Post-traumatic stress disorder and cardiometabolic dysfunction: Molecular mechanisms and therapeutic targets.

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Learn more: PMC Disclaimer | PMC Copyright Notice iScience . 2026 Mar 21;29(4):115447. doi: 10.1016/j.isci.2026.115447 Search in PMC Search in PubMed View in NLM Catalog Add to search Post-traumatic stress disorder and cardiometabolic dysfunction: Molecular mechanisms and therapeutic targets Juhyun Song Juhyun Song 1 Department of Anatomy, Chonnam National University Medical School, Hwasun, Jeollanam-do 58128, Republic of Korea Find articles by Juhyun Song 1, ∗ Author information Article notes Copyright and License information 1 Department of Anatomy, Chonnam National University Medical School, Hwasun, Jeollanam-do 58128, Republic of Korea ∗ Corresponding author [email protected] Collection date 2026 Apr 17. © 2026 The Author This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). PMC Copyright notice PMCID: PMC13090624  PMID: 42006341 Summary Post-traumatic stress disorder (PTSD) is a complex psychiatric condition affecting approximately 6.1% of the US population and is characterized by intrusive memories, trauma avoidance, emotional dysregulation, and hyperarousal. The disorder is associated with significant neurobiological changes, including structural and functional alterations in key brain regions such as the amygdala, hippocampus, corpus callosum, prefrontal cortex, and premotor cortex. Neurologically, PTSD is marked by heightened amygdala activity, reduced ventromedial prefrontal cortex activation, and significant cognitive impairments, particularly in verbal and autobiographical memory. Physiological dysregulation is evident in lowered cortisol levels, autonomic nervous system dysfunction, elevated sympathetic arousal, and systemic inflammation. Recent research has highlighted a critical, mutual relationship between PTSD and metabolic syndrome, with PTSD patients exhibiting increased susceptibility to cardiovascular disease and metabolic imbalances. These connections are mediated by complex neuroendocrine mechanisms, primarily involving activation of the sympathetic nervous system and dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis. This review examines emerging evidence linking PTSD with metabolic dysfunction, focusing on cardiovascular inflammation and the renin-angiotensin system. Understanding these intricate interactions is crucial for advancing comprehensive management strategies and identifying potential therapeutic interventions. Subject areas: Health sciences, medicine, psychiatry, cardiovascular medicine, endocrinology Graphical abstract Open in a new tab Health sciences; Medicine; Psychiatry; Cardiovascular medicine; Endocrinology Introduction Post-traumatic stress disorder (PTSD) is a debilitating psychiatric condition that emerges following exposure to actual or threatened death, serious injury, sexual assault, or other severe traumatic experiences including natural disasters, accidents, and combat situations. 1 , 2 Clinically, PTSD is defined by four core symptom clusters: intrusive re-experiencing of the traumatic event, persistent avoidance of trauma-related stimuli, negative alterations in cognition and mood, and marked hyperarousal. 3 , 4 A particularly disabling feature is verbal memory dysfunction, most prominently in autobiographical memory. 5 Epidemiologically, PTSD carries a lifetime prevalence of approximately 6.1% in the United States under Diagnostic and Statistical Manual of Mental Disorders, 5 th Edition (DSM-5) criteria, with global estimates of 3.9% in the general population. 6 Critically, PTSD is not confined to psychological morbidity alone. Individuals with PTSD demonstrate a 2- to 3-fold increased risk of developing cardiovascular disease (CVD), 7 including coronary artery disease, hypertension, heart failure, and stroke, independent of traditional risk factors such as smoking, physical inactivity, and comorbid depression. Furthermore, PTSD is strongly associated with components of metabolic syndrome—including obesity, type 2 diabetes, dyslipidemia, and hypertension—establishing a clear clinical overlap between psychiatric trauma and cardiometabolic dysfunction. 8 , 9 , 10 , 11 , 12 The neurobiological substrate of PTSD involves characteristic structural and functional alterations across multiple brain regions. Reduced hippocampal volume—which negatively correlates with PTSD duration 13 —alongside heightened amygdala reactivity and diminished ventromedial prefrontal cortex (vmPFC) activity collectively reflect a state of exaggerated threat appraisal and impaired fear extinction 14 , 15 , 16 , 17 ( Figure 1 ). Additional structural anomalies have been documented in the corpus callosum, 18 prefrontal cortex, 19 and premotor cortex. 20 At the neuroendocrine level, the hypothalamic-pituitary-adrenal (HPA) axis serves as the principal mediator linking psychological stress to systemic physiological dysregulation ( Figure 2 ). In PTSD, chronic stress drives hypothalamic release of corticotropin-releasing hormone (CRH), which stimulates pituitary secretion of adrenocorticotropic hormone (ACTH). Despite this upstream activation, adrenal cortisol output is paradoxically reduced—a phenomenon attributed to glucocorticoid receptor (GR) hypersensitivity and enhanced negative feedback. 21 , 22 This hypocortisolemia perpetuates a pro-inflammatory state, impairs hippocampal neurogenesis, and promotes mitochondrial dysfunction and excessive reactive oxygen species (ROS) production in neurons and glia 22 , 23 ( Figures 1 and 2 ). Concurrently, ACTH-driven adrenal medullary hyperactivation elevates circulating norepinephrine, sustaining sympathetic arousal that manifests as tachycardia, hypertension, and dyslipidemia through enhanced lipolysis—providing a direct mechanistic bridge from neuroendocrine dysregulation to cardiometabolic pathology 17 , 23 , 24 , 25 ( Figure 1 ). HPA axis activity is regulated through a glucocorticoid-mediated negative feedback loop operating at the level of the hypothalamus and pituitary gland ( Figure 3 ). Figure 1. Open in a new tab Neuroendocrine mechanisms driving amygdala hyperactivation in post-traumatic stress disorder (PTSD) This schematic illustrates the stress-induced pathways contributing to amygdala hyperactivation in PTSD. Stress exposure stimulates the hypothalamus, triggering the release of corticotropin-releasing hormone (CRH), which acts on the anterior pituitary gland. Concurrently, activation of the ghrelin-growth hormone (GH) pathway promotes the secretion of growth-hormone-releasing hormone (GHRH) and GH. Both GHRH and GH exert a positive, stimulatory effect (+) directly on the amygdala. This subsequent amygdala hyperactivation mediates several critical physiological and behavioral responses, including the activation of the sympathetic autonomic system (SNS) and the HPA axis, alongside the manifestation of anxiety, avoidance behavior, and enhanced fear memory retention. CRH, corticotropin-releasing hormone; GH, growth hormone; GHRH, growth-hormone-releasing hormone; HPA axis, hypothalamic-pituitary-adrenal axis; PTSD, post-traumatic stress disorder; SNS, sympathetic autonomic system (sympathetic nervous system); (+), stimulatory effect/positive regulation. Figure 2. Open in a new tab Dysregulation of the HPA axis and systemic responses in PTSD This schematic diagram illustrates the complex neuroendocrine pathways activated by stress in PTSD. Stress stimulates the hypothalamus to release corticotropin-releasing hormone (CRH), which in turn prompts the anterior pituitary to secrete adrenocorticotropic hormone (ACTH). ACTH acts on the adrenal gland, stimulating the adrenal cortex to produce cortisol and the adrenal medulla to release norepinephrine. Additionally, stomach-derived ghrelin exerts a stimulatory effect (+) on the pituitary gland. Cortisol engages in a negative feedback loop (−), inhibiting both the HPA axis and gastric