Mental stress: A novel cardiovascular risk factor

Abstract

Many acute coronary syndromes or strokes occur in patients without arterial hypertension, diabetes mellitus, dyslipidaemia, or smoking habits. Therefore, it is essential to identify new cardiovascular (CV) risk factors, among which psychosocial elements are gaining increasing importance. Recent guidelines recognize psychosocial factors, such as mental stress, as risk modifiers that can improve risk prediction and clinical decision-making. Stressful stimuli are processed by cortical and subcortical brain regions, which, through the autonomic nervous system and the hypothalamic-pituitary-adrenal axis, generate neuroendocrine, hemodynamic, and immune changes. Mental stress can be acute or chronic. Acute stress results from sudden emotions and may trigger acute cardiac or cerebral events. Chronic stress, instead, develops from prolonged exposure to family, work, or financial problems. It can induce endothelial dysfunction and low-grade systemic inflammation, contributing to atherogenesis. Like physical stress tests, mental stress tests can provoke transient myocardial ischemia even without significant coronary obstruction. Therapeutic strategies reducing adrenergic activity or mitigating negative emotions associated with psychological stress may lower CV risk. This narrative review synthesizes current epidemiological data on interactions between stress and CV disease, explores potential mechanisms, and outlines future research directions for holistic treatment approaches.

Key Words: Stress; Cardiovascular diseases; Risk factors; Epidemiology; Prevention

Core Tip: Many acute coronary syndromes and strokes occur in patients without traditional risk factors. This highlights the growing importance of psychosocial factors, especially mental stress, as recognized by recent guidelines. Acute stress can trigger severe cardiovascular (CV) events, while chronic stress - often linked to ongoing personal or professional issues - promotes inflammation and endothelial dysfunction, contributing to atherosclerosis. Mental stress tests can induce transient myocardial ischemia even without significant coronary obstruction. Therapeutic strategies targeting stress reduction may help lower CV risk. This narrative review synthesizes epidemiological data and explores potential mechanisms regarding interactions between stress and CV disease, outlining future research directions.

INTRODUCTION

Recent breakthroughs in preventive cardiology and pharmacotherapy have markedly broadened the therapeutic armamentarium against atherosclerosis-related cardiovascular disease (CVD), contributing to a substantial decline in CVD mortality. Nevertheless, atherosclerosis-driven conditions continue to represent a major cause of death worldwide. Moreover, although the contribution of traditional risk factors is well established, a non-negligible proportion of acute coronary syndromes (ACS) and strokes arises in individuals without overt hypertension, diabetes mellitus, dyslipidemia, or smoking exposure. In parallel, contemporary research has reframed coronary artery disease (CAD), moving beyond the outdated concept of atherosclerosis as a merely passive lipid deposition within the arterial intima culminating in luminal obstruction or thrombosis. Current paradigms instead underline the central contribution of inflammatory and immune pathways to plaque initiation, progression, and destabilisation. Within this evolving framework, the identification of non-traditional determinants of CVD risk has become increasingly relevant[1]. Among these, psychosocial factors - rooted in social context, individual personality traits, and negative affective states, including mental stress - have emerged as important and independent contributors to cardiovascular (CV) risk[2,3]. In modern psychiatry, stress-related syndromes encompass acute stress reactions, chronic stress-related disorders (e.g., adjustment disorders), and post-traumatic stress disorder (PTSD)[4,5].

The hypothesis that psychological stress influences heart disease is not new. In the nineteenth century, Da Costa described “Soldier’s Heart” among American Civil War soldiers, a clinical picture that resembles contemporary PTSD and is characterized by heightened CV reactivity (CVR)[6]. Subsequently, with the development of psychoanalytic approaches, psychiatric symptomatology was often considered separately from somatic disease processes. More recently, psychosomatic medicine has re-emphasised the biological embedding of psychological states, describing mind-body interactions and the engagement of multiple physiological systems in disease pathogenesis, thereby reinforcing the association between stress and CVD[6]. Interest in this topic has increased further, supported by prospective epidemiological cohorts and mechanistic studies. Although psychological stress is broadly accepted as a factor involved in CVD onset and progression, reported associations differ according to the methods used to quantify stress and to the magnitude of risk estimates[7,8]. While definitive causal inference remains challenging, the most recent European Society of Cardiology (ESC) guidance recognizes psychosocial factors as “risk modifiers” that may improve risk stratification and support clinical decision-making[3,9].

Psychosocial stress may be conceptualized as a state arising when perceived external demands exceed an individual’s adaptive resources or homeostatic reserve[3,10]. Major stressor domains include significant life events, adverse work-related conditions, and chronic family or relational conflicts, all of which have been consistently linked to increased CV risk[11]. In addition, structural and socioeconomic inequities - such as reduced access to healthy foods, limited opportunities for physical activity, and exposure to unsafe environments and violence - generate sustained stress burdens that disproportionately affect disadvantaged populations[7]. Importantly, stress perception and coping responses vary widely across individuals, reflecting complex interactions among unconscious appraisal mechanisms, personality traits, prior life experiences, genetic susceptibility, and modifiable lifestyle factors including nutrition and physical fitness[12].

The physiological response to psychological stress has been extensively described[8]. It is regulated by higher-order brain regions (corticolimbic regions), which determine CV changes via their influence on medullary nuclei, having outputs to the autonomic nervous system reflexes[8,10]. CV responses to stress are closely integrated with behaviour via descending “brain-to-heart” command signals and ascending interoceptive feedback loops[10]. This bidirectional set of functional connections, linking central nervous system processing with autonomic control of cardiac activity, is commonly referred to as the neuro-cardiac axis[13]. Despite major advances, the precise neural circuitry that translates emotional stress into cardiac and behavioural responses remains incompletely defined[10].

In patients with established CVD, psychological distress is increasingly considered both a contributing factor to disease development and progression and a consequence of living with chronic cardiac illness[14]. Stress exposure may be acute, often eliciting adaptive arousal, yet in susceptible individuals it may precipitate transient myocardial ischaemia, arrhythmias, or even sudden cardiac death (SCD), particularly in the presence of advanced atherosclerosis or in Takotsubo cardiomyopathy[3]. Chronic stress appears to be of greater clinical relevance, as it has been associated with recurrent CV events and increased mortality, likely mediated - at least in part - by accelerated atherosclerotic process[3,15,16]. Emotional distress may also influence patterns of healthcare utilization, contributing to increased clinical consultations and medical contacts[17].

Although the association between psychological stress and CVD is well documented[13], the mechanistic pathways and causal directionality remain only partially understood[8,10]. Proposed explanatory models include shared genetic vulnerability, behavioural pathways (e.g., smoking, alcohol consumption), reduced adherence to preventive measures and pharmacotherapy, and direct biological effects mediated through haemodynamic, vascular, endocrine, autonomic, and immune dysregulation. Stress-related perturbations in the hypothalamic-pituitary-adrenal (HPA) axis and sustained autonomic imbalance may contribute to endothelial dysfunction, systemic inflammation, and a prothrombotic milieu[3,8,13]. Nonetheless, additional prospective investigations and real-world evidence are required to clarify the temporal relationships and clinical relevance of these mechanisms[8].

From a clinical perspective, integrating psychosocial stress management and promotion of mental well-being into contemporary CV care has become increasingly important[3]. However, structured psychological assessment remains underused in cardiology practice[8]. Despite robust evidence supporting a bidirectional association between mental health and CVD, stress-focused interventions are infrequently implemented. Although multiple clinical trials have explored different stress-reduction strategies, adequately powered randomized studies are still needed to confirm their effectiveness in improving hard CV outcome. Consistently, the recent ESC consensus statement underscores the limited evidence base currently available to guide routine clinical management[3]. In this narrative review, we summarize current epidemiological evidence on stress - CVD interactions, discuss plausible biological mechanisms, and propose future research priorities to support more holistic and integrated preventive strategies.

Although this is a narrative review, a methodological description regarding how the literature was identified and selected would benefit this paper from greater transparency. We conducted a comprehensive literature search using PubMed, Web of Science, and Scopus up to September 30, 2026. Search terms included “Stress” AND (“Cardiovascular” OR “Atherosclerosis” OR “Coronary Heart Disease” OR “Heart failure” OR “Arrhythmias”). We included randomized controlled trials (RCTs), observational studies, meta-analyses, and systematic reviews without language limitation. The inclusion criteria for the studies were: Human and animal studies. Exclusion criteria were non-peer-reviewed sources.

ACUTE STRESS AND CVD

Acute stress may be elicited by sudden emotional responses, including fear or anger[18], as well as by external stressors such as exposure to intense noise[19-21], abrupt variations in ambient temperature[22], bereavement[23], large-scale natural disasters (earthquakes, floods, hurricanes, tsunamis)[24-26], acts of war[27,28], criminal or terrorist attacks[29,30], and major political events (e.g., elections)[31]. Even common daily situations - including watching competitive sports events[32,33] or driving in heavy urban traffic - may act as acute stress triggers in susceptible individuals[34].

Short-term psychological stress activates an immediate neuroendocrine and autonomic response that can transiently increase vulnerability to acute CV events, particularly in predisposed subjects[35]. Reported stress-related manifestations include Takotsubo syndrome, angina, acute myocardial infarction (AMI), arrhythmias, transient left ventricular systolic dysfunction, stroke, and transient ischemic attacks[35]. Emerging evidence also indicates that limited social participation - defined by reduced frequency of engagement in social activities - is associated with diminished CVR to acute psychological stress[36], suggesting that social context may modulate physiological stress responses. Major clinical conditions associated with acute stress are outlined below.

Takotsubo syndrome

Takotsubo cardiomyopathy - also known as stress cardiomyopathy, apical ballooning syndrome, or “Broken Heart Syndrome” - was first described in 1990 by Dr. Sato at Hiroshima City Hospital[37]. It is now recognized globally as a distinct clinical entity and accounts for approximately 2%-3% of cases initially suspected to represent ACS[37]. The condition predominantly affects post-menopausal women and typically follows severe emotional or physical stressors[37].

Although the precise mechanisms remain incompletely defined, available evidence supports a central role for an acute catecholaminergic surge triggered by emotional or physical stress, which may induce direct myocardial injury (myocytolysis) through calcium overload, together with coronary vasospasm and microvascular constriction[37-39]. Myocardial stunning appears to be more closely related to extremely high circulating adrenaline concentrations than to direct activation of cardiac sympathetic nerve terminals[40]. A recent meta-analysis demonstrated significantly higher post-stress plasma norepinephrine levels among Takotsubo patients [Hedges’ g = 0.50; 95% confidence interval (CI): 0.17-0.84; P = 0.003], with a borderline increase in stress-induced norepinephrine (g = 0.28; 95%CI: -0.05 to 0.61; P = 0.09) compared with controls[41]. Experimental data from a female rodent model further suggest that stress-induced Takotsubo-like cardiomyopathy may cause persistent metabolic reprogramming, characterized by disruption of glucose pathways and progressive structural injury, potentially leading to irreversible cardiac dysfunction[42].

Clinically, patients frequently present with acute chest pain and electrocardiographic abnormalities that resemble ACS (e.g., ST-segment elevation or T-wave inversion), despite the presence of normal coronary arteries or non-flow-limiting CAD[37]. The defining feature is transient left ventricular wall motion abnormality, classically characterized by akinesia of the apical segments with hyperkinesia of basal segments, producing the typical “apical ballooning” pattern[37]. Another hallmark is the relatively modest rise in cardiac biomarkers, which is often disproportionate to the extent of regional dysfunction.

Cardiac magnetic resonance imaging (MRI) is increasingly applied to support diagnosis and, importantly, to differentiate Takotsubo syndrome from ACS when coronary anatomy is abnormal or potentially confounding[43]. Overall short-term prognosis is generally favourable; however, acute dyspnoea, hypotension, and cardiogenic shock can occur at initial presentation[39]. Additional serious complications include ventricular rupture, left ventricular apical thrombosis, and Torsade de pointes ventricular tachycardia[44]. Transient right ventricular dysfunction is also reported and appears associated with higher complication rates, prolonged hospitalization, and more severe impairment of left ventricular systolic function. In risk stratification studies, reduced ejection fraction and a Tpe/QT ratio > 0.27 have been identified as predictors of in-hospital major adverse cardiovascular events (MACE)[45]. Although case reports indicate that left ventricular dysfunction frequently resolves rapidly after stress withdrawal[46], epidemiological studies show a non-trivial long-term burden of morbidity and mortality, for reasons that remain poorly understood[39].

At present, no evidence-based specific therapy exists for Takotsubo cardiomyopathy, largely due to the absence of RCTs. In routine practice, treatment often includes beta-blockers, angiotensin-converting enzyme inhibitors, and angiotensin II receptor blockers[37,39,43]. A recent position statement from the ESC Heart Failure Association provides a detailed overview of Takotsubo syndrome, addressing nomenclature and definitions, diagnostic criteria, clinical subtypes and anatomical variants, triggers and epidemiology, pathophysiology and presentation, complications, prognosis, and current therapeutic approaches[47]. Nonetheless, major gaps remain, particularly concerning underlying mechanisms, improved diagnostic and prognostic tools, and optimal management strategies[39].

ACS

Severe emotional stress has been consistently associated with an increased risk of AMI[48,49]. Psychological determinants have also been hypothesized to contribute to the pathophysiology of spontaneous coronary artery dissection (SCAD), a condition characterized by the formation of a false lumen due to intramural hematoma within the coronary arterial wall, potentially compromising coronary perfusion[50,51]. However, a recent meta-analysis comparing SCAD patients with control populations (ACS or AMI) did not identify a significant association between SCAD and chronic moderate-to-high psychological stress[51]. These data suggest that while acute emotional triggers may be involved in SCAD onset, chronic psychological stress is unlikely to represent a major independent risk factor.

Arrhythmias and SCD

Women appear to be more susceptible to acute stress-related arrhythmias[24]. Notably, in individuals without previously documented CVD, the aetiology of SCD remains unexplained in nearly half of cases even after systematic diagnostic evaluation[52]. Observational evidence accumulated over decades has suggested a relationship between anxiety/psychological stress and SCD, although the magnitude and direct causal role remain uncertain. Anxiety may indirectly predispose individuals to SCD by increasing the likelihood of CVD and diabetes mellitus via unhealthy lifestyle behaviours and metabolic disturbances[53,54]. Acute emotional stress can also destabilize cardiac repolarization through autonomic activation, thereby facilitating malignant ventricular arrhythmias. In this context, self-reported psychosocial stress has been linked to a significantly higher risk of premature ventricular complexes during recovery following treadmill exercise testing in asymptomatic individuals[55]. Table 1 summarizes selected recent studies examining the association between acute stress and CVD.

Table 1 Some recent studies on the cardiac effects of acute stress.

Ref.	Setting	Main results
Mostofsky et al[18], 2014	Systematic review of 9 studies	Despite the heterogeneity, all studies found a higher rate of CV events (heart attacks, strokes, and disturbances in cardiac rhythm) in the 2 hours following outbursts of anger
Walker et al[19], 2016	Healthy participants were monitored during no noise, LF (31.5-125 Hz) or HF (500-2000 Hz) noise exposure scenarios lasting 40 minutes. ECGs were processed for measures of HRV	After adjusting for noise frequency, during LF noise exposure, HF, LF, and SDNN were reduced of 32% (-57, -6.2), 34% (-52, -15), and 16% (-26, -6.1); during HF noise exposure, a 21% (-39, -2.3) reduction in LF was found
Modena et al[24], 2017	Global access of patients who arrived at the ED of the three main hospitals in 2012, when two earthquakes hit the province of Modena and Reggio Emilia, compared with that one detected in the same departments and in the same interval of time in 2010	No statistically significant differences in number of cases in relation to gender. The gender analysis showed a prevalence of ACS (P = 0.03) in men, whereas women presented more strokes and TIAs (P = 0.05), atrial fibrillation (P = 0.05), DVT/PE (P = 0.05), and TTS (P = 0.05)
Chatignoux et al[29], 2018	Annual hospital discharge with a primary diagnosis of ACS, heart failure, or stroke from the French Hospital Discharge Database was used to differentiate “unusual” variations in daily hospitalization numbers in the 15 days following the terrorist attacks in Paris and Nice in 2015 and 2016 from the expected rate	The daily number of hospitalizations for heart failure and stroke was higher in the 15 days following each attack. However, multivariate analysis showed no significant variation. Watching events on television was not sufficiently potent trigger for CVD, although it may have led to an increase in hospitalizations for stress or anxiety
Babaie et al[26], 2021	Systematic review of full text articles which considered CVD at the time of flood, storm, and earthquake	Prevalence of CVD increases after disasters. Mental stress after disasters is one of the most significant challenges
Franzen et al[34], 2022	Multi-centre prospective trial at three German sites during the UEFA Soccer Cup 2012 and 2021 comprising healthy participants and patients hospitalized with CVD during matches of the German national team (GP) and no GP	Central BP and HR increased significantly during GP as well as no GP matches and remained elevated beyond the end of the matches. Likewise, arterial stiffness parameters and vascular resistance were higher during the matches and remained elevated after the matches
Olsson et al[50], 2021	Nationwide, retrospective postal survey with case-control design. All individuals suffering an AMI during the Christmas holidays in Sweden completed a questionnaire of about 27 potential AMI-triggers	Patients with AMI on Christmas experienced more stress (37% vs 21%, P = 0.002), compared to the control group
Chang Liu et al[53], 2021	Individuals who experienced SCA, divided into an unexplained SCA or explained SCA subgroup, completed the Recent Life Changes Questionnaire, Student Stress Scale, or Social Readjustment Rating Scale for Non-Adults recalling events during the preceding year; all measure stress in LCUs	No significant difference in LCU score between the control group and the SCA group (248181 LCU vs 252227 LCU; P > 0.05). The explained SCA subgroup had significantly lower mean LCU scores than the unexplained SCA subgroup (163183 LCU vs 308237 LCU; P = 0.030)
Rosman et al[32], 2021	Retrospective case-crossover study during 2016 United States presidential election linking cardiac device data, electronic health records, and historic voter registration records from patients with ICD	Significant increase in the incidence of composite outcomes for any arrhythmia (IRR = 1.77, 95%CI: 1.42-2.21), supraventricular arrhythmia (IRR = 1.82, 95%CI: 1.36-2.43), and ventricular arrhythmia (IRR = 1.6 95%CI: 1.22-2.10) during the election period. There was an increase in AF, SVT, non-sustained VT, and daily AF burden (P < 0.001)
Batelaan et al[55], 2021	Systematic review of various types of observational studies examining the association between anxiety or mental stress and SCA	For anxiety, the overall picture suggests that it predisposes for SCA in physically healthy populations (unadjusted OR = 2.44; 95%CI: 1.06-5.59). However, in populations at risk for SCA, associations were heterogeneous but not significant
Weber et al[36], 2022	Systematic review of 107 publications assessing acute physiological stress responses primarily through salivary cortisol and cardiovascular outcomes	Direct, non-moderated positive associations between acute stress exposure and concurrent cortisol levels (44%), SBP (44%), DBP (53%) and HR (53%)

CV: Cardiovascular; LF: Low frequency; HF: High frequency; ECGs: Electrocardiograms; HRV: Heart rate variability; SDNN: Standard deviation of N-N intervals; ED: Emergency department; ACS: Acute coronary syndrome; TIA: Transient ischemic attack; DVT/PE: Deep venous thrombosis and pulmonary embolism; TTS: Takotsubo syndrome; CVD: Cardiovascular disease; GP: German participation; BP: Blood pressure; HR: Heart rate; AMI: Acute myocardial infarction; SCA: Sudden cardiac arrest; LCU: Life change units; ICD: Implantable cardiac defibrillator; IRR: Incidence risk ratio; CI: Confidence interval; AF: Atrial fibrillation; SVT: Supraventricular tachycardia; VT: Ventricular tachycardia; OR: Odds ratio; SBP: Systolic blood pressure; DBP: Diastolic blood pressure.

CHRONIC CONSEQUENCES OF ACUTE STRESS

Acute stressors - even when circumscribed in time - may exert harmful effects on the CV system not only immediately, but also with a delayed trajectory. Two paradigmatic examples are PTSD and early-life stress.

PTSD

PTSD is a complex and debilitating trauma- and stressor-related disorder characterized by a persistent maladaptive stress response that may emerge across the lifespan after exposure to severe traumatic events that threaten safety or bodily integrity. Typical precipitating experiences include violent assault, natural or man-made disasters, and military combat. Clinically, PTSD is marked by intrusive trauma-related memories, avoidance behaviours, physiological hyperarousal, negative mood and cognitive changes, flashbacks, nightmares, and emotional numbing, with substantial impairment in quality of life (QoL)[5,56,57]. The PTSD Checklist for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition is a validated instrument widely used to assess symptoms related to lifetime exposure to potentially traumatic events; notably, it can also be applied to potentially life-threatening CV events, which represent persistent “internal” stressors rather than external trauma[58]. Chronic stress-related dysregulation is often conceptualized through the construct of allostatic load (AL), defined as the cumulative physiological burden across neuroendocrine, metabolic, CV, and inflammatory systems and commonly operationalized as a composite of dichotomized biomarkers[59]. Higher PTSD Checklist for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition scores, reflecting cumulative trauma exposure, have been associated with increased AL in adults with PTSD (P = 0.04)[59], consistent with evidence that individuals with PTSD develop age-related health conditions earlier than the general population.

PTSD is now recognized as a significant risk factor for both the development and progression of CV risk factors and overt CVD. Overall, PTSD has been associated with an approximately 25%-50% increased risk of CVD - including heart failure (HF), ACS, and CVrelated mortality - even after adjustment for sociodemographic characteristics, comorbidities, and servicerelated factors[3,60]. Much of this evidence derives from military and veteran cohorts[61-63]. For example, in a large retrospective study of 398769 women veterans, PTSD was associated with a higher incidence of coronary heart disease (CHD), particularly among younger women [hazard ratio (HR) = 1.44, 95%CI: 1.38-1.50][62]. Similar associations were observed for atherosclerotic CVD in United States Army personnel [odds ratio (OR) = 2.7, 95%CI: 2.2-3.3][63] and for MACEs in a South African insured population [adjusted HR (aHR) = 1.16, 95%CI: 1.05-1.28][64].

