulate cardiovascular function through the induction of HSPs, the improvement of nitric oxide bioactivity, and the attenuation of sympathetic activity. Given the relevance of these findings, it is important to consider investing in public policies that reduce exposure to heat stress in at-risk populations, as well as encouraging longitudinal studies that evaluate epigenetic and molecular markers associated with early-onset hypertension. Understanding these mechanisms is crucial for developing more effective preventive strategies to address the silent progression of cardiovascular disease in increasingly younger age groups.

This study was supported by grants from the Pro-Rectory of Research and Postgraduate Studies of the Federal Rural University of Rio de Janeiro, the Brazilian Council for Scientific and Technological Development (CNPq - 140562/2023-0)

Our sincere thanks to the Department of Physiological Sciences and the Department of Physical Education of the Federal Rural University of Rio de Janeiro, both of which were decisive in carrying out this work.

The authors declares that there are no conflicts of interest.

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