Role of a Heart Center for Women in the Prevention and Diagnosis of Atherosclerotic Cardiovascular Disease in Women

Abstract

There are sex differences in how atherosclerotic cardiovascular disease (ASCVD) manifests and progresses. Appropriate management requires not only recognition of sex‐based clinical differences but in the social disparities may influence outcomes. The establishment of heart centers for women emerged as a response to the escalating deaths in women from cardiovascular disease from 1984 to 2000. Since then, studies have provided further insights into sex differences in ASCVD management. Preventing ASCVD remains crucial in reducing morbidity and death from cardiovascular events in women. Heart centers for women play a crucial role in managing ASCVD in women, with health care professionals at the forefront of this effort. This article summarizes the most current guideline‐supported therapies and diagnostic tools essential for preventing and treating ASCVD in women. It also emphasizes the critical importance of acknowledging social determinants of health, fostering empathy and understanding among health care professionals, and asserts that increasing women's participation in cardiovascular trials is vital for advancing research and improving outcomes.

Nonstandard Abbreviations and Acronyms

AHA

American Heart Association

CFR

coronary flow reserve

CMD

coronary microvascular dysfunction

CVH

cardiovascular health

GLP‐1RA

glucagon‐like peptide‐1 receptor agonists

HCW

heart center for women

HOPE

Heart Outcomes in Pregnancy Expectations

IHD

ischemic heart disease

MACE

major adverse cardiovascular event

NCDR

National Cardiovascular Data Registry

RECHARGE

Revascularization, Choices, Among Underrepresented Groups Evaluation

SURMOUNT

Surveillance of a New Product for Weight Management

WISE

Women's Ischemia Syndrome Evaluation

The year 2000 marked a significant turning point in the history of cardiovascular disease (CVD) in women. The Women's Health Initiative Study revealed increased cardiovascular events in older postmenopausal women undergoing oral hormone replacement therapy. ¹ This study prompted a reevaluation of hormone replacement therapy and inspired a shift toward sex‐sensitive approaches in cardiovascular care. Subsequent initiatives by various medical organizations and clinicians led to a remarkable decline in CVD death in women from 2000 to 2010 (Figure 1). ¹ , ² Since 2012, the CVD mortality rate has been lower in women than in men, a testament to the concerted efforts of many health care organizations and providers. However, the recent rise in CVD deaths since 2010 in both women and men, as depicted in Figure 1, underscores the ongoing need for efforts to prevent atherosclerotic coronary artery disease (CAD). ²

Figure 1. CVD mortality trends in US men and women, 1980 to 2022. ² .

CVD excludes congenital cardiovascular defects (ICD‐10 codes 100–199). The overall comparability for CVD between ICD‐9 (1979–1988) and ICD‐10 (1999–2015) is 0.9962. No comparability ratios were applied. CVD indicates cardiovascular disease; ICD‐9, International Classification of Diseases, Ninth Revision; and ICD‐10, International Classification of Diseases, Tenth Revision.

To elevate the standard of care for women with atherosclerotic CVD (ASCVD), researchers have delved into the critical differences in CVD related to sex, igniting a powerful call to action. Between 1996 and 2016, the presence of female authors in cardiology journals saw a remarkable increase, signaling a shift toward inclusivity in the field. The majority of these groundbreaking publications center on the nuances of sex differences in CVD and the tailored management of cardiovascular conditions affecting women, underscoring the importance of sex‐sensitive approaches in health care. ³ Heart centers for women (HCWs) must stay current and consistently implement the latest guideline‐directed medical therapies, as these guidelines have been proven effective in reducing cardiovascular events. ⁴

The establishment of HCWs emerged as a response to the escalating deaths from CVD in women from 1984 to 2000 (Figure 1). ² Since then, data have evolved, and more recent studies have provided further insights into sex differences in ischemic heart disease (IHD) management. HCWs play a crucial role in managing IHD in women, with health care professionals at the forefront of this effort. ⁵ Acknowledging the importance of closing the gap in mortality rate between the sexes, the American College of Cardiology website now has a toolkit on how to start a women's heart program. ⁶ This article will examine the primary and secondary prevention of atherosclerosis, a vital aspect of improving ASCVD outcomes in women, and the integral role of HCWs in preventing and diagnosing ASCVD. Additionally, this article summarizes the most current therapies and diagnostic tools essential for preventing and diagnosing IHD in women (Figure 2). It also emphasizes the critical importance of acknowledging social determinants of health, fostering empathy and understanding among health care professionals, and asserts that increasing women's participation in cardiovascular trials is vital for advancing research and improving outcomes.

Figure 2. Prevention and diagnosis of ischemic heart disease—the role of a heart center for women.

AHA indicates American Heart Association; apoB, apolipoprotein B; CT, computed tomography; DASH, Dietary Approaches to Stop Hypertension; GIP, Glucose‐dependent insulinotropic polypeptide; GLP1‐RA, glucagon‐like peptide‐1 receptor agonists; hsCRP, high‐sensitivity C‐reactive protein; MEPA, Mediterranean Eating Pattern for Americans; MRI, magnetic resonance imaging; SGLT2is, sodium–glucose cotransporter 2 inhibitors; PET, positron emission tomography; and SDOH, social determinants of health.