Population-based data further link PTSD to cardiometabolic abnormalities and symptomatic disease, with especially high odds for AMI[65]. Prospective cohorts - including the World Trade Center Heart study and post-Hurricane Katrina survivors - consistently demonstrate elevated risks of AMI, stroke, and incident CVD among individuals with PTSD, with evidence of racial and age-related effect modification[66]. Meta-analyses reinforce these findings, confirming increased risks of overall CVD, AMI, and stroke associated with PTSD[67,68].

The mechanisms underlying the PTSD-CVD association are multifactorial and incompletely understood. PTSD has been linked to systemic inflammation and to a range of adverse health behaviours - including unhealthy diet, physical inactivity, obesity, sleep disturbance, smoking, substance misuse, and suboptimal medication adherence - that independently contribute to CV risk[3,69]. Sexspecific patterns have emerged, with PTSD associated with a higher lifetime prevalence of hypertension in men but not women in some cohorts[70], and stronger longitudinal associations observed in younger individuals and males[63]. Importantly, in women veterans, conventional risk factors accounted for less than onequarter of the PTSD-CHD association, suggesting substantial residual risk beyond traditional pathways[62] and underscoring the importance of sex-specific considerations[71,72].

More granular analyses indicate that CV risk may vary across PTSD symptom clusters. In the ADVANCE study of United Kingdom military personnel, avoidance symptoms were associated with higher systolic blood pressure (SBP), emotional numbing with impaired glucose disposal, hyperarousal with elevated triglycerides, and intrusive symptoms with increased visceral adiposity[73]. These findings support biological heterogeneity within PTSD and suggest that specific symptom dimensions may differentially influence cardiometabolic risk.

Autonomic dysregulation has been proposed as a central mechanistic pathway linking PTSD to CVD. Heightened sympathetic nervous system (SNS) activity, reduced parasympathetic tone, impaired baroreflex sensitivity, and blood pressure (BP) instability may collectively increase CV vulnerability[3]. Consistent with this model, PTSD in young women has been associated with elevated brachial and central BP, increased arterial stiffness, and blunted parasympathetic cardiac control[74], while exaggerated vasoconstrictive responses to trauma related cues may further amplify risk[75].

Evidence of coronary microvascular dysfunction provides additional biological plausibility. In positron emission tomography (PET) imaging studies of twins, myocardial flow reserve was progressively lower in individuals with late onset or longstanding PTSD compared with those without PTSD[76]. Neuroimaging data suggests that compensatory neural adaptations may partially offset autonomic imbalance[77]. In the AURORA study, PTSD severity moderated associations between hypothalamic connectivity and CV indices - including BP, heart rate (HR), and HR variability (HRV) - highlighting complex interactions between central stress networks and peripheral autonomic regulation[77].

HRV, a marker of autonomic flexibility and a predictor of CV mortality, is consistently reduced in PTSD. Polysomnographic studies demonstrate lower high frequency HRV during non-REM sleep in affected individuals[78], while ambulatory monitoring suggests that PTSD symptoms predict subsequent reductions in HRV over short time intervals[79]. PTSD may also impair self-management and adherence to medical recommendations, although findings are heterogeneous across studies[3].

Beyond incident disease, PTSD carries important prognostic implications in individuals with established CVD. Among survivors of ACS, PTSD has been associated with an approximately two-fold increase in recurrent CV events and mortality over three years[80]. In stable CAD, persistent psychological distress predicts higher CVD incidence and all-cause mortality[81], while in HF populations, perceived stress may be more strongly associated with functional decline and poor health status than traditional clinical markers[82]. Prospective data further indicate a markedly increased risk of HF hospitalization among patients with PTSD, independent of demographic and clinical covariates, supporting shared neuroendocrine and autonomic pathways in disease progression[60,83,84].

The relationship between PTSD and CVD is bidirectional and clinically complex. A substantial proportion of patients experience psychological distress following AMI[14], and nearly one fifth may meet criteria for PTSD[85]. PTSD symptoms after cardiac events are associated with illness perception, fear of death, loneliness, age, and reduced social support[85]. Conversely, major cardiac events can precipitate PTSD[15,86,87], which in turn is linked to impaired recovery, reduced QoL, and increased risk of recurrent events and mortality[15,87]. Sociodemographic factors, including higher education and predominantly mental work, have also been associated with greater perceived stress among patients with CVD[88].

Cardiac disease-induced post-traumatic stress symptoms (CDI-PTSS), often subthreshold for formal PTSD diagnosis, are common and vary across CVD phenotypes[3]. Meta-analytic evidence estimates a prevalence of nearly 12% for ACS-induced PTSD and confirms an association with increased CHD risk[89], while approximately one-quarter of transient ischemic attack and stroke survivors report PTSD symptoms[4]. Greater intrusion symptom severity after a first AMI predicts recurrent MACE and all-cause mortality, and individuals with persistent PTSD symptoms experience higher subsequent CV event rates[3,90].

Sex-specific prognostic effects have been observed, with PTSD conferring higher all-cause and CV mortality risk among women but not men in the CHART-2 registry following the Great East Japan Earthquake[91]. CDI-PTSS has also been linked to non-fatal CV readmissions, and bidirectional associations extend to atrial fibrillation, in which stress and autonomic dysregulation may influence both disease onset and psychological sequelae[92].

Interpretation of the prognostic impact of CDI-PTSS remains challenging, given the predominance of cross-sectional and retrospective designs and difficulties in disentangling psychological effects from index event severity. While some studies report null associations with MACE, the recurrent observation of elevated CV risk among patients with CDI-PTSS highlights the need for rigorously designed prospective studies[3].

Finally, genetic research has emerged as a promising frontier. Genome-wide association studies demonstrate shared genetic liability between PTSD and CAD, hypertension, and HF, with potential mediators including insomnia, smoking, adiposity, and inflammation[93]. Mendelian randomization analyses support a causal contribution of PTSD to CAD and HF. Extensive overlap in genetic architecture has been identified across multiple genomic regions, imaging traits, and health behaviours, implicating neuronal, immune, metabolic, and calcium-related pathways[94]. A systematic review further identified numerous candidate genes, with the glucocorticoid receptor (NR3C1) and tumour necrosis factor-α emerging as key upstream regulators; several PTSD risk genes also confer independent risk for CVD and type 2 diabetes, underscoring shared cardiometabolic and inflammatory mechanisms[95].

Long-term effects of early life stress

Adverse childhood experiences (ACEs) refer to subjectively perceived threats - often chronic and variable in severity - to the safety or integrity of the child, family, or broader social environment. These include physical, sexual, and emotional abuse; neglect; caregiver mental illness; and socioeconomic adversity, all of which may disrupt normal physical and psychological development. In children sustaining injuries, consistent predictors of persistent PTSD include pre-injury psychological difficulties, subjective appraisal of trauma severity or life threat, elevated HR immediately post-trauma, beliefs about early symptoms, active thought suppression, and parental post-traumatic stress[96].

Several conceptual frameworks - the stress reactivity model, biological sensitivity to context theory, and the developmental origins of health and disease hypothesis - converge on the premise that adverse early environments shape heightened or maladaptive stress responsivity[97]. Persistent effects of childhood and adolescent adversity may manifest as dysregulated CV stress responses, ranging from exaggerated to blunted patterns. Such alterations can increase susceptibility to neuroendocrine and autonomic perturbations during later “homotypic” stress exposures, thereby contributing to adverse health trajectories[98,99]. This concept is supported by epidemiological observations and by experimental animal models of chronic postnatal stress, including maternal separation paradigms[100].

An American Heart Association scientific statement, together with multiple studies, has documented associations between childhood adversity and adverse cardiometabolic outcomes, including CVD, type 2 diabetes mellitus, dyslipidaemia, hypertension, abdominal obesity, all-cause mortality, and a range of mental disorders (substance use disorders and depression) in adulthood[3,101-104]. Although causal mechanisms remain incompletely defined, chronic early-life stress may promote low-grade systemic inflammation and dysregulation of the HPA axis, potentially contributing to these long-term comorbidities[101].

Both the number and severity of ACEs appear to relate to higher CVD risk[101]. In patients with implantable cardioverter-defibrillators (ICDs), a high-risk ACE profile (≥ 4) was associated with increased odds of anxiety (OR = 3.68, 95%CI: 1.37-9.84, P = 0.009), depression (OR = 4.08, 95%CI: 1.67-9.97, P = 0.002), and PTSD symptoms (OR = 2.20, 95%CI: 1.03-5.21, P = 0.041)[105]. Among practicing male physicians, higher ACE scores - reflecting abuse, neglect, and household dysfunction prior to age 18 - were directly associated with reduced endothelium-independent and endothelium-dependent coronary flow reserve (CFR)[106]. Registry-based data from Denmark and Sweden further suggest that maternal bereavement during the year before or during pregnancy was not generally associated with offspring CHD or stroke (aHR = 0.98; 95%CI: 0.85-1.13 and aHR = 1.04; 95%CI: 0.94-1.16, respectively). However, bereavement during the third trimester was associated with higher ischemic heart disease risk (aHR = 1.50; 95%CI: 1.06-2.13), and bereavement due to CVD or stroke was linked to increased risk (aHR = 1.22, 95%CI: 1.03-1.44)[107]. Clinicians should be aware of the relationship between ACEs and later CVD. When ACEs emerge during clinical history-taking, healthcare professionals should counsel patients regarding potential long-term health implications and facilitate referral to appropriate preventive and supportive services[3,101].

CHRONIC STRESS AND CVD

Chronic stress can be defined as a non-specific systemic response that develops after sustained exposure to adverse internal or external stimuli[108]. When stressors persist - particularly in individuals with underlying genetic susceptibility - environmental influences may further intensify and perpetuate stress reactivity[109,110].

Chronic psychosocial stress most often reflects prolonged exposure to unfavourable social conditions, including poor social support, poverty, discrimination (racial, gender, religious), adverse work environments, intimate partner violence, and environmental pollution[16,111]. These stressors represent the interface through which psychological experiences become embedded within social context and translate into downstream pathophysiological change[7]. Psychosocial stressors are commonly grouped into three domains: Major life changes, work-related conditions, and family or relational conflict[11]. Chronic stress is more frequently observed among individuals with depression, anxiety, and type A/D personality traits[16,111], and is also common after cardiac surgery[112]. Recent work has introduced the construct of “cardiac distress”, a persistent negative emotional state spanning multiple psychosocial dimensions that challenges coping capacity and self-concept; higher distress scores have been reported in younger individuals and in women[113].

Growing evidence indicates that chronic stress adversely affects cardiovascular health (CVH) metrics, including physical activity, HR, BP), and diet quality[97,114-117]. In pooled analyses of 7978 participants from the Multi-Ethnic Study of Atherosclerosis and MASALA cohorts, high chronic stress was associated with a 2.7-point lower Life’s Essential Eight CVH score compared with no stress, after multivariable adjustment[118].

A large literature further supports associations between psychological distress, stress-related CVR, and both subclinical markers (elevated BP, increased left ventricular mass, ventricular remodelling, carotid atherosclerosis) and overt cardio-cerebrovascular events[53,119-121]. These relationships have been reported as independent of familial background and psychiatric comorbidity in several analyses[122-124]. Notably, psychosocial factors appear comparable in magnitude to conventional risk factors in predicting CVD[125-129].

The INTERHEART case-control study (11119 AMI cases; 13648 controls across 52 countries) provided pivotal evidence linking psychosocial stress with AMI: Stress at home, stress at work, financial stress, and major life events were all more common among cases than controls[130]. Permanent stress at home was associated with an OR of 2.12 (99%CI: 1.68-2.65), while general stress showed ORs of 1.45 for intermittent and 2.17 for permanent stress[130].

Following INTERHEART, multiple studies reinforced the association between chronic stress and CVD. Long-term stress indexed by hair cortisol concentration (HCC) has been correlated with hypertension, hypercholesterolemia, body mass index, and waist circumference, particularly among women[131]. Elevated HCC has also been associated with higher prevalence of AMI, type 2 diabetes, atrial fibrillation, and coronary bypass surgery[132]. A systematic review and meta-analysis reported chronic stress in 58% of individuals with established CVD[133]. Perceived stress tends to be higher in women and predicts poorer post-AMI recovery across QoL and mental health domains[3].

High levels of distress - encompassing depression, anxiety, anger, perceived stress, and PTSD - have been shown to predict both first and recurrent CHD events (HR = 2.27 for highest tertile; 95%CI: 1.69-3.06)[134]. Similarly, higher scores on the Chinese Perceived Stress Scale (PSS) were associated with increased short-term risk of MACE (HR = 6.48; 95%CI: 2.98-14.11)[135]. In HF, chronic stress has been linked to adverse longitudinal trajectories, including reduced QoL and greater susceptibility to clinical events[82,136,137]. In the United Kingdom Biobank (399998 participants), chronic stress was associated with higher odds of CVD, hypertension, diabetes, and obesity[138]. Meta-analytic evidence further supports financial stress as a predictor of major cardiac outcomes (HR = 1.19; 95%CI: 1.00-1.47)[139].

Genetically informed analyses have provided additional support for potential causal pathways. Mendelian randomization studies suggest that low satisfaction with family relationships and financial stress increase the risk of stroke, CHD, AMI, and HF[140,141]. Social relational factors are also clinically relevant: Loneliness - defined as a subjective negative experience arising from insufficient meaningful relationships - and social isolation - an objective paucity of social contacts - have both been associated with increased CVD risk[3]. Meta-analyses report an approximately 1.5-fold higher risk of CHD among socially isolated adults[142]. While several authors have argued that observed stress - CVD associations may be partly influenced by baseline illness severity or reporting bias, links with hard CV outcomes remain persuasive[143].

Job stress

Job stress represents a specific manifestation of chronic stress driven by psychosocial demands within the workplace. Given that working-age adults spend a substantial proportion of life at work, occupational stress is an important determinant of long-term health. Changes in labour markets and organizational models in developed settings have increased exposure to work-related stressors[144]. Among contemporary psychosocial stressors, goal-striving stress - reflecting fear of failure - appears particularly relevant[145]. The coronavirus disease 2019 pandemic added further pressures, including job loss, income reduction, bereavement, social isolation, and lifestyle disruption, contributing to globally heightened stress levels[146,147]. Economic crises characterized by unemployment, intensified workloads, staff reductions, and wage cuts may further aggravate occupational stress and worsen mental health[110,148,149].

Two major conceptual models are commonly used to operationalize job stress[150-153]: (1) The High Demand-Low Control-Support model, reflecting an imbalance between job demands and perceived control/support; and (2) The Effort-Reward Imbalance model, reflecting disproportionate effort relative to rewards. Low job support has been associated with higher CV risk scores and lower well-being indices compared with high support[154]. Conversely, some data suggest that engagement in high-stress tasks may coexist with higher well-being than passive work, and that goal-striving stress may correlate with a lower likelihood of obesity[145,155].

Burnout, a syndrome arising from sustained occupational stress, has been associated with job dissatisfaction, absenteeism, presenteeism, and disability pensions. A systematic review identified burnout as a predictor of hypercholesterolemia, type 2 diabetes, CHD, CVD-related hospitalization, and premature mortality (< 45 years)[156].

Work-related stress may also promote maladaptive health behaviours - smoking, physical inactivity, and excessive alcohol intake - that compound CV risk[3,157]. In large-scale analyses, negative work-to-family spillover has been associated with adverse lipid biomarkers, including higher triglycerides (β = 0.094, P = 0.001) and lower high-density lipoprotein cholesterol (β = -0.098, P < 0.001), after adjustment for confounders[158]. Job stress is also associated with altered CVR[159]. and has been robustly linked to hypertension, insomnia, and negative affectivity (NA)[3,160].

Remote work introduces overlap between professional and domestic demands. While it may improve perceived comfort, lack of a dedicated workspace and prolonged working hours have been associated with reduced cardiac vagal modulation, potentially increasing CVD risk[161].

Multiple studies confirm associations between occupational stress and CV morbidity[151,162-165] and mortality[157,166-168]. In INTERHEART, among employed participants, several periods of work stress were reported by 23% of cases vs 17.9% of controls, and permanent stress by 10% vs 5%, respectively. Corresponding ORs were 1.38 (99%CI: 1.19-1.61) for intermittent stress and 2.14 (99%CI: 1.73-2.64) for permanent stress[130]. In Multi-Ethnic Study of Atherosclerosis, approximately 20% reported work-related stress; in adjusted models, stress was associated with lower odds of achieving average [adjusted OR (aOR) = 0.75; 95%CI: 0.62-0.92] and optimal (aOR = 0.73; 95%CI: 0.58-0.92) CVH scores[169].

Additional studies have linked job strain to altered left ventricular contractility, greater coronary calcification, and reduced chronic disease-free life expectancy[170,171]. Workplace bullying has also been associated with increased CHD and stroke risk[3]. A systematic review of 31 observational studies (n = 323978 participants across 17 countries) identified long working hours, night shifts, and high job strain as major occupational stressors associated with hypertension, CHD, and cardiometabolic disorders[172]. In a meta-analysis[173] applying attributable fraction estimates to national French exposure prevalence data (SUMER survey, 2003), 8.8%-10.2% of CHD morbidity and 9.4%-11.2% of CHD mortality in men were attributed to job strain exposure, with total costs estimated at 1.8-3 billion euros[173]. Conversely, unemployment is also associated with adverse lifestyle patterns, biological risk factors, and higher CVD prevalence[174].

Risk factors for CVD in the context of chronic stress

Personality: Type D (“distressed”) personality, described by Johan Denollet in 1996, is defined by the combination of NA and social inhibition (SI), with a tendency to suppress emotional expression and avoid social interactions. It has emerged as a non-traditional risk factor with both behavioural and biological correlations. The co-occurrence of NA and SI promotes chronic emotional distress and social isolation, which may adversely influence CV function. Evidence suggests that individuals with type D personality, particularly men, exhibit exaggerated CV responses to socially evaluative stressors[175]. Conversely, type D has been associated with lower SBP reactivity to acute stress in women, potentially reflecting blunted CVR[176]. HCC - used as a retrospective marker of long-term cortisol exposure - may partially mediate associations between chronic stress and type D, as both NA and SI have been linked to greater cortisol reactivity to stress[131,177]. A meta-analysis confirmed associations between type D personality and increased CVD risk as well as poorer prognosis among patients with established disease; prevalence estimates suggested a raw proportion of 0.36 for this association[178].

Gender: Psychosocial stress is a major determinant of CVH in women, both as a precipitating factor and because of CVD. Women experience a disproportionate burden of adverse psychosocial stressors during young adulthood and midlife, and reproductive transitions (menarche, pregnancy, menopause) may further increase vulnerability[179]. Midlife women are also more frequently exposed to early-life adversity and show an approximately two-fold higher prevalence of stress-related mental disorders (anxiety, depression, PTSD) compared with men after traumatic events[180,181]. Chronic stressors - including caregiving, socioeconomic hardship, intimate partner violence, gender-related barriers to healthcare, occupational stress, and perceived discrimination - may increase CVD risk through inflammatory pathways[181,182]. Mental health conditions, more prevalent among women, may further amplify CV risk through sex-specific mechanisms[183]. Although perceived discrimination and general stress correlate with clinical and subclinical CVD in midlife women[121,184], some studies also report modest but significant associations in men[185]. Data from the United States Research Goes Red Registry showed age-dependent differences: Toxic stress was associated with increased odds of CVD in women < 55 years (OR = 1.79; 95%CI: 1.03-3.11), but not in women ≥ 55 years[186]. Preclinical studies consistently show detrimental effects of stress on female CVH, although molecular mechanisms remain incompletely defined. Female CHD pathogenesis may be more complex, involving inflammation, contractile dysfunction, bioenergetic impairment, and structural remodelling[187]. Women with established CVD also commonly experience higher psychosocial stress - manifesting as anxiety, depression, and fear of recurrence - adversely affecting recovery and long-term outcomes[188].

Genetic factors and ethnicity: Individuals with elevated neuroticism polygenic risk scores, derived from European-ancestry cohorts in the Mass General Brigham Biobank, demonstrate higher CVD risk under socioeconomic disadvantage, potentially mediated through neural, autonomic, and immune pathways[189]. Among those with higher neuroticism polygenic risk scores, lower household income correlated with MACE (OR = 1.22, P = 0.005), stress-related neural activity (standardized β = 0.14, P = 0.003), and reduced HRV (β = -0.05, P = 0.041)[189]. Stress burden is disproportionately higher among Black and Hispanic populations[190]. Populations in the Global South may also face greater exposure to stressors related to development challenges, natural disasters, and armed conflict[191].

Protective factors against stress-related CV risk

Personality: Traits such as extraversion, gratitude, and openness to experience have been associated with more adaptive stress responses and better CVH[192,193]. Higher life enjoyment - a positive psychological state reflecting engagement with one’s environment - and participation in group leisure activities have been linked to reduced incidence and mortality from CVD in middle-aged men[194-196]. Improved mastery imagery ability may allow individuals to interpret stress-related arousal as performance-enhancing, thereby functioning as a coping strategy[197]. In patients with ICDs, higher mindfulness scores were associated with lower odds of PTSD symptoms (OR = 0.94; 95%CI: 0.89-0.98; P = 0.011)[198].

Spirituality: A systematic review suggests an inverse association between religiosity/spirituality and CVR to acute stress, particularly when measures capture intrinsic religiosity and internalized beliefs such as meaning and purpose; however, spiritual struggles may attenuate these potential benefits[199].

