Multiple extensive population-based studies consistently demonstrate that ASCVD is more prevalent in men until midlife, after which women's incidence sharply increases post-menopause. In the United States, men aged 40–59 years exhibit approximately 2.6-fold higher prevalence of ASCVD than women (95% CI 2.4–2.8) (1, 12). After age 60, this disparity significantly diminishes, and by age 75 and older, the prevalence in women slightly surpasses that in men (27.1% vs. 26.0%, RR 1.04, 95% CI 1.01–1.07) (13). Mortality rates are comparatively lower in premenopausal women but increase post-menopause, with a 52% rise in ASCVD-related mortality among women aged 75 years or older relative to men (HR 1.52, 95% CI 1.44- 1.4401.60) (14). Conversely, PAH exhibits an opposite sex distribution, with women accounting for approximately 65%–80% of idiopathic PAH cases across major registries such as COMPERA, REVEAL, and ASPIRE (15–17) (Table 1). Despite the higher incidence in women, they consistently demonstrate superior adjusted survival rates (see Table 1). These quantitative registry findings substantiate the sex paradox, wherein females demonstrate greater susceptibility to PAH yet exhibit better survival outcomes, thereby supporting the influential role of hormonal and molecular sex modifiers in the disease process.

Pulmonary arterial medial hypertrophy and structural changes in distal arterioles have been observed in patients with advanced ASCVD, indicating that systemic vascular pathology extends beyond the coronary and systemic arterial beds (18). Histopathological and imaging studies suggest that atherosclerosis-related endothelial dysfunction and inflammation are not confined to the coronary or systemic arterial beds but can extend to the pulmonary circulation. Patients with advanced ASCVD exhibit pulmonary arterial medial hypertrophy, endothelial dysfunction, and distal arteriolar remodeling, even in the absence of overt left heart failure (19, 20). Systemic inflammation, oxidative stress, and circulating pro-atherogenic mediators can impair pulmonary endothelial nitric oxide (NO) signaling and promote smooth muscle cell proliferation in ASCVD. These pulmonary vascular changes often mirror those seen in PAH (5, 19–21), suggesting a common pathophysiological mechanism for ASCVD and PAH (Figure 1). Clinical studies further associate ASCVD with reduced pulmonary vascular compliance and early exertional dyspnea, suggesting subclinical pulmonary vascular involvement that precedes clinically apparent pulmonary hypertension (20, 21). This emerging link underscores the need of reevaluate how systemic atherosclerosis may predispose individuals to pulmonary vascular dysfunction, thereby blurring the traditional distinctions between right- and left–heart–related vascular diseases.

Both ASCVD and PAH, although affecting different vascular areas, share several common risk factors such as hypertension, diabetes mellitus, smoking, obesity, obstructive sleep apnea (OSA), and chronic pulmonary or cardiac conditions (22–24). Elevated systemic blood pressure, abnormal metabolic profiles, and tobacco use promote vascular inflammation and dysfunction, leading to the formation of atherosclerotic plaques (25, 26). Similarly, factors like obesity, OSA, chronic pulmonary or cardiac diseases, and genetic predispositions also raise the risk of PAH (27, 28). Importantly, conditions like OSA serve as a connecting link, worsening systemic hypertension and cardiovascular stress, while also increasing pulmonary artery pressure through intermittent hypoxia and endothelial damage (29). This overlap highlights the potential interconnection of the mechanistic functions of the two diseases at the systemic, cellular, and molecular levels. Table 2 outlines the risk factors and sex differences linked to ASCVD and PAH.

This article aims to summarize the similarities between ASCVD and PAH regarding sex as a key biological factor, and to address the significant knowledge gap between preclinical animal studies and clinical data related to the two diseases, especially concerning sex disparities. Gaining a more comprehensive understanding of these mechanisms will not only clarify sex disparities but also help develop targeted therapeutic and preventive strategies, ultimately advancing personalized medicine for both women's and men's cardiovascular health.