function, while also negatively impacting the prefrontal cortex and hippocampus. Conversely, norepinephrine exerts a positive effect (+) on these brain regions. Systemically, cortisol drives energy compensations (increased gluconeogenesis and lipogenesis), whereas norepinephrine mediates fight-or-flight mechanisms (increased heart rate, blood pressure, and lipolysis). Ultimately, the neuroendocrine impact on the prefrontal cortex and hippocampus leads to cognitive decline, characterized by decreased regional volumes and increased neuroinflammation. ACTH, adrenocorticotropic hormone; CRH, corticotropin-releasing hormone; HPA axis, hypothalamic-pituitary-adrenal axis; PTSD, post-traumatic stress disorder; (+), stimulatory effect/positive regulation; (−), inhibitory effect/negative feedback/downregulation. Figure 3. Open in a new tab Glucocorticoid-mediated neuroinflammation and cellular dysfunction in PTSD This schematic outlines the downstream effects of stress-induced HPA axis activation on cellular and molecular processes in PTSD. Stress initiates the cascade by stimulating the hypothalamus to release corticotropin-releasing hormone (CRH), which signals the anterior pituitary to secrete adrenocorticotropic hormone (ACTH). ACTH then stimulates the adrenal cortex to release glucocorticoids. While glucocorticoids exert a standard negative feedback loop (−) on the HPA axis to regulate the stress response, their elevated levels in this context exert a positive, stimulatory effect (+) on several pathological pathways in the brain. Specifically, glucocorticoids drive a cascade of inflammation and altered neurogenesis, characterized by an increased general inflammatory response, inhibition of neutrophil activation, impaired neurogenesis, and altered consolidation of extinction memory. Furthermore, this pathway leads to cellular distress, including mitochondrial dysfunction in neurons, excessive production of reactive oxygen species (ROS) in both neurons and glia, and the prominent activation of microglia. ACTH, adrenocorticotropic hormone; CRH, corticotropin-releasing hormone; HPA axis, hypothalamic-pituitary-adrenal axis; PTSD, post-traumatic stress disorder; ROS, reactive oxygen species; (+), stimulatory effect/positive regulation; (−), inhibitory effect/negative feedback. Despite growing epidemiological evidence linking PTSD to cardiovascular and metabolic disease, existing reviews have primarily characterized these associations at a descriptive, systems level. Three critical mechanistic domains remain inadequately integrated into a unified framework. First, the bidirectional interplay between cholesterol metabolism and neuroinflammation has not been mechanistically characterized in the context of PTSD; dysregulated lipid homeostasis contributes to both neuronal membrane dysfunction and systemic vascular inflammation, yet the neuroinflammatory cascades that amplify this lipid-vascular axis—including pro-inflammatory-cytokine-mediated neurotransmitter disruption and epigenetic reprogramming of immune-related genes—remain fragmented across disciplines. Second, the renin-angiotensin system (RAS)—a key regulator of both cardiovascular homeostasis and central stress circuitry—has not been positioned as a unifying molecular bridge between PTSD neurobiology and cardiometabolic risk; the angiotensin II type 1 receptor (AT1R)/AT2R signaling axis and its interactions with fear-memory consolidation, neurovascular inflammation, and sympathetic tone represent a substantially underexplored therapeutic target. Third, the convergence of HPA axis dysfunction with mitochondrial bioenergetic failure—a mechanism that simultaneously drives neurodegeneration and endothelial dysfunction—has not been articulated as a shared pathophysiological node; in particular, the downstream consequences of this convergence, including glucocorticoid-driven microglial activation, oxidative stress, and systemic immune cell dysregulation, have not been integrated into a unified framework linking psychiatric and cardiometabolic deterioration. The absence of this integrated mechanistic perspective represents a critical gap that limits the development of targeted, mechanism-based therapeutic strategies for PTSD-associated cardiometabolic disease. This review aims to address these gaps by elucidating the molecular mechanisms through which PTSD pathophysiology and cardiometabolic dysfunction converge and mutually reinforce disease progression. Specifically, we synthesize current evidence across three interconnected mechanistic axes: first, the cholesterol-neuroinflammation axis, encompassing dysregulated lipid metabolism and its amplification through neuroinflammatory cascades as dual drivers of central neurodegeneration and peripheral atherosclerotic risk; second, the RAS-fear circuit, wherein angiotensin signaling modulates amygdala-dependent fear memory, neurovascular inflammation, and sympathetic cardiovascular control; and third, the HPA-mitochondria link, through which glucocorticoid-mediated mitochondrial dysfunction and resultant microglial activation and systemic immune dysregulation serve as common cellular mechanisms underlying both psychiatric and cardiovascular pathology. By integrating evidence from preclinical models, translational studies, and clinical trials within a single mechanistic framework, this review provides a comprehensive translational roadmap for the identification and therapeutic targeting of shared molecular nodes in PTSD-associated cardiometabolic disease. Establishing this integrated mechanistic framework is of critical scientific and clinical importance because it fundamentally reframes PTSD and cardiometabolic disease—traditionally managed as independent comorbidities—as manifestations of shared molecular pathology. This reconceptualization carries direct translational consequences: the repeated failure of receptor-specific monotherapies in recent clinical trials underscores that single-target pharmacological approaches are insufficient against the redundant, multisystemic nature of PTSD-associated cardiovascular risk. By delineating convergent molecular nodes including AT1R-mediated fear-cardiovascular coupling, cholesterol-driven neuroinflammation-atherosclerosis synergy, and glucocorticoid-mitochondrial bioenergetic failure, this review provides a rational foundation for developing biomarker-stratified, dual-target therapeutic strategies that concurrently address psychiatric and cardiometabolic deterioration, an approach that remains absent from current treatment guidelines and clinical practice. The cholesterol-neuroinflammation axis: Dysregulated lipid metabolism as a driver of central and peripheral vascular pathology in PTSD Epidemiological evidence linking PTSD to CVD and dyslipidemia The relationship between PTSD and CVD is complex and driven by converging, mutually reinforcing mechanisms—including shared neuroendocrine dysregulation, chronic neuroinflammation, and autonomic dysfunction—with profound clinical implications for risk stratification and integrated therapeutic strategies. Epidemiological studies consistently demonstrate that PTSD increases the risk of CVD 3-fold, 26 , 27 significantly elevating CVD-related morbidity 28 , 29 ( Table 1 ). This interplay is often conceptualized as the “mind-heart-body connection” 68 and manifests in conditions such as stress-induced cardiomyopathy, 30 highlighting the intricate psychophysiological interactions between cardiac function and anxiety mindsets. 