Risk Factors for ASCVD

Lipids and Blood Pressure

Maintaining lipid levels and blood pressure within a recommended range is a cornerstone of CAD prevention and constitutes a class I recommendation in the American College of Cardiology/American Heart Association (AHA) guidelines. ⁷ , ⁸ , ⁹ This is especially important for women, as several, often unacknowledged, risk enhancers exist for this population, including a history of premature menopause (before age 40 years) and pregnancy‐associated conditions such as preeclampsia, as well as chronic inflammatory conditions like lupus and rheumatoid arthritis, which have a higher prevalence in women, and enhance the risk of ASCVD. Additionally, emerging biomarkers for premature CAD include high‐sensitivity C‐reactive protein, lipoprotein(a), and apolipoprotein B, can be incorporated into the workup for women who fit the appropriate screening profile identified by providers. ⁸

With respect to the management of cholesterol, many of the medical interventions for these conditions are poorly tolerated by women. While few trials have specifically reported statin‐induced adverse effects by sex, women are more likely to report experiencing muscle symptoms and discontinue therapy compared with men. ¹⁰ Strategies to manage these side effects include a thorough review of concomitant medications for potential drug interactions are needed. Table 1, ¹¹ , ¹² , ¹³ , ¹⁴ , ¹⁵ , ¹⁶ lists other lipid‐lowering medications that can help reduce low‐density lipoprotein cholesterol to the target level, based on the patient's risk, which can be added or used in place of statins. The mechanism of action and the percentage of women in each study are included. In the context of an HCW, doctors, pharmacists, and nutritionists can educate patients on these medications and their alternatives when first‐line therapy is poorly tolerated. While patients may otherwise forgo medication, resulting in noncompliance and ongoing uncontrolled cholesterol, a comprehensive team that can educate and counsel women may improve compliance with lipid‐lowering medication.

Table 1.

Nonstatin Lipid‐Lowering Agents

Medication	Mechanism of action	LDL reduction, %	Women studied in RCT, %
Ezetimibe	Inhibits cholesterol from being absorbed into enterocytes via the Niemann–Pick C1–like‐1 protein, leading to a reduction of decrease of transporting cholesterol to the liver and increased clearance of cholesterol from the blood	20–25	24.3 IMPROVE‐IT trial (Cannon, 2015) 11
Bempedoic acid	ATP citrate lyase inhibitor that targets cholesterol synthesis upstream of HMG‐CoA reductase. Like statins, it reduces hepatic cholesterol synthesis and raises LDL receptor expression, thereby increasing the clearance of LDL cholesterol from the circulation	24.5	48.2 CLEAR trial (Nissen, 2023) 16
Bempedoic acid and ezetimibe	Bempedoic acid and ezetimibe work synergistically; bempedoic acid reduces cholesterol synthesis, and ezetimibe reduces cholesterol absorption from the intestines	28.5	61.6 CLEAR Tranquility trial (Ballantyne, 2018) 14
PCSK9 inhibitors
Evolocumab	A fully humanized monoclonal antibody that targets and inhibits PCSK9 directly results in increased LDL receptor recycling in the liver and enhanced clearance of LDL cholesterol	45–65	24.5 FOURIER trial (Sabatine, 2017) 13
Alirocumab			37.8 ODYSSEY LONG TERM trial (Robinson, 2015) 12
Inclisiran	Small interfering RNA that inhibits the production of PCSK9 protein that targets PCSK9 mRNA, preventing the translation into PCSK9 protein	50	30.6 ORION‐11 trial (Ray, 2022) 15

CLEAR Tranquility Trial indicates evaluation of the efficacy and safety of bempedoic acid (ETC‐1002) as add‐on to ezetimibe therapy in patients with elevated LDL‐C; CLEAR trial, evaluation of major cardiovascular events in participants with, or at high risk for, cardiovascular disease who are statin intolerant treated with bempedoic acid; FOURIER trial, further cardiovascular outcomes research with PCSK9 Inhibition in subjects with elevated risk; HMG‐CoA, 3‐hydroxy‐3‐methylglutaryl coenzyme A; IMPROVE‐IT trial, improved reduction of outcomes: Vtyurin efficacy international trial; LDL, low‐density lipoprotein; ODYSSEY LONG TERM Trial, long‐term safety and tolerability of alirocumab versus placebo on top of lipid‐modifying therapy in high cardiovascular risk patients with hypercholesterolemia; ORION‐11 Trial, inclisiran for subjects with ASCVD or ASCVD‐risk equivalents and elevated low‐density lipoprotein cholesterol; PCSK9, proprotein convertase subtilisin/kexin type 9; and RCT, randomized controlled trial.

Similarly, women may be more prone to specific side effects from antihypertensive medications. Women tend to experience a higher incidence of angiotensin‐converting enzyme inhibitor–induced cough, edema with calcium channel blockers, and electrolyte imbalances such as hypokalemia and hyponatremia with diuretics. ¹⁷ , ¹⁸ For instance, thiazide diuretics may offer particular benefits for older women due to their ability to reduce calcium excretion, which can help prevent osteoporosis. ¹⁹ Recognizing the need for close follow‐up, monitoring and counseling may keep patients compliant with the appropriate medications for their tailored treatment.

Cigarette Smoking

Tobacco use is increasing in women worldwide. ²⁰ While the morbidity and mortality risks of smoking are well established in both sexes, a meta‐analysis of 2.4 million participants who smoke cigarettes showed a 25% increase in CAD risk in women compared with men. ²¹ Secondhand exposure is also seen at higher rates in nonsmoking women and lower socioeconomic groups. ²² HCWs are in a unique position to provide social counseling for patients to optimize CAD prevention and monitor closely for symptoms of CAD and its comorbidities, such as hypertension.

Sleep

Disparities in sleep health are multifactorial and include socioeconomic factors, job demands, and health care access, highlighting the need for equitable interventions. Sex‐specific differences also underscore the importance of targeted sleep health policies. Future research can leverage machine learning and wearable technology to improve sleep tracking and assessment. ²³

Importantly for women, menopause can negatively impact sleep and put women at risk for developing obstructive sleep apnea. Again, there are notable differences in symptom presentation of obstructive sleep apnea between sexes; men often report more severe daytime sleepiness, while women may experience subtler symptoms such as insomnia and fatigue. This disparity can sometimes lead to underdiagnosis in women. Additionally, weight gain of 10%, which is common with metabolism change during menopause, is associated with a 32% increase in obstructive sleep apnea severity. ²⁴ Importantly, the high association between obstructive sleep apnea, obesity, and heart failure with preserved ejection fraction make the expedient diagnosis and management of this condition particularly relevant to cardiac care in women. The incorporation of nutritionists and specialized pharmacists to help with weight management is discussed later in this article.

