Contemporary approaches to investigating psychological health and CVH have increasingly focused on positive psychological dimensions – optimism, well-being, purpose, gratitude, happiness, sense of purpose, positive affect, and ikigai (i.e., a Japanese concept meaning a motivating force that provides a sense of purpose) – to determine the potential salubrious effects [14, 15, 95–99]. Despite disparate definitions, optimism is consistently and independently related to IHD risk and related-mortality, and these associations are robust for women and men [14, 100]. For example, using 8 years of prospective data from 70,021 women participating in the Nurses’ Health Study, optimism was associated with a 38% lower risk of CVD-related mortality [101]. In another prospective study of 664 men and women aged ≤65 years (15% women), optimism during MI-related hospitalization was associated with a lower risk of mortality over the next 20 years [102]. Unfortunately, sex-stratified analyses were not conducted. Moreover, it is not clear if people who are healthier or recovering more optimally post-MI are simply more optimistic. Evidence reflecting other positive constructs and IHD risk is more sparse, and associations by sex are often not pursued. In a prospective investigation of 126,255 participants in the U.K. Biobank who were free of IHD at baseline (55% women), those with the lowest psychological wellbeing score (based on happiness, life satisfaction, depression, and neuroticism) had the greatest risk for CAD 12 years later, with a stronger association in women [103]. As observed with other negative, psychological constructs, additional longitudinal data will help to determine which positive psychological factors protect women’s CVH.

Building on the vast literature supporting psychological factors in women’s IHD risk, there are excellent, evidence-based behavioral and pharmacological treatments for managing stress, depression, anxiety, PTSD and related psychological factors (e.g., cognitive behavioral therapy [CBT], interpersonal therapy [IPT], mindfulness-based stress reduction, selective serotonin reuptake inhibitors [SSRIs] serotonin and norepinephrine reuptake inhibitors [SNRIs]), including in the context of IHD prevention [104]. Among behavioral treatment options, CBT has been the most studied in RCTs of patients at risk for or diagnosed with IHD. CBT is an empirically validated psychotherapy that is efficacious for targeting depression, anxiety, and PTSD in women and men [105–108]. In a recent review and meta-analysis of RCTs among patients with CAD, CBT was effective in reducing depression symptoms, especially in the 1-3 months post-intervention, with promising results for longer follow-up (6 months post-intervention) [109]. CBT is also more effective when delivered at moderate and high frequencies (i.e., defined as 8-12 or >13 sessions). A second meta-analysis showed that CBT is associated with a reduced risk of cardiovascular events, MI, and angina duration and intensity [110]. Finally, a Cochrane review and meta-analysis of RCTs investigating effects of CBT and other varied behavioral interventions among patients with IHD, showed that psychological interventions were associated with a 21% lower risk of cardiovascular mortality across 12 years [111]. While most RCTs have focused on CBT to mitigate psychological concerns, there is growing interest in bolstering positive psychological factors – e.g., targeting optimism, gratitude, resiliency, and happiness. Meta-analyses have shown that positive interventions are effective in improving distress and well-being among women and men with CVD [112, 113], which is certainly an area for scientific growth.

Combining behavioral and pharmacotherapy appears to be most effective for managing psychological health in relation to IHD, and receiving both treatments versus only one type of treatment is associated with lower healthcare utilization and all-cause mortality among patients with IHD [114]. Based on decades of data, SSRIs are well-regarded as safe to use in patients with IHD: SSRIs are less cardiotoxic than the earlier class of tricyclics, and are less likely to cause dependency than benzodiazepines; but there is mixed data about their short- and long-term cardiovascular effects [105, 115]. A number of well-known RCTs have included combined behavioral and pharmacological interventions, primarily among patients with depression – the Enhancing Recovery in Coronary Heart Disease Patients (ENRICHD) Trial targeted major depression after MI, the Coronary Patients Evaluation Study (COPES)[116] and the Comparison of Depression Interventions after Acute Coronary Syndrome (CODIACS) Vanguard Trial each investigated depression among post-ACS patients [117], the Bypassing the Blues (BtB) Trial was designed to mitigate depression following CABG [118], and the Canadian Cardiac Randomized Evaluation of Antidepressant and Psychotherapy Efficacy (CREATE) Trial focused on patients with CAD and depression [119]. Based on these and other studies of single modalities, the strongest evidence from RCTs supports the use of behavioral treatments – especially CBT, care coordination, and cardiac rehabilitation/exercise combined with pharmacotherapy – together with pharmacotherapy to treat psychological health [105]. Still, there is a paucity of evidence that psychological treatment can prevent IHD overall, including insufficient data from women. Regrettably, many RCTs have small sample sizes and included a low proportion of women and minorities, and the subsequent meta-analyses have often neglected to (or been unable to) report sex-stratified findings [120–123]. Thus, it remains unknown if a given behavioral and/or pharmacological intervention is effective in dually addressing psychological health and IHD risk, and if effects differ by sex. Rigorous trials that dually prioritize both the recruitment of women from diverse racial, ethnic, and socioeconomic backgrounds, and sex-specific reporting of results are needed [111]. To guide these efforts, results from earlier trials must be explored for women and men separately.