69 Table 1. PTSD-associated cardiovascular and metabolic dysfunctions Category of dysfunction Specific manifestation Key effects Evidence level Clinical translation status Key limitation of study Reference Cardiovascular risk factors & events increased CVD risk 3-fold increase in CVD risk; significantly elevated morbidity strong established/clinical observational nature limits causal inference Edmondson et al. 26 ; Edmondson et al. 27 ; Brackbill et al. 28 ; Ahmadi et al. 29 Cardiac physiological changes elevated HR, reduced HRV, increased norepinephrine, LV dysfunction, elevated BP indicates excessive sympathetic drive and persistent cardiovascular strain strong established/clinical heterogeneity in cardiovascular measurement protocols Novo et al. 30 ; Ehlers et al. 31 ; Ge et al. 32 ; Hendrickson et al. 33 ; Schneider et al. 34 ; Dyball et al. 35 ; Edmondson et al. 36 ; Seligowski et al. 37 Specific cardiovascular events heart failure, stroke, acute myocarditis, atherosclerosis, myocardial infarction demonstrates direct translation of trauma into structural/ischemic heart disease strong established/Clinical difficult to isolate PTSD from lifestyle confounders (e.g., smoking) O'Donnell et al. 2 ; Edmondson et al. 27 ; Chong Lau et al. 38 ; Lima et al. 39 ; Gharios et al. 40 Hypertension & arterial stiffness 77% higher incidence of hypertension and increased arterial stiffness chronic mechanical stress on vasculature promoting atherogenesis strong established/clinical impact of concurrent antihypertensive medications is often unadjusted Howard et al. 41 ; Walczewska et al. 42 Autonomic nervous system dysregulation reduced parasympathetic tone, elevated systemic cardio-inflammation links psychological hyperarousal directly to systemic physiological wear strong phase II/clinical vagal tone measurements (e.g., HRV) vary across clinical settings Kim et al. 24 ; Schneider et al. 34 ; Seligowski et al. 43 Endothelial dysfunction impaired endothelial function, hypercoagulability (vWF, factor VIII) triggers early-stage vascular aging and thrombotic risk moderate phase II/clinical relies heavily on indirect circulating biomarkers Seligowski et al. 44 ; Sumner et al. 45 ; Robicsek et al. 46 Vascular markers higher ICAM-1, VCAM-1, fibrinogen, CRP sustains a pro-atherogenic and pro-thrombotic peripheral environment strong clinical inflammatory markers are highly non-specific to PTSD Plantinga et al. 47 ; von Känel et al. 48 ; Seligowski et al. 43 ; Eraly et al. 49 Genetic predisposition shared polygenic risk scores (PRS) between PTSD and CVD suggests common heritable pathways rather than pure stress-induced causality. preliminary preclinical/research lacks sufficient diversity in ancestral genomic data Seligowski et al. 50 ; Kong et al. 51 ; Lim et al. 52 Metabolic & lipid dysregulation lower HDL-c, higher TC, TG, and LDL-c exacerbates peripheral atherosclerosis and central nervous system myelin/synapse issues strong clinical dietary and metabolic baseline confounders are frequently omitted Tae et al. 53 ; Jergović et al. 54 ; Dzubur Kulenović et al. 55 ; Karlović et al. 56 ; Vries et al. 57 ; et al. 58 Cortisol’s impact on lipids increased lipolysis, free fatty acids, VLDL; reduced LDL-receptor activity HPA axis dysregulation mechanically forces adverse lipid profiles moderate phase II/clinical timing of cortisol measurements lacks standardization Ma et al. 59 ; Djurhuus et al. 60 CNS consequences of dyslipidemia altered lipid rafts, disrupted serotonin/dopamine transporter expression impairs fear extinction circuitry by destabilizing neuro-membranes speculative preclinical challenging to validate in vivo human lipid raft dynamics Cermenati et al. 61 ; Liu et al. 62 ; Sebastião et al. 63 ; Brunner et al. 64 ; Salter et al. 65 ; Huang et al. 66 Genotype-specific lipid effects increased cholesterol in female TT homozygotes of LDLR rs5925 suggests precision medicine potential for specific trauma-exposed demographics preliminary preclinical/research requires large-scale replication across diverse cohorts Wang et al. 67 Open in a new tab The cardiovascular consequences of PTSD can be organized into four pathophysiological domains: autonomic dysregulation, structural and functional cardiac changes, vascular and hematologic alterations, and systemic inflammation. Autonomic dysregulation represents the most immediate cardiovascular consequence of PTSD. PTSD can induce elevated heart rate, 31 reduced heart rate variability, 32 and increased norepinephrine levels, 33 reflecting excessive sympathetic drive and reduced parasympathetic nervous system activation. 34 This autonomic imbalance is closely linked to dysregulation of the HPA axis, abnormalities in the sympathetic adrenal system, 35 , 36 and elevated blood pressure 37 ( Table 1 ). Anxiety and stress further influence the autonomic system, contributing to sustained hypertension and hypercoagulability in PTSD. 36 , 41 These autonomic disturbances translate directly into structural and functional cardiac changes. PTSD patients exhibit elevated cardiac biomarkers, left ventricular dysfunction, and electrocardiogram abnormalities 30 ( Table 1 ). Epidemiological research has demonstrated that PTSD increases the risk of various cardiovascular events, including heart failure, stroke, atherosclerosis, cardiac arrest, hypertension, thrombosis, and myocardial infarction 2 , 27 , 38 , 39 , 40 ( Table 1 ). Patients with PTSD have a 60% higher risk of coronary heart disease, hypertension, and stroke compared to individuals without PTSD 70 and show a 77% higher incidence of hypertension and increased arterial stiffness compared to the general population 42 ( Table 1 ). At the vascular level, PTSD is associated with endothelial dysfunction and pro-thrombotic alterations. PTSD patients demonstrate impaired endothelial function 44 , 45 and hypercoagulability, including elevated von Willebrand factor antigen and factor VIII activity in the coagulation cascade, 46 as well as increased aortic pulse wave velocity and arterial stiffness 42 ( Table 1 ). Moreover, PTSD patients exhibit higher levels of vascular markers including intercellular adhesion molecule 1 (ICAM-1), 47 vascular cell adhesion molecule 1 (VCAM-1), and fibrinogen 48 in blood ( Table 1 ). Finally, systemic inflammation provides a unifying mechanism connecting these domains. PTSD is associated with an elevated systemic cardio-inflammation response 24 , 43 and increased CRP levels 49 ( Table 1 ). This chronic inflammatory state intersects critically with lipid metabolism, as detailed below. Genetic evidence further supports a shared biological basis for PTSD and CVD beyond stress-mediated pathways. A large-scale genomic analysis leveraging genome-wide association study (GWAS) summary statistics demonstrated significant positive genetic correlations between PTSD and coronary artery disease and showed that incorporating PTSD polygenic risk scores (PRSs) into cardiovascular risk prediction models significantly improved prediction accuracy for incident coronary events. 50 At the single-gene level, an insertion/deletion polymorphism in the angiotensin-converting enzyme (ACE) gene has been identified in PTSD cohorts, with the deletion allele associated with both PTSD susceptibility and elevated blood pressure, providing a direct molecular link between genetic predisposition to trauma-related psychopathology and cardiovascular risk. 51 A recent scoping review synthesizing the broader genetic literature confirmed that shared genetic loci between PTSD and CVD are enriched in pathways related to inflammation, autonomic regulation, and lipid metabolism, reinforcing the concept of common heritable mechanisms rather than simple comorbidity. 52 Moreover, PTSD patients also exhibit higher levels of vascular markers including ICAM-1, 47 VCAM-1, fibrinogen, 48 and CRP levels 49 in blood ( Table 1 ). Given this evidence, further investigations of the mechanisms linking PTSD and CVD pathology are necessary to develop appropriate therapeutic strategies for PTSD patients with CVD. PTSD-associated dyslipidemia and its consequences for central nervous system function High body mass index (BMI) and increased body weight, which are common in diabetes, obesity, and CVD, are risk factors for dyslipidemia. 