Dietary Assessment

The AHA currently recommends the use of Mediterranean‐style dietary patterns to monitor individual diet quality on the basis of large randomized trials that demonstrate an association with a reduction in vascular events. ²⁵ , ²⁶ With the help of a nutritionist, HCWs are able to educate patients on guideline‐recommended diets (Table 2). While further research is needed to determine whether and which dietary patterns may be ideal for women at various stages of life, it is notable that the now validated dietary screener tool recommended by the 2022 Presidential Advisory Committee, known as the Mediterranean Eating Pattern for Americans Screener was developed and tested by the Rush HCW in partnership with the Rush Department of Clinical Nutrition. ²⁷

Table 2.

Comparison of DASH, Healthy Eating Index, and Mediterranean Dietary Patterns

Category	DASH diet pattern	Healthy Eating Index	Mediterranean eating pattern
Primary or original goal	Lower blood pressure	Adhere to US dietary guidelines	Promotes heart health, weight management, and longevity
Fruits	4–5 servings/d (fresh, frozen, or canned without added sugar)	2 servings/d (varies by age/sex)	2–3 servings/d (a variety of fresh, seasonal fruits)
Vegetables	4–5 servings/d	3 servings/d(varies by age/sex)	3–4 servings/d
Grains	6–8 servings/d (preferably whole grains)	6 servings/d (half should be whole grains)	4–6 servings/d (whole grains such as barley, oats, and whole wheat)
Dairy Low‐fat or fat‐free	2–3 servings/d	2–3 servings/d	Limited to moderate intake (include fermented dairy, eg, yogurt)
Protein (lean meats, poultry, fish)	≤2 servings/d	2–3 servings/d (includes eggs, plant proteins)	2–3 servings/wk (fish, shellfish, plant‐based proteins) with poultry/lean meats in moderation
Nuts, seeds, and legumes	4–5 servings/wk	Incorporated as part of a varied plant protein source	4–5 servings/wk (focus on nuts, seeds, and legumes as plant‐based protein sources)
Fat	Emphasizes healthy fats (eg, olive oil, nuts, seeds)	Limits saturated fats, with a focus on healthy fats from plants	Emphasizes healthy fats, extra virgin olive oil
Sodium	Limits sodium to 1500–2300 mg/d	Limits sodium to ≤1.1 g/1000 calories based on the 2300 mg limit	Very low sodium intake, with emphasis on fresh, local ingredients
Added sugars	Limits added sugars to <5% of total daily calories	Limits added sugars to <10% of total daily calories	Limits added sugars, with a preference for natural sweeteners (eg, honey)
Alcohol	Moderate consumption, if any (up to 1 drink/d for women, 2 for men)	Moderation encouraged, aligned with general dietary guidelines	1–2 servings/d (primarily wine, often consumed with meals) but may be adjusted on the basis of new study findings
Calcium	Higher calcium intake encouraged through dairy or fortified foods	Adequate calcium intake is recommended but not specifically emphasized	Adequate calcium from dairy (mainly cheese and yogurt) and plant‐based sources
Saturated fats	<6% of total calories	<10% of total calories from saturated fats	<8%–10% of total calories from saturated fats (focus on monounsaturated fats)
Whole grains	Emphasis on whole grains over refined grains	Emphasizes whole grains, consistent with general dietary guidelines	Emphasis on whole grains like barley, brown rice, and whole wheat
Legumes	Emphasized as a source of protein and fiber	Often included as part of a varied diet, focusing on plant proteins	Emphasizes legumes (lentils, chickpeas, beans) as a primary protein source
Processed foods	Limits processed foods, especially those high in sugar and fat	Discourages processed foods high in sugar, sodium, and unhealthy fats	Minimizes processed foods, prioritizing fresh, seasonal, and local ingredients

DASH indicates Dietary Approaches to Stop Hypertension.

Dietary screeners are rapid tools that can quickly identify individuals with poor diet quality who would benefit from dietary counseling to promote cardiovascular health (CVH). These tools are frequently used during HCW visits. The brief screener contains 16 questions about the daily or weekly frequency of intake of 9 different foods/food groups beneficial to one's health and 6 components to limit (Figure 3). ²⁸ The total score can be used to assess diet quality across health care settings in adult and pediatric populations; the higher the score, the better the diet quality (Figure 4A–4C). The Mediterranean Eating Pattern for Americans screener can be administered in person or remotely across diverse populations and is available in the Research Electronic Data Capture shared library with patients scoring ≤8 referred to a registered dietitian for medical nutrition therapy. ²⁸ Ideally, patients should be screened regularly and engaged in diet behaviors that should be measurable and tracked over time.

Figure 3. Mediterranean Eating Pattern for Americans Screener. ²⁸ .

Figure 4. MEPA Screener scoring and annual screen for assessing a patient's diet.

A, MEPA annual screen for assessing a patient's diet; B, Quantification of CVH metric: adults (aged ≥20 years) for MEPA Screener; C, MEPA Screener scoring. CVH indicates cardiovascular health; and MEPA, Mediterranean Eating Pattern for Americans.

Nutrition intervention is an integral component of a proactive approach to establishing and maintaining healthy eating habits, which have been consistently shown to improve CVH. ²⁹ HCWs should include registered dietitian nutritionists who can guide patients in discerning between healthy and unhealthy components of their meal patterns while recognizing culturally specific foods, identifying food insecurity, and using valid brief tools as part of the CVH metric (Figure 2).

Physical Activity Coaching

Differences in exercise physiology among men and women influence each sex's risk for CVD. A study found that women derived greater gains in all‐cause and cardiovascular death with equivalent and fewer weekly minutes of physical activity. ³⁰ While men reached their maximum survival benefit at 300 min/wk, women achieved similar benefits at 140 min/wk. This benefit continued to improve as women approached 300 min/wk. However, despite this advantage, women surveyed found the time commitment to exercise much more challenging due to their multiple roles, including jobs, family responsibilities, and caring for older parents. ³¹

Various forms of exercise have demonstrated preventative benefits for women, including aerobic and strength training. Muscle strength is vital for a more robust metabolism, achieving a healthier cardiovascular level, and protecting the skeletal system, especially as women age and are more prone to becoming frail. ³² High‐intensity interval training is a specific form of aerobic exercise that women find desirable, given its shorter time requirements, while achieving impactful results. ³³

Meditation, yoga, and traditional Chinese exercise have become increasingly popular worldwide due to their gentle movements, low risk, ease of training, and long‐term adherence. ³⁴ Traditional Chinese exercise specifically combines spiritual meditation with moderate postures, musculoskeletal stretching, and deep breathing, making it a gentle yet effective muscle‐strengthening practice.