The proposed pathophysiological mechanisms that underlie psychological-IHD associations among adults include both behavioral and biological pathways, and sex differences in these pathways have previously been reviewed in depth [54, 124–127]. To summarize, psychological health can influence cardiovascular risk via cardiometabolic metrics and related behaviors (e.g., blood pressure, diet, exercise, sleep, smoking, obesity, adherence), immune system regulation and inflammatory responses, the autonomic nervous system and neuroendocrine system, platelet aggregation and endothelial function, and genetic factors [54]. Among these systems, three mechanistic pathways are notable. First, negative psychological factors may alter primary stress-responsive systems – the hypothalamic-pituitary-adrenal (HPA) axis, sympathetic-adrenal-medullary (SAM) system, and sympathetic nervous system (SNS) – provoking subsequent changes in blood pressure, lipid, and glucose regulation, which can then promote atherosclerosis [128]. In a second pathway, women’s psychological risk profile may promote vulnerability to abnormal coronary vasomotion and microvascular disease [129]. Women are more likely to show MSIMI and other distinct physiological changes in response to mental stress [10, 38, 39], which may directly lead to epicardial and microcirculatory dysfunction. Third, women’s psychological health may affect their IHD risk via estrogen regulation. Estrogen protects against atherosclerosis by regulating lipid levels, promoting endothelium dependent vasodilation, enhancing bioavailability of nitric oxide from endothelial cells, and contributing to beneficial hemostatic effects [130]. Conversely, circulating estrogens can promote inflammation to a greater extent among women [126]. Women who experience significant psychosocial stress and other psychological health concerns show changes in estrogen physiology – e.g., ovarian dysfunction and hypoestrogenism [130]. Other emerging cardiovascular risk factors for women include age at menarche; polycystic ovarian syndrome; pregnancy-related factors (e.g., parity, gravidity, and infertility) and conditions of pregnancy (e.g., hypertensive disorders of pregnancy and gestational diabetes); menopause and related symptoms; and autoimmune conditions [131, 132]. Ultimately, this knowledge base evokes more questions than answers about the mechanisms linking women’s psychological health with risk for IHD and further large scale investigations are essential to describe the multisystem biological and behavioral mechanisms specific to women.

To optimally assess and support IHD prevention for women, in line with the American Heart Association’s ‘Life’s Essential 8’ approach [3] – i.e., addressing diet, physical activity, sleep, nicotine exposure, weight, blood pressure, lipids, and glucose – equal attention should be paid to a ninth domain – addressing psychological health [2] (see Figure 1).

Primordial and primary IHD prevention could begin in adolescence and young adulthood, when psychological health concerns become more common for younger women versus their male peers [133, 134], and include education about psychological symptoms and awareness along with risk factors for future IHD. Throughout younger, middle, and late adulthood women’s psychological health could then be addressed in concert with CVH, guided by a biological and biographical framework that includes a woman’s family history, lived experiences and current social circumstances, menstrual history, pregnancy, menopause, and changes due to aging [135, 136].