71 Several studies have shown that PTSD patients exhibit impaired lipid profiles, 53 , 54 , 55 which has far-reaching consequences affecting central nervous system (CNS) function through alterations in synaptogenesis, myelin formation, neurotransmission, and neurotransmitter stability 61 , 62 , 63 ( Table 1 ). The lipid profile in PTSD is characterized by dyslipidemia, with studies showing patients exhibiting lower high-density lipoprotein cholesterol (HDL-C) levels, higher total cholesterol (TC), elevated triglycerides (TGs), and increased low-density lipoprotein cholesterol (LDL-C) compared to control subjects 53 , 54 , 56 , 57 , 58 ( Table 1 ). In PTSD patients, increased cortisol levels elevate lipolysis, free fatty acid levels, and very-low-density lipoprotein (VLDL) secretion. 59 This cortisol-induced reduction in LDL receptor activity leads to elevated LDL levels. 60 These lipid abnormalities affect lipid raft formation in synaptosomal membranes, disrupting serotonin receptor and dopamine transporter expression 64 , 65 , 72 ( Table 1 ). PTSD patients exhibit reduced serotonin levels in the dorsal raphe nucleus and elevated dopamine concentrations, which may disrupt fear circuits by modulating the mesolimbic system. 73 An imbalance in HDL-C levels has also been linked to anxiety-related behavior. 66 Recent research has identified a link between PTSD and increased cholesterol levels, specifically in female TT homozygotes of the LDLR rs5925 polymorphism, 67 suggesting the potential for genotype-specific interventions ( Table 1 ). Neuroinflammatory amplification of the cholesterol-vascular axis The lipid-driven pathology described above does not operate in isolation but is critically amplified by a concurrent state of chronic neuroinflammation in PTSD. PTSD sufferers are at an increased risk of various inflammatory diseases, including multiple sclerosis, inflammatory bowel disease, and rheumatoid arthritis. 74 , 75 Recent studies have highlighted a strong association between PTSD, autoimmune disorders, and inflammatory disease. 76 Individuals with PTSD show elevated levels of inflammatory markers, such as C-reactive protein (CRP), and show increased activation of inflammatory pathways. 77 , 78 Neuroinflammation in PTSD has been linked to cognitive decline, reduced prefrontal cortex function, and an increased risk of dementia 79 , 80 , 81 , 82 ( Table 2 ; Figure 3 ). Patients with PTSD also excessively produce pro-inflammatory cytokines such as interleukin-6 (IL-6), 89 CRP, 90 and homocysteine 91 and activate nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) inflammatory signaling 92 , 93 ( Table 2 ). This pro-inflammatory milieu directly intersects with the cholesterol-neurotransmitter disruption described in PTSD-associated dyslipidemia and its consequences for CNS function: cytokines may reduce dopamine levels by decreasing tetrahydrobiopterin (BH4) bioavailability, which inhibits dopaminergic metabolism, 133 while neuroinflammation disrupts glutamatergic regulation by raising glutamate levels, contributing to the motivational deficits and emotional blunting observed in PTSD. 134 Inflammatory responses in PTSD also lead to lower levels of gamma-aminobutyric acid (GABA) in the insula region of the brain, 135 with activation of NF-κB and p38 mitogen-activated protein kinase (MAPK) signaling demonstrated in PTSD animal models. 136 Notably, PTSD is characterized by a reduced level of IL-17, a cytokine that promotes hippocampal neurogenesis and enhances synaptic plasticity and spatial memory 137 ; its reduction is thought to impair social functioning and memory. 138 Genome-wide analyses have further reported changes in DNA methylation and RNA expression in immune-function-related genes in PTSD patients 127 , 128 ( Table 2 ), suggesting that epigenetic reprogramming may perpetuate the neuroinflammatory state that amplifies cholesterol-driven neuronal and vascular damage. Collectively, these findings demonstrate that dyslipidemia and neuroinflammation operate as synergistic, bidirectional drivers within a single pathological axis: lipid abnormalities destabilize neuronal membranes and neurotransmitter systems, while chronic neuroinflammation accelerates both central neurodegeneration and peripheral atherosclerotic progression in PTSD. Table 2. Molecular mechanisms linking PTSD to cardiometabolic dysregulation Pathway PTSD-associated molecular change Molecular mechanism Cardiometabolic outcomes Clinical research & evidence context Reference HPA axis core dysregulation hypothalamic CRH increase, altered pituitary ACTH, hypocortisolemia glucocorticoid receptor hypersensitivity drives negative feedback, disrupting stress hormone homeostasis low-grade systemic inflammation and insulin resistance clinical cohorts frequently exhibit blunted cortisol awakening responses linked to metabolic syndrome severity Yehuda et al. 21 ; Daskalakis et al. 22 ; Herman et al. 83 ; Lawrence et al. 84 ; Daskalakis et al. 85 CRH signaling increased CRH in plasma/CSF elevated CRH triggers anxiety-like behaviors and interfaces directly with immune responses (e.g., mast cells) amplifies metabolic strain and central hyperarousal high CSF CRH levels consistently observed in combat veterans with chronic PTSD Baker et al. 86 ; Nezi et al. 87 ; van Gaalen et al. 88 Pro-inflammatory bias increased IL-1β, TNF-α, IL-6, CRP; reduced IL-10 HPA disruption lifts glucocorticoid-mediated immunosuppression, favoring a pro-inflammatory cytokine storm accelerates atherothrombotic progression and endothelial injury elevated circulating CRP and IL-6 are robustly correlated with clinical PTSD symptom severity Wang et al. 89 ; Michopoulos et al. 90 ; Jendricko et al. 91 ; Rohleder et al. 92 ; Tursich et al. 93 ; Lunkenheimer et al. 94 ; Koirala et al. 95 ; Ogłodek et al. 96 RAS hyperactivation elevated systemic and central angiotensin II (Ang II) and aldosterone chronic stress activates RAAS, elevating sympathetic tone via AT1R binding in the brain and periphery chronic hypertension and vascular structural damage clinical population studies confirm increased plasma renin and aldosterone in traumatized individuals Zhou et al. 97 ; Shkreli et al. 98 ; Grippo et al. 99 ; Saavedra et al. 100 ; Terock et al. 101 ; Terock et al. 102 AT1R & fear circuitry enhanced Ang II/AT1R signaling in amygdala AT1R activation sustains fear memory consolidation; blockade facilitates extinction sustained autonomic stress signals leading to cardiovascular wear translational evidence supports AT1R as a dual target, though recent clinical trials highlight complexity Seligowski et al. 103 ; Swiercz et al. 104 ; Yu et al. 105 ; Khoury et al. 106 ; Smith et al. 107 Neurovascular inflammation (BBB) increased leukocyte adhesion and BBB hyperpermeability Ang II induces microvascular inflammation and oxidative stress, breaking down the BBB endothelial dysfunction and progressive vascular injury blood biomarkers of BBB disruption correlate with cognitive decline in PTSD patients Bang et al. 108 ; Zhang et al. 109 ; Quiñones et al. 110 ; Young et al. 111 ; Swartz et al. 112 Oxidative stress (redox imbalance) increased ROS, malondialdehyde; reduced antioxidant enzymes thiol-based redox systems are impaired, causing direct lipid peroxidation and mitochondrial strain promotes cellular apoptosis in vascular endothelial cells clinical data show elevated 8-OHdG and malondialdehyde in trauma survivors vs. controls Ulrich et al. 113 ; de Munter et al. 114 ; Atli et al. 115 ; Manukhina et al. 116 ; Kurhan et al. 117 ; Zhou et al. 118 Mitochondrial dysfunction & TSPO suppressed TSPO levels, mtDNA-mediated NLRP3 activation TSPO deficiency impairs microglial resilience; damaged mitochondria release mtDNA to trigger inflammasomes reduced metabolic flexibility and sustained cardio-inflammation PET imaging reveals reduced TSPO expression (microglial marker) in human PTSD brains Yao et al. 119 ; Bhatt et al. 120 ; Picard et al. 121 ; Lushchak et al. 122 ; Bian et al. 123 ; Su et al. 124 ; Zhang et al. 125 ; Ji et al. 126 Epigenetic/Immune transcriptome altered DNA methylation, shifted monocyte gene expression epigenetic reprogramming sustains a hyper-reactive innate immune profile (e.g., increased monocytes/neutrophils) chronic low-grade inflammation driving long-term metabolic risk multi-omics on patient blood shows significant methylation changes in immune-related genes Smith et al. 127 ; Neylan et al. 128 ; Skarpa et al. 129 ; van de Wouw et al. 130 ; Tang et al. 131 ; Dhabhar et al. 132 Open in a new tab The convergence of dyslipidemia and neuroinflammation within a single mechanistic axis underscores the need for comprehensive, interdisciplinary care strategies that address the psychological, neuroinflammatory, and cardiovascular aspects of patient health simultaneously. Further research is essential to elucidate how lipid-driven and inflammation-driven pathologies interact at the molecular level and to develop targeted interventions that concurrently normalize lipid profiles, suppress neuroinflammatory cascades, and mitigate cardiovascular risk in PTSD patients. The RAS-fear circuit: Angiotensin signaling at the interface of fear memory and sympathetic cardiovascular control Central and peripheral RAS activation in PTSD The RAS is a pivotal neuroendocrine pathway with profound implications for physiological regulation. It serves as a critical mechanistic link between PTSD and cardiovascular pathophysiology 97 , 98 ( Table 2 ; Figure 4 ). Central components of the RAS, particularly angiotensin II and its receptor subtypes (AT1R and AT2R) are closely involved in fear processing and stress-related neurobiological responses 103 , 104 , 105 ( Table 2 ; Figure 4 ). Angiotensin II, the primary effector molecule of the RAS, exerts its physiological effects by binding differentially to AT1R and AT2R receptors. 139 The conversion of angiotensin I to angiotensin II by ACE triggers a complex neuromodulatory mechanism, wherein angiotensin II modulates noradrenergic neurotransmission by inhibiting norepinephrine reuptake and enhancing its synaptic release 140 ( Table 2 ; Figure 4 ). Under chronic stress conditions, the renin-angiotensin-aldosterone system (RAAS) is activated, leading to increased levels of angiotensin II and aldosterone 99 ( Table 2 ). PTSD pathogenesis is intrinsically linked to RAS hyperactivation, resulting in elevated angiotensin II production in both the central and peripheral nervous systems 100 ( Table 2 ; Figure 4 ). Clinical studies have consistently shown increased renin and aldosterone concentrations in PTSD patients, further indicating neuroendocrine dysregulation. 101 , 102 Therapeutic approaches targeting the RAS, including ACE inhibitors and angiotensin receptor blockers, have shown promise in alleviating PTSD symptoms. 103 , 106 Figure 4. Open in a new tab Renin-angiotensin system in PTSD Angiotensin I is converted from angiotensinogen through the action of renin. Angiotensin II is converted from angiotensin I through the action of angiotensin converting enzyme (ACE). Angiotensin (1–9) and angiotensin (1–7) are converted from angiotensin I through the action of ACE2 and ACE. AT2R activation exerts counter-regulatory effects opposing AT1R signaling, including vasodilation, anti-inflammatory actions, and anxiolytic effects. Angiotensin II promotes reactive oxygen species (ROS) production through angiotensin II type 1 receptor 1 (AT1R)-protein kinase C (PKC)-Rac1 and induces the production of pro-inflammatory cytokines such as tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), and matrix metalloproteinase 9 (MMP-9) through AT1R-nuclear factor kappa-light chain enhancer of activated B cells (NF-κβ). Subsequently, activated AT1R-NF-κβ signaling causes increased inflammatory response, increased blood-brain barrier (BBB) permeability, endothelial dysfunction, vasoconstriction, and cellular apoptosis. Angiotensin II increases PKC-β and blocks insulin receptor substrate (IRS) insulin signaling and ultimately triggers insulin resistance by binding AT1R. Angiotensin (1–7) binds with angiotensin receptor Mas (MasR) and subsequently leads to decreased blood pressure, reduced sympathetic autonomic nervous system, increased anti-proliferation, anti-inflammatory response, and activated vascular protection system. Also, angiotensin II binds with AT2R and inhibits cyclooxygenase-2 (COX2)-prostaglandin E2 (PGE2) signaling, leading to increased oxidative stress and inflammation. Angiotensin II inhibits nitric oxide (NO) signaling and attenuates vasodilation through AT2R. Angiotensin II could promote anti-inflammatory response, vasodilation, increased neurite growth, improved cognitive function, and reduced BBB permeability through AT2R. AT1R/AT2R signaling in fear memory and neurovascular inflammation Neuroanatomical studies have identified AT2R receptors in key neural substrates such as the medial prefrontal cortex interneurons and amygdala—areas critical for fear memory processing. 105 , 107 Activation of AT2R has been shown to modulate neuronal excitability, reducing both excitatory and inhibitory neuronal firing rates. 141 The blood-brain barrier (BBB), a specialized neurovascular unit composed of endothelial cells, astrocytes, and pericytes, serves as a critical physiological interface in the CNS. 108 Angiotensin II signaling can promote neuroinflammation, which results in increased leukocyte adhesion and BBB hyperpermeability. 109 Importantly, this RAS-driven neuroinflammatory state has direct functional consequences for fear circuitry: inflammation has been linked to impaired fear memory extinction 110 , 111 and enhanced amygdala activation 112 in PTSD, suggesting that AT1R-mediated neuroinflammation not only damages the neurovasculature but also perpetuates the core psychiatric pathology of the disorder by preventing the resolution of fear memories. Preclinical studies in PTSD animal models have demonstrated that ACE inhibitors can effectively suppress RAS component expression, pro-inflammatory cytokine production, and microglial activation within the hypothalamic paraventricular nucleus. 142 Translational research has consistently demonstrated that RAS-targeting pharmacological agents—including ACE inhibitors and angiotensin II receptor blockers—not only modulate blood pressure but also mitigate neurobiological dysfunction associated with PTSD 106 , 143 ( Table 2 ). For instance, AT1R inhibition in the hypothalamic paraventricular nucleus has been shown to regulate the HPA axis and subsequently suppress anxiety behavior in PTSD models. 144 Similarly, AT1R inhibitor improves fear extinction memory function. 145 Preclinical studies have provided valuable insights into the role of angiotensin II in memory processes, suggesting that it enhances avoidance memory, while pharmacological inhibition of the AT1R modulates HPA axis stress responses. 146 , 147 , 148 RAS molecular signaling cascades and therapeutic implications Collectively, angiotensin I is converted from angiotensinogen through the action of renin. Angiotensin II is converted from angiotensin I through the action of ACE. Angiotensin (1–9) and angiotensin (1–7) are converted from angiotensin I through the action of ACE2 and ACE. Angiotensin II promotes ROS production through AT1R-protein kinase C (PKC)-Rac1 and induces the production of pro-inflammatory cytokines such as tumor necrosis factor alpha (TNF-α), IL-1β, and matrix metalloproteinase-9 (MMP-9) through AT1R-NF-κβ ( Table 2 ; Figure 4 ). Subsequently, activated AT1R-NF-κβ signaling causes increased inflammatory response, increased BBB permeability, endothelial dysfunction, vasoconstriction, and cellular apoptosis. Angiotensin II increases PKC-β and blocks insulin receptor substrate (IRS) insulin signaling and ultimately triggers insulin resistance by binding AT1R ( Figure 4 ). Angiotensin (1–7) binds with angiotensin receptor Mas (MasR) and subsequently leads to decreased blood pressure, reduced sympathetic autonomic nervous system, increased anti-proliferation, anti-inflammatory response, and activated vascular protection system. Also, angiotensin II binds with AT2R and activates cyclooxygenase-2 (COX2)-prostaglandin E2 (PGE2) signaling, leading to increased oxidative stress and inflammation. 