Socio-cultural context: The association between stress and CV outcomes may be moderated by emotion regulation strategies, particularly expressive suppression. Suppression is linked to adverse outcomes in Western populations but not necessarily in Eastern populations. In analyses from the midlife in Japan and midlife in the United States studies (adjusted for demographic and behavioural factors), marked cultural differences were observed among individuals with high suppression (r = -0.10; 95%CI: -0.19 to -0.01)[200]. Among Americans, higher stress correlated with higher CVD risk irrespective of reappraisal or suppression levels (r > 0.11; P < 0.07), whereas among Japanese individuals with high suppression, greater stress was associated with lower CVD risk (r = -0.09; 95%CI: -0.23 to 0.05)[200].

Social support: Social presence and perceived support contribute to interpersonal emotion regulation and may attenuate stress and negative affect[201]. The quality of perceived support predicts lower BP reactivity to laboratory stressors, whereas the quantity of daily support may correlate with higher ambulatory HR, independent of social contact during measurement[202]. In the Coronary Artery Risk Development in Young Adults study, however, social support was not a significant effect modifier[203]. Table 2 summarizes selected recent studies examining the association between chronic stress and CVD.

Table 2 Some recent studies on the cardiovascular effects of chronic stress.

Ref.	Setting	Main results
Li et al[163], 2015	Systematic review of 5 papers derived from 4 prospective studies conducted in Sweden and Canada	Significant effect of work stress (based on the Demand Control model or the Effort-Reward Imbalance model) on the risk of recurrent CHD events (HR = 1.65, 95%CI: 1.23-2.22)
Endrighi et al[138], 2016	HF patients longitudinally evaluated for psychological stress and CV hospitalizations/death	Patients reporting high average perceived stress a higher likelihood of adverse events compared to those with lower stress (OR = 1.10, 95%CI: 1.04-1.17). Perceived stress was elevated after a CV hospitalization (P = 0.004). An association between stress and adverse events was present when accounting for prior hospitalizations (P = 0.05)
Hirokawa et al[159], 2016	Between 2001 and 2009 in Osaka, Japan, authors examined 928 healthy Japanese employees from two occupational statuses: Managers/professionals and general workers. Changes in stress reactivity were calculated as the difference between the measured variables during the tasks and the rest period	Men showed inverse associations between quantitative job overload and DBP, HR, and LF/HF HRV, between physical demands and SBP, DBP, and between a poor physical environment and HF. Men also had positive associations between qualitative job overload and HR, and between physical demands and peripheral blood flow (all P < 0.05). Significant associations between job stress and changes in stress reactivity were observed in male managers/professionals and female general workers (P < 0.05)
Theorell et al[164], 2016	Systematic review of associations between occupational exposures and CHD. Ninety-six articles of high or medium high scientific quality were finally included	Moderately strong evidence for a relationship between job strain and small decision latitude on one hand and CHD incidence on the other hand. Limited evidence was found for pressing work, effort-reward imbalance, low support, lack of justice, lack of skill discretion, insecure employment, night work, long working week, and noise in relation to CHD
Jacob and Kostev[162], 2017	The study population consisted of 7374 patients who experienced a workplace conflict and 7374 controls for analysis identified by 699 general practitioners (Frankfurt, Germany)	After a maximum of five years of follow-up, 2.9% of subjects who experienced workplace conflict were affected by CVD, while 14% in the control group (P < 0.001). Workplace conflict was associated with a 163-fold increase in the risk of developing CVD. Finally, the impact of workplace conflict was higher for AMI than for angina pectoris and stroke (respectively OR = 2.03, 1.79, and 1.56)
Stewart et al[82], 2017	A total of 950 participants in the LIPID trial completed General Health Questionnaires-30. Cox proportional hazards models evaluated the risk of CV and total mortality by increasing levels of psychological distress over a median of 12.1 years	Patients with persistent moderate or greater psychological stress had a higher risk of both CV death (aHR = 3.94, 95%CI: 2.05-7.56, P < 0.001) and all-cause mortality (aHR = 2.85, 95%CI: 1.74-4.66, P < 0.001) compared with patients with no distress. In contrast, patients who reported persistent mild distress did not have an increased risk of CV or all-cause mortality during follow-up
Hagström et al[121], 2018	Psychosocial stress was assessed by a questionnaire in 14577 patients with stable CHD on optimal secondary preventive therapy in the prospective randomized STABILITY clinical trial	After 3.7 years of follow-up, financial stress was associated with increased risk (HR, 95%CI) of CV death (1.19, 1.08-1.30) and the primary composite endpoint of CV death, nonfatal AMI or nonfatal stroke (1.17, 1.10-1.24)
Lecca et al[154], 2018	Overall, 568 healthy workers of a flight logistic company were evaluated using the Health and Safety Executive questionnaire, the Framingham Heart Study General CVD Risk Prediction Score, and the WHO general well-being index (WHO-5)	Low job support significantly increases the CVD risk score and decreases the WHO well-being index with reference to subjects reporting high support on the job. In addition, job control, job support, low strain, and high demand coupled with high control (active job) showed a beneficial effect on psychological well-being
Stewart et al[122], 2018	Systematic review of literature (37 studies examining stress in mid-life and either CVD endpoints or subclinical CVD outcomes)	Significant risk of CVD due to stress. Most studies showed that mid-life women experiencing greater levels of stress had more subclinical CVD, as indicated by CIMT, flow-mediated dilation and arterial stiffness
Virtanen and Kivimäki[166], 2018	Large-scale meta-analyses with published and individual participant observational data on more than 740000 men and women free of CVD	Link between long working hours (≥ 55 hours a week) and the onset of CVD. Overall, 1.12-fold (95%CI: 1.03-1.21) increased risk of CHD and 1.21-fold (95%CI: 1.01-1.45) increased risk of stroke
Cabeza de Baca et al[116], 2019	The cross-sectional association between financial strain and ICH were examined in the Women’s Health Study follow-up cohort (n = 22048; mean age= 72 ± 6.0 years)	Number of financial stressors was associated with lower ideal cardiovascular health after adjustment for potential confounders (1 financial stressor: β = -0.10, 95%CI: -0.13 to -0.07; 2 financial stressor: β = -0.20, 95%CI: -0.26 to -0.15; 3+ financial stressor: β = -0.44, 95%CI: -0.50 to -0.38)
Burroughs Peña et al[183], 2019	In 25062 women participating in the Women’s Health Study, authors examined the relationship between CPS and ICH, as defined by the American Heart Association Strategic 2020 goals. A CPS score summarized acute (e.g., negative life events) and chronic stressors (e.g., work, work-family spillover, financial, discrimination, relationship, and neighbourhood) and traumatic life event stress reported on a stress questionnaire	White women had the lowest mean CPS scores (White: 161.7 ± 50.4; Hispanic: 171.2 ± 51.7; Black: 172.5 ± 54.9; Asian: 170.8 ± 50.6; P overall < 0.01). Mean ICH scores varied by race/ethnicity (P < 0.01) and were significantly lower in Black women and higher in Asian women when compared to White women (β coefficient and 95%CI: Hispanics -0.02: -0.13 to -0.09; Blacks -0.34: -0.43 to -0.25; Asians 0.34: 0.24-0.45). Interactions between CPS and race/ethnicity in ICH models were not significant
Endrighi et al[83], 2019	In a prospective cohort study (BETRHEART), 144 HF patients were evaluated for stress (PSS) and anger at baseline and every 2 weeks for 3 months. Functional status (6MWT) and health status (KCCQ) were also measured	Average PSS and greater than usual increases in PSS were associated with worsened KCCQ scores. Greater than usual increases in PSS were associated with worsened 6MWT. Average anger levels were associated with worsened KCCQ, and increases in anger were associated with worsened 6MWT
Moran et al[126], 2019	The Jackson Heart Study is a longitudinal cohort study of cardiovascular disease risks in 2256 African Americans in the Jackson, Mississippi metropolitan statistical area. Financial stress was assessed from the Jackson Heart Study Weekly Stress Inventory	Participants with moderate to high (vs no) financial stress were more likely to have incident CHD events after controlling for demographics, SES, access to care, and traditional clinical risk factors (HR = 2.42, 95%CI: 1.13-5.17). The association between financial stress and CHD was no longer statistically significant adjusting for three specific risk factors: Depression, smoking status, and diabetes (HR = 199, 95%CI: 0.91-4.39)
Song et al[124], 2019	Population based, sibling-controlled cohort study on 136637 patients in the Swedish National Patient Register with stress related disorders, including PTSD, acute stress reaction, adjustment disorder, and other stress reactions, with a follow-up of 27 years	The crude incidence rate of any CVD was 10.5, 8.4, and 6.9 per 1000 person years among exposed patients, their unaffected full siblings, and the matched unexposed individuals, respectively. In sibling-based comparisons, the HR for any CVD was 1.64 (95%CI: 1.45-1.84), with the highest subtype specific HR observed for heart failure (6.95, 1.88-25.68). Stress related disorders were more strongly associated with early onset CVD (HR = 1.4, 1.32-1.49) for attained age < 50 than later onset ones (1.24, 1.18-1.30) for attained age ≥ 50 (P = 0.002)
Wu et al[151], 2019	The Taiwan bus driver cohort study recruited 1650 professional drivers	Occupational drivers with high overcommitment scores had an elevated risk for CVD (HR = 1.71; 95%CI: 1.04-2.82). Regarding target disease, overcommitment had an increased risk for CVD (HR = 1.27; 95%CI: 1.05-1.54) and CHD (HR = 1.32; 95%CI: 1.05-1.65)
Smaardijk et al[185], 2020	Metanalysis identified studies (44 articles including 227647 women and 321894 men) assessing the risk of psychological factors (anger/hostility, anxiety, depression, psychological distress, social support, type A behaviour pattern, type D personality, and PTSD) for MACE in samples with CHD	The association between psychological factors (all combined) and MACE was stronger in men (HR = 1.37, 95%CI: 1.27-1.48) than in women (HR = 1.21, 95%CI: 1.12-1.30; P = 0.017). A subset of the studies focusing on women showed significant associations between anger/hostility, depression, and distress with MACE. For men, statistically significant associations were found for anxiety, depression, and distress with MACE
Crom and Trappe[132], 2021	40 patients with an acute STEMI confirmed by ECG. The control group consisted of 80 patients without CAD	Patients with STEMI did not show significantly higher HCC compared to controls, nor was there correlation with the extent of AMI. Correlations were found between HCC and T2DM (P = 0.046, OR = 6.346), low high-density lipoprotein cholesterol concentration (P = 0.107), glycated haemoglobin concentration (P = 0.083), and chronic HF (P = 0.110)
Li et al[167], 2021	Prospective cohort study identified hypertensive workers from the population-based MONICA/KORA study in Southern Germany, who were free of any CVD and diabetes, interviewed at baseline for work stress (high demand plus low control) and impaired sleep (difficulties falling asleep and/or maintaining sleep)	In comparison to participants with low work stress and non-impaired sleep, participants with work stress (HR = 1.56, 95%CI: 0.81-2.98), or impaired sleep (HR = 1.76, 95%CI: 0.96-3.22) had an increased risk of CVD, while participants with both work stress and impaired sleep had the highest risk of CVD mortality (HR = 2.94, 95%CI: 1.18-7.33). Similar risk patterns were found for CHD mortality
Cain-Shields et al[146], 2022	The relationship between GSS and incident hypertension, diabetes, and obesity among 4485 participants in the Jackson Heart Study	Among men, those with high (vs low) GSS were 41% less likely to become obese over a mean period of eight years: 0.59 (0.36, 0.95), P = 0.03
Gaffey et al[120], 2022	Systematic review (28 studies on 58331 participants without a past psychiatric diagnosis, screened at baseline for depression, anxiety, PTSD, stress, and followed for > 6 months)	Subjects reporting high psychological distress showed a 28% greater risk of incident CVD compared to those with low or no distress
Kautzky et al[184], 2022	Healthy women were assessed for glucose metabolism, fatty liver index and anthropometric parameters. Psychological stress assessment included the “Brief Symptom Inventory”, and PSS. Biological stress response was evaluated with HRV and cortisol levels	Burnout and PSS scores were associated with insulin secretion, sputum cortisol, thyroid-stimulating hormone, anthropometric measures, and gender role. Brief Symptom Inventory ratings for psychiatric symptom dimensions were associated with insulin resistance, sex hormones, anthropometric measures, and gender role
Kubera et al[104], 2022	From the Whitehall II cohort data of 4969 men and 2138 women were analysed. Psychological stress (General Health Questionnaire) and body shape were measured	Increase in the expected hazard to develop CHD with high psychological stress (P = 0.017) in both genders. Subjects with consistently high psychological stress had a 24-fold (men) or 2.3-fold (women) higher risk for later CHD events compared to never-stressed subjects. Subjects with a high sum score of childhood experiences had a 10% increased hazard to develop fatal or non-fatal CHD events in adulthood
Gao et al[89], 2022	In stable CHD patients the Chinese version of the PSS was used. Patients were divided into HPS (Chinese version of the PSS ≥ 31) and NHPS groups	The log-rank analysis showed that risk of cardiovascular events with HPS was higher than NHPS (P = 0.012). After adjusting for demographic, lifestyle, and clinical information, the HPS group had significantly increased risk of events within 24 months (HR = 1.369, 95%CI: 1.037-1.807, P = 0.027), but less impact after 24 months
Birdit et al[115], 2023	A total of 238 individuals from the Stress and Well-being in Everyday Life Study reported life event stress. Of those individuals, 169 completed an ecological momentary assessment study in which they reported stress exposure every 3 hours, and 164 wore a heart rate monitor for up to 5 days	The study revealed 2 longitudinal trajectories of life event stress: Moderate-increasing and low-decreasing. Individuals in the moderate-increasing stress trajectory reported greater daily stress exposure. Black individuals in the low-decreasing trajectory and White individuals in the moderate-increasing trajectory showed positive associations between daily stress and heart rate
Söderberg et al[160], 2023	Cross-sectional study was conducted in a sub-cohort of the SCAPIS. Psychosocial exposure was evaluated with the job demand-control model and analysed according to the standard categorization: High strain (high demands-low control), active, passive (low demands-low control) and low strain	High strain was linked to increased adjusted PR for low HDL cholesterol in women (PR = 1.76; 95%CI: 1.25-2.48). High strain was also related to moderately increased PR for metabolic syndrome in men (PR = 1.25; 95%CI: 1.02-1.52). In addition, passive work was associated with diastolic hypertension in women (adjusted PR = 1.29; 95%CI: 1.05-1.59)
Lavigne-Robichaud et al[152], 2023	Prospective cohort in Quebec, Canada. In six thousand four hundred sixty-five white-collar workers without cardiovascular disease followed for 18 years job strain and ERI were measured with validated questionnaires	Exposure to either job strain or ERI was associated with an adjusted 49% CHD risk increase (HR = 1.49, 95%CI: 1.07-2.09). Combined exposure to job strain and ERI was associated with an adjusted 103% CHD risk increase (HR = 2.03, 95%CI: 1.38-2.97)
Pogosova et al[127], 2023	Patients with arterial hypertension and CHD managed in primary health care institutions in multi-year prospective COMETA study, using a VAS for assessment of stress level	The composite endpoint that included all-cause death and/or severe adverse cardiovascular outcomes was significantly associated with a high (VAS score ≥ 8) stress level (OR = 1.53; 95%CI: 1.00-2.33, P = 0.04)
Wendel et al[98], 2023	In 213 adults participating in the Pittsburgh Cold Study 3, early environment stress was assessed by four self-report measures consistent with the biological sensitivity to context theory. Average HR and mean BP reactivity to the TSTT were assessed on two occasions	Results generally did not support the stress reactivity hypothesis; little evidence that high-stress early environments were reliably associated with exaggerated CV reactivity or slower CV recovery. There was some support for the biological sensitivity to context theory; both high-stress and low-stress early environments were associated with exaggerated CV reactivity
Won et al[112], 2024	Retrospective observational study using data from the National Hospital Ambulatory Care Survey, Federal Reserve Economic Database, National Bureau of Economic Research, and CVD groupings from National Vital Statistics and Center for Medicare and Medicaid Services from 1999 to 2020 to analyse ED visits in relation to macroeconomic indicators	A significantly higher proportion of CVD ED visits related to HF and other acute CHD was observed during recessionary time periods both directly and with a 6-month lead and lag (P < 0.05). The proportion of aortic aneurysm and dissection and atherosclerotic CVD ED visits was significantly higher (P = 0.024) in the recession period with a 6-month lead and lag
Swarup et al[140], 2024	Meta-analysis (7 studies) on the association between financial stress and the incidence of major cardiac outcome	A significant association was found between financial stress and major cardiac outcomes (combined HR = 1.191, 95%CI: 1.00-1.47, P < 0.001)
Osibogun et al[117], 2024	Cross-sectional analysis of 6453 adults from the Multi-Ethnic Study of Atherosclerosis. Financial strain was assessed by questionnaire and responses were categorized as yes or no. ICH was measured from 7 metrics (smoking, BMI, physical activity, diet, total cholesterol, blood glucose and blood pressure)	Participants who reported financial strain had lower odds of average (OR = 0.82, 95%CI: 0.71-0.94) and optimal (0.73, 0.62-0.87) ICH scores. However, in the fully adjusted model, the association was only significant for optimal ICH scores (0.81, 0.68-0.97)
Ajibewa et al[203], 2024	Data from 3401 adults from the Coronary Artery Risk Development in Young Adults study, with no prior CVD event were analysed. Chronic stress lasting ≥ 6 months across five life domains (work, financial, relationships, health of self, and health of close other) was self-reported	Chronic stress was associated with lowered survival (time ratio = 0.92; 95%CI: 0.854-0.989), when adjusted for sociodemographic and lifestyle variables but no longer significant when adjusting for clinical factors. Social support was not a significant modifier (P > 0.05)
Méndez-Chacón[129], 2026	In the Costa Rica Longevity and Healthy Aging Study, multiple logistic regression models were used to analyse the relationship between stress and chronic diseases	Stress related to the health of close relatives is associated with an increased risk of developing cardiovascular events. Financial stress was associated with twice the risk of developing hypertension
Gopep et al[118], 2025	Cross-sectional analysis using publicly available data from 18, adults in the National Health and Nutrition Examination Survey	After adjustment, stress was significantly linked to higher odds of hypertension (β = 0.3, P < 0.03)
Ayaz Khan et al[123], 2025	Overall, 385 young adults from Islamabad, Pakistan completed the PSS in conjunction with the Hill-Bone Compliance to High Blood Pressure Therapy Scale	Perceived stress was moderately positively correlated with blood pressure control (P < 0.001). The greater the stress, the less effective blood pressure is controlled (P < 0.001)
Kutal et al[128], 2025	In young patients with a first-ever CIS and sex/age-matched stroke-free controls from 19 European centres self-perceived stress was assessed using a modified version of the PSS. Scores were categorized into low (0-13), moderate (14-26), and high (27-40) perceived stress	Patients were more often at least moderately stressed compared with controls (46.2% vs 33.3%, P < 0.001). Higher self-perceived stress as a discrete measure was independently associated with CIS (aOR = 1.04 per point increase; 95%CI: 1.01-1.07). Categorical PSS score analysis showed an independent association between moderate stress and CIS (OR = 1.47; 95%CI: 1.00-2.14), but not with high stress (2.62; 0.81-8.45)
Eleazu et al[190], 2025	In participants from the Dallas Heart Study phase 2 without prevalent CVD, individual chronic stress subcomponents (generalized stress, psychosocial, financial, and neighbourhood stress) were standardized and integrated to create a novel CSS	CSS was higher among participants who were younger, women, and Black or Hispanic individuals, with lower income and educational attainment (P < 0.0001 for each). In multivariable regression models, higher CSS associated with hypertension, smoking, higher BMI, haemoglobin A1C, high sensitivity C-reactive protein, and sedentary time (P < 0.01 for each). Over a median follow-up of 12.4 years, higher CSS associated with atherosclerotic CVD (aHR = 1.22 per SD, 95%CI: 1.01-1.47) and global CVD (aHR = 1.2, 95%CI: 1.03-1.40)
Hallab et al[139], 2025	Data from the multiethnic ≥ 50-year-old study population (2173 participants), a subset of the Health and Aging Brain Study: Health Disparities study	Having chronic stress is associated with 53% higher odds of disclosing concomitant CVD (aOR = 1.53, 1.1-2.53), 31% of type 2 diabetes (aOR = 1.31, 1.06-1.62), 23% of hypertension (aOR = 1.23, 1.02-1.49), and 30% obesity (aOR = 1.3, 1.09-1.55)
Nakhutina and McFarlane[125], 2025	From the National Health Interview Survey (2004-2013) (284497 individuals) psychological distress was measured using the Six-Item Kessler Psychological Distress Scale (a score of ≥ 13 indicated distress)	Unadjusted OR for stroke among psychologically distressed individuals was 3.1 (95%CI: 2.8-3.3; P < 0.01). After adjusting, the odds of stroke in those with psychological distress was nearly threefold (OR = 2.7; 95%CI: 2.3-3.2; P < 0.01). Classical risk factors attenuated this association, but the relationship remained highly significant (OR = 2.17, 95%CI: 1.81.3-2.60; P < 0.01)
Liu et al[141], 2025	A total of 7493 participants from Wave 3 (2015) of the China Health and Retirement Longitudinal Study were included. Stressful life events were assessed using five simple questions. CMM was defined as having two or more cardiometabolic diseases, including diabetes, heart disease and stroke	The prevalence of CMM increased with the number of stressful life events, ranging from 5.73% for one stressful life event to 6.61% for two or more. In the fully adjusted model, the OR (95%CI) for CMM were 149 (1.01-2.20) for participants experiencing marital problems. Compared with no stressful life events, an increasing number of stressful life events was associated with a higher risk of CMM (P < 0.001)
Lavigne-Robichaud et al[153], 2025	Prospective cohort study including 6295 employees without CVD at baseline from Quebec, Canada	During 15-year follow-up, the attributable fraction for job strain was 18.2% (95%CI 1.8-34.7), and for ERI 3.3% (95%CI: 1.6-8.2). Combined exposure to both stressors resulted in an attributable fraction of 19.5% (95%CI: 0.7-38.4)

CHD: Coronary heart disease; HR: Hazard ratio; CI: Confidence interval; HF: Heart failure; CV: Cardiovascular; OR: Odds ratio; DBP: Diastolic blood pressure; LF: Low frequency; HRV: Heart rate variability; SBP: Systolic blood pressure; CVD: Cardiovascular disease; LIPID: Long-Term Intervention with Pravastatin in Ischaemic Disease; aHR: Adjusted hazard ratio; AMI: Acute myocardial infarction; WHO: World Health Organization; CIMT: Carotid intima media thickness; ICH: Ideal cardiovascular health; BMI: Body mass index; CPS: Cumulative psychosocial stress; PSS: Perceived stress score; 6MWT: Six minutes walking test; KCCQ: Kansas City Cardiomyopathy Questionnaire; PTSD: Post-traumatic stress disorder; MACE: Major adverse cardiovascular events; STEMI: ST elevation myocardial infarction; ECG: Electrocardiogram; CAD: Coronary artery disease; HCC: Hair cholesterol concentration; T2DM: Type 2 diabetes mellitus; GSS: Goal striving stress; CHD: Coronary heart disease; HPS: High perceived stress; NHPS: Non-high perceived stress; SCAPIS: Swedish CArdioPulmonary bioImage Study; PR: Prevalence ratio; HDL: High-density lipoprotein; ERI: Effort reward imbalance; VAS: Visual analogue scale; BP: Blood pressure; TSTT: Trier Social Stress Test; ED: Emergency department; CIS: Cryptogenic ischemic stroke; CSS: Composite stress score; aOR: Adjusted odds ratio; CMM: Cardiometabolic multimorbidity.