An initial step to address women’s psychological health in IHD prevention and management across their healthspan involves routine and uniform screening, particularly for negative psychological factors – psychosocial stress, depression, anxiety, trauma or PTSD, social isolation or loneliness, or anger [137]. Notably, since 2002 the U.S. Preventive Service Task Force has highlighted the burden of depression in health and healthcare and the importance of depression screening among all adults [138]. More recently, the USPSTF recommended separate screening for anxiety [139]. Although depression and anxiety disproportionately affect women in general and those with IHD [49, 51, 58], regrettably this care remains the exception in cardiovascular medicine rather than the norm. Consideration of positive psychological attributes – happiness, meaning, and purpose – is also valuable for conceptualizing women’s IHD risk profile, factors affecting their motivation and confidence in IHD risk factor management, or adherence to treatment plans [112, 113]; women who show greater psychological well-being are more likely to engage in healthy lifestyle behaviors and are better equipped to manage stressful life events [2]. Brief, validated screeners are available to efficiently assess psychological health among women and their results are associated with IHD incidence and outcomes [73, 137]. Some of the most well-known measures include the 4- or 10-item Perceived Stress Scale [140]; the Patient Health Questionnaire (PHQ-2 or PHQ-9) or the National Institutes of Health’s (NIH) Patient-Reported Outcomes Measurement Information System (PROMIS^®) 4-item measure for depression [141, 142]; the Generalized Anxiety Disorder measure (GAD-2 or GAD-7) or the 4-item PROMIS screener for anxiety [142, 143]; the 8-item Short Post-Traumatic Stress Disorder Rating Interview (SPRINT) [144]; the NIH Toolbox 5-item Loneliness Measure [145]; the 5-item PROMIS Emotional Distress/Anger measure [142]; and the NIH Toolbox’s 5-item General Life Satisfaction or 4-item Meaning and Purpose measures [145].

While there is no clinical biomarker of psychological distress or well-being, using screeners can prompt discussion, referrals, and interventions to aid and mitigate women’s psychological symptoms, efforts that may directly or indirectly improve inflammation and autonomic nervous system regulation, and can then have salutary CVH benefits (e.g., lower blood pressure; better endothelial function) [54, 93, 128]. Symptoms that meet diagnostic criteria for a psychiatric disorder should prompt referral to a behavioral medicine or mental health provider, or to a multidisciplinary integrated prevention team that holistically manages CVH – ideally including a clinician with behavioral health expertise. A whole-person care approach can help patients and providers alike to draw connections between psychological health, cardiovascular risk factors, and anginal symptoms – with attention to underlying genetic, biological, and sociocultural factors that may be sex-specific. As a standard of care, shared decision making should be used to balance any tradeoffs in treatment for psychological health with IHD risk management for women [146, 147].

In addition to regular screening for psychological health, specific milestones in a woman’s development should prompt discussion of psychological health in relation to CVD risk and management. For example, a diagnosis of polycystic ovarian syndrome or premature menopause – both risk factors for IHD [148, 149] – can be associated with depression, anxiety, and psychosocial stress [150, 151]. As another example, assessing psychological health in the pre-, ante-, and postpartum periods is helpful to identify and address postpartum stress, depression, anxiety, or PTSD and may help to support healthy lifestyle behaviors throughout adjustment to parenthood and the childbearing years [152]. Women with lower symptoms of antepartum depression are more likely to exercise regularly and throughout pregnancy and have a lower risk for hypertensive disorders of pregnancy [153, 154]. Reciprocally, women who experience hypertension, preeclampsia, or eclampsia are also at risk for postpartum depression, adverse pregnancy outcomes, and future cardiovascular events [155, 156]. Thus, a hypertension diagnosis should flag an in-depth assessment of cardiovascular risk including psychological health. In the menopausal years, hormonal shifts can dually promote vulnerability to psychological distress and cardiovascular instability [157, 158]. Blood pressure and cholesterol increase in women, and there is an emergence of endothelial and microvascular dysfunction [159]. How these biological shifts share common pathways with psychological health, or how psychological health and CVH interact with one another, is likely complex [41, 129, 160]. Addressing both factors simultaneously is important for managing new cardiovascular risk factors and symptoms and to support psychological wellbeing through this transitional period. Finally, as women age, there is a higher risk for IHD, as well as diastolic dysfunction complicated by heart failure, and atrial fibrillation [161–163]. Women tend to live longer than men and may find themselves at an increased risk for social isolation [164]. This experience may limit physical activity and social support, increase sedentary time, and lead to symptoms of depression and loneliness. Thus, there are ample, obvious opportunities for assessing and managing psychological health in tandem with IHD to provide more holistic cardiovascular care and to preserve CVH for women.