PAH demonstrates a well-known estrogen paradox, where women are more often affected but surprisingly have better survival rates compared to men. Registry data consistently show a higher prevalence in females in PAH cohorts and better survival outcomes (Table 1), but traditional risk profiles do not fully explain these sex differences, prompting further mechanistic research (55). Mechanistic insights implicate estrogen signaling, receptor biology, and metabolic pathways in modulating pulmonary vascular and RV responses. Activation of both estrogen receptors ERɑ and ERβ in cultured pulmonary artery endothelial cells (PAECs) increases production of endothelial nitric oxide synthase (eNOS) and causes vasodilation (58). Additionally, ERβ-mediated signaling is specifically associated with increased prostacyclin production, a NO-independent mechanism that promotes systemic vasodilation and protects against platelet aggregation (59). In PAH, estradiol can decrease pulmonary arterial muscularization, reduce lung inflammation and fibrosis, and promote pulmonary neoangiogenesis, thereby improving pulmonary function in women (54). Moreover, animal studies demonstrate that ovariectomy worsens PAH phenotypes, while estrogen repletion improves pulmonary vascular remodeling and enhances RV adaptation (60), supporting a protective role for estrogen in cardiopulmonary health. However, other studies suggest that estradiol can also aggravate PAH by modulating the bone morphogenetic protein receptor type II (BMPR2) pathway (61). Loss-of-function mutations in BMPR2 are the most common genetic cause of heritable PAH and are associated with a worse prognosis in both males and females (62). Additionally, sex differences in RV function and adaptation are increasingly recognized as central to the paradox; women tend to maintain better RV contractility and coupling under increased afterload, which correlates with improved survival outcomes (53–55). Multiple non-exclusive mechanisms have been proposed below for the “estrogen paradox in PAH”:

Testosterone and its metabolite dihydrotestosterone (DHT) influence vascular function in both ASCVD and PAH (Figure 2), although their roles remain less clearly defined. Beyond serving as a precursor for estradiol, testosterone exerts direct vascular effects through androgen receptor (AR) signaling in endothelial and smooth muscle cells (69). Physiological testosterone levels promote NO production, suppress vascular inflammation, and improve lipid metabolism, whereas testosterone deficiency is associated with increased ASCVD risk, metabolic syndrome, and endothelial dysfunction (70–73). Of note, in postmenopausal women, DHT levels decline to near-undetectable levels, which may partially explain the steep rise in atherosclerotic disease risk after age 50 (74). In PAH, high- but not low testosterone levels in men correlate with worse RV function and reduced survival, suggesting that testosterone may have a detrimental rather than protective effect in RV adaptation (75). Moreover, in experimental PAH studies, testosterone has been shown to mediate pulmonary vascular remodeling and vasodilation; however, this effect is limited to isolated vessels (76). Because in vivo studies of testosterone confirmed its detrimental effects on RV outcomes, it does not consistently offer complete protection against disease progression. Furthermore, due to limited data availability, its impact on pulmonary vascular remodeling, metabolism, and PASMC proliferation warrants further study.

Clinical insights into androgen signaling are further provided by studies of androgen deprivation therapy (ADT) in prostate cancer. ADT is associated with increased risk of myocardial infarction, stroke, heart failure, and metabolic dysfunction, highlighting the cardioprotective role of androgens (77, 78). These findings reinforce the importance of balanced androgen signaling in vascular health and suggest that excessive suppression of androgen pathways may have adverse cardiovascular consequences (79). Because testosterone serves as a precursor for estradiol via aromatization, it contributes to age-related hormonal changes affecting ASCVD risk in women. Notably, aromatase (estrogen synthase) is expressed in vascular endothelial cells, smooth muscle cells, and cardiomyocytes, enabling local conversion of testosterone to E2 within the vessel wall (Figure 2). This local production is believed to contribute to cardiovascular health by mediating the protective effects of E2 (80). By contrast, in PAH, evidence supports increased aromatase activity in pulmonary vascular lesions, which may amplify estrogen signaling independently of circulating hormone levels, thereby contributing to sex-specific vascular remodeling (81). This local estrogen production may partially explain why hormonal effects persist even in postmenopausal women and aging men. Given that estrogen metabolites, rather than estradiol alone, appear central to PAH pathobiology, clarifying the interplay between testosterone, AR signaling, and downstream conversion to E2 and DHT remains an important future direction.