149 , 150 Angiotensin II stimulates nitric oxide (NO) signaling and promotes vasodilation through AT2R. 151 Angiotensin II could promote anti-inflammatory response, vasodilation, increased neurite growth, improved cognitive function, and reduced BBB permeability through AT2R ( Figure 4 ; Table 2 ). Taken together, these findings highlight the RAS as a sophisticated and promising therapeutic target that simultaneously engages fear circuitry, neurovascular inflammation, and peripheral cardiovascular regulation, positioning it as a uniquely integrative node for addressing both the psychiatric and cardiometabolic manifestations of PTSD. The HPA-mitochondria link: Glucocorticoid-mediated bioenergetic failure and immune dysregulation in PTSD HPA axis dysregulation and neuroendocrine cascades in PTSD Activating the HPA axis releases hormones such as CRH and ACTH, which regulate digestion, immune responses, energy expenditure, and autonomous functions. 83 The disrupted HPA axis triggers the excessive secretion of pro-inflammatory cytokines including IL-1β and TNF-α and a reduction in anti-inflammatory cytokines, such as IL-10 94 , 95 , 96 ( Table 2 ). PTSD patients commonly exhibit dysregulated HPA axes 84 alongside a hyperactive sympathetic nervous system (SNS) 85 ( Table 2 ). The limbic system, including the ventral hippocampus and central amygdala, influences HPA axis activation and is found in glucocorticoid receptors 152 , 153 ( Table 2 ). Abnormal HPA axis activity, whether hyperactive or hypoactive, contributes to PTSD development 22 by affecting the secretion of hormones such as cortisol, 34 , 154 which leads to inflammation. Patients with PTSD demonstrate increased CRH secretion in the paraventricular nucleus of the hypothalamus and elevated ACTH levels in the anterior lobe of the pituitary gland 155 ( Table 2 ). ACTH stimulates the release of norepinephrine, epinephrine, and cortisol. 156 Epinephrine and cortisol are known to regulate immune response and energy metabolism in the CNS, and their secretion is modulated by a negative feedback circuit during stressful conditions 157 ( Table 2 ). CRH, which is the primary effector molecule of the HPA axis, is elevated in both the plasma and cerebrospinal fluid in patients with PTSD 86 , 87 and induces anxiety-like behaviors in PTSD animal models 88 ( Table 2 ). Elevated ACTH levels and altered cortisol concentrations are also observed in patients with PTSD 158 , 159 , 160 ( Table 2 ). Lower ACTH levels enhance anti-inflammatory effects, 161 while higher cortisol concentrations help suppress inflammation by promoting anti-inflammatory cytokine production 162 ( Table 2 ). CRH can also trigger inflammation through mast cell activation in PTSD 87 ( Table 2 ). Beyond these neuroendocrine cascades, HPA axis dysregulation exerts profound downstream effects on cellular bioenergetics and innate immune function through its direct impact on microglial activation and mitochondrial integrity. Glucocorticoid-driven oxidative stress, microglial activation, and mitochondrial dysfunction Elevated norepinephrine 163 and cortisol levels further stimulate pro-inflammatory cytokine production 164 and overactivate the SNS, leading to severe inflammation 165 ( Table 2 ). This HPA-driven inflammatory milieu converges on cellular redox systems: studies suggest that inflammation blocks the thiol-based redox system, leading to increased ROS generation in PTSD. 113 PTSD is associated with increased ROS levels, increased malondialdehyde (a lipid peroxidation marker), reduced antioxidant enzyme activity, and higher 8-hydroxy-2′-deoxyguanosine (8-OHdG) serum concentrations, 114 , 115 , 116 , 117 as well as increased RANTES levels 118 ( Figure 3 ). In the CNS, microglia and astrocytes play a crucial role in mediating the neuroinflammatory consequences of HPA axis dysregulation by producing inflammatory mediators. 79 Microglia regulate inflammatory and immune responses through phagocytosis, inflammatory mediator production, and synaptic pruning. 166 In PTSD models, elevated expression of chemokine receptor 1 (CX3CR1) in microglia, along with ionized calcium-binding adapter molecule (IBA1) as a marker of microglial activation, have been observed in the corticolimbic circuit. 167 Critically, microglia activation in the hippocampus is directly linked to the HPA axis and psychobehavioral responses in PTSD-like models 168 ( Figure 3 ), establishing a mechanistic bridge between neuroendocrine dysregulation and cellular neuroinflammation. This microglial-HPA interplay converges on mitochondrial function. Deficiency of the 18 kDa translocator protein (TSPO), an outer mitochondrial membrane protein, suppresses microglial activation, which in turn allows mitochondria to be damaged by oxidative stress. 119 Lower TSPO levels in PTSD patients are associated with suppressed neuroimmune responses and more severe PTSD symptoms. 120 Mitochondria are associated with the catabolism pathway of catecholamines such as serotonin, dopamine, epinephrine, and norepinephrine. 121 Patients with PTSD exhibit mitochondrial dysfunction 122 and increased mitochondrial permeability. 94 This dysfunction leads to abnormal secretion of neurotransmitters such as dopamine, norepinephrine, and serotonin. 169 , 170 , 171 Dopamine, which regulates mood, behavior, and cognitive function, is affected in PTSD, with re-experiencing symptoms linked to dysregulation of dopaminergic pathways. 172 Abnormal cortisol levels in PTSD are linked to steroidogenesis in mitochondria, 173 and reduced activation of cytochrome p450 1A2 (CYP1A2) impairs mitochondrial potential, disrupting electron transport and mitochondrial function 123 , 124 ( Table 2 ). Mitochondrial DNA can activate the NLRP3 inflammasome, which contributes to the immune response. 125 NLRP3 inflammasome activation is observed in glial cells in PTSD mouse models. 126 Systemic immune dysregulation as a downstream consequence of HPA-mitochondrial failure The convergence of HPA axis dysregulation and mitochondrial dysfunction propagates beyond the CNS to produce widespread peripheral immune alterations. One study observed increased cytokine secretion and immune T cell proliferation in PTSD. 174 Several studies have reported that PTSD is associated with elevated circulating monocytes, 129 , 130 increased neutrophil proportions, 131 and suppressed innate cell activity 132 ( Table 2 ). PTSD also shows reduced natural killer (NK) cell activity, reduced immune cell proliferation, and dendritic cell imbalance. 175 , 176 , 177 , 178 One study demonstrated that neutrophil function is enhanced during acute stress but reduced during chronic stress, leading to diminished phagocytic activity. 179 Furthermore, patients with PTSD show a downshift in the proportion of regulatory T and naive T cells, 180 , 181 along with an altered CD4:CD8 T cell ratio, with increased CD8 effector T cells and decreased naive T cells. 182 Collectively, these immune cell alterations reflect the systemic reach of HPA-mitochondrial failure: glucocorticoid-mediated immunosuppression and mitochondria-driven inflammasome activation jointly reshape the innate and adaptive immune landscape, sustaining the chronic low-grade inflammatory state that perpetuates both neuropsychiatric symptoms and cardiometabolic risk in PTSD. Preclinical models of PTSD-cardiometabolic dysfunction Preclinical animal models are essential tools for elucidating the complex, bidirectional molecular mechanisms between PTSD and cardiovascular and metabolic diseases. Recent studies have moved beyond merely observing behavioral and psychological changes, focusing instead on simulating the physical and molecular damage that severe stress inflicts on systemic metabolism and the cardiovascular system. Behavioral stress paradigms and cardiac remodeling Contextual fear conditioning According to recently established mouse model studies, subjects exhibiting severe PTSD-like behaviors display distinct, sex-dependent ventricular diastolic dysfunction. Contextual fear conditioning (CFC)—in which rodents learn to associate a neutral environment (context) with an aversive unconditioned stimulus (typically foot shock)—provides an unparalleled mechanistic platform for interrogating the neural substrates of fear memory encoding, consolidation, retrieval, and extinction, all of which are impaired in PTSD. 183 Unlike SPS, which delivers multimodal acute stress, CFC allows experimental precision in isolating the specific contributions of discrete molecular pathways to fear-dependent cardiometabolic dysregulation. Particularly in female mice, significant increases in left atrial enlargement, reduced ejection fraction, and the expression of collagen accumulation and cardiac-fibrosis-related genes (Col3a1 and Lox) within heart tissues were observed, proving that trauma is directly involved in the pathological remodeling of the cardiac structure. 