Given that inactivity and obesity are increasingly common risk factors, the benefits of regular physical activity are especially important to emphasize when managing female patients. Dietitians advise patients to incorporate physical activity as part of their consultation with an HCW.

Impact of Sex and Social Determinants of Health in CAD

Health‐related behaviors, socioeconomic status, and environmental influences, also known as social determinants of health, account for 80% to 90% of health outcomes. ³⁵ It follows that recognizing how these factors influence a patient's health may improve compliance and overall care for women. ³⁶

Sex biases in health care also manifest in treatment disparities. Female physicians are more likely to intensify therapies for hypertension and hyperlipidemia in female patients. ³⁷ Women are less likely to receive aggressive treatment for cardiovascular conditions compared with men. Studies have shown that women are referred to cardiac rehabilitation programs at significantly lower rates, ≈39.6% compared with 60% for men. ³⁸ Notably, women are also underrepresented in clinical trials, leading to insufficient data on treatment effects for them. ³⁹

Environmental factors, such as exposure to violence and socioeconomic barriers, further influence CVD risk. For example, women experiencing intimate partner violence have a 31% increased risk of developing later CVD. ⁴⁰ Women also delay seeking medical attention compared with men in response to cardiovascular symptoms. ⁴¹ One study found that women took longer to arrive at the hospital for acute myocardial infarction, with average delays ranging from 1.8 to 7.2 hours compared with 1.4 to 3.5 hours for men. When interviewed, factors like feeling dismissed by male health care providers contribute to this reluctance. ⁴⁰

HCWs aim to provide a comprehensive team including social workers, translators, psychologists, psychiatrists, and specialty pharmacists, who can all help patients with psychological, financial, and personal situations. ⁵

Specialized Care in Diabetes and Obesity

While the link between diabetes and CVD has been well established, it has only recently been demonstrated that several medications traditionally indicated for obesity have cardioprotective properties. This advancement in CVD management is especially relevant to the cardiovascular care of women, as diabetes is a more potent risk factor for CVD and worse outcomes in women than in men. ⁴²

Semaglutide, dulaglutide, and liraglutide (all glucagon‐like peptide‐1 receptor agonists [GLP‐1RAs]) have all shown positive outcomes in managing CVD in patients with diabetes. ⁴³ Based on the current data, expert consensus recommends that a GLP‐1RA be considered for patients who are overweight or obese with a history of CVD and that it be prioritized in patients with type 2 diabetes and an elevated risk of CVD, regardless of glycosylated hemoglobin level or current diabetes therapies, including metformin. For patients with diabetes with hypoglycemia and low or normal glycosylated hemoglobin, the 2023 European Society of Cardiology guidelines still recommend GLP‐1RAs irrespective of metformin therapy, and recommend considering the removal of other diabetic medications to initiate GLP‐1RA to reduce the risk of CVD. ⁴⁴

Tirzepatide, a dual agonist of both GLP‐1 and glucose‐dependent nsulinotropic polypeptide receptors, is an important addition to the current fleet of obesity medications. It is unique in that, in addition to its action on the GLP‐1 receptor, its mechanism of action includes activation of glucose‐dependent nsulinotropic polypeptide receptors in the brain, which is proposed to mediate satiety and peripheral glucose metabolism. The SURMOUNT (Surveillance of a New Product for Weight Management) trial demonstrated a 20% net weight loss with tirzepatide in patients with obesity at all doses over a 72‐week study period. Notably, the majority of participants in this trial were women (71%) with 3‐year follow‐up demonstrating a markedly lower risk of progression to type 2 diabetes. ⁴⁵

Access to these medications and their side effects poses challenges. Multidisciplinary care involving various health care providers is necessary. Future directions include conducting additional trials to further understand the long‐term benefits and safety of GLP‐1RAs and dual GLP‐1/glucose‐dependent nsulinotropic polypeptide agonists in the prevention of CVD in women. A multidisciplinary approach to the administration and monitoring of these drugs is necessary and should involve physicians, nurses, advanced practice providers, specialty pharmacists, nutritionists, and physical therapists.

Specialized Care in Pregnancy

Ideally, a cardio‐obstetrics team can provide comprehensive care for women with ASCVD risk factors to assess the patient's maternal cardiovascular risk, obstetric and fetal risks, and outcomes. Counseling on cardiac medication safety throughout the pregnancy and lactation phases in women with diabetes, high blood pressure, and lipids is a foundational aim of the HCW. The cardio‐obstetrics team can provide a network of referrals to include obstetricians, maternal–fetal medicine specialists, anesthesiologists, geneticists, neurologists, nurses, and pharmacists, who can develop a comprehensive strategy for management of CVD during all phases of the pregnancy. ⁴⁶

Pregnancy is a particularly vulnerable time for a woman's CVH, as many first‐line medications for cardiac prevention have been contraindicated during pregnancy. In an effort to continue CVD management in this population, in 2021, the US Food and Drug Administration removed a previous warning about using statins during pregnancy to allow providers to consider use in pregnant women who are at high risk for severe cardiovascular events, including familial hypercholesterolemia and prior ASCVD. ⁴⁷ Pravastatin, in particular, has been postulated to increase uterine blood flow and has been studied in the prevention of preeclampsia. A trial of 1120 patients showed no difference in delivery rates, incidence of preeclampsia, gestational hypertension, or neonatal morbidity with its ongoing use during pregnancy. ⁴⁸