MicroRNAs (miRNAs) are increasingly recognized as critical regulators of vascular homeostasis and disease progression, with accumulating evidence that their expression and function are sex dependent. In both ASCVD and PAH, dysregulated miRNA profiles contribute to endothelial dysfunction, smooth muscle cell proliferation, inflammation, and adverse cardiac remodeling (104). Among these, miR-29, miR-124, and miR-204 have emerged as key sex-sensitive regulators across systemic and pulmonary vasculature. MiR-29 regulates extracellular matrix turnover and fibrosis; its downregulation promotes vascular stiffening and remodeling in ASCVD and PAH, with evidence of estrogen-sensitive regulation (104). MiR-124 suppresses inflammatory and proliferative signaling in PASMCs and is reduced in PAH, particularly in female-derived cells (105). MiR-204 is consistently downregulated in PAH and contributes to STAT3 activation, inflammation, and vascular remodeling; estrogen-mediated suppression of miR-204 provides a mechanistic link between sex hormones and PAH susceptibility (105, 106). Collectively, these miRNAs represent shared, sex-modulated regulators across systemic and pulmonary vascular disease.

Sex differences in metabolic substrate utilization significantly influence vascular disease progression and cardiac adaptation. In ASCVD, men exhibit more adverse lipid profiles and impaired fatty acid oxidation, whereas premenopausal women demonstrate greater metabolic flexibility, an advantage lost after estrogen decline in menopause (107). In PAH, pulmonary vascular cells and the RV undergo metabolic reprogramming toward glycolysis. Female RV cells maintain more efficient mitochondrial oxidative metabolism and fatty acid utilization, contributing to superior RV adaptation and survival compared to males (47, 108). These sex-specific metabolic phenotypes highlight metabolomics as a critical determinant of disease severity and outcomes.

Emerging evidence implicates the gut microbiome as a sex-dependent modulator of cardiovascular disease. In ASCVD, microbiota-derived metabolites such as trimethylamine N-oxide (TMAO) are higher in men and correlate with increased atherosclerotic risk, whereas estrogen suppresses TMA-producing microbial pathways (109, 110). Although data on the gut microbiome in PAH are limited, altered microbial diversity has been linked to systemic inflammation and metabolic dysfunction, suggesting that sex-dependent microbiome-immune interactions may contribute to pulmonary vascular remodeling and RV dysfunction (111).

Epigenetic mechanisms, such as DNA methylation and histone modifications, mediate long-term effects of sex hormones on vascular gene expression. Estrogen receptor signaling promotes histone acetylation and transcription of vasoprotective genes, while estrogen loss is associated with pro-atherogenic epigenetic changes (112). In PAH, epigenetic repression of BMPR2 and anti-proliferative pathways contributes to disease progression, with sex hormones influencing these epigenetic markers and potentially explaining sex-specific penetrance in mutation carriers (113).

Sex differences in mitochondrial function critically influence RV adaptation in PAH. Female RV mitochondria exhibit enhanced oxidative capacity, improved antioxidant defenses, and resistance to oxidative stress, largely mediated by estrogen-dependent pathways (114, 115). In contrast, male RVs demonstrate greater mitochondrial dysfunction and oxidative injury under pressure overload, contributing to worse survival rates (115). These findings underscore mitochondrial metabolism as a sex-specific determinant of PAH and outcomes.

Sex should be explicitly included in clinical risk stratification algorithms for both ASCVD and PAH. In PAH, existing tools like REVEAL and COMPERA already factor in sex, but growing evidence indicates that more detailed stratification is necessary based on other sex-specific factors, including menopausal status, cardiometabolic burden, and RV adaptive capacity (15, 16, 33, 144). Conversely, ASCVD appears earlier in men but progresses more quickly in postmenopausal women after the loss of estrogen-related vascular protection (1). Therefore, postmenopausal women with PAH and men with PAH who have metabolic risks should receive routine ASCVD screening. Likewise, female patients with ASCVD who present with unexplained dyspnea or RV dysfunction should be evaluated for PAH. These points support a sex-informed, bidirectional risk assessment approach across both conditions.