184 Predator-based psychosocial stress A model combining exposure to predator odor (e.g., fox urine) with social defeat excellently mimics human complex PTSD. The predator scent stress model—in which rodents are exposed to predator-derived volatile cues (e.g., cat urine, trimethylthiazoline)—induces robust, species-relevant innate fear responses without requiring prior associative learning, making it particularly suitable for modeling the unbidden, in voluntary quality of PTSD intrusive symptoms. 154 Porcine stress syndrome (PSS) animals demonstrate persistent behavioral sensitization (anxiety-like behavior, exaggerated acoustic startle, and impaired prepulse inhibition) that endures weeks beyond the acute stressor, mirroring the chronic nature of PTSD symptomatology. 154 Serotonin and transcriptomic analyses of the heart tissues in this model revealed symptoms of acute myocarditis alongside NF-κB-mediated inflammatory responses and epithelial-to-mesenchymal transitions. 185 Single prolonged stress: Modeling HPA-cardiovascular coupling The SPS model, first systematically characterized by Liberzon and colleagues, remains the most widely employed paradigm for studying PTSD-like HPA axis abnormalities in rodents. 186 The protocol involves sequential exposure of rats to restraint stress (2 h), forced swim (20 min), and ether-induced loss of consciousness, followed by a mandatory 7-day isolation period before behavioral assessment. 186 This sequencing is designed to replicate the overwhelming, inescapable character of traumatic experience and the subsequent sensitization of neuroendocrine stress circuitry. Molecular and neuroendocrine validation Hyperactivation of the RAS and autonomic nervous system Restraint and chronic stress models clearly demonstrate a rapid surge in circulating angiotensin II levels and increased AT1R binding in the brain. This preclinical evidence supports the pathophysiology of the RAS-fear circuit discussed in this review, illustrating how it stimulates the SNS and ultimately leads to hypertension and vascular damage. 187 , 188 Gut-brain axis and metabolomic shifts Recent metabolomics-based animal model studies have confirmed that trauma exposure induces liver inflammation within 24 h and causes long-term abnormalities in the plasma metabolome (particularly disruptions in gut-microbiota-derived metabolites). This suggests that increased intestinal permeability and dysbiosis, combined with HPA axis dysregulation, act as a core pathway promoting systemic metabolic syndrome. 189 , 190 Limitations and future research directions While current rodent models effectively reflect molecular networks such as inflammation, tissue fibrosis, and RAS activation, physiological limitations exist in perfectly mimicking complex, human-specific metabolic syndromes (e.g., obesity and severe atherosclerosis). Therefore, to more accurately target pathophysiological mechanisms in the future, integrative translational research is essential. This includes utilizing primate models—which share similar lipid metabolism and cardiovascular structures with humans—or transgenic models with specific manipulated cardiometabolic factors 191 Review scopes and methodology This narrative review synthesizes peer-reviewed literature published between 1992 and 2026, identified through PubMed, Web of Science, and Scopus using search terms including “PTSD,” “cardiovascular disease,” “renin-angiotensin system,” and “cardiometabolic dysfunction.” During the selection process, priority was given to the most recent and highly relevant findings. Pharmacological challenges and clinical trial perspectives Despite advances in identifying the molecular mechanisms underlying PTSD and cardiometabolic dysfunction, translating these findings into effective pharmacological interventions remains a significant clinical challenge. Currently, selective serotonin reuptake inhibitors (SSRIs), such as sertraline and paroxetine, are the only Food and Drug Administration (FDA)-approved medications for PTSD 192 , 193 ( Table 3 ). While they exhibit clinical success in modulating central serotonergic tone to mitigate depressive symptoms and hyperarousal, meta-analyses indicate that their overall effect sizes are modest, with nearly half of treated patients failing to achieve clinical remission. Furthermore, from a comparative pharmacology perspective, long-term SSRI therapy presents a critical therapeutic paradox for this specific patient population; these agents are frequently associated with metabolic side effects, including weight gain, insulin resistance, and dyslipidemia. Consequently, standard first-line PTSD pharmacotherapy may inadvertently exacerbate the very cardiometabolic risks discussed earlier in this review. Table 3. Pharmacological trials and clinical evidences for PTSD Pharmacological agent/target Molecular change Mechanism Cardiometabolic outcome Clinical evidence level Reference SSRIs (e.g., sertraline, paroxetine) modulates central serotonergic tone inhibits serotonin reuptake to alleviate depressive and hyperarousal symptoms negative: frequently exacerbates weight gain, insulin resistance, and dyslipidemia strong (FDA-approved, but with metabolic side effects) Hoskins et al. 192 ; Sidik et al. 193 Prazosin (alpha-1 antagonist) decreases central adrenergic signaling blocks excessive sympathetic noradrenergic activity during sleep (alpha-1 receptor) neutral: failed to outperform placebo in the VA Cooperative trial; highlights autonomic heterogeneity strong (evidence of trial failure/limitations) Raskind et al. 194 Losartan (AT1R blocker) suppresses AT1R-mediated signaling blocks Gαq/PLC/PKC-mediated LTP in the amygdala and reduces systemic neuroinflammation positive/mixed: reduces BP and inflammatory tone, but LOSe-PTSD trial showed limited psychiatric benefit over placebo moderate (translational gap identified) Khoury et al. 106 ; Stein et al. 195 Statins (HMG-CoA reductase inhibitors) suppresses NF-κB and microglial activation offers pleiotropic anti-inflammatory benefits in fear circuits independent of LDL reduction positive: simultaneous dual-domain benefit (atherosclerosis reduction + neuroinflammation suppression) preliminary/speculative Molero et al. 196 Mifepristone (HPA-targeting agent) modulates glucocorticoid receptor (GR) antagonizes GR to reset the dysfunctional HPA negative feedback loop neutral/mixed: inconsistent results due to biological heterogeneity (e.g., varying baseline cortisol) speculative Golier et al. 197 Open in a new tab The management of specific hyperarousal symptoms, such as trauma-related nightmares, has also encountered notable clinical trial setbacks. Prazosin, a centrally acting alpha-1 adrenergic receptor antagonist, was historically relied upon based on the mechanism of blocking excessive sympathetic signaling during sleep 194 ( Table 3 ). However, a robust, large-scale, multi-site clinical trial (the VA Cooperative Studies Program) recently demonstrated that prazosin failed to significantly outperform a placebo in reducing distressing dreams or improving overall sleep quality. 