The 2017 American College of Cardiology/AHA hypertension guidelines do not suggest any differences in blood pressure thresholds or antihypertensive management of men and women, except during pregnancy. ⁹ According to data from the Registry of Pregnancy and Cardiac Disease, pregnant women, or those planning to become pregnant, should avoid angiotensin‐converting enzyme inhibitors and angiotensin receptor blockers due to an increased risk of congenital anomalies in the first trimester. ⁴⁹ More safety data are found with nifedipine and labetalol. There are limited but acceptable safety data on hydralazine, hydrochlorothiazide, clonidine, and nitroglycerin. ⁵⁰

Adverse pregnancy outcomes are risk enhancers for CVD, and postpartum care for women with these complications is discussed in the following sections. ⁸

Tailored Coronary Artery Assessment

Coronary Artery Calcification

To increase early diagnosis of CAD in women, the medical community has started to focus on CVD risk factors that present earlier in women and may provide an opportunity to prevent or identify disease in its early stages. Currently, the ASCVD risk score and the coronary artery calcification (CAC) score are 2 widely used tools for predicting cardiovascular events, each with its advantages and limitations. ⁵¹ The ASCVD risk calculator assesses a patient's 10‐year risk of cardiovascular events on the basis of traditional risk factors, including sex, blood pressure, diabetes, and cholesterol levels. The ASCVD risk score is recommended for adults aged 40 to 75 years who do not already have CAD and are not on statin therapy but may benefit from primary prevention. While the score is not specific to women, the calculator is beneficial in identifying risk factors that often affect women disproportionately, such as high blood pressure and diabetes. ⁴² The Predicting Risk of Cardiovascular Disease EVENTs calculator, which incorporates both a 10‐ and 30‐year risk of CVD is another recently validated tool supported by the AHA ⁵² but has not yet been incorporated into screening guidelines.

The CAC score measures calcium deposits in the coronary arteries using computed tomography imaging. ⁵³ CAC can be used in conjunction with the ASCVD score to further enhance cardiovascular assessment. A CAC score is typically not recommended for low‐risk patients (ASCVD score of ≤5%) but may be useful in young, asymptomatic adults with severely elevated traditional risk factors.

For patients with an ASCVD risk score in the intermediate‐risk range (7.5%–20%), adding CAC testing may offer additional insight in recategorizing a patient's ASCVD risk. ⁵⁴ A CAC score of >100 or in the 75th percentile or higher, indicates an elevated risk of a major adverse cardiovascular event, enforcing the importance of initiating statin therapy. A CAC score of ≥300 carries similar risks to those seen in patients with established cardiovascular conditions, warranting management strategies as recommended for secondary prevention. ⁵⁵

While the CAC and ASCVD scores are useful tools for assessing cardiovascular risks, they do not fully account for sex‐specific factors beyond traditional risk indicators. When using CAC scoring and ASCVD calculators for women, adopting a holistic and life‐stage approach for optimal risk assessment is valuable. CAC scoring is generally not useful in young women because early‐stage atherosclerosis may not exhibit calcification. Computed tomographic angiography is more useful in detecting noncalcified atherosclerotic plaque. As a result, CAC scoring may overlook early atherosclerotic changes that could still progress into clinically significant CVD later in life. ⁵⁶

Similarly, the 10‐year ASCVD risk score's effectiveness is limited for younger women, as it is most accurate for individuals aged 40 to 79 years. ⁵⁶ This age focus can result in an underestimation of risk in younger women, particularly those with additional risk factors, autoimmune diseases, and elevated lipoprotein(a), which may elevate cardiovascular risk outside of traditional metrics. ⁵⁷

In the childbearing years, pregnancy complications like gestational hypertension or preeclampsia elevate future cardiovascular risks, as these conditions often lead to early subclinical cardiovascular changes. ⁵⁸ However, the ASCVD risk calculator may underestimate the cardiovascular risk in women in this population as the calculator does not include pregnancy‐related complications. ⁵⁹ These additional risk factors are incorporated into the most current American College of Cardiology/AHA lipid guidelines as risk enhancers, but formal risk assessment tools have not yet adopted them in their assessment. ⁸

Given the limitations of risk assessment in women, and since CAC and ASCVD scores do not fully capture cardiovascular risk in women, a history of sex‐specific risk factors may be better‐assessed in a HCW. In the future, including additional risk factors, such as pregnancy complications, early menopause, autoimmune conditions, and family history of early CVD, may enhance accuracy, which can guide clinician–patient discussions globally. Using a tailored, life‐stage approach enables the early identification and implementation of prevention strategies that align with each woman's unique CVH needs.

Breast Artery Calcifications

Breast arterial calcifications, calcium deposits in breast arteries often incidentally detected on routine mammography, may be used as a surrogate marker of systemic vascular disease in women. Multiple studies have shown a strong correlation between breast arterial calcifications and CAD. ⁶⁰ Recognizing breast arterial calcifications as a potential opportunity to identify patients who are at elevated cardiovascular risk early can enable clinicians to implement proactive, preventative strategies such as lifestyle intervention. This approach may significantly reduce the long‐term burden of cardiovascular events and better align with sex‐specific, personalized cardiovascular care for women. Further research, perhaps using machine learning to aid in the identification of high‐risk patients, is needed to validate using breast arterial calcifications as a reliable nontraditional risk marker within the current cardiovascular risk assessment framework. ⁶⁰

CAD Imaging

Cardiac imaging is an essential tool in the diagnosis and management of patients presenting with chest pain. Women often present differently with atypical symptoms and may have female‐specific risk factors such as autoimmune disorders, preterm delivery, gestational diabetes, pregnancy‐related hypertension, and persistence of weight gain after pregnancy. ⁶¹ The combination of overlooked cardiovascular risk factors and atypical presentation can lead to misdiagnosis and delay in therapy. ⁶²