Recognition of sex differences in circulating cardiovascular biomarkers has significant implications for the early detection and risk stratification of both ASCVD and PAH. Women generally exhibit higher circulating levels of natriuretic peptides, such as B-type natriuretic peptide (BNP) and N-terminal pro B-type natriuretic peptide (NT-proBNP), than men of comparable age and hemodynamic status (145, 146). This phenomenon has been documented across multiple populations (147) and can influence the interpretation of cardiac stress markers. Similarly, concentrations of high-sensitivity cardiac troponin (hs-cTn) vary by sex, with men typically having higher baseline values and women exhibiting lower 99th-percentile reference limits (148), necessitating sex-specific thresholds in diagnostic algorithms. These differences mirror physiological variations in cardiac structure, metabolism, and hormonal regulation, and are not limited to heart failure but extend to a broader spectrum of cardiovascular conditions. Recognizing these sex-specific biomarker distributions holds clinical significance; the application of uniform cutpoints may delay diagnosis or result in underrecognition of myocardial injury and ventricular dysfunction in women. Conversely, sex-adjusted thresholds have the potential to enhance diagnostic sensitivity, prognostication, and equitable clinical care in both ASCVD and PAH without compromising specificity.

In addition to circulating biomarkers, advances in cardiopulmonary imaging are enhancing the detection of vascular and RV dysfunction in individuals at risk for, or diagnosed with, ASCVD and PAH. Non-invasive echocardiographic markers such as pulmonary artery acceleration time (PAcT), RV–pulmonary artery (RV-PA) coupling indices, and RV longitudinal strain provide surrogate measures of pulmonary vascular load and RV performance and may detect subclinical dysfunction before the development of overt pulmonary hypertension or symptomatic RV failure (149, 150). Significantly, emerging evidence indicates sex-related differences in RV adaptation and imaging phenotypes: female patients with PAH exhibit greater RV contractility and RV-PA coupling than their male counterparts, despite comparable afterload (47). This variability may help explain the observed sex disparities in clinical outcomes and can be identified through imaging evaluations, such as RV strain and RV–PA coupling measures. Cardiac magnetic resonance imaging (CMR) offers highly reproducible measurements of RV volumes, mass, and functional adaptation, establishing itself as the benchmark for detecting subtle myocardial remodeling. Population-based research indicates sex-dependent differences in RV strain and function in CMR (151), and these distinctions should inform clinical assessment and interpretation.

Furthermore, CT-based assessments, which include quantitative measures of pulmonary vascular pruning and the concurrent evaluation of coronary artery calcium, enable the comprehensive characterization of pulmonary and systemic vascular disease burdens within a single imaging session (152). Notably, quantitative CT measures of pulmonary vascular pruning have been shown to reflect the loss of small pulmonary vessels, to serve as an imaging surrogate for pulmonary vascular disease, and to have prognostic value for mortality and cardiopulmonary outcomes in PAH (152). Coronary artery calcium scoring on CT is a well-established marker of systemic atherosclerotic burden and cardiovascular risk (153). These imaging biomarkers can often be derived from the same or similar chest CT data, enabling simultaneous assessment of both pulmonary and systemic vascular disease. While these advanced imaging techniques provide additional diagnostic and prognostic information beyond biomarkers alone, routine population-wide screening for ASCVD and PAH using high-resolution imaging is unlikely to be cost-effective. Targeted screening strategies that incorporate clinical risk factors, including biological sex and metabolic risk, biomarker profiles, and sex-informed non-invasive imaging in higher-risk groups are more practical and may support earlier diagnosis and treatment, aligning with current guidelines that emphasize risk-based rather than universal screening.

Sex-specific differences in therapeutic responses have become a significant consideration in managing ASCVD and PAH, and emphasize the translational importance of sex as a biological variable (12, 13, 154, 155). Clinical evidence indicates that although both women and men derive substantial benefits from standard lipid-lowering therapies, notable disparities exist in response magnitude and treatment patterns in ASCVD patients. For example, while statins effectively reduce low-density lipoprotein cholesterol (LDL-C) and major adverse cardiovascular events (MACE) in both sexes, women are generally less likely to be prescribed high-intensity statin therapy and to achieve guideline-recommended LDL-C targets than men (156–158). Observational and registry data for PCSK9 inhibitors show that, although these agents reduce LDL-C and cardiovascular events across sexes, sex differences in LDL-C reduction have been reported, with men sometimes achieving greater percentage reductions and women less frequently reaching lipid goals despite similar treatment indication (159, 160). Additionally, disparities in the initiation and intensification of therapies such as ezetimibe and PCSK9 inhibitors following myocardial infarction have been observed by sex (161), suggesting differences in clinical practice and response.