194 The failure of this trial highlights a critical issue in PTSD psychopharmacology: the extreme pathophysiological heterogeneity of the disorder. It suggests that the broad application of receptor-specific monotherapies may fail unless targeted at specific clinical subtypes exhibiting objectively elevated baseline adrenergic activity. Similarly, therapies targeting the RAS have revealed a striking translational gap between preclinical success and clinical efficacy. As detailed in previous sections, AT1R antagonists like losartan showed immense promise in rodent models by effectively reducing neuroinflammation and facilitating fear extinction. Yet, a recent 10-week randomized, placebo-controlled clinical trial (LOSe-PTSD) found no significant benefit of losartan over placebo in reducing CAPS-5 symptom severity in human patients 195 ( Table 3 ). The primary reason for such drug failures is likely the redundant and multisystemic nature of PTSD. While blocking the AT1R may suppress one inflammatory or fear-promoting node, compensatory mechanisms within the HPA axis or alternative inflammatory cascades (e.g., NF-κB/cytokine signaling) may override the blockade. Ultimately, these clinical trial critiques underscore that future pharmacological strategies must move beyond single-target paradigms. Precision medicine approaches—utilizing baseline inflammatory, metabolic, or autonomic biomarkers to stratify patients—and rational polypharmacy will be essential to overcome current translational hurdles. Clinical implications and conclusions This review has delineated the molecular architecture through which PTSD and cardiometabolic disease constitute a self-reinforcing pathological continuum rather than independent comorbidities. Across three mechanistically interconnected axes—the RAS-fear circuit, the cholesterol-neuroinflammation axis, and the HPA-mitochondria link—convergent evidence from epidemiological, preclinical, and clinical domains reveals that the neuroendocrine and inflammatory sequelae of trauma do not remain confined to the brain but propagate systemically to drive endothelial dysfunction, dyslipidemia, autonomic imbalance, and accelerated atherosclerosis. Epidemiological data consistently demonstrate a 2- to 3-fold elevation in CVD risk among individuals with PTSD—encompassing coronary artery disease, hypertension, and stroke—independent of classical risk factors. 2 , 27 At the molecular level, AT1R-mediated hyperactivation of the RAS sustains both fear memory consolidation in the basolateral amygdala and peripheral vasoconstriction, cortisol-driven dyslipidemia simultaneously impairs neuronal membrane integrity and promotes atherogenic lipid deposition, and glucocorticoid-mediated mitochondrial dysfunction disrupts bioenergetics in hippocampal neurons and vascular endothelial cells alike—establishing a shared cellular pathology that renders psychiatric and cardiometabolic deterioration mutually amplifying. These mechanistic convergences carry direct and actionable clinical implications. First, they demand a paradigm shift toward integrated cardiometabolic screening within routine psychiatric care. Clinicians managing PTSD should systematically assess lipid profiles, high-sensitivity CRP (hs-CRP), fasting glucose, and autonomic function indices such as heart rate variability (HRV)—not as ancillary investigations but as core components of the initial and longitudinal evaluation. 198 Early identification of subclinical metabolic derangements enables pre-emptive cardiovascular intervention before structural organ damage accrues. 199 Second, the shared mechanistic substrate linking fear circuitry to vascular biology reframes the pharmacological landscape in a clinically consequential way. Rather than treating PTSD-associated cardiovascular risk as a sequential problem requiring separate psychiatric and cardiological prescriptions, the RAS-fear circuit and cholesterol-neuroinflammation axes identify agents capable of simultaneous dual-domain benefit. AT1R blockers, for instance, enhance fear extinction through inhibition of Gαq/PLC/PKC-mediated amygdala LTP while concurrently reducing blood pressure and neuroinflammatory tone—a mechanistic duality that conventional SSRI monotherapy, with its known cardiovascular liabilities, cannot replicate 106 ( Table 3 ). Statins similarly offer pleiotropic anti-inflammatory benefit in PTSD-relevant neural circuits through NF-κB and microglial suppression, independent of LDL reduction. 196 Critically, the failure of prazosin in the large-scale VA cooperative studies program trial and the inconsistent results of HPA-targeting agents (e.g., mifepristone) underscore a fundamental limitation of current trial design: the biological heterogeneity of PTSD—spanning noradrenergic, inflammatory, and glucocorticoid subtypes—demands biomarker-stratified patient selection rather than population-level randomization. 194 , 197 Future pharmacological trials must incorporate validated neuroendocrine and inflammatory biomarkers (plasma norepinephrine, cortisol/ACTH ratio, hs-CRP, and renin/aldosterone) as stratification criteria and must adopt multi-domain outcome frameworks that assess fear circuit function, autonomic regulation, and cardiometabolic parameters concurrently alongside established psychiatric scales (CAPS-5 and PCL-5) 85 , 90 ( Table 3 ). Third, the translational gap between mechanistic discovery and clinical application necessitates a deliberately collaborative model of care integrating psychiatry, cardiology, and endocrinology. PTSD must be reconceptualized as a systemic disorder in which psychological trauma initiates a cascade of molecular events that simultaneously dysregulate central fear circuitry and peripheral cardiometabolic homeostasis. Managing only the former while neglecting the latter will predictably yield incomplete therapeutic responses and accelerated organ-level morbidity. Equally, addressing cardiovascular risk in isolation—without targeting the neuroendocrine and neuroinflammatory drivers that sustain it—will fail to interrupt the self-amplifying cycle at its mechanistic origin. In conclusion, the evidence synthesized in this review establishes that PTSD and cardiometabolic dysfunction are unified by shared molecular nodes that represent both the mechanism of their comorbidity and the most rational targets for their concurrent treatment. Realizing this, therapeutic potential will require precision medicine frameworks that match pharmacological strategies to individual neuroendocrine and inflammatory profiles, multi-domain clinical trials that measure psychiatric and cardiometabolic outcomes with equal rigor, and interdisciplinary clinical models capable of delivering integrated care across the mind-heart-body axis. The convergence of these disciplines represents not merely a conceptual advance but an urgent clinical imperative for improving the long-term health outcomes of a globally prevalent and chronically undertreated patient population. Acknowledgments The author would like to thank BioRender for making the figures. This research was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (grant nos. RS-2025-02213506 and RS-2025-19612989) (J.S.). This research was supported by a grant of the Korea Health Technology R&D project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (RS-2025-19252970) (J.S.). Author contributions J.S., conceptualized the study, wrote the original draft, supervised the project, acquired funding, and revised the manuscript. All authors read and approved the final version of the manuscript. Declaration of interests The authors declare that they have no competing interests. References 1. Friedman M.J., Resick P.A., Bryant R.A., Brewin C.R. Considering PTSD for DSM-5. Depress. Anxiety. 2011;28:750–769. doi: 10.1002/da.20767. [ DOI ] [ PubMed ] [ Google Scholar ] 2. 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