Compared with men, women tend to have a lower incidence of obstructive CAD and a higher prevalence of ischemia with nonobstructive coronary arteries. ⁶¹ The term IHD is the more appropriate term to encompass all the pathophysiology responsible for ischemia in women, such as myocardial infarction or ischemia due to atherosclerotic disease, coronary microvascular dysfunction (CMD), coronary endothelial dysfunction, and coronary vasospasm, coronary embolization, and spontaneous CAD. ³⁶

CMD is common in both sexes and encompasses a spectrum of nonobstructive, nonepicardial diseases that include abnormalities in the structure or the function of the coronary microvasculature. Since two thirds of the coronary circulation is microvascular, there has been an increasing focus on this area. ⁶³

CMD and vasospasm of the epicardial arteries are the 2 most common causes of ischemia with nonobstructive coronary arteries. ⁶⁴ Initially thought to be benign, the WISE (Women's Ischemia Syndrome Evaluation) study demonstrated that despite the absence of obstructive CAD in a majority of these women, women with ischemia with nonobstructive coronary arteries had higher rates of major adverse cardiovascular events (MACEs), including death, nonfatal myocardial infarction, nonfatal stroke, and heart failure hospitalization compared with patients with normal coronary arteries. ⁶⁵

Patients with CMD have persistent anginal symptoms that affect their quality of life and lead to frequent emergency room and hospital visits, which, in turn, may lead to unnecessary testing and costs. Thus, early diagnosis of CMD and intervention are crucial to improving outcomes and costs. Several stress imaging tests can diagnose CMD, while invasive coronary angiography can help diagnose coronary vasospasm and differentiate endotypes of CMD.

Among patients with stable angina and no evidence of significant epicardial CAD, assessment for CMD or vasospasm improves quality of life and reduces angina by giving providers a paradigm for intervention. ⁶⁶ While previously these patients' symptoms may have been dismissed, increased recognition of CMD has provided diagnostic closure and expanded risk stratification for MACEs in women through the development of targeted treatment paradigms. Table 3 shows the different modalities and their abilities to assess CMD, coronary endothelial function, other cardiac pathologies, and their radiation exposure. ⁶⁷

Table 3.

Diagnostic Imaging Modalities in Ischemic Heart Disease

Mode and ability to assess	Epicardial ischemia	CMD: coronary endothelial‐independent dysfunction	CMD: coronary endothelial‐dependent dysfunction	Other cardiac pathologies	Radiation safety data||
CAC	No	No	No	Aortic aneurysm	0.4–2.1 mSv
Stress echocardiography	Yes	Yes*	No	Aortic dissection, pericarditis, stress cardiomyopathy	0
SPECT Stress Test	Yes	No	No	Left ventricular dysfunction, CAC	2.3–23 mSv
PET Stress Test	Yes	Yes	No	Left ventricular dysfunction, CAC	2–7 mSv
CMR Stress Test	Yes	Yes†	Yes‡	Myocarditis, pericarditis, and stress cardiomyopathy	0
CCTA	No§	No	No	Myocardial bridge, pericarditis, spontaneous CAD	0.5–30 mSv
Invasive coronary function testing	Yes	Yes	Yes	Coronary vasospasm, myocardial bridge, spontaneous CAD	2–20 mSv

CAC indicates coronary artery calcification; CAD, coronary artery dissection; CMD, coronary microvascular dysfunction; CMR, cardiac magnetic resonance imaging; CCTA, coronary computed tomography angiogram; and SPECT, single‐photon emission computed tomographyd.

^*There is a limited but validated role for stress echocardiography with stress ECG in the diagnosis of CMD.

^† Possible only with quantitative perfusion analysis.

^‡ There is a limited, but validated role for cardiac stress magnetic resonance imaging in the diagnosis of endothelial dysfunction.

^§ If done with perfusion, ischemia can be assessed.

^|| <1 mSv is considered safe for a single diagnostic test.

Stress Echocardiography

In the emergency department, point‐of‐care echocardiography can assess for wall motion abnormalities as well as alternative causes of acute chest pain, such as aortic dissection, pericarditis, and pulmonary embolism, and is the initial step in the diagnosis of stress cardiomyopathy, which has a 9:1 female‐to‐male preponderance, especially in postmenopausal women. ⁶⁸ In the setting of stable chest pain, stress echocardiography (either exercise or pharmacologic) is commonly used in the assessment of ischemia with reasonable sensitivity and specificity. ⁶⁹ There is a limited role of echocardiography in the assessment of coronary flow reserve to detect CMD. However, this has been conceptualized by Doppler assessment of left anterior descending artery flow by administering a vasodilator. ⁷⁰

Nuclear Stress Testing in Women

Nuclear stress testing has enhanced the diagnosis and prognostication of IHD in women. It is indicated in the evaluation of both stable chest pain and transient acute symptoms in those at intermediate risk for ASCVD after an acute coronary syndrome has been ruled out. ³⁶

While the classic exercise stress test provides valuable physiologic data, electrocardiographic changes with exercise are less specific for IHD in younger women since hormonal influences may cause false positive electrocardiographic changes. On the other hand, electrocardiographic changes may be the first sign of CMD in women in an otherwise normal stress echocardiogram test. Alternatively, pharmacologic stress (typically using regadenoson) may be used for ischemic risk assessment for obstructive CAD in those unable to achieve adequate physical exertion. This is particularly important for women with IHD, as they tend to present at older ages and often have more function‐limiting comorbidities compared with their male counterparts. ³⁶

While attenuation from breast soft tissue and smaller left ventricular size had once limited the specificity of nuclear stress testing for women, differences in test accuracy by sex have been eliminated by new advances in nuclear imaging technology. Attenuation correction, new single‐photon emission computed tomography camera technology, and the introduction of cardiac positron emission tomography (PET) myocardial perfusion imaging have improved spatial, contrast, and temporal resolution, resulting in improved diagnostic accuracy for female patients. ⁷¹ PET imaging offers distinct advantages, including lower radiation exposure, and the ability to quantify myocardial blood flow and flow reserve. ⁷²