Observational and registry data in PAH suggest that female patients often exhibit better functional and hemodynamic responses to endothelin receptor antagonists and may experience more favorable RV adaptation and survival than male patients. In contrast, male sex has been associated with poorer RV adaptation and outcomes in many cohorts. The influence of sex on response to phosphodiesterase-5 inhibitors and on pulmonary vascular resistance changes remains less clearly defined (131, 144, 162, 163). Prostacyclin therapies improve functional and hemodynamic outcomes in both women and men with PAH; however, observational and mechanistic studies suggest that sex-dependent differences in RV adaptation, and possibly mitochondrial and oxidative signaling, may influence variability in RV response and tolerability to these agents (40, 47). Building on these observations, Sex-informed therapeutic strategies are now entering clinical testing in PAH, including estrogen pathway modulation with aromatase inhibitors such as anastrozole, which has been shown to lower circulating estradiol and improve exercise capacity in PAH patients (164), and the clinical evaluation of estrogen receptor antagonists such as fulvestrant in postmenopausal women with PAH is underway (165).

While most therapies approved for PAH target the pulmonary vasculature, accumulating evidence suggests that certain agents used to manage PAH may also exert beneficial effects across a broader spectrum of cardiovascular diseases, including ASCVD. For instance, phosphodiesterase-5 inhibitors (such as sildenafil and tadalafil), which are standard treatments for PAH, have been associated in observational studies and clinical trials with improved systemic endothelial function, reduced inflammatory markers, and a decreased risk of myocardial infarction and heart failure (166), suggesting potential cardioprotective effects beyond the pulmonary circulation. Likewise, endothelin receptor antagonists (including bosentan and ambrisentan) have demonstrated anti-atherosclerotic properties and endothelial benefits in preclinical models and small-scale clinical studies, including those involving peripheral artery disease, where they enhanced vascular function and lowered the risk of adverse events (167). Although comprehensive randomized clinical trials specifically assessing PAH drugs within primary or secondary ASCVD populations remain limited, these translational insights support the premise that agents modulating the nitric oxide-cyclic guanosine monophosphate (NO-cGMP) and endothelin pathways may provide therapeutic benefits across a range of cardiopulmonary vascular diseases, emphasizing shared mechanisms in PAH and ASCVD and encouraging further clinical investigation.

As statins are the primary agents in ASCVD owing to their potent LDL-cholesterol-lowering and plaque-stabilizing properties, their role in PAH has been extensively studied with mixed and largely inconclusive outcomes (168). In animal models of PAH, statins demonstrate beneficial vascular effects: they enhance endothelial function, reduce pulmonary vascular remodeling and RV hypertrophy, and lower inflammatory mediators (168), providing a mechanistic basis for their potential benefits. However, in human studies, evidence has not consistently shown clear improvements in function or hemodynamics. Early randomized trials, such as the Simvastatin as a Treatment for Pulmonary Hypertension study, observed reductions in RV mass and neurohormonal biomarkers (e.g., NT-proBNP) over short periods but no long-term benefits on exercise capacity, pulmonary pressures, or clinical outcomes (169). Systematic reviews and meta-analyses of available randomized and observational studies indicate that statins do not significantly improve key clinical endpoints in PAH, including the 6-minute walk distance, pulmonary artery pressure, cardiac index, or pulmonary vascular resistance (170). The disparity between animal models and human trials may be due to differences in disease mechanisms or the relative importance of lipid-independent (“pleiotropic”) effects of statins in pulmonary vs. systemic vascular tissues. Despite these mixed results, statin therapy is generally safe and well tolerated in PAH patients, with ongoing research focusing on better-powered or subtype-specific studies to determine if certain PAH phenotypes (or comorbid pulmonary hypertension groups) could benefit.