PATHOPHYSIOLOGICAL ISSUES

In the seventeenth century, the London neuroanatomist Thomas Willis correctly identified the brain - rather than the heart, as assumed in antiquity - as the origin of emotions[204]. This insight contributed to the conceptual foundations of psychoneuroendocrineimmunology, the discipline examining interactions among psychological processes and nervous and immune systems[13,205]. Hans Hugo Bruno Selye (1907-1982), widely considered a founder of modern stress research, published over 1500 articles and 30 volumes on stress physiology. Nearly a century ago, he proposed that stress persists during exposure to non-specific demands and distinguished acute stress from the cumulative response to persistent stressors, termed the “general adaptation syndrome” (Selye’s syndrome).

Stress reflects both external exposures and the behavioural/biological responses they evoke; when perceived demands exceed adaptive capacity, this response may become “distress”[92,206]. The Yerkes-Dodson law posits that performance improves with arousal up to an optimal level; beyond this threshold, excessive or insufficient stimulation promotes distress, whereas moderate stimulation may represent eustress.

In rodent models of chronic social defeat, two phenotypes are typically described: Susceptible animals, characterized by social avoidance and depression-like behaviours, and resilient animals, which do not exhibit these alterations[207]. The biopsychosocial model of challenge and threat conceptualizes a continuum in which favourable demand-resource appraisals correspond to more efficient CV responses and better performance (challenge state), whereas maladaptive appraisals are associated with poorer outcomes (threat state), including depressive symptoms[208]. Task engagement - indexed by increases in HR and ventricular contractility - represents a prerequisite for both states[208].

Emotionally salient stressors are processed by interconnected cortical and subcortical regions including the prefrontal and insular cortices, anterior cingulate gyrus, amygdala, hypothalamus, and hippocampus, as shown in rodent and human neuroimaging studies[208-212]. This network integrates contextual information, memory, and prior experience to guide appraisal and response[16,210]. The amygdala has a central role; in PTSD models, its AMPA receptors modulate CV activity, potentially through inhibitory pathways[213].

Through these networks, the brain translates emotional stimuli into biological stress responses affecting central and peripheral metabolism, hormonal trafficking, and coordinated hemodynamic, neuroendocrine, and immune changes - collectively described as the “fight-or-flight” response[16,183,210,214]. Although evolutionarily protective during physical threats, this response may become maladaptive in modern settings dominated by social and symbolic stressors[210].

Increasing evidence supports the brain-heart axis, connecting frontal and limbic regions to the brainstem and peripheral organs via the autonomic nervous system, as a key regulator of CV homeostasis[215,216]. Acute psychological stress activates the sympatho-adrenal medullary system, renin-angiotensin system, and the HPA axis[98,212,217,218]. Dysregulated stress reactivity may contribute to adverse health outcomes[217]. Pre-autonomic relays to brainstem and spinal cord nuclei may promote dysautonomia, impaired baroreflex function, sympathetic overactivity, altered norepinephrine reuptake, and parasympathetic withdrawal[219,220], culminating in stress hormone release and inflammatory cytokine production. Prolonged activation may induce neurotransmitter imbalance, neuroinflammation, and epigenetic changes, increasing vulnerability to depression, anxiety, and PTSD - conditions to which women may be particularly susceptible due to hormonal transitions and heightened stress responsivity[86]. Mental distress correlates with stress-related CV reactions even after accounting for potential confounders[221].

Both exaggerated and blunted baseline sympatho-adrenal medullary/HPA reactivity have been associated with adverse outcomes[217]. Hyperreactivity has been linked to higher CV risk and shorter telomere length, whereas blunted CVR may reflect impaired motivation and reduced task engagement rather than limited physiological capacity[113,207,222]. Hyporesponsivity predicts future obesity, depression, anxiety, PTSD symptoms, musculoskeletal pain, cognitive decline, and lower bone mass[217].

Chronic stress induces systemic physiological alterations[206]. Impaired emotion regulation and psychological stress may contribute to CVD via autonomic dysfunction, including impaired baroreflex and chemoreflex function and reduced HRV[78,206,223,224]. Stress also acts through direct neuronal, endocrine, autonomic, and immune pathways, and indirectly by fostering behaviours that accelerate CVD progression[91]. Damage to cerebral stress-processing regions has been associated with arrhythmias, myocardial injury, and higher circulating concentrations of brain natriuretic peptide, catecholamines, and glucose[208]. Corticolimbic activation can increase BP and HR, alter contractility, and raise CV risk[78,156,209,223]. HR may serve as a pragmatic marker of the interaction between vascular morbidity and psychological distress[72,225]. Chronic stress also promotes neurohormonal changes that activate apoptotic pathways in cardiomyocytes, contributing to myocardial dysfunction, ischemia, infarction, HF, and arrhythmias[12].

Overall, the cumulative result may be a hyperadrenergic milieu that predisposes to cardiomyopathy, arrhythmogenesis, coronary ischemia, hypertension, and stress-related HF[219,226]. Additional mediators include FK506-binding protein 5, a glucocorticoid receptor co-chaperone, and disruption of telomere maintenance[225]. Dysregulation of the HPA axis and SNS can promote hypercoagulability, hypertension, dyslipidaemia, and chronic inflammation[5]. Activation of intrinsic coagulation pathways has been proposed as one mechanism by which perceived stress may precipitate CV events[227].

Cardiac MRI studies suggest sex-specific vulnerability to subclinical myocardial alterations: Women with high perceived stress show significantly longer T1 times than low-stress counterparts, with similar trends for T2 in at-risk groups; no significant differences were observed in men. In women, perceived stress scores predicted T1 values, whereas no such association was seen in men[228]. Animal data are consistent: PTSD-like mouse models demonstrate sex-dependent diastolic dysfunction and increased cardiac fibrosis, more pronounced in females[229]. In Wistar rats, stress aggravates myocardial injury after AMI by amplifying inflammation and endothelial dysfunction and is accompanied by hippocampal injury[230]. Chronic stress may also disrupt the gut microbiota and the gut-brain axis, thereby worsening systemic inflammation and mental health outcomes[231]. A meta-analysis of 33 studies (43641 participants) reported higher CV risk among individuals with elevated stress hormones (norepinephrine, epinephrine, and cortisol)[47]. Below, we discuss selected mechanistic components linking stress to CV risk.

The autonomic nervous system

Since the early anatomical descriptions by Thomas Willis, the SNS has been recognized as central to CV homeostasis, counterbalanced by the parasympathetic nervous system. Cardiac β1-adrenoreceptors are exposed to cortisol from the adrenal cortex and norepinephrine released from sympathetic nerve terminals. CV regulation is further modulated by immune cells derived from spleen and bone marrow, renal renin-angiotensin system signalling, catecholamines from the adrenal medulla, and peripheral acetylcholine pathways[231].

The human autonomic nervous system operates hierarchically, recruiting evolutionarily recent adaptive responses before engaging more primitive strategies. Three behavioural patterns - social communication, mobilization, and immobilization - are mediated by distinct neural circuits. Social communication is supported by the myelinated vagus originating from the nucleus ambiguous and promotes calm states through inhibition of sympathetic cardiac influence. Mobilization is mediated by the SNS and increases metabolic demand and HR, whereas immobilization involves the phylogenetically oldest vagal pathway arising from the dorsal motor nucleus and is associated with a “feigned death” response. At rest, ventral vagal activity dampens sympathetic reactivity, while extreme threat may activate dorsal vagal pathways, leading to a potentially hazardous “shutdown” response in humans.

Techniques such as microneurography and regional norepinephrine spillover measurements provide robust evidence of sympathetic overactivity in several CV disorders[212]. Increasing attention has been directed toward “stresstriggered” heart disease, in which dysregulated brain-heart autonomic control precipitates acute cardiac events following emotional stress[39]. Excessive sympathetic activation represents a key mechanism linking psychological stress to cardiomyopathy, arrhythmogenesis, coronary ischemia, hypertension, and stress-related HF[219,232,233]. In PTSD, heightened cardiac sympathetic outflow combined with vagal inhibition appears central[234], with consistent findings of increased SNS activity, reduced parasympathetic nervous system tone, and impaired baroreflex sensitivity[235]. In women with PTSD, inflammatory activation and autonomic dysfunction, including reduced baroreflex sensitivity, exaggerated sympathetic reactivity, and diminished parasympathetic tone, have also been reported[180].

Patients with panic disorder exhibit sympathetic activation during panic attacks, sometimes associated with coronary spasm[52]. Sustained sympathetic tone may further contribute to hypertension via smooth muscle proliferation and vascular hypertrophy[236]. In contrast, obesityrelated hypertension does not consistently demonstrate sympathetic augmentation, a finding proposed to underlie the “obesity paradox”, whereby obese hypertensive individuals show longer survival compared with those of normal weight[203].

Arrhythmias

Sympathetic neural overactivity contributes substantially to arrhythmic risk and SCD, particularly when norepinephrine reuptake is impaired and individual sympathetic fibres discharge in multiple bursts within a single cardiac cycle[203]. Emotional stress may further destabilize repolarization through lateralized autonomic stimulation and consequent spatial heterogeneity of repolarization[236]. In addition, direct effects on cardiac ion channels may facilitate malignant ventricular arrhythmias, including ventricular fibrillation[53].

Within PTSD, symptom clusters may have distinct CV correlates. Emotional numbing - characterized by anhedonia, cognitive dysregulation, and detachment - has been associated with lower HRV as measured by the root mean square of successive differences, whereas PTSD diagnosis per se was not[237]. This supports the concept that symptom constellations may correspond to specific CV profiles[237].

Endothelial dysfunction

Under physiological conditions, sympathetic nerves and vascular endothelium regulate vascular tone through balanced, opposing influences. Mental stress can disrupt this equilibrium via multiple pathways, including increased SNS activity, hypothalamic corticotropin-releasing hormone signalling, cortisol-mediated inhibition of nitric oxide synthesis, altered haemostasis, oxidative stress, dysregulated intracellular signalling, impaired lipid metabolism, and increased pro-inflammatory cytokine release[75,107,220,225,236]. These changes may activate macrophages, promote foam cell formation, and accelerate atherosclerotic plaque development and progression[238]. Longitudinal evidence indicates that PTSD is associated with impaired coronary microcirculatory function and progressive deterioration over time[75]. Heightened vulnerability of women to psychosocial stress may partially explain their greater propensity for abnormal coronary vasomotion and microvascular disease[179].

Such alterations may precipitate mental stress-induced myocardial ischemia (MSIMI), which can occur even in the absence of obstructive coronary disease. MSIMI typically develops at lower cardiac workloads than exercise-induced ischemia, supporting a dominant role for paradoxical vasoconstriction and microvascular dysfunction[16], and potentially contributing to AMI or direct myocardial injury[239]. In one study of women with chest pain and non-obstructive CAD, mental stress was associated with coronary endothelial dysfunction (CED). Macrovascular CED was defined as a ≤ 10% change in coronary diameter after acetylcholine, and microvascular CED as a ≤ 50% change in coronary blood flow; the OR for any CED was 2.7 (95%CI: 1.24-6.25; P = 0.0156)[240].

A meta-analysis of seven studies assessed the impact of acute psychological stress on central pulse wave velocity (PWV) in adults without overt CVD. Moderate acute stress significantly increased PWV vs baseline [standardized mean difference (SMD) = -0.51; 95%CI: 0.34-0.68; P < 0.0001], consistent with stress-related worsening of arterial stiffness[241].

In a study of 60 male physicians stratified by burnout status, PET was used to quantify endothelium-dependent CFR during cold pressor testing and endothelium-independent CFR during adenosine hyperaemia. A significant interaction between NA and SI was independently associated with higher endothelium-dependent CFR, which increased with higher SI when NA was high, and with higher NA when SI was high[242].

Among healthy young adults, chronic stress exposure (β = -0.24, P = 0.045) - but not stress appraisal or perceived stress assessed by the PSS - was associated with impaired endothelial function measured by brachial artery flow-mediated dilation (FMD)[243]. Experimental paradigms of chronic unpredictable mild stress and chronic social defeat similarly demonstrate predominant microvascular (rather than macrovascular) dysfunction on ultrasonography and laser Doppler assessments[244].

Inflammation

Inflammation, together with oxidative imbalance, constitutes a key biological mechanism through which stress influences CV risk across all stages of atherogenesis[2,210,238,239]. Experimental studies show that acute mental stress elicits transient increases in inflammatory markers and indicate that both pharmacological and behavioural interventions may attenuate these responses[245]. Sympathetic activation during stress, coupled with withdrawal of parasympathetic anti-inflammatory reflexes, is thought to promote low-grade sterile systemic inflammation. This process likely involves a neural-hematopoietic-arterial axis linking stress-related neural circuits, bone marrow activation, reactive oxygen species generation, leukocyte mobilization, and their recruitment to arterial walls and atherosclerotic plaques[2,236,239].

Population-based evidence supports inflammation as a mediator between chronic stress exposure and CVD, with consistent associations reported between stress burden and heightened immune-inflammatory activity[211,246]. HCC has been correlated with leukocyte counts and high-sensitivity C-reactive protein (hs-CRP), suggesting an integrated relationship between cumulative stress exposure, immune activation, and inflammatory tone[131].

Clinical and translational studies provide converging support for these pathways. In a large hospital-based biobank, the association between PTSD and MACE was mediated by stress-related neural activity, HRV, and hs-CRP (all P < 0.05)[76]. Similarly, interleukin-6 statistically mediated associations between chronic stress and CVD (P = 0.012)[137]. Experimental models further implicate upstream inflammatory signalling, with stress-exposed mice showing activation of the NLRP3 inflammasome via endoplasmic reticulum stress and Janus kinase/signal transducer and activator of transcription pathways[247]. In humans, acute psychosocial stressors, such as spousal bereavement, have been associated with increased pro-inflammatory cytokine production by lipopolysaccharide-stimulated peripheral blood leukocytes[248]. Despite this growing body of evidence, interpretation remains limited by the predominantly cross-sectional design of available studies, restricting causal inference and highlighting the need for longitudinal and mechanistic investigations.

Risk factors

Several mechanisms plausibly link post-AMI psychological distress to higher future cardiac risk, including reduced physical activity, persistent smoking, excessive alcohol intake, unhealthy diet, obesity, poor sleep, limited social support, reduced medication adherence, and lower participation in cardiac rehabilitation (CR)[14]. Epidemiological data further suggest that stress contributes to CVD in part by increasing the incidence of traditional risk factors such as smoking, hypertension, insulin resistance, and obesity[7]. PTSD has also been associated with tobacco use[14,60].

Higueras-Fresnillo et al[249] reported inverse associations between severe psychological distress and CVH as measured by the American Heart Association Life’s Essential 8 score, which includes four health behaviours and four health factors.

In the Korean Work, Health, and Sleep Study, high-risk emotional labour (Korean Emotional Labour Scale-11) was associated with higher odds of smoking, physical inactivity, and insufficient sleep; hypertension, diabetes, and dyslipidaemia were more frequent in the high-risk group, particularly among men[250].

An epigenome-wide mediation analysis in the multi-ethnic Health and Retirement Study identified CpG sites linked to expression pathways involving DNA methylation, cytokine signalling, receptor activity, and neuronal development; these sites mediated associations between psychosocial stress and body mass index, waist circumference, high-density lipoprotein cholesterol, and hs-CRP[251].

Experimental models offer additional mechanistic insight. Repeated social defeat stress increased systemic inflammation and sensitized BP responses to low-dose angiotensin II[252]. In male Sprague Dawley rats, single prolonged stress did not produce sustained hypertension but induced transient increases in BP and HR and altered expression of hypertension-related genes (vasopressin, AT1R, FOSL1) in the hypothalamic paraventricular nucleus. Mitochondrial reactive oxygen species colocalized with AT1R- and FOSL1-expressing cells, suggesting that oxidative stress may amplify sympathetic activation and stress responsivity, thereby increasing CV vulnerability[253].

In a Chinese cohort (n = 933), a cross-sectional and bidirectional Mendelian randomization analysis found that higher psychological stress was associated with higher hypertension risk in men (OR = 1.341; 95%CI: 1.023-1.758; P = 0.034). Conversely, hypertension was associated with higher psychological stress in men (OR = 1.545; 95%CI: 1.113-2.145; P = 0.009) and in the overall cohort (OR = 1.327; 95%CI: 1.025-1.718; P = 0.032)[254].

PTSD-related risk profiles often overlap with metabolic syndrome features[72,255]. Persistent stress may also predict divergent body composition trajectories, with weight gain in some individuals and weight loss in others[102]. Sex-specific differences in behaviours and stress-hormone responses have been proposed to explain the stress-obesity association in men more than women[144]. However, a meta-analysis of eight studies found no overall association between job strain and weight gain (pooled OR = 1.04; 95%CI: 0.99-1.09) or obesity (OR = 1.00; 95%CI: 0.89-1.13); reductions in job strain over time were not associated with lower obesity risk[256]. Physical inactivity and other sedentary markers have been associated with blunted cortisol reactivity[257].

Adverse lipoprotein profiles are strongly shaped by sociodemographic factors and stress exposure[258]. In a cross-sectional study of hospital administrative staff assessed with the Osipow questionnaire, triglyceride levels and stress measures differed significantly (P < 0.05); total cholesterol and glucose were lower in the low-to-moderate stress group than in the high-stress group[259]. Animal studies indicate that mice susceptible to chronic social defeat stress derive attenuated benefit from low-density lipoprotein cholesterol lowering therapy compared with resilient mice; human imaging findings are directionally consistent, showing less reduction in systemic or arterial inflammation with low-density lipoprotein cholesterol lowering in individuals with higher neural stress markers[260].

Atherosclerosis

Chronic stress has been implicated across the continuum of atherogenesis, from plaque initiation to progression, destabilization, and rupture in coronary or carotid territories[261]. In a midlife cohort without chronic clinical illnesses followed for approximately three years, longitudinal changes in psychological stress were positively associated with parallel changes in carotid intima media thickness (CIMT), and cardiometabolic risk factors did not moderate this association[262]. A systematic review of four cohort and six cross-sectional studies reported a significant positive association between work-related stress and CIMT[164]. Conversely, when atherosclerotic inflammation and burden were quantified with 18F-fluorodeoxyglucose PET/MRI, no significant differences were observed between individuals with PTSD and controls[263]. In SCAPIS, financial stress was weakly associated with coronary CTA stenosis, coronary artery calcification ≥ 1, and carotid plaque presence (OR = 1.10-1.21; 95%CI: 1.02-1.32) after adjustment for age, sex, and site; these associations were attenuated and no longer significant after further adjustment for socioeconomic factors and health behaviours[248].

Thrombosis

Psychological stress influences haemostasis through complex neurohormonal pathways whereby cortisol, adrenaline, and noradrenaline affect coagulation factors and platelet function, potentially creating a hypercoagulable state and increasing thrombotic risk[264]. Stress has been linked to higher fibrinogen and D-dimer levels. In a prospective cohort derived from a cross-sectional sample of inpatients with suspected CHD, high perceived stress (PSS-10 > 16) was associated with shorter activated partial thromboplastin time (APTT) (P = 0.009); shortened APTT (≤ 35.0 seconds) correlated with higher PSS-10 scores (P = 0.003). In regression analyses adjusted for prothrombin time, each 1-point increase in PSS-10 corresponded to an approximately 0.13-second decrease in APTT (P = 0.001)[227].

ACEs in early life

Early-life stress exposure, processed centrally and mediated by glucocorticoid receptor activation, may impair cardiac development by reducing cardiomyocyte numbers, altering myocardial growth and trabeculation, and decreasing mitotic activity, ultimately predisposing to contractile dysfunction[264]. Gene-environment interaction studies suggest that the COMT rs4680 polymorphism contributes to inter-individual variability in physiological responses to ACEs[265]. A meta-analysis of 83 studies reported that ACE exposure is associated with dysregulation across multiple components of the human stress-response system, most prominently blunted CV and cortisol reactivity to stress[266]. Table 3 summarizes laboratory investigations of stress-heart interactions, and Figure 1 illustrates conceptual links between stress and CVD.