PET Stress Testing

The ability of PET stress testing to quantify coronary flow and flow reserve makes it an ideal tool for assessing chest pain in women, as it has high accuracy for the noninvasive assessment of both obstructive CAD and CMD. Coronary flow reserve (CFR) is the ratio of coronary blood flow at maximal dilation in response to a vasodilator, compared with baseline. A CFR <2 on a stress PET has been shown to predict MACEs independently of clinical risk, left ventricular function, major regional perfusion defects, and the presence of coronary artery calcium. ⁶³ The chest pain guidelines recommend PET with CFR assessment for detecting suspected ischemia with nonobstructive coronary arteries. ³⁶

Stress Cardiac Magnetic Resonance Imaging

Stress perfusion cardiac magnetic resonance imaging (CMR) is a comprehensive, noninvasive imaging modality that provides detailed information on cardiac anatomy and function, tissue characterization, myocardial ischemia, and valvular function. In the setting of chest pain, CMR stress testing can be used to assess ischemia. The most established technique is first‐pass perfusion imaging of the myocardium before and after the administration of a vasodilator with the use of a gadolinium‐based contrast agent. Stress perfusion CMR is a reliable test with a sensitivity and specificity of 0.86 to 0.89 and 0.8 to 0.85, respectively. ⁷³ More recently, emerging techniques allow for the quantification of myocardial perfusion, which has improved the detection of myocardial ischemia and CMD. ⁷⁴

In addition, CMR can assess coronary endothelial function when performed with the isometric hand‐grip exercise, which is an endothelial‐dependent stressor. ⁷⁵ CMR is also useful for establishing alternative diagnoses for chest pain, such as myocarditis, pericarditis, and stress cardiomyopathy. Parametric mapping techniques allow for more accurate assessment of edema or inflammation, fibrosis, and scar. Furthermore, CMR is performed without radiation. ⁷⁶

Quantitative perfusion analysis in stress CMR is an emerging technique that, similar to PET, enables the quantification of myocardial blood flow and myocardial blood flow reserve. It can differentiate CMD from multivessel CAD. ⁷⁷ Quantitative perfusion in stress CMR has also demonstrated prognostic utility. Stress myocardial blood flow and myocardial perfusion reserve, as determined by quantitative stress CMR, are both independently associated with death and major adverse cardiovascular events. Stress CMR's advantages include added assessment of cardiac function, infarct, and viability. ⁷⁴

Computed Coronary Tomographic Angiography

Computed coronary tomographic angiography (CCTA) has emerged as a highly sensitive tool in detecting, characterizing, and quantifying coronary atherosclerotic plaques. Subsequently, the advent of computed tomography (CT)‐guided fractional flow reserve has significantly improved the specificity of CCTA in detecting functionally significant stenoses. ⁷⁸ CCTA is currently recognized by the current chest pain guidelines as a first‐line tool in low‐ to intermediate risk patients. ³⁶ Among women with stable chest pain, CCTA demonstrates superior prognostic power compared with functional stress testing. ⁷⁹ Furthermore, the use of CCTA among women has demonstrated shorter lengths of stay and lower hospitalization rates. ⁸⁰

CCTA has also been suggested for use in low‐risk patients with non–ST‐segment–elevation myocardial infarction and in type 2 myocardial infarction. ⁸¹ In the setting of spontaneous CAD, CCTA is a useful noninvasive tool in diagnosing dissection, especially in recurrent cases. ⁸² For the diagnosis of myocardial bridging, CCTA more readily characterizes the myocardial bridge severity compared with invasive angiography and is a more sensitive modality for diagnosis than invasive angiography and intravascular imaging. ⁸³

Additional utilities of CCTA include myocardial perfusion and assessment of myocardial flow reserve. Myocardial perfusion CCTA can be performed before and after administering a vasodilator (such as adenosine and regadenoson) with the administration of contrast during dynamic, retrospective ECG‐gated imaging over several cardiac cycles. In the absence of obstructive CAD, stress‐induced perfusion defects can indicate microvascular dysfunction. ⁸⁴

Recent advances in CT technology have allowed for additional techniques to emerge. Photon‐counting CT scanners have improved spatial resolution of 0.2 mm, which has allowed for more accurate assessment of calcified lesions, coronary stents, and spontaneous CAD. Both traditional dual‐energy CT scanners and photon counting CT scanners are able to generate iodine‐based image maps for the assessment of delayed enhancement as well as the calculation of extracellular volume. ⁸⁵ These are accomplished with an additional scan ≈5 to 7 minutes following contrast administration.

Invasive Coronary Function Testing

Invasive coronary function testing is the gold standard for diagnosing CMD and coronary artery vasospasm. Coronary function testing entails a diagnostic angiographic procedure to evaluate endothelial‐dependent and endothelial‐independent dysfunction and microvascular and macrovascular coronary spasm. Historically, a Doppler wire was used to assess intracoronary hemodynamics. However, the thermodilution method is now used more frequently. Following diagnostic angiography to exclude obstructive epicardial disease, CMD is diagnosed by injecting intracoronary adenosine, acetylcholine, and nitroglycerin to evaluate intracoronary hemodynamics, including CFR and index of microvascular resistance. Specialized CMD and vasomotor dysfunction HCW programs have been successful. Since women are the majority of patients with CMD, it is important for an HCW to have the capability to assess this noninvasively and if needed, invasively. ⁸⁶

In the setting of invasive coronary function testing, CFR represents the ratio of coronary blood flow at maximal dilation in response to intracoronary adenosine compared with baseline. The index of microvascular resistance, a derivation of Ohm's law, is calculated from the change in pressure across the microcirculation divided by flow. A CFR of <2.0 and an index of microvascular resistance of >25 indicate endothelial‐independent CMD. Low‐dose intracoronary acetylcholine is then injected to assess for endothelial‐dependent CMD or microvascular spasm. Transient narrowing of the epicardial arteries after injecting high‐dose intracoronary acetylcholine is diagnostic of coronary spasm. Intracoronary nitroglycerin is subsequently injected to reverse the effects of acetylcholine and relieve coronary spasm. A previous paper has been published outlining the role of HCWs in treating the various causes of IHD. The paper describes the various modalities of diagnosing and treating the various causes of ischemia in women including obstructive CAD, CMD, vasospasm, spontaneous CAD, stress cardiomyopathy, and myocardial bridge. ⁸⁷