Figure 1 A tentative, simplified illustration of the main conceptual links between stress and cardiovascular disease. Adapted from[2,7,8,10,181,187,206,211,221,232,239,255,392]. Stressful stimuli are processed by cortical and subcortical brain regions and transmitted to the hypothalamus, then to the anterior pituitary gland and locus coeruleus. Through the autonomic nervous system and the hypothalamus-pituitary-adrenal axis, these signals trigger neuroendocrine, hemodynamic, and immune changes. Both components of the stress response can contribute to cardiovascular disease. Signals via the autonomic nervous system reach the heart, adrenal cortex, bone marrow, spleen, kidneys, lymph nodes, and ganglia. In the acute phase, these pathways lead to increased heart rate, blood pressure, and vasoconstriction, along with generalized inflammation, platelet activation, immune activation, and metabolic disturbances. Catecholamines, acting through macrophages, promote acute-phase reactions, cytokine release, and adhesion molecule expression, resulting in low-grade inflammation. Oxidative stress (characterized by reduced antioxidant defences and increased reactive oxygen species and lipid oxidation) and endothelial dysfunction (marked by decreased flow-mediated dilation, nitric oxide bioavailability, and endothelial nitric oxide synthase activity) are involved in all stages of atherosclerosis. Chronic stress also induces hyperactivation of the hypothalamus-pituitary-adrenal axis, leading to glucocorticoids release, which disrupts circuits regulating stress response and homeostasis. This overactivation of immune effector cells contributes to insulin resistance, dyslipidaemia, and visceral adiposity. Concurrently, unhealthy behavioural responses may occur. The combined effect of these processes ultimately results in the development of various acute cardiovascular diseases. CRH: Corticotropin-releasing hormone; ACTH: Adrenocorticotropic hormone; PSNS: Parasympathetic nervous system; GC: Glucocorticoids; HR: Heart rate; HRV: Heart rate variability; BP: Blood pressure; CRP: C-reactive protein; SCD: Sudden cardiac death; ACS: Acute coronary syndromes.

Table 3 Some recent laboratory studies on the cardiac effects of stress in animal studies.

Ref.	Setting	Main results
Morais-Silva et al[207], 2019	Using a chronic SDS protocol followed by the social interaction test, authors identified Wistar rats as resilient or susceptible to SDS	Susceptible animals showed increased depressive-like behaviours with resting tachycardia and decreased HRV due to increased sympathetic tone in the heart and a less effective baroreflex. In contrast, resilient rats were protected from these alterations by increased vagal tone, resulting in greater HRV values
Batschauer et al[225], 2020	Male Wistar rats were divided into four groups: Control-SD, control-HFD, CVS-SD, and CVS-HFD. The control-HFD and CVS-HFD groups were fed with HFD for six weeks. The CVS-HFD and CVS-SD groups were exposed to a CVS protocol in the last ten days of the six weeks	HFD promoted metabolic disorders and increased angiotensin II and leptin blood levels (P < 0.05). CVS or HFD increased BP and the SNS modulation of the heart and vessels and decreased baroreflex activity (P < 0.05). Combining CVS and HFD exacerbated the cardiac SNS response and increased basal HR (P < 0.05)
Hinterdobler et al[261], 2021	Cell-tracking experiments in animal models of acute mental stress	In mice in which leucocytes deplete rapidly from the blood after a single episode of acute mental stress, stress exposure leads to prompt uptake of inflammatory leucocytes from the blood to distinct tissues including heart, and, if present, atherosclerotic plaques. Acute stress enhances leucocyte influx into mouse atherosclerotic plaques by modulating endothelial cells and increases adhesion molecule expression and chemokine release through locally derived norepinephrine. Either chemical or surgical disruption of norepinephrine signalling diminished stress-induced leucocyte migration into mouse atherosclerotic plaques
Wu et al[233], 2021	PTSD and the potential association with the activities of the RVLM and the Mhb were studied. Multi-channel in vivo recordings were used to simultaneously acquire spontaneous neuronal firing and peripheral physiological indices, and FG retrograde tracing technique was used to observe the projections of labelled neurons in the Mhb	The discharge frequency of RVLM and Mhb neurons, the SBP, and the MAP in the PTSD group were all increased significantly compared with those in control group (P < 0.05). Mhb neurons were retrogradely labelled by FG through microinjection into the RVLM. In the control group, electrical stimulation in the Mhb increased HR at 100-300 μA (P < 0.05), elevated SBP and MAP at 200-300 μA (P < 0.05) and remarkably increased the RVLM neuronal discharge frequency at 100-500 μA (P < 0.05 or P < 0.01). In the PTSD group, however, only the discharge frequency of RVLM neurons was increased by the electrical stimulation at 100-300 μA (P < 0.05)
Bangsumruaj et al[219], 2022	Adult male Sprague Dawley rats exposed to 4-week CMS were used as an animal model for daily stress exposure in humans	CMS had lower body weight and higher sucrose intake. The HRV revealed that CMS increased autonomic activity without affecting its balance. The increased RAAS activity with upregulated angiotensin type 1 receptor mRNA expression was shown in CMS and correlated with stress
Duarte et al[100], 2023	Adult rats subjected to a 10-day protocol of RRS, habituating] or CVS (non-habituating) during adolescence, adulthood, or repeated exposure to either RRS or CVS in adolescence and adulthood	CVS increased basal circulating corticosterone levels and caused adrenal hypertrophy in the adolescence + adulthood group, an effect not identified in animals subjected to this stressor only in adulthood or adolescence. CVS also caused a sympathetically mediated resting tachycardia in the adulthood group. Moreover, the impairment in baroreflex function observed in the adulthood group subjected to CVS was shifted to an improvement in animals subjected to repeated exposure to this stressor during adolescence and adulthood
Wu et al[214], 2023	A compound stress method combining electrical stimulation and single prolonged stress was used to prepare a PTSD model, and the difference of weight gain before and after modelling and the elevated plus maze were used to assess the PTSD model. In addition, the distribution of retrogradely labelled neurons was observed using the FG retrograde tracking technique. To further investigate the effects, ACSF, non-selective amygdala glutamate receptors blocker KYN and AMPA receptor blocker CNQX were microinjected into the CeA in the PTSD rats	Compared with the control group, the PTSD group exhibited significantly lower weight gain (P < 0.01) and significantly decreased ratio of open arm time (P < 0.05). Retrograde labelling of neurons was observed in the CeA after microinjection of 0.5 μL FG in the RVLM. The content of AMPA receptor in the PTSD group was lower than that in the control group (P < 0.05), while there was no significant difference in RVLM neuron firing frequency and HR following ACSF injection. However, increases in RVLM neuron firing frequency and HR were observed after the injection of KYN or CNQX into the CeA (P < 0.05) in the PTSD group
Scott et al[215], 2025	Authors employed CSDS in adult male mice. CSDS results in increases in body mass, that are accompanied by elevated lean and fluid mass, as well as several somatic indices of chronic stress. Moreover, mice exposed to CSDS exhibit increased anxiety-like behaviour, spending more time in the closed arms of the elevated plus maze and less time in the center of an open field arena	Initial social defeat sessions result in increases in BP, activity, and temperature in comparison with control mice. Interestingly, while BP returns to basal levels by the start of the light cycle for the first few days of defeat, 14 days of CSDS results in sustained BP elevations, lower activity and lower body temperature. Finally, the results of HRV, spontaneous baroreflex sensitivity and adrenal transcriptome analyses were consistent with CSDS-induced autonomic dysfunction

SDS: Social defeat stress; HRV: Heart rate variability; RRS: Repeated restraint stress; CVS: Chronic variable stress; HR: Heart rate; LF: Low frequency; SBP: Systolic blood pressure; SD: Standard chow diet; HFD: High fat diet; BP: Blood pressure; SNS: Sympathetic nervous system; PTSD: Post-traumatic stress disorder; RVLM: Rostral ventrolateral medulla; Mhb: Medial habenular nucleus; FG: FluoroGold; MAP: Mean arterial pressure; CMS: Chronic mild stress; RAAS: Renin angiotensin aldosterone system; ACSF: Artificial cerebrospinal fluid; KYN: Kynurenic acid; CeA: Central nucleus of the amygdala; CSDS: Chronic social defeat stress.

PROVOCATIVE STRESS TESTS

Laboratory paradigms that induce acute psychological stress - implemented in both animal and human research - have provided a robust experimental framework to investigate how stress influences CV physiology, immune function, vascular reactivity, mental stress-induced ischemia, neurobiological responses, and downstream clinical outcomes[267-270].

Widely adopted protocols include the Montreal Imaging Stress Task, mental arithmetic (MA)[97,234,271,272], the Trier Social Stress Test (TSST)[192,273-275], the Stroop color-word test[276], the Paced Auditory Serial Addition Task[277], other public speaking tasks[278-282], and trauma recall procedures[283,284]. Among these, the TSST remains the most frequently applied paradigm for quantifying stress levels, evaluating individual differences in reactivity, and comparing physiological responses across groups[200,285,286]. The Montreal Imaging Stress Task is particularly common in neuroimaging settings. Overall, these tasks reliably elicit measurable stress responses, although a subset of participants demonstrates attenuated (blunted) reactivity[287,288]. Importantly, the increasing availability of smartphones and wearable sensors has opened new opportunities for non-invasive CV monitoring in real-world contexts[289,290], and virtual reality (VR) environments have also been developed to standardize and enhance stress induction procedures[291].

Physiological and psychophysiological measures

Stress reactivity is commonly quantified through indices of SNS activation, CV function, brain activity, cortisol secretion, and skeletal muscle tone[292-295]. Practical and frequently used measures include HR[174,296-299], BP[191,265,300-302], and HRV[33,303-306]. Additional readouts include immune cell dynamics[307], reduced CVR attributed to impaired parasympathetic withdrawal[276,285,302,308,309], and increases in carotid-femoral PWV, a surrogate of aortic stiffness[310,311]. More specialized methods include high-resolution brain positron emission tomography[312,313], myocardial perfusion imaging[220,314], FMD[315,316], CIMT[317], direct recording of muscle sympathetic nerve activity[318], transcutaneous median nerve stimulation[319], and reactive hyperaemia tonometry[320,321].

Neurocardiac interactions and stress-induced ischemia

Acute mental stress activates the adrenal medulla and may elicit a region-specific sympathetic response preferentially targeting cardiac vascular regulation while largely sparing skeletal muscle vasculature[39]. Cortical modulation of cardiac function involves prefrontal and temporal regions; during MA tasks, parasympathetic withdrawal may occur early, followed by delayed sympathetic activation[271,322].

Notably, approximately 70% of patients who present with angina and objective myocardial ischemia have no obstructive coronary stenoses on angiography. This clinical syndrome - ischemia with no obstructive CAD is increasingly recognized as prognostically and symptomatically relevant. Coronary microvascular dysfunction and coronary vasospasm represent key phenotypes of stress-related vasomotor disorders. Mental stress may provoke MSIMI in patients with or without obstructive CAD, and the underlying mechanisms differ from those driving pharmacologic stress ischemia[323,324]. MSIMI is often unrecognized, yet it carries prognostic implications and negatively affects QoL[325]. Diagnostic criteria and therapeutic strategies continue to evolve, and simple screening tools applicable at community level are currently lacking for silent CAD or mild HF[39,325].

Psychosocial and demographic moderators

Higher life satisfaction appears associated with a stress-response pattern consistent with “challenge” rather than “threat” during mental stress paradigms. Conversely, maladaptive responses are more prevalent among individuals with low SES[141], Black populations[315,320], and women[179], potentially reflecting sex-related differences in neural activation patterns and autonomic regulation[236,326].

Meta-analytic evidence

A systematic review focusing on HR rhythms and patterns suggested that time-series analytical approaches - including autoregressive integrated moving average, detrended fluctuation analysis, and autocorrelation plots - may provide useful signals for detecting stress events[327]. In a systematic review of 171 TSST studies, physiological responses were consistently stronger than subjective psychological responses, with autonomic activation exceeding HPA axis responses. Negative affective changes were more pronounced than positive ones. Correlations were robust within autonomic indices but weak across physiological and psychological domains, with the notable exception of HR and negative affect[328]. Another meta-analysis (26 studies) found no overall association between socioeconomic status and CVR (r = 0.008), although higher socioeconomic status predicted more favourable recovery (r = -0.14) and moderated stressor-type effects[329]. Virtual TSST paradigms produced effect sizes comparable to those of traditional TSST for cortisol, HR, and self-reported stress[330].

Prognostic value

Exaggerated peripheral microvascular constriction and heightened CVR during acute mental stress may reflect impaired coronary flow regulation and predict adverse outcomes[280,314,331]. In pooled analyses of two prospective cohorts including 918 individuals with stable CAD - the Mental Stress Ischemia Prognosis Study and the Myocardial Infarction and Mental Stress Study 2 - MSIMI elicited by public speaking and conventional stress ischemia (exercise or pharmacologic) were evaluated using single-photon emission computed tomography[267]. MSIMI was associated with significantly higher rates of CV death or nonfatal AMI (HR = 2.5) compared with the absence of ischemia, and risk was additive in the presence of concomitant conventional stress ischemia. After adjustment for demographic and traditional risk factors, several stress-response signatures remained independently associated with adverse outcomes: A blunted hemodynamic response (rate-pressure product), a larger stress-related reduction in endothelial function (brachial artery FMD) and increased peripheral vasoconstriction in both cohorts. Incorporation of a CVR risk score improved discrimination, increasing the C-statistic by 10% (P < 0.001)[332].

In the same pooled cohort[333], Holter electrocardiographic monitoring during standardized mental stress testing (speech task) enabled autonomic assessment using low frequency (LF) HRV measured in 5-minute intervals before, during, and after stress induction. Over a median follow-up of 5.6 years, a stress-induced decrease in LF HRV (observed in 67% of participants) was associated with substantially increased CV mortality risk (HR = 3.48; 95%CI: 3.25-3.73). Low resting LF HRV (lowest quartile) was independently associated with mortality (HR = 1.75; 95%CI: 1.58-1.94) compared with higher resting LF HRV (upper three quartiles). The combination of stress-induced LF HRV reduction and low resting LF HRV identified the highest-risk subgroup (HR = 5.73; 95%CI: 5.33-6.15). Similar associations were described for high frequency HRV[333].

Genomic approaches have further suggested biological susceptibility to stress-related vascular dysregulation. Single-nucleotide polymorphisms associated with stress-induced vasomotion have been described, including rs6466396 on chromosome 7, which was associated with an 80% higher risk of adverse events[334]. Additionally, peripheral microvascular dysfunction during mental stress predicted adverse outcomes in women but not in men, supporting a potentially sex-specific pathway linking stress exposure to CV risk[316]. Key studies using mental stress testing paradigms are summarized in Table 4.

Table 4 Some recent studies on laboratory induction of stress.

Ref.	Setting	Main results
Meyer et al[235], 2016	Hospitalized female PTSD patients and controls completed standardized laboratory-based stress testing including a MA test and an audiotape recording of a crying infant	Controls and PTSD patients both showed a significantly increased HR and reduced pre-ejection period from baseline rest to the arithmetic stressor. Parasympathetic activation caused by the crying infant stressor was blunted in PTSD patients as compared to healthy individuals. Under the crying infant condition, a vagal dominance was observed only in controls
Brindle et al[297], 2016	Multivariate cluster analysis examined the relationship between HR and BP reactivity patterns and hypertension in a large prospective cohort (age range 55-60 years). Four clusters emerged with statistically different SBP, DBP and HR reactivity patterns	Cluster 1 was characterised by a relatively exaggerated BP and HR rate response while the responses of cluster 2 were in line with the sample mean. Cluster 3 was characterised by blunted CV stress reactivity and cluster 4 by an exaggerated BP and modest HR response. Membership to cluster 4 conferred an increased risk of hypertension at 5-year follow-up (HR = 2.98, 95%CI: 1.50-5.90, P < 0.01)
Wang et al[272], 2016	A total of 34 young healthy male subjects were recruited and performed a MA task	MA task increased HR, SBP, DBP, and CO. The HFr power component of HRV decreased during MA, but the normalized LF power component and LF/HFr ratio of HRV increased only at the late stage
Sherwood et al[301], 2017	Overall, 199 outpatients diagnosed with HF, with ejection fraction ≤ 40%, underwent an evaluation of BP and HR reactivity to a laboratory-based simulated public-speaking stressor. Cox proportional hazards regression models were used to examine the prospective association between BP and HR reactivity on a combined endpoint of death or CV hospitalization over a 5-year median follow-up period	Both SBP and DBP reactivity were inversely related to risk of death or CV hospitalization (P < 0.01) after controlling for established risk factors. HR reactivity was unrelated to outcome (P = 0.12). High SBP reactivity, compared to intermediate SBP reactivity, was associated with lower risk (HR = 0.498, 95%CI: 0.335-0.742, P = 0.0019); while low SBP reactivity did not differ from intermediate reactivity. For DBP, high reactivity was marginally associated with lower risk compared to intermediate DBP reactivity (HR = 0.767, 95%CI: 0.515-1.14, P = 0.193), while low DBP reactivity was associated with greater risk (HR = 1.49, 95%CI: 1.027-2.155, P = 0.0359)
Ginty et al[99], 2017	Data from 64 participants were collected. HR, SBP, and DBP were measured at baseline and during a standard MA stress task	Individuals who experienced abuse showed diminished CVR to acute psychological stress, specifically by the history of sexual abuse
Xie et al[273], 2017	In total, 25 male subjects were recruited. RR intervals, SBP, DBP, SV, CO, and SVR values were collected during rest and MA. BRS was derived using the transfer function method	MA was characterized by increased HR, SBP, DBP, and CO with decreased BRS attributable to prolonged parasympathetic withdrawal. Moreover, cardiovascular coupling was disrupted in MA
Xin et al[193], 2017	The stress response to a standardized laboratory stress induction procedure (TSST) was measured with a combination of cardiovascular reactivity, hypothalamic-pituitary-adrenal axis reactivity, and subjective affect in healthy individuals	Higher neuroticism predicted lower HR stress reactivity, lower cortisol stress response, more decline of positive affect and lower subjective controllability. Individuals higher in extraversion showed smaller cortisol activation to stress and less increase of negative affect. In addition, higher openness score was associated with lower cortisol stress response
Antoun et al[35], 2018	Twenty healthy adults performed three tasks: Control, driving and exercise plus driving. HR, HRV, BP and cortisol were measured to quantify the acute stress response to each condition	HR was elevated and HRV was reduced during the driving task compared with control. HR was elevated and HRV was reduced comparing the exercise plus driving with the driving condition
Chou et al[284], 2018	Individuals with PTSD recalled a traumatic memory	Significant increase in parasympathetic activity during trauma recall, with greater parasympathetic dominance being indicative of greater state depersonalisation/derealisation. Overall, decreases in HR during trauma recall were associated with increased fear and perceived threat; flashbacks were accompanied by short-term increases in HR
Emery et al[279], 2018	Cardiac activity was recorded via ECG during a standardized speech stress task with three phases: 5-minute rest, 5-minute speech, and 5-minute recovery	Women exhibited higher HR than did men and greater HR reactivity in response to the speech stress. However, women also exhibited greater HRV in both the time and frequency domains
O'Súilleabháin et al[298], 2018	In a sample of 62 healthy young female adults, CV responsivity during a stress exposure was examined	Significant linear interaction for openness across the entire exposure for SBP, and CO. A significant between-subjects effect for HR also emerged. Those highest in openness exhibited an increasingly adaptive myocardial hemodynamic response profile throughout the exposure
Grinberg et al[223], 2018	Authors examined the association between adults’ subjective separation-related distress and changes in HR and BP across the acute-stress laboratory paradigm	Adults who reported greater separation-related distress exhibited higher initial BP, a slower linear increase in BP, and significantly slower declines in DBP following the acute stress task
Kibler[280], 2018	The sample consisted of 50 trauma-exposed civilian women ranging from 19 years to 49 years of age. Cardiovascular recovery was assessed after oral speaking stressor as percentage return to baseline; the recovery measures consisted of impedance cardiography-derived CO and TPR, HR and BP	Total PTSD severity was associated with less CO recovery, r = -0.39, P = 0.006; this effect was similar across PTSD symptom categories. However, only PTSD severity in the avoidance cluster was associated with less TPR recovery, r = -0.29, P = 0.047. Total PTSD severity was associated with greater threat appraisal, r = 0.30, P = 0.035, and greater threat appraisal was associated with less CO recovery, r = -0.33, P = 0.019
Zaffalon et al[304], 2018	In a total of 96 young women divided into SW and AW, the R-R interval was recorded to quantify the cardiac autonomic modulation at rest and in response to the Stroop Color Test	The physical health domain of quality of life was compromised in the SW group. The SW group presented higher HR, lower variance of RR interval and higher cardiac sympathovagal balance (LF/HF) both at rest and in response to the mental stress test
Delliaux et al[305], 2019	A 1-hour computerized switching task (letter recognition) was performed by 24 subjects while monitoring their performance (accuracy, response time) and ECG. The HRV was evaluated from the beat-to-beat RR intervals in time-, frequency-, and informational- domains, before and during the task	The HR, BP, and baroreflex function were unchanged, whereas most of the HRV parameters markedly decreased. The maximum decrease occurred during the first 15 minutes of the task, before starting to return to the baseline values reached at the end of the task. The RR interval dimension correlation decrease was the most significant (P < 0.001)
Kim et al[281], 2019	Overall, 549 patients with stable CAD underwent mental stress testing with a standardized public speaking stressor and followed prospectively for cardiovascular endpoints. Digital pulse wave amplitude was continuously measured using PAT. sPAT was calculated and dichotomized by into “low” and “high” sPAT ratio groups	The median sPAT ratio was 0.68 (IQR: 0.48-0.88), indicating 32% vasoconstriction with mental stress. Men were more likely to have low sPAT ratio than women (OR = 1.79, P = 0.007) while those on beta blockers were less likely to have low sPAT ratio (OR = 0.52, P = 0.003). After adjusting for demographic and cardiovascular risk factors, medications, and rate-pressure product change during mental stress, those with low sPAT ratio were at significantly higher risk of adverse outcomes (HR = 1.77, 95%CI: 1.12-2.80)
Lima et al[282], 2019	Cohort study of 569 individuals with stable CAD conducted at a university-affiliated hospital network. Participants were subjected to a laboratory mental stress task (public speaking)	FMD decreased from a mean (SD) of 4.8% (3.7%) before mental stress to 3.9% (3.6%) after (23% reduction; P < 0.001). The presence of transient endothelial dysfunction with mental stress was associated with a 78% increase (HR = 1.78, 95%CI: 1.15-2.76) in the incidence of MACE
Riordan et al[174], 2019	A sample of 76 healthy undergraduate students completed the DS14 type D measure, before undergoing a traditional cardiovascular reactivity protocol. SBP, DBP, and HR were monitored throughout	No associations were evident for BP. However, a significant personality × sex × social context interaction on HR reactivity was found; here type D was associated with a higher HR response to the social task amongst males, while type D females typically exhibited blunted reactions
Sullivan et al[283], 2019	The study used data from 632 patients with CAD. Patients’ residential addresses were geocoded with poverty data. SBP, DBP, HR, rate-pressure product, epinephrine, interleukin-6, and hs-CRP were measured before and after a public speaking stress task	After adjusting for potential confounders, participants living in high (vs low) poverty neighbourhoods had similar hemodynamic values at rest and lower values during mental stress for SBP (P = 0.07), HR (P = 0.02) and rate-pressure product (P = 0.01). There were no significant differences in inflammatory and epinephrine responses to mental stress
Wittbrodt et al[313], 2019	Participants with CAD underwent brain imaging with HIGH RESOLUTION POSITRON EMISSION TOMOGRAPHY and radiolabelled water during control (verbal counting, neutral speaking) and mental stress (MA, public speaking). Traumatic events in childhood were assessed with the ETI-SR-SF and participants were separated by presence (ETI+) or absence (ETI-)	Compared to ETI-, ETI+ experienced greater (P < 0.005) activations during mental stress within the left anterior cingulate, left occipital lobe, bilateral frontal lobe and deactivations (P < 0.005) within the left insula, left parahippocampal gyrus, right dorsal anterior cingulate, bilateral cerebellum, bilateral fusiform gyrus, left inferior temporal gyrus, right occipital lobe, and right parietal lobe. Significant (P < 0.005) positive correlations between brain activation and ETI-SR-SF scores were observed within the left hippocampus, bilateral frontal lobe, left occipital cuneus, right parietal precuneus, and bilateral temporal lobe
Lee et al[274], 2020	In a sample of 125 undergraduates, during a modified TSST, appraisals of the stressor were assessed and BP and HR were measured	PTSD symptoms are associated with current physical health (resting BP and HR) and more negative appraisals of the stressor; in turn, more negative appraisals were associated with increases in cardiovascular response
Liu et al[324], 2020	A total of 77 patients with known CAD underwent echocardiography before and during MA stress task. MSIMI was diagnosed by new or worsening wall motion abnormalities greater than or equal to a 5% reduction of left ventricle ejection fraction	MA induced a significant increase in stromal cell-derived factor-1α and monocyte chemoattractant protein-1 in all subjects; 20.78% of the patients with known CAD developed MSIMI during the arithmetic task. MSIMI positive patients had significantly lower baseline levels of interleukin-1β and tumour necrosis factor-α, but a higher response in levels of stromal cell-derived factor-1α than MSIMI negative patients
Lucas et al[290], 2020	Authors examined changes in HR tracked via an Apple Watch during three typical work shifts in a retail store setting	Increase in HR during a work shift to a level observed during a moderate stressor (P < 0.0001). Female subjects demonstrated a significantly elevated maximum HR, a larger change in HR, and a larger percent change in HR compared with males (all P < 0.05)
Widmer et al[322], 2020	In a prospective study 417 patients with ACS were enrolled in two sites at the United States and Qatar. Response to three different mental stress examinations (Stroop colour word, MA, and Spiral Omnibus) as assessed by ratio of reactive hyperaemia tonometry (EndoPAT)	Women were more likely to experience MACE in the year following ACS (RR = 2.42, 95%CI: 1.53-3.84, P = 0.044) and had a significantly lower mental stress ratio compared to women who did not (P = 0.04). In multivariate analyses, baseline peripheral endothelial dysfunction (EndoPAT < 1.7) (P = 0.005) and mental stress ratio (P = 0.0069, were independently predictive of MACE in women, but not men
Schneider et al[299], 2021	Participants completed the life experience survey and positive and negative affect schedule and undertook a standardized social-evaluative stress task. Cardiac activity was measured via HR and non-linear HRV indices sample entropy, SD1, SD2 and SD1/SD2 ratio	Higher HR reactivity in individuals reporting higher number and impact of negative and total life events. Life-events are associated with elevated HR and diminished HR complexity in response to acute stress
Kim et al[224], 2021	Using smartphones, ten young participants completed ecological assessments 6 times a day for two weeks regarding their current affective state. They also wore a chest-mounted HR monitor and a wrist accelerometer to monitor cardiovascular response and physical activity, respectively	Higher HR and lower HRV were related to subsequent greater feelings of stress at the 5-minute and 30-minute time intervals
Formolo et al[277], 2022	Sixty-six young men underwent anthropometric and body fat assessment (dual-energy X-ray absorptiometry) and carotid artery ultrasonography. Accelerometers assessed physical activity levels and sleep efficiency. MS was induced through the Stroop colour-word test while BP, HR, and cardiac interval were measured	An interaction between fat mass index and time for HR reactivity was observed. Cardiac interval variability analysis showed that only participants with normal fat displayed parasympathetic withdrawal during MS (P < 0.05). Multiple linear regression analysis supported the role of adiposity and autonomic modulation in the HR reactivity to MS and showed involvement of carotid distensibility and sleep efficiency (P < 0.05). Carotid distensibility was the only predictor for BP reactivity (P < 0.05)
Zhang et al[309], 2022	The scale of CTQ was administered to 192 healthy undergraduates who underwent continuous cardiovascular monitoring while facing two consecutive psychosocial stress (public speaking tasks	Childhood maltreatment was negatively associated with HR and cardiac output reactivity to the first stress exposure and HR reactivity to the second stress exposure
Lee et al[303], 2022	Using a cross-sectional observational design, 84 trauma-exposed community adults who endorsed at least one core PTSD symptom were enrolled. Participants completed a physical exam, self-reports of trauma history and PTSD symptoms, and BP and HRV frequency-domain measurements during rest, stressor (MA task), and recovery	Arousal/reactivity was not associated with BP or HRV reactivity but with a higher LF/HF ratio during recovery reflecting sympathetic predominance. During the stressor, more avoidance and intrusion were associated with increased DBP from baseline; more avoidance was associated with parasympathetic predominance (lower LF/HF); and more negative cognitions/mood was associated with decreased SBP, DBP, and LF from baseline. During recovery, more intrusion and negative cognitions/mood were associated with increased SBP from baseline; less negative cognitions/mood was associated with sympathetic predominance (higher LF/HF)
Legaz et al[274], 2022	Hypertensive patients and healthy controls groups performed TSST. During both stages, a sensitive HRV parameter (the LF/HF ratio) and an online neurophysiological measure. the HEP were assessed. Neuroanatomical data via voxel-based morphometry were obtained for correlation with online markers	Relative to controls, hypertensive patients exhibited increased LF/HF ratio and greater HEP modulations during baseline, reduced changes between baseline and stress periods, and lack of significant stress-related HRV modulations associated with the grey matter volume of putative frontrostriatal regions. They presented signs of stress-related autonomic imbalance, reflected in a potential basal stress overload and a lack of responsiveness to acute psychosocial stress, accompanied by neuro-physio-anatomical alterations
Griffin and Howard[192], 2022	Forty-eight participants completed a standardized laboratory stress paradigm incorporating a 20-minute acclimatization period, a 10-minute baseline, and two 5-minute speech tasks separated by a 10-minute rest period. CV parameters were measured using the Finometer Pro	Greater habitual use of suppression was associated with exaggerated BP responding to both tasks. However, only in response to the negative-emotion task was greater use of reappraisal associated with a challenge-oriented cardiovascular response
McLoughlin et al[276], 2022	Eighty-six participants reported their exposure to lifetime non-sport and sport-specific stressors before completing two consecutive TSST, while cardiovascular (i.e., HR) and endocrine (i.e., salivary cortisol) data were recorded	Exposure to a moderate number of lifetime non-sport and sport-specific stressors was associated with adaptive cardiovascular reactivity, whereas very low or very high stressor exposure was related to maladaptive reactivity. Moreover, experiencing a very low number of lifetime non-sport (but not sport-specific) stressors was associated with poorer habituation. In contrast, lifetime stressor severity was unrelated to cardiovascular reactivity. Finally, greater lifetime non-sport and sport-specific stressor counts were associated with blunted cortisol reactivity and poorer habituation
Winzeler et al[310], 2017	One hundred eighteen healthy young women provided data on ACEs and underwent psychosocial stress testing. SBP and RSA, quantified by HF-HRV variability, were assessed as measures of sympathetic and parasympathetic CV activity, respectively	The effect of ACEs on HR reactivity was mediated by SBP reactivity but not by RSA reactivity. ACEs were associated with reduced SBP at rest. ACEs were associated with down-regulation in a measure of sympathetic but no alteration in a measure of parasympathetic cardiovascular stress reactivity in adulthood
Almuwaqqat et al[315], 2023	Authors studied 300 patients with a recent AMI. Patients underwent myocardial perfusion imaging with mental stress and were followed for 5 years	A diffuse MSIMI increment of 1 standard deviation was associated with a 40% higher risk for adverse events (HR = 1.4, 95%CI: 1.2-1.5). In sex-specific analysis, higher levels of MSIMI (per SD increment) were associated with 53% higher risk of adverse events in women (HR = 1.5, 95%CI: 1.2-2.0) but not in men (HR = 0.9, 95%CI: 0.5-1.4), P = 0.001
Bremner et al[221], 2023	CHD patients underwent cardiac imaging with Tc-99m sestamibi single photon emission tomography at rest and during a public speaking mental stress task. Patients returned for a second day and underwent positron emission tomography imaging of the brain, heart, bone marrow, aorta (indicating inflammation) and subcutaneous adipose tissue, after injection of 18F2-fluoro-2-deoxyglucose for assessment of glucose uptake followed mental stress	Patients with MSIMI showed a pattern of increased uptake in the heart, medial prefrontal cortex, and adipose tissue with stress. In the heart disease group, activity increases with stress in the medial prefrontal brain and amygdala correlated with stress-induced increases in spleen (P = 0.038 and P = 0.04 respectfully). Stress-induced frontal lobe increased uptake correlated with stress-induced aorta uptake (P = 0.016). Activity in insula and medial prefrontal cortex was correlated with post-stress activity in bone marrow and adipose tissue. Increases in medial prefrontal activity with stress correlated with increased cardiac glucose uptake with stress, suggestive of myocardial ischemia (P = 0.004)
Gentilin et al[312], 2023	The carotid hf-PWV index, MAP, PP, TPR, and HR were measured in 26 young at rest and throughout a 10-minute bout of MA stress	Mental stress increased hf-PWV, MAP, PP, and HR from baseline throughout the entire stimulation period (P < 0.005). TPR diminished in the first minute of stimulation (P < 0.001) in both sexes and increased in the last minutes in women only (P < 0.005). Hf-PWV was lower in women than men (P < 0.001) at rest and during mental stress, but the changes from baseline were similar
Lee et al[300], 2023	A sample of 92 adolescent girls self-reported early life stressors. SBP, DBP, and HR were continuously measured before, during, and after a laboratory peer rejection paradigm	Adolescent girls with higher early life stress had lower, not higher, HR during the recovery period. Early life stress was not associated with SBP or DBP recovery. Additionally, early life stress was not associated with SBP, DBP, or HR reactivity
Liu et al[196], 2023	In 883 treatment-naive individuals from a longitudinal cohort study of Midlife in the United States, symptoms of stress were assessed by PSS. Cardiovascular reactivity was measured using standardized, laboratory-based stressful tasks	Treatment-naive individuals with higher stress levels (PSS ≥ 27) had blunted cardiovascular reactivity multivariate linear regression showed that stress was associated with reduced SBP and DBP reactivity but with a nonsignificant association with HR reactivity (P = 0.056)
Lü et al[266], 2023	The CTQ was administered to 359 junior school students who underwent a two-successive stress exposures protocol with continuous cardiovascular monitoring. HR and SBP, DBP, and their saliva samples for deoxyribonucleic acid genotyping were collected	ELA was associated with blunted HR reactivity to the first and second stress exposures, blunted SBP reactivity to the first stress exposure, and attenuated SBP habituation to repeated stress exposures. Moreover, COMT rs4680 moderated these associations, such that the associations between ELA and blunted HR, SBP, and DBP reactivity to the first stress and disrupted DBP habituation to repeated stress exposures only existed in GA/AA genotype carriers
Mrug et al[287], 2023	The sample included 1027 adolescents and young adults who reported on ELS exposure and coping styles. Participants completed a standardized TSST, with HR and BP measured before, during, and after. Self-reports of negative emotions during the TSST indexed emotional stress reactivity	ELS was associated with lower HR stress reactivity; avoidant coping was related to lower SBP and DBP during stress and lower SBP during recovery; and higher emotion-oriented coping and lower task-oriented coping predicted greater emotional stress reactivity. A consistent pattern emerged where emotion-oriented coping amplified the associations between ELS and maladaptive stress responses (blunted cardiovascular stress reactivity and recovery; enhanced emotional stress reactivity), whereas lower levels of emotion-oriented coping were associated with resilient profiles among those who experienced ELS (lower resting HR; lower emotional stress reactivity; average HR and BP stress reactivity and recovery)
Okoh et al[316], 2023	In 812 patients with stable CHD at a university-affiliated hospital network, FMD was assessed before and 30 minutes after mental stress. TED was defined as a lower post-stress FMD than prestress	FMD significantly declined with mental stress in both groups. TED occurred more often in Black than non-Black patients (aOR = 1.6, 95%CI: 1.5-1.7). Black participants had a 419% higher risk of either cardiovascular death or nonfatal AMI than non-Black participants (95%CI: 1.01-1.95). TED with mental stress explained 69% of this excess risk
O’Riordan et al[176], 2023	Undergraduate students competed a standardised cardiovascular reactivity experimental protocol consisting of resting baseline and stressor phase (MA), with SBP, DBP and HR monitored throughout	The continuous Type D interaction term (negative affect × social inhibition) significantly predicted lower SBP reactivity to the MA stressor amongst women, independent of confounding variables. This remained significant after adjustment for anxiety and depressive symptoms
Perez Alday et al[269], 2023	Overall, 238 male Veteran twins listened to audio recordings of a one-minute neutral script followed by a one-minute trauma script. Authors examined two HRV metrics: DC and log-LF power from beat-to-beat intervals extracted from ambulatory ECG and assessed longitudinal PTSD status with a structured clinical interview and the severity with the PTSD symptoms scale	PTSD status and acute PTSD symptom severity were not associated with DC or log-LF measured during the neutral session but were significantly associated with lower DC and log-LF during the traumatic script listening session. Long-standing PTSD was associated with a 038 (95%CI: -0.83 to -0.08) and 0.79 (-1.30 to -0.29) standardized unit lower DC and log-LF, respectively, compared to no history of PTSD
Sullivan et al[317], 2023	In the MIMS2 study, 263 patients hospitalized for an AMI were prospectively followed for 5 years. Reactive hyperaemia index and flow-mediated dilation were used to measure microvascular and endothelial function, respectively, before and 30 minutes after a public-speaking mental stress task	Worse microvascular response to stress (for each SD decrease in the reactive hyperaemia index) was associated with 50% greater risk of MACE (HR = 1.5, 95%CI: 1.05-2.13; P = 0.03) among women only (sex interaction: P = 0.03). Worse TED in response to stress (for each SD decrease in flow-mediated dilation) was associated with a 35% greater risk of MACE (HR = 1.35, 95%CI: 1.07-1.71; P = 0.01); the association was similar in women and men
Tyra et al[270], 2023	A sample of 453 participants completed a repeated stress paradigm, which consisted of two 10-minute baselines and two identical 4-minute stress tasks, separated by a 10-minute recovery period. HR was measured continuously; SBP/DBP every 2 minutes. Participants completed the ERQ and DERS	Impulse control difficulties when distressed (a DERS subscale) were significantly associated with blunted SBP, DBP, and HR reactivity to both stressors, as well as impaired HR habituation across the stressors. None of the ERQ subscales (cognitive reappraisal, expressive suppression) were found to be associated with cardiovascular stress reactivity or habituation
Ji et al[288], 2024	Chinese adolescents first reported their childhood trauma and social anxiety using the Childhood Trauma Questionnaire and the Social Interaction Anxiety Scale, then participated in a social stress task, during which their cardiovascular data (HR, SBP, DBP) were monitored	The results showed that high levels of childhood trauma were associated with blunted HR, SBP, and DBP reactivity, which in turn were associated with high levels of social anxiety. Mediation analysis indicated that childhood trauma was indirectly associated with social anxiety via blunted cardiovascular reactivity
Gallagher et al[286], 2024	Two hundred and six participants from the Pittsburgh Cold Study underwent a modified version of the TSTT	Social network size was positively associated with DBP reactivity (β = 0.19, 95%CI: 0.05-0.29, P = 0.005), while loneliness was not. In addition, social network size moderated the loneliness-DBP reactivity relationship
Sinnot et al[289], 2024	The study aimed to examine the influence of both PTSS and self-blame (negative appraisal after trauma, commonly sexual) on BP and HR reactivity measured before, during, and after a laboratory-based sexual trauma reminder among 72 young adult women who have experienced sexual trauma	Higher PTSS predicted lower DBP reactivity during the trauma reminder. Higher levels of self-blame predicted higher HR and SBP reactivity during and after the trauma reminder. Overall, these findings suggest that survivors of sexual trauma with higher levels of PTSS experience a blunting reaction of DBP when exposed to trauma reminders
Almuwaqqat et al[314], 2024	In 427 patients with stable CAD undergoing a laboratory-based MS test, CPCs were enumerated using flow cytometry as CD34-expressing mononuclear cells before and 45 minutes after stress. Changes in brain regional blood flow with MS were measured using high resolution-positron emission tomography	MS increased CPC counts by a mean of 150 cells/mL (15%), P < 0.001. Greater limbic lobe activity, indicative of activation of emotion-regulating centres, was associated with greater CPC mobilization (P < 0.005). After adjustment, greater CPC mobilization was associated with a higher adjusted risk of adverse events during a 5-year follow-up; a rise of 1000 cells/mL was associated with a 50% higher risk of cardiovascular death/MI (HR = 1.5, 95%CI: 1.1-2.2)
Osei et al[325], 2024	Authors examined the relationship between stress-induced autonomic dysfunction, measured by low HRV using Holter monitoring, and MSIMI in patients with stable CAD before and during a standardized laboratory-based speech stressor. HRV at rest and stress were categorized into low HRV vs high HRV; the low category was used as an indicator of autonomic dysfunction	Compared with high HRV during stress, low HRV during stress (both HF and LF) was associated with higher odds of MSIMI after adjusting for demographic and clinical factors (OR for HF HRV: 2.1, 95%CI: 1.3-3.3; OR for LF HRV: 2.1, 95%CI: 1.3-3.3). LF HRV at rest was also associated with MSIMI but with slightly reduced effect estimates
Rasero et al[318], 2025	Midlife adults from two different cohorts underwent two information-conflict tasks, in which patterns of hemodynamic brain responses exhibited a generalizable association with carotid artery intima-media thickness, which was mediated by an area-under-the-curve measure of aggregate SBP reactivity	Task-averaged patterns of hemodynamic brain responses exhibited a generalizable association with CA-IMT, which was mediated by an area-under-the-curve measure of aggregate SBP reactivity. Importantly, this effect held in sensitivity analyses. Implicated brain areas in this mediation included the ventromedial prefrontal cortex, anterior cingulate cortex, insula and amygdala
Nawar et al[291], 2024	This pilot study investigated data from a validated, multimodal, wearable patch to examine physiological correlations of laboratory-based hypertensive stress responses. The device collected ECG and photoplethysmogram signals during a protocol involving a public speaking stressor	MAP changes correlated significantly with changes in HR (P < 0.001, r = 0.69), left ventricular ejection time (P < 0.001, r = -0.63), pulse arrival time (P < 0.001, r = -0.58), and pulse transit time (P < 0.001, r = -0.56) captured by the patch
Martin et al[76], 2024	In 179 older male twins from the Vietnam Era Twin Registry, lifetime history of PTSD and last month PTSD symptoms were assessed. Participants listened to neutral and personalized trauma scripts while peripheral vascular tone (peripheral arterial tonometry ratio) and systemic vascular tone (TVC) were measured	Compared to their brothers without PTSD, during trauma recall, participants with a history of PTSD had greater increases in peripheral (β = -1.01, 95%CI: -1.72 to -0.30) and systemic (TVC: β = -1.12, 95%CI: -1.97 to -0.27) vasoconstriction after adjusting. Analysis of current PTSD symptom severity showed consistent results
Maffei et al[201], 2025	A version of TSST was employed to experimentally induce stress in a sample of 40 dyads, each comprising a target participant who was paired with a second participant, acting as a supporter. In half of the dyads the target and the supporter were in a romantic relationship (partner group), while in the other half not (stranger group)	Participants in the partner group exhibited a lower HR during the acute stress compared to the participants in the stranger group, highlighting that the buffering of the physiological stress activity is stronger within close relationships. Nonetheless, participants in the partner group reported more anxiety and stress during the task
Strotsava and Brindle[271], 2025	Participants completed the CTQ and a socially evaluative MA stressor in the laboratory. HR, BP, and baroreflex function were measured during both baseline and stress conditions. Stress reactivity was defined as the change in HR, BP, or baroreflex function from baseline to stress	HR and BP significantly increased and baroreflex function significantly decreased in response to mental stress (all P < 0.001). However, after controlling for sex, cohort, baseline values, and perceived stress, no significant associations emerged between CTQ scores, total or subscales, and either cardiovascular or baroreflex reactivity (all P ≥ 0.55)
Bigalke et al[319], 2025	In adult volunteers beat-by-beat blood pressure (finger plethysmography), heart rate, and MSNA reactivity (microneurography) were recorded during a 10-minute quiet rest followed by the TSST	Endorsement of a threat appraisal was positively associated with changes in MSNA burst frequency (P = 0.018), burst incidence (P = 0.009), and total MSNA (P = 0.037) during the speech stress period. Moreover, increase in threat appraisal across tasks was associated with elevated MSNA burst frequency (P = 0.023), incidence (P = 0.030), and total MSNA (P = 0.027) responsiveness
Tyra et al[293], 2025	Participants completed a 10-minute baseline, 5-minute speech preparation, and 5-minute speech delivery, which was repeated after a 10-minute recovery. They were randomly assigned to either suppression or control instructions before the second speech prep. HR, SBP/DBP, and pre-ejection period were measured throughout. Habitual use of suppression was assessed using the Emotion Regulation Questionnaire	All participants exhibited significant CV habituation, irrespective of condition, suggesting instructed suppression did not hinder habituation. Instructed suppression was not associated with changes in perceived psychological stress or positive affect across tasks; however, instructed suppression was associated with greater habituation of negative affect
Costello et al[294], 2025	This study used previously collected data from the Pittsburgh Cold Study 3. One-hundred and eighty-nine participants completed two separate, identical, standardized stress-testing protocols and had their BP and HR monitored throughout a baseline, stress task and recovery phase	Delta change score from task, percent change task and area under the curve with respect to ground demonstrated the strongest temporal stability for blood pressure and HR recovery between visits
Zhou et al[320], 2025	Using data collected from involving acute mental stress and TMNS (with stress-mitigating effect), authors examined the ability of six plausibly explainable physio-markers to capture cardiovascular responses to acute mental stress and TMNS	The synthetic multi-modal variable showed explainable responses to acute mental stress and TMNS in more experiments. It also exhibited superior consistency, balanced sensitivity, and robustness compared to individual physio-markers
Martin et al[321], 2025	Using a cross-sectional design, authors assessed childhood trauma and HR and BP responses to public speaking in AMI survivors	Black participants showed significantly lower HR and SBP and DBP reactivity to mental stress compared with White participants. High childhood trauma was independently associated with lower HR and SBP reactivity. Black participants with high trauma had the lowest HR (β = -8.2; 95%CI: -11.2 to -5.2) SBP (β = -7.7; 95%CI: -11.9 to -3.5), and DBP reactivity (β = -2.9; 95%CI: -5.4 to -0.4) relative to White participants with low trauma
Linsley et al[278], 2025	Participants completed passive (IAPS and active PASAT) stress task cardiovascular measures (including SBP, DBP, HR) and blood samples determining inflammatory responses (circulating and stimulated IL-6, SIRI, NLR, TNF-α, and P- and E-selectin) were collected	Cardiovascular measures were higher during the PASAT than IAPS (P < 0.001). Circulating IL-6 levels increased from baseline to 45-minute after both tasks (P ≤ 0.001), with no difference between 45-minute post-PASAT and 45-minute post-IAPS. SIRI increased from baseline to post-IAPS (P = 0.013), 45-minute post-IAPS (P = 0.004), and 45-minute post-PASAT (P < 0.001). No difference in SIRI between 45-minute post-PASAT and 45-minute post-IAPS existed. NLR increased from baseline to 45-minute post-PASAT (P = 0.008). There were no significant time effects for TNF-α, P-selectin, or E-selectin
Lee et al[295], 2025	Authors conducted a laboratory-based study with 84 adult trauma survivors to test threat and challenge appraisals as mediators of the relationships of positive states of mind with HRV responses to stress	Stronger appraisal of challenges mediated the effects of more positive states of mind on lower LF during recovery. Threat appraisal was not a significant mediator of any association between positive states of mind and HRV reactivity or recovery. Challenge appraisal may explain the association between greater positive states of mind and lower sympathetic arousal during recovery
Goldberg et al[285], 2025	Overall, 67 participants underwent BP measurements during baseline, after a 5-10-minute GR task, and during a 10-minute recovery period. Repeated measures compared SBP and DBP at baseline and 0-, 5-, and 10-minute post-GR. Participants meeting PGD criteria were descriptively compared to individuals reporting grief severity below the median of the Prolonged Grief-13 questionnaire and to those above the median without PGD	SBP and DBP increased post-GR and remained elevated during the 10-minute recovery (SBP: P = 0.009; DBP: P = 0.03). Pairwise comparisons revealed significant differences between SBP and DBP at baseline compared to post-GR measurements. Descriptively, the PGD subgroup showed higher baseline values, similarly pronounced reactivity compared to the rest of the sample, and a delayed decline in SBP and DBP, particularly compared to participants with low grief severity
Naliboff et al[296], 2025	Fifty healthy women designated as HS based on above threshold scores on a measure of perceived stress were compared to 50 women with LS. Psychological, autonomic nervous system and plasma metabolite assessments were obtained before, during and after exposure to multiple tasks including viewing affective pictures, performing stressful MA and figure ground discrimination	The HS group showed a greater increase in negative affect when challenged with a laboratory stressor (P < 0.001) and in response to neutral affective pictures (P = 0.040); this same group showed overall less sympathetic arousal than the LS group during a MA challenge (P = 0.034). The HS group had a higher plasma metabolite tryptophan/kynurenine ratio than the LS group at baseline, but this did not change with stress