Role of HCW in Clinical Trials

Despite CVD being the leading cause of death among women in the United States, women are significantly underrepresented in clinical trials across most areas of cardiovascular medicine. ⁸⁸ Differences in physiology and hormonal responses between sexes can lead to unique variations in how men and women respond to drugs and treatments. Additionally, biological changes during pregnancy, postpartum, lactation, and menopause create a more complex physiological landscape for women, which may further impact their responses to therapies compared with men. ⁸⁸ , ⁸⁹

Historically, cardiovascular trials have predominantly included White male participants, with results often generalized to women of all ages. A study examining 740 cardiovascular clinical trials registered on ClinicalTrials.gov from 2010 to 2017 revealed that of >800 000 participants, only 38.2% were women. ⁹⁰ While representation in hypertensive and pulmonary hypertensive studies was relatively equal, the inclusion of women was significantly lower in trials related to arrhythmias, acute coronary syndrome, stroke, coronary disease, and heart failure. ⁸⁸ , ⁹⁰

The inclusion of women in trials concerning ischemia and percutaneous coronary intervention remains inadequate. A systematic review conducted in 2020, which analyzed pooled data from 21 randomized percutaneous coronary intervention trials, focused on MACEs and ischemia‐driven target lesion revascularization across sexes. The review indicated that women represented only 27.8% of the total 32 877 patients studied and had a higher risk of MACEs and ischemia‐driven target lesion revascularization at the 5‐year mark. ⁹¹

The underrepresentation of women in clinical trials stems from several factors, including fewer referrals to cardiology specialists, ageism, and logistical challenges like transportation and child care. Historical biases also play a role; for instance, early trials in the 1960s often excluded women due to concerns about fetal malformations from thalidomide. In 1977, the US Food and Drug Administration recommended excluding women of childbearing age from phase I and II trials, further reinforcing a focus on men and leading to generalized findings for women. ⁸⁸ , ⁹²

In 1993, the National Institutes of Health Revitalization Act was enacted, mandating the inclusion of women and minorities in National Institutes of Health–funded research. Although this initiative has improved the representation of women in clinical trials, a significant sex gap persists. Pregnant and lactating women, in particular, are often excluded from trials despite CVD being a major cause of maternal death. This “protection by exclusion” approach ultimately harms pregnant and lactating women, as conditions like gestational hypertension, preeclampsia, and peripartum cardiomyopathy significantly affect both current and future CVH for mothers and their children. ⁸⁹ , ⁹²

Most cardiovascular therapies, including exercise recommendations, have little to no evidence in the pregnant population due to uncertainty of the effects on the fetus. The results of studies conducted in nonpregnant patients cannot be applied to pregnant women due to significant physiological differences. ⁸⁸ Pregnant women and those of childbearing age should be included in studies with more careful monitoring, allowing guidelines to include recommendations supported by evidence for this vulnerable population. ⁸⁹ , ⁹² Current data from registries, such as the HOPE (Heart Outcomes in Pregnancy Expectations), which aims to study the effects of CVD in pregnant women, should be incorporated into larger registries, such as the NCDR (National Cardiovascular Data Registry), to facilitate better inclusion of women in larger‐scale trials.

Not only are women underrepresented as participants in clinical trials, but they are also underrepresented in clinical leadership positions. ⁸⁸ , ⁸⁹ , ⁹² Among cardiovascular trials published from 2014 to 2018, only 9.3% of first authors and 10% of senior authors were women. This difference was even more apparent in procedural trials and heart failure trials. ⁹² Having female clinical leaders consistently improves the enrollment of women and minorities in trials. ⁸⁹ , ⁹²

As an effort to continue to address the disparities seen across clinical trials, the RECHARGE (Revascularization, Choices, Among Underrepresented Groups Evaluatio) multicenter randomized study has 2 separate arms focusing on the recruitment of women and underrepresented minorities (Black race and Hispanic ethnicity) to compare percutaneous coronary intervention versus coronary artery bypass graft surgery in patients with multivessel disease or left main CAD with the primary end points of quality of life and death. ⁹³

Future Goals for the Care of Women to Prevent and Diagnose ASCVD

In 2018, a white paper on HCWs discussed the future goals for HCW programs. These included efforts to improve clinical care, community engagement, and increase the enrollment of women in clinical trials. Since then, we have seen much progress in the clinical care of women, including a significant decrease in cardiovascular outcomes that predominantly affect women such as heart failure with preserved ejection fraction and diabetes. Hyperlipidemia can now be treated with drugs that women can better tolerate. Guidelines specifically note sex differences in treating patients. However, there are still no guideline‐directed medical treatments for CMD, and many women are unaware of their risk for ASCVD. There is now interest in women‐only trials to improve treatment for ASCVD since most clinical trials repeatedly underenroll women.

Conclusions

HCWs play a crucial role in preventing and diagnosing IHD in women. Their primary focus is identifying and addressing risk factors specific to women. This includes assessing socioeconomic risks, managing lipid and hypertension levels during pregnancy, and concentrating on issues related to diabetes and obesity. Additionally, these centers provide tailored assessments of coronary microvascular health, exercise coaching, and dietary evaluations. They also promote medical research by ensuring that women participate as subjects and leaders in clinical trials. Figure 2 summarizes an HCW's role in caring for women with IHD. While there is still much work to be done, the future looks promising, with increased awareness and the implementation of optimal care for women at risk for CVD.

Sources of Funding

The primary source of funding for this research was provided by the Rush Heart Center for Women.

Disclosures

Dr Volgman serves on the consulting or advisory boards of Chiesi Pharmaceuticals, BMS, Janssen, Regeneron, Sanofi, and Zoll. Additional research funding is provided by Janssen and Novartis. She personally owns stock in Apple, Inc. There are no other disclosures for other authors.