PTSD: Post-traumatic stress disorder; MA: Mental arithmetic; HR: Heart rate; BP: Blood pressure; SBP: Systolic blood pressure; DBP: Diastolic blood pressure; CV: Cardiovascular; HR: Hazard ratio; CI: Confidence interval; CO: Cardiac output; HFr: High frequency; HRV: Heart rate variability; LF: Low frequence; CVR: Cardiovascular reactivity; SV: Stroke volume; SVR: Systemic vascular resistances; BRS: Baroreflex sensitivity; TSST: Trier Social Stress Test; ECG: Electrocardiogram; TPR: Total peripheral resistance; SW: Sedentary women; AW: Active women; CAD: Coronary artery disease; PAT: Peripheral artery tonometry; sPAT: Stress/rest peripheral artery tonometry ratio; IQR: Interquartile range; OR: Odds ratio; SD: Standard deviation; MACE: Major adverse cardiovascular events; hs-CRP: High sensitivity C reactive protein; ETI: Early trauma inventory; MSIMI: Mental stress induced myocardial ischemia; ACS: Acute coronary syndrome; RR: Risk ratio; MS: Mental stress; CTQ: Childhood trauma questionnaire; HEP: Heartbeat-evoked potential; RSA: Respiratory sinus arrhythmia; ACEs: Adverse childhood experiences; hf-PWV: Heart-femoral pulse wave velocity; MAP: Mean arterial pressure; PP: Pulse pressure; PSS: Perceived Social Stress; ELA: Early life adversity; FMD: Flow-mediated dilation; TED: Transient endothelial dysfunction; aOR: Adjusted odds ratio; DC: Deceleration capacity; MIMS2: Myocardial Infarction and Mental Stress 2; ERQ: Emotion Regulation Questionnaire; DERS: Difficulties in Emotion Regulation Scale; PTSS: Posttraumatic stress symptoms; CPC: Circulation progenitor cell; TVC: Total vascular conductance; MSNA: Muscle sympathetic nerve activity; TMNS: Transcutaneous median nerve stimulation; AMI: Acute myocardial infarction; IAPS: International Affective Picture System; PASAT: Paced Auditory Serial Addition Test; IL: Interleukin; SIRI: Systemic inflammation response index; NLR: Neutrophil/Lymphocyte ratio; TNF: Tumor necrosis factor; GR: Grief recall; PGD: Prolonged grief disorder; HS: High stress; LS: Low stress.

INTERVENTIONS FOR STRESS MANAGEMENT

A central clinical question is whether stress should be considered a modifiable risk factor for CVD. Strategies that reduce adrenergic activation or alleviate the negative emotional burden associated with chronic stress are plausibly expected to lower CV risk and related adverse outcomes, including incident CVD[233]. Pharmacological attenuation of sympathetic overactivity - via centrally acting agents, peripheral α- and β-adrenergic receptor blockade, or newer strategies such as renal sympathetic denervation - has shown benefit in specific stress-related disorders[212].

In parallel, non-pharmacological approaches aimed at restoring autonomic balance by reducing sympathetic overdrive have demonstrated clinical promise. Mind-body interventions seek to elicit a “relaxation response”, reduce perceived stress, and improve QoL, supporting more holistic CV care models. Beyond symptom reduction, such approaches may enhance patient empowerment by fostering active self-management alongside stress mitigation. Recent studies have accelerated clinical translation of experimental observations on therapies targeting stress-related dysautonomia and may complement standard pharmacotherapy[335]. Wearable technologies represent another emerging strategy, potentially enabling earlier identification of stress episodes and timely intervention[291]. Nevertheless, the current evidence base is largely derived from small pilot investigations, often subject to bias and limited statistical power; robust long-term outcome data remain scarce[336].

Interventions for individuals with PTSD

Evidence supporting prevention and management of CDI-PTSS is still limited[337]. Preliminary studies of exposure-based psychotherapies suggest acceptable safety in individuals with CVD. In one trial involving patients with PTSD symptoms after a CV event randomized to imaginal exposure vs control, symptom improvement was reported, although between-group differences did not reach statistical significance[338]. In a comparative study of eye movement desensitization and reprocessing (EMDR) vs imaginal exposure among 42 patients with PTSD triggered by life-threatening CV events (including surgery, myocardial infarction, and cardiac arrest), EMDR significantly reduced CDI-PTSS[339]. First-line approaches such as prolonged exposure and VR-based exposure may also improve CV functioning and reduce risk[337]. However, an RCT testing trauma-focused counselling within 48 hours of admission for distressed ACS patients showed fewer benefits than general stress management in the control group[340]. A systematic review of 44 studies reported mixed evidence for the impact of PTSD treatment on tonic CV function, while stronger evidence supported reductions in CVR to trauma-related stressors, particularly in high-quality cognitive behavioural therapy (CBT) studies[337].

A meta-analysis of nine RCTs and quasi-experimental studies assessing psychological interventions after AMI demonstrated significant reductions in PTSD symptoms (SMD = -0.43; 95%CI: -0.70 to -0.16; P = 0.002)[341]. Subgroup analyses suggested that treatment components may influence effectiveness, with EMDR and CBT showing moderate effects (SMD = -0.40; 95%CI: -0.74 to -0.07; P = 0.02)[341]. In addition, device-guided slow breathing delivered via smartphone applications has been shown to acutely reduce BP and muscle sympathetic activity, improve baroreflex sensitivity, and sustain reductions in sympathetic reactivity during mental stress among individuals with PTSD[342-344].

Stress management techniques

Mindfulness, meditation, and progressive muscle relaxation are commonly used stress management strategies with potential benefits for cognitive resilience, emotion regulation, and relaxation[3]. However, their specific role in patients with CVD requires careful interpretation grounded in outcome-focused evidence[3].

Mindfulness-based interventions: Mindfulness-based interventions (MBIs), among the most extensively studied mind-body approaches, train attentional and somatic regulation strategies to support coping with illness and stress[345-348]. Mindfulness entails sustained present-moment awareness and may strengthen resilience and emotion regulation[349]. Evidence suggests that MBIs improve psychological well-being and may favourably influence CV markers in individuals with CVD[3]. Post-percutaneous coronary intervention studies in CHD populations have reported encouraging results. Interventions including mindfulness-based stress reduction, mindfulness-based CBT, and the Learning 2 BREATHE program generally improve well-being and reduce anxiety, depression, and pain in patients and caregivers, and can be effectively delivered in virtual formats[3]. Neuroimaging studies have reported structural and functional brain changes associated with mindfulness practices, supporting their potential scalability and low-cost implementation, especially during healthcare disruptions such as coronavirus disease 2019[350]. A systematic review and meta-analysis of eight RCTs (n = 623) reported a significant reduction in stress among CAD patients receiving MBIs (SMD = -0.69; 95%CI: -1.27 to -0.12; P = 0.02)[351]. Biofeedback and device-guided breathing integrated into MBIs have been associated with improvements in self-efficacy, health-related QoL, HRV, and recovery from stress, particularly in chronic HF populations[344,352,353].

Meditation: Meditation typically emphasizes controlled breathing and visualization, with parasympathetic activation contributing to relaxation and reductions in stress hormone signalling[342,354,355]. Available evidence suggests potential reductions in stress and improvements in CV outcomes[350]. Different meditation techniques may modulate central and peripheral neurophysiology, contributing to BP regulation, improved insulin sensitivity, reduced lipid peroxidation, and attenuation of cellular senescence[356]. Given its accessibility and low cost, meditation may represent a cost-effective adjunct to standard therapy. An American Heart Association scientific statement reviewing meditation and CV risk concluded that, while neuroanatomical studies suggest long-term neural and CV benefits, mechanisms remain uncertain[357]. Therefore, meditation may be considered an adjunct to guideline-directed risk reduction, given minimal risk and low cost[357]. Tai Chi may transiently improve attention and reduce perceived stress[358,359]. However, meta-analytic evidence indicates that adding distress management to CR may offer limited incremental benefit, arguing for cautious integration into CR pathways[360]. A Cochrane review of 81 RCTs on mindfulness-based interventions and transcendental meditation reported substantial heterogeneity and unclear bias risk, limiting certainty; evidence regarding clinical CV endpoints remains sparse, with limited data on BP and psychological outcomes in individuals at risk or with established CVD[361].

Progressive muscle relaxation: Progressive muscle relaxation (PMR) involves sequential contraction and relaxation of muscle groups to counteract stress-related physiological activation (elevated HR, increased BP, muscle tension). PMR has been associated with reduced anxiety and improved HRV in patients with CVD[362].

Yoga

Yoga is a traditional mind-body discipline integrating postures, breathing exercises, and meditative practices and has been proposed as a stress-reduction approach[363-367]. Available data suggest potential benefits for physical fitness, stress modulation, and reduction of CVD risk factors, including through techniques such as Hatha yoga, Marjaryasana, Kapalabhati, and Halasana[366,368,369]. Mechanisms include improved autonomic regulation, reductions in oxidative/inflammatory stress, enhanced endothelial function, and epigenetic adaptations[364]. Yoga practitioners often show parasympathetic predominance vs controls[370]. By promoting healthier lifestyles and autonomic balance, yoga may delay the onset of modifiable CV risk factors. However, a 16-week Bikram yoga program did not significantly increase high frequency HRV power or improve other CVD risk factors[368]. An updated Cochrane review on yoga for secondary prevention in CAD identified no eligible RCTs meeting inclusion criteria, precluding pooled estimates and leaving effectiveness uncertain[371]. Nonetheless, regular yoga practice in any form is considered reasonable for mitigating early autonomic dysfunction[372].

Music listening

Music-based interventions are safe, low-cost complementary strategies used to reduce anxiety and distress while improving physiological parameters[373]. Benefits appear greatest when individuals can select music based on preference. Music listening may also improve SBP, HR, and sleep quality[374,375]. In a systematic review of 10 RCTs, SBP showed a trend toward reduction from 144 mmHg (95%CI: 137-152) to 134 mmHg (95%CI: 124-144), and diastolic BP (DBP) from 84 mmHg (95%CI: 78-89) to 78 mmHg (95%CI: 73-84) after music interventions[376]. A Cochrane review reported only a modest effect on psychological distress in individuals with CAD (mean difference = -1.26; 95%CI: -2.30 to -0.22; P = 0.02)[374].

Other interventions

Pet ownership has been proposed as a non-pharmacological approach for stress reduction and potential CV risk mitigation[377]. Epidemiological studies report lower CVD rates among dog owners. Non-randomized data suggest that service-dog companionship may increase physical activity and reduce resting HR among United States military veterans. On days when individuals cared for a familiar service dog-in-training, activity levels increased and were accompanied by a small reduction in activity-adjusted HR[378].

Vacations may also exert sustained physiological benefits by attenuating the association between stress and ambulatory HR in the weeks preceding planned time off[379]. Similarly, the ThermStress protocol - a short residential thermal spa program - has been proposed for prevention of occupational burnout and work-related stress in professional settings[380].

Integrating psychological assessment into routine cardiology care may address barriers to optimal ICD management. Early recognition and treatment of mood disturbances in ICD recipients have been linked to improved QoL and CV outcomes[381]. Simple interventions, such as squeezing stress balls during coronary angiography, have been associated with reduced anxiety and pain, supported by decreases in State-Trait Anxiety Inventory scores (P < 0.05)[382].

A systematic review and meta-analysis of 15 RCTs evaluated mind-body medicine techniques (meditation, mindfulness-based stress reduction, relaxation exercises) for BP reduction in patients with CVD. Mind-body medicine interventions significantly reduced SBP vs conventional care (SMD = -0.78; 95%CI: -1.36 to -0.20; P = 0.01), while effects on DBP were not significant[383]. Another systematic review reported positive effects of relaxation techniques - including PMR, diaphragmatic breathing, and biofeedback - on CVH and psychological well-being by increasing parasympathetic tone and reducing BP, anxiety, and stress in hypertensive and CVD populations. Benson’s relaxation and jaw relaxation were also associated with better QoL and CV outcomes[384]. A meta-analysis further demonstrated an overall beneficial impact of stress-reducing interventions on HRV, including improvements in short-term standard deviation of N-N intervals (P = 0.004) and LF power (P < 0.001)[385].

Environmental interventions

Environmental enrichment refers to exposure to novel stimuli that provide physical and cognitive engagement and may reverse adverse behavioural and CV consequences of social isolation. Such strategies may influence behaviour, cognition, and neurobiology, improving stress responsivity in humans and animal models. The benefits of social network size and perceived support are well established, and interaction with friends has been associated with improved emotional well-being, consistent with social integration frameworks[386]. Importantly, qualitative features of social networks may be more influential than network size[285].

Workplace interventions

Direct evidence demonstrating that reduction of workplace stressors lowers CV risk remains limited. Nonetheless, policy initiatives promoting healthy work environments are expanding, and in several countries prevention of excessive occupational stress is a legal requirement[167].

Physical activity and CR

Lifestyle-based prevention strategies are central to CAD management, improving both CV and psychological well-being. Benefits of moderate-to-vigorous activity and structured exercise on physiological and psychological health - including stress reactivity - are well established[387,388]. Physically active individuals generally show lower stress reactivity and faster recovery than sedentary controls, and these profiles improve following exercise interventions[389]. Aerobic training reduces sympathetic reactivity (e.g., lower HR) and improves CV efficiency (e.g., lower CVR and shorter recovery), while higher activity volumes are associated with attenuated HR, cortisol, and immune responses to stress[256]. Resistance training may also reduce CV stress responses and improve mental health outcomes[390].

CR, a multidisciplinary program implemented after acute cardiac events, reduces rehospitalization and mortality while also providing coping tools for daily stressors[391]. Exercise-based CR improves baseline autonomic function and neuro-CV stress reactivity in CAD. Combined strength and endurance training enhances adaptive capacity and remains central to CV risk reduction[12]. In in-hospital CR cohorts, perceived stress did not differ by sex but was higher among individuals with HF. Functional outcomes were not predicted by psychological measures, whereas clinical outcomes correlated with coping strategies, including social support and positive attitude[392]. Resilience and adaptive coping may act as protective factors, supporting integration of mental health care within CR programs[86]. The TEACH multicentre RCT tested a telephone-delivered intervention (TeamCare) delivered by non-physician care managers addressing both psychological and medical factors in distressed CHD patients. At 12 months, TeamCare participants showed higher heart QoL treatment response than usual care (19% vs 10%) and greater reductions in perceived stress[393].

Immersive VR is emerging as a potential adjunct to CR. In UCLA cardiology clinics, State-Trait Anxiety Inventory scores decreased after a VR intervention (median = 31, interquartile range: 28-38 vs median = 24, interquartile range: 29-25; P < 0.001), with participants reporting a subjective “distance from stress”[394]. HR decreased (mean 73 ± 8 bpm vs 67 ± 6 bpm; P < 0.001), BP was unchanged, and HRV patterns suggested increasing vagal tone over time[394]. A meta-analysis of eight RCTs reported a large rehabilitative effect of immersive VR on stress reduction (mean difference = -14.96; 95%CI: -20.1 to -9.8; P < 0.001)[395].

Psychotherapies

Psychological distress contributes to CVD risk largely through behavioural pathways; therefore, interventions are expected to be most effective when they combine distress reduction with modification of health behaviours[396]. Voluntary trauma recall, a key element of exposure-based therapy, can evoke dissociative experiences including flashbacks, depersonalization, and derealization[283]. Experimental research indicates that instructed cognitive reappraisal is associated with more adaptive CV responses - lower CVR (e.g., reduced BP) and a challenge-oriented profile (higher cardiac output with lower total peripheral resistance). In contrast, expressive suppression is associated with heightened CVR (e.g., higher HR and BP)[191]. In ACS patients experiencing distress, early counselling may reduce the likelihood of post-traumatic responses. Some evidence suggests dialectical behaviour therapy may be more effective than CBT in strengthening emotion-focused coping[397]. Relaxation-based interventions may reduce the cognitive and physiological burden of worry. A review of 16 behavioural stress-reduction programs across > 200 studies suggested that such interventions may augment medical therapies and, in selected settings, even reverse disease progression[398].

Digital solutions have expanded access to stress management, including internet-based CBT, telephone-delivered CBT, and online stress management training. A random-effects meta-analysis of six RCTs reported significant improvements in mental health-related QoL (12-item Short-Form Health Survey subscale) in intervention groups vs controls (SMD = 0.38; MD = 3.89; P < 0.001)[399].

Pharmacological therapy

In a national cohort of 27170 individuals with PTSD from the Korean National Health Insurance Database, antidepressant exposure was associated with increased MACE risk in a dose-response relationship (HR = 1.34; 95%CI: 1.18-1.53). This association may reflect confounding by indication or PTSD severity; importantly, antidepressants remain first-line pharmacological therapy for PTSD in current guidance[400]. The strongest associations were observed for selective serotonin reuptake inhibitors (HR = 1.24; 95%CI: 1.08-1.44) and tricyclic antidepressants (HR = 1.33; 95%CI: 1.13-1.56), whereas serotonin-norepinephrine reuptake inhibitors were not associated with increased MACE risk[400].

Key intervention studies addressing stress and CVD are summarized in Table 5. Despite some encouraging findings, intervention trials remain inconclusive regarding whether psychological therapies can modify affective traits or mental disorders sufficiently to reduce their impact on CVD outcomes[401]. Heterogeneity in design, sample size, and methodology limits generalizability. Moreover, sex imbalances and short follow-up may have compromised the validity of several trials.

Table 5 Some recent studies on various interventions against stress.

Ref.	Setting	Main results
Hewett et al[369], 2017	Eligible adults were randomized to an experimental group or a CTRL group. Experimental group participants were instructed to attend three to five supervised Bikram yoga classes per week for 16 weeks at local studios	No significant change in the high-frequency component of HRV (P = 0.912) or in any secondary outcome between groups. Regression analyses revealed that higher attendance in the experimental group was associated with significant reductions in DBP (P = 0.039), body fat percentage (P = 0.001), fat mass (P = 0.003), and BMI (P = 0.05)
Cheung et al[359], 2018	Twenty TC practitioners and 20 non-practitioners volunteered joined the study. After baseline measurements were taken, the TC group performed TC for 10 minutes while their cognitive states and cardiovascular responses were concurrently monitored. Stress levels were measured using PSS	Perceived stress level decreased from baseline to post-test in exclusively the TC group (P = 0.005). HR increased during TC (P = 0.001) and decreased thereafter (P = 0.001)
von Känel et al[340], 2018	Within 48 hours of hospital admission, patients with high distress during ACS were randomized to a single-session intervention of either trauma-focused counselling or an active control intervention targeting the general role of stress in patients with heart disease. Blind interviewer-rated PTSD (primary outcome) and additional health outcomes were assessed at 3 months of follow-up	No difference in interviewer-rated PTSD between trauma-focused counselling (mean = 11.33; 95%CI: 923-13.43) and stress counselling (9.88; 7.36-12.40; P = 0.40), global psychological distress (5.15, 4.07-6.23, vs 3.80, 2.60-5.00; P = 0.11), and the risk for CV-related hospitalization/all-cause mortality (OR = 0.67; 95%CI: 0.37-1.23). Self-rated PTSD indicated less beneficial effects with trauma-focused (6.54; 4.95-8.14) vs stress counselling (3.74; 2.39-5.08; P = 0.017)
Jalali et al[346], 2019	Overall, 60 patients were selected, clinically interviewed by a cardiologist and randomized to two groups; experimental and control, to investigate the effectiveness of a mindfulness-based stress reduction; then they completed General Self-Efficacy Scale and 36-item Short Form Survey	The mean pre-test scores of self-efficacy and QoL of patients were not significantly different between the experimental and control groups (P = 0.05). However, the mean scores of the two variables were found to be significantly different between the experimental group and the control group on the post-test and follow-up (P = 0.01)
Bourassa et al[338], 2021	Secondary analysis of a large intervention study of active-duty soldiers with PTSD randomized to an exposure therapy-either or a waitlist control condition	Changes in resting HR and HR reactivity were not significantly correlated with either self-reported or clinician-rated PTSD symptom change
Chandler et al[343], 2020	Twelve-month RCT of a breathing meditation smart phone app (TT) involving pre-hypertensive adults. The TT app captures continuous real-time HR from a user’s fingertip placed over a video camera lens during sessions. Users receive both immediate feedback graphs, showing their HR changes, and motivational and social reinforcement SMS text messages. Each group received a twice-daily dosage schedule of TT or walking	Mixed modelling results revealed a significant group x time effect for SBP (P < 0.01). The TT group showed greater SBP reductions at months 3 (-8.0 vs -1.9), 6 (-10.0 vs -0.7), and 12 (-11.6 mmHg vs-0.4 mmHg); all P values < 0.04
Chelidoni et al[345], 2020	The study aimed to assess the effectiveness of a brief app-based breathing intervention (BioBase) in enhancing physiological recovery among employees who were induced to cognitive and emotional stress. Interbeat (RR) intervals were recorded continuously for 5 minutes at baseline and during cognitive and emotional stress induction. The session ended with a 5-minute recovery period during which participants were randomly allocated into 3 conditions: Commercially available app-based breathing BioBase, mindfulness body scan, or CTRL	Subjective tension significantly increased following stress induction. HRV significantly decreased following the stress period. In the recovery phase, the root mean square of successive RR interval differences (P = 0.002), the percentage of successive RR intervals that differed by > 50 milliseconds (P = 0.008), and HF (P = 0.01) were significantly higher in the BioBase breathing condition than in the mindfulness body scan and the CTRL groups
Fonkoue et al[344], 2020	Veterans with PTSD were studied and randomized to either 8 weeks of daily DGB or of sham device (Sham). BP, HR, and MSNA were measured at rest and during mental math. Arterial BRS was assessed using the modified Oxford technique	Resting MSNA, BP, and HR remained comparable before and after 8 weeks in both groups. Likewise, the change in sympathetic and cardiovagal BRS was not different. DGB significantly decreased MSNA reactivity to mental math when expressed as burst frequency (P = 0.012) or burst incidence (P = 0.008) compared with Sham. Pulse pressure reactivity was also comparable
Hruska et al[380], 2020	Fifty-four workers eligible for paid vacation time were recruited; stress ratings obtained via weekly surveys and ambulatory HR readings obtained via a wrist-worn consumer device were collected before and after the vacation	A statistically significant interaction was observed between weekly stress and the period leading up to the vacation on ambulatory HR (P = 0.01). The relationship between weekly stress and HR was stronger when the vacation was further away in the future and imparted less of an effect as the vacation approached
Kirk et al[347], 2020	Fully randomized 10-day longitudinal trial of mindfulness practice, explicitly controlling for practice effects with an active-control group (music listening) and CTRL group. To assess chronic CV effects, authors asked participants to complete 2-day HRV pre- and post-intervention measurement sessions	Increased HRV during the daily practice sessions in both the mindfulness and active-control group indicating that both interventions were effective in decreasing acute physiological stress. For the chronic phase increased HRV in both the day- and nighttime indicating increased sleep quality, specifically in the mindfulness group
Lachowska et al[354], 2020	BP and HR were measured in 21 patients with HFrEF (23.9% ± 5.9%) at rest, during laboratory stressors handgrip, mental and CPT, before and after acute SLOWB, and 12 weeks after SLOWB home training (30 minutes daily). HRQoL (MacNew questionaries) was assessed before and 12 weeks after SLOWB home training	Both acute and long-term SLOWB significantly reduced BP and HR responses to mental stress (P < 0.05), but not to isometric and cold pressor tests. SLOWB improved scores of all domains of QoL (P < 0.05) at 12 weeks follow-up
Nourisaeed et al[398], 2021	Overall, patients after AMI were randomly divided into 3 groups of 15 individuals (2 interventions including cognitive-behavioural therapy and dialectical behavioural therapy, and 1 CTRL group). In the IG, participants underwent 8 weekly 90-minute sessions. Data were collected including the Ways of Coping Questionnaire, and the PSS-14	Significant main effects of group (P = 0.005) and time (P < 0.001), and a significant group-by-time interaction (P < 0.001) on PSS. For problem-focused coping scores, findings indicated significant main effects of group (P = 0.002) and time (P < 0.001), and a significant group-by-time interaction (P < 0.001). For emotion-focused coping scores, significant main effects of group (P < 0.001) and time (P < 0.001), and a significant group-by-time interaction (P < 0.001) were observed
Kunikullaya Ubrangala et al[374], 2022	Single session of auditory stimulation with three different ‘Modes’ of Indian music (Mode/Raga Miyan ki Todi, Malkauns, and Puriya) musical stimuli on anxiety, biomarkers of stress, and CV parameters were measured among 140 healthy young adults. The outcome measurements of the State-Trait Anxiety Inventory, BP, and HRV were collected	State anxiety was reduced significantly with raga Puriya (P = 0.018), followed by raga Malkauns and raga Miyan Ki Todi. All the groups showed a significant reduction in sAA. Raga Miyan ki Todi and Puriya caused an arousal effect (as evidenced by HRV) during the intervention and significant relaxation after the intervention (both P < 0.005). Raga Malkauns and the CTRL group had a sustained rise in parasympathetic activity over 30 minutes
Balakrishnan et al[371], 2023	Cross-sectional study, conducted at a regional university and community wellness centre, included convenience sampling of Hatha yoga practitioners and healthy controls	Compared with CTRL group, the yoga group had significantly greater mean HF power (P = 0.04) and mean HF normalized units (P = 0.02) and a significantly lower LF/HF ratio (1.1 ± 0.5 vs 2.2 ± 1.1; P = 0.01). No significant intergroup differences were observed for LF power, or any time-domain measures of HRV
Banerjee et al[373], 2023	Participants were subjected to a 10-item yoga questionnaire. Based on Likert scale scoring, 32 subjects (group I) were selected as long-term yogic breathing practitioners, and autonomic function tests using HRV and a provocative stress test and CV reactivity to HUT	A highly significant decrease in values of both high HF and LF variables was observed in group ІІ as compared to group I. A highly significant rise in LF/HF has been observed in group ІІ compared to group I (P = 0.004), indicating a greater withdrawal of vagal tone during the HUT test and during recovery (P = 0.001)
Bhagat et al[366], 2023	Pre-training measurements of SBP, DBP, HRV, and BRS were done, and the Medical Student Stressor Questionnaire was administered to participants. They were then trained in RYM	RYM training decreased DBP (P = 0.01) but not SBP. BRS showed a trend towards an increase after RYM practice, but it was not statistically significant (P = 0.44). The SDNN (P = 0.03), LF (P = 0.003), and HF (P = 0.04) showed a statistically significant change
Raj et al[367], 2023	Cross-sectional study included 202 yoga and 181 non-yoga participants	Following adjustments, cfPWV was significantly lower in yoga participants with a mean difference: -0.28 (95%CI: -0.55 to 0.08)
Ng et al[387], 2024	Participants from the Stress and Well-being in Everyday Life Study which included adults residing in the United States provided background and social network information in a baseline interview, followed by a 4-day ecological assessment in which they reported social encounters every 3 hours	At times when individuals encountered friends (particularly positive encounters), they exhibited a momentary reduction in HRV (within-person association). But those with more friend encounters during the study period had higher HRV than those with fewer friend encounters during the study period
Zou et al[349], 2024	This study was a 2-arm, parallel-group RCT. Patients with ACS recruited at 2 tertiary hospitals in Jinan, China were randomly assigned to a Mindfulness Psycho-Behavioural Intervention group or control group. The 6-week intervention consisted of 1 face-to-face session (phase I) and 5 weekly WeChat (Tencent Holdings Ltd) - delivered sessions (phase II) on mindfulness training and health education and lifestyle modification	Significantly greater improvements were observed in psychological stress (β = -1.186, 95%CI: 1.678-0.694, P < 0.001), physical HRQoL (β = 0.088, 95%CI: 0.008-0.167, P = 0.03), emotional HRQoL (β = 0.294, 95%CI: 0.169-0.419, P < 0.001), and general HRQoL (β = 0.147, 95%CI: 0.070-0.224) at T1, as well as dietary behaviour (β = 0.069, 95%CI: 0.003-0.136, P = 0.04), physical activity level (β = 177.542, 95%CI: -39.073 to 316.011, P = 0.01), and SBP (β = -3.326, 95%CI: -5.928 to 0.725, P = 0.01) at T2
Weiss et al[356], 2024	Controlled non-randomized longitudinal pilot intervention study enrolling individuals with CVD. After the first interview, a 12-week Metta meditation course starts for the IG, while the CTRL group will receive no intervention	The health-promoting personal competencies of sense of coherence, resilience, and self-compassion were not strengthened by the practice of Metta meditation in individuals with cardiovascular disease. However, there was a significant reduction in perceived stress and improved stress coping skills in the IG. Furthermore, the frequency of rehospitalization differed significantly in the pre-post comparison
Zureigat et al[389], 2024	A subset of participants from the Mass General Brigham Biobank adults who completed a PA period underwent 18F-fluorodeoxyglucose positron emission tomography/computed tomographic imaging. Stress-related neural activity was measured as the ratio of resting AmygAC	Greater PA was associated with both lower AmygAC (standardized β = -0.245; 95%CI: -0.444 to -0.046; P = 0.016) and CVD events (HR = 0.802; 95%CI: 0.719-0.896; P < 0.001). AmygAC reductions partially mediated PA’s CVD benefit (OR = 0.96; 95%CI: 0.92-0.99; P < 0.05)
Cui et al[360], 2025	Patients with CCS were randomly assigned to 12 weeks of either a TCCRP or a CECRP	Within the TCCRP group, the Chinese version of the PSS score significantly decreased (P < 0.05) from baseline to the end of the intervention. Notably, in the CECRP group, the Chinese PSS score increased (P < 0.05) at the end of the intervention. The antioxidant enzymes catalase and glutathione peroxidase levels increased markedly in the TCCRP group after the intervention (P < 0.001). Chinese version of the PSS was positively correlated with oxidised low-density lipoprotein (P < 0.05)
Johnson and Ezouah[368], 2025	In this 4-week pilot study, grounded in Pender’s Health Promotion Model, participants engaged in daily online health education and yoga activities through YouTube videos. Using Fitbit trackers, electronic blood pressure monitors, and web-based logs, the study measured metabolic syndrome risk factors and sedentary behaviour. Participant experiences were further explored through postintervention focus groups aiming to contextualize the intervention’s impact	Specifically, viewing over one-half of the instructional videos (P = 0.04) and daily BP monitoring (P = 0.02) were key to participant adherence. The qualitative focus group data unveiled 4 major themes: (1) Accountability, emphasizing the shift toward self-prioritization and collective health responsibility; (2) Increased awareness, highlighting enhanced understanding of health behaviours and metabolic syndrome risks; (3) Health benefits, noting observed improvements in blood pressure and stress levels; and (4) Unanticipated stressors, identifying external factors that challenged engagement
Canella et al[348], 2025	This one-group pretest-posttest quasi-experimental design recruited adult volunteers to partake in a standard 8-week MBSR program. The main outcomes were psychological well-being (perceived stress, anxiety and awareness) and stress-related biomarkers (SBP, DBP, salivary cortisol, IL-6 and IL-8 levels, plasma carotenoids concentration)	MBSR decreased stress (P = 0.002) and anxiety (P = 0.05) and increased awareness (P = 0.01). MBSR also significantly lowered SBP and DBP (P = 0.02 and 0.001), cortisol (P = 0.01), and IL-6 and IL-8 pro-inflammatory cytokines (P = 0.02 and 0.03), and enhanced carotenoids (P = 0.03). A strong positive correlation between ΔPSS and ΔSTAI-Y1 (P = 0.008), ΔSTAI-Y1 and ΔIL8 (P = 0.0007), and ΔPSS and ΔIL8 (P = 0.04), and significant negative correlations were observed between ΔPSS and ΔMAAS (P = 0.0003), ΔSTAI-Y1 and ΔMAAS (P = 0.04), and ΔMAAS and ΔIL8 (P = 0.003)

CTRL: Control; HRV: Heart rate variability; DBP: Diastolic blood pressure; BMI: Body mass index; TC: Tai Chi; PSS: Perceived Stress Scale; HR: Heart rate; ACS: Acute coronary syndrome; PTSD: Post-traumatic stress disorder; CI: Confidence interval; CV: Cardiovascular; OR: Odds ratio; QoL: Quality of life; RCT: Randomized controlled trial; TT: Tension Tamer; SBP: Systolic blood pressure; HF: High frequency; DGB: Device-guided slow breathing; BP: Blood pressure; MSNA: Muscle sympathetic activity; BRS: Baroreflex sensitivity; HFrEF: Heart failure with reduced ejection fraction; CPT: Cold pressure test; SLOWB: Slow breathing; AMI: Acute myocardial infarction; sAA: Salivary alpha-amylase; LF: Low frequency; HUT: Head up tilt; RYM: Raj Yoga meditation; SDNN: Standard deviation of N-N intervals; cfPWV: Carotid femoral pulse wave velocity; CI: Confidence interval; HRQoL: Health-related quality of life; CVD: Cardiovascular disease; IG: Intervention group; PA: Physical Activity; AmygAC: Amygdalar-to-cortical activity; HR: Hazard ratio; CCS: Chronic coronary syndrome; TCCRP: Tai Chi cardiac rehabilitation programme; CECRP: Conventional exercise cardiac rehabilitation programme; MBSR: Mindfulness Based Stress Reduction; IL: Interleukin; STAI: State-Trait Anxiety Inventory.

CONCLUSION

As this is a narrative review, its limitation is that some degree of selection bias is possible due to the absence of a systematic approach. However, we hope it may represent a particularly useful resource for clinicians and researchers interested in stress-related CV risk. Table 6 shows, in summary, the main key points relative to this topic.

Table 6 Key points.

Topic	Summary
Changing paradigm	Atherosclerosis is now viewed as an “inflammatory/immune-driven” disease, not just passive lipid buildup
Residual risk	Many acute coronary syndromes or strokes occur without classic risk factors (arterial hypertension, diabetes, dyslipidaemia, smoking)
Psychosocial factors	Stress, negative affect, and psychosocial context are independent cardiovascular risk contributors
Stress syndromes	Modern stress-related disorders include acute stress reactions, adjustment disorders, and PTSD
Guidelines positioning	ESC guidance recognizes psychosocial factors as risk modifiers to refine cardiovascular risk assessment, encouraging clinicians to incorporate psychosocial evaluation into care decisions
What stress is	Stress occurs when perceived demands exceed coping resources/homeostatic reserve; this explains inter-individual variability in cardiovascular impact and vulnerability
Main stressor domains	Major life events, adverse work conditions, and family conflict are repeatedly linked to higher cardiovascular risk. This identifies “high-yield” psychosocial exposures relevant for clinical history-taking
High risk populations	Type D personality, individuals with elevated neuroticism polygenic risk scores, women, Black and Hispanic people show a greater cardiovascular risk
Social inequities	Socioeconomic/structural factors and inequities (unsafe environments, limited healthy options) create chronic stress burdens, hitting disadvantaged groups harder
Neuro-cardiac axis	Stress responses are regulated by corticolimbic regions influencing autonomic outputs (“brain-to-heart” pathways with feedback loops)
Acute stress outcomes	Acute triggers (anger/fear, bereavement, disasters, noise, temperature shifts, sports, traffic) can precipitate myocardial infarction, arrhythmia, stroke/TIA, and transient left ventricle dysfunction in predisposed individuals
Takotsubo syndrome	Stress cardiomyopathy accounts for approximately 2%-3% of suspected acute coronary syndromes, often in post-menopausal women; it is linked to catecholamine surge, microvascular spasm, and myocardial stunning
Arrhythmias	Acute stress can destabilize repolarization via autonomic activation; anxiety may increase sudden cardiac risk directly/indirectly
PTSD & cardiovascular risk	PTSD a major, clinically meaningful risk state, is associated with approximately 25%-50% higher cardiovascular risk, including coronary heart disease, heart failure, stroke and mortality; mechanisms include inflammation, unhealthy behaviors, autonomic imbalance, and microvascular dysfunction
Chronic stress & prevention	Chronic stress correlates with poorer cardiovascular health metrics and recurrent events; interventions integrating mental well-being into cardiovascular care (mindfulness, cognitive behavioural therapy, breathing techniques, exercise/cardiac rehabilitation, etc.) show promise, but hard-outcome evidence remains limited and structured assessment is underused

PTSD: Post-traumatic stress disorder; ESC: European Society of Cardiology; TIA: Transient ischemic attack.

Research examining links between mental stress, atherosclerosis, and broader CVD outcomes remains at a relatively early stage. Although the brain-heart axis is extensively described in the literature, it is rarely incorporated into routine cardiology practice. Despite patient awareness that stress represents a major risk factor, formal clinical pathways and guideline recommendations remain limited. Recent conceptual progress includes updated models of mental disorders, investigation of cognitive-emotional interactions, and integrative frameworks linking stress mechanisms with neuroscience, health behaviours, and social cognition[401]. Expanding genome-wide association studies in PTSD will facilitate Mendelian randomization analyses to test hypotheses regarding the presence, magnitude, and directionality of causal effects between PTSD and CVD outcomes.

Routine screening for emotional distress is not universally recommended for all CVD patients and currently remains largely limited to depression screening in selected populations. Instead, psychosocial factors should be incorporated into standard clinical history-taking, informed by clinician judgment and the objectives of the visit. Cardiometabolic risk factors should be systematically assessed, and preventive strategies - dietary, lifestyle, and pharmacological - implemented to improve long-term outcomes and QoL[254]. These observations also support tailored psychological interventions to reduce adverse stress-related consequences, strengthen protective behaviours, and optimize outcomes after CR[392]. Future research should validate standardized measures of emotional distress in individuals with or at risk for CVD.

The most effective psychosocial interventions appear to be multicomponent programs combining CBT-based stress management with healthy behaviour modifications, particularly regular exercise[340]. While psychological interventions generally improve distress in cardiac populations, a critical unresolved issue is whether treatments that directly target the brain-heart axis - such as neuromodulatory approaches aimed at improving autonomic function - can reduce hard CV endpoints and all-cause mortality[215,236]. Evidence regarding the prognostic benefit of treating post-myocardial psychological distress remains mixed and of variable quality, emphasizing the need for high-quality trials, especially in patients with clinically meaningful anxiety, depressive symptoms, stress-related disorders, and PTSD. Nevertheless, multiple approaches can reduce distress and thereby improve emotional well-being, QoL, and holistic patient-centred care. Ultimately, clinicians should aim to treat not only the disease but the individual as a whole[254]. Large, rigorously designed prospective studies - including diverse and high-risk groups such as women - are warranted to determine whether interventions targeting stress or underlying neurobiological and immune dysregulation can prevent or improve CVD risk and outcomes[211,402-404].