ASCVD in Women is Different: A Review of Pathophysiology, Risk Factors, Presentation

Karol Watson, MD, PhD, director of the UCLA-Barbra Streisand Women’s Heart Health program, in Los Angeles, discussed sex-specific considerations in the prevention and management of atherosclerotic cardiovascular disease (ASCVD), as part of a clinical triad on CVD prevention in specific populations at the 2025 ACP Internal Medicine Meeting in New Orleans.

Karol E Watson, MD, PhD

Courtesy of UCLA Health

Throughout her presentation, she focused on how traditional approaches to cardiovascular care have often failed to address the unique presentations, risk factors, and pathophysiology of heart disease in women.

"Hearts and Husbands”

Watson opened with an interesting reminder: the American Heart Association's first conference on women and heart disease in 1964 was titled "Hearts and Husbands," focusing primarily on how wives could care for their husbands with heart disease. The significant contrast with contemporary understanding underscores how far cardiology has come in recognizing women's cardiovascular health as a distinct clinical entity.

Despite this progress, Watson offered another reminder: that heart disease remains the leading cause of death for women in the United States as of 2020 data.

Nothing is "Atypical" for Women

Coronary artery disease (CAD) develops differently in women, Watson continued While men tend to develop focal, obstructive lesions in major epicardial vessels, women often present with diffuse atherosclerosis, microvascular dysfunction, and plaque erosion rather than rupture.

This pathophysiological difference explains why women with significant ischemia may have "normal" coronary arteries on traditional angiography—the atherosclerosis can effectively hide in ways that standard imaging might miss.

Perhaps one of the most clinically significant differences is symptom presentation, according to Watson. She contrasted the "classic" male symptoms (crushing central chest pain, left arm pain, diaphoresis) with what have traditionally been labeled "atypical" symptoms in women: Unusual fatigue, sleep disturbance, shortness of breath, weakness, anxiety, throat, jaw, neck, and back pain, and indigestion. While the symptoms are typical, the persistent male-centric framing of cardiac care continues to delay diagnosis and treatment, she stressed.

Watson cited a study by Lichtman et al that found 29.5% of women with acute MI had sought medical care for similar symptoms previously, compared to 22.1% of men (P <.001). Even more concerning, clinicians did not consider these symptoms cardiac in origin for 53.4% of women versus 36.7% of men (p<0.001).

Risk Factors: Not Created Equal

The 2004 INTERHEART study, a case-control study of 27,098 participants across 52 countries, revealed important sex differences in the significance of common risk factors for heart disease:

• Smoking, dyslipidemia, hypertension, obesity, poor diet, and psychosocial factors affected both sexes similarly
• Exercise had significantly greater protective effects for women
• Alcohol consumption showed significantly greater protective effects for women
• Diabetes conveyed significantly greater risk for women

Loss of estrogen during menopause places women at higher risk for CVD, Watson reminded the audience. Before onset of menopause, women have approximately one-fifth the rate of heart disease as men. Ten years after the end of the climacteric, the rate of myocardial infarction among women equals that among men. In a similar vein, she shared research from the early 1990s showing that women with diabetes face a disproportionately higher CVD risk, demonstrating that the presence of diabetes negates the premenopausal cardioprotection afforded by estrogen.

Watson also reviewed data that show sex differences in the impact of dietary choices. A study examining carbohydrate intake by glycemic index (GI) demonstrated that high-GI foods were associated with increasing CHD risk in women across quartiles (P for trend =.04), while men showed no significant trend (P =.94). Watson emphasized that even dietary advice for cardiovascular prevention may need to be tailored differently for women versus men.

Sex-Specific Risk Factors

Women face distinct cardiovascular risk factors related to reproductive hormonal transitions, Watson stressed, including auto-immune diseases, treatment for breast cancer, psychological factors (stress, anxiety, depression), and reproductive lifecycle transitions.

She shared research indicating that each reproductive phase presents specific cardiovascular considerations and that times of reproductive hormone transition are periods of high cardiovascular risk. Pubertal BMI change, but not childhood BMI, showed an odds ratio of 1.28 (95% CI 1.10-1.50) for coronary artery calcification. Findings from the Women’s Ischemia Syndrome Evaluation Study published in 2019, showed that early menarche (age 10 years or younger) was associated with elevated cardiovascular risk in later life. Menstrual cycle irregularities, ie, cycle regularity and lengths, are also associated with increased risk for cardiovascular disease.

Data from Sweden (1973-2018) demonstrated that adverse pregnancy outcomes correlate with cardiovascular risk extending decades after delivery. Pre-menopausal women experience approximately one-fifth the heart disease rate of men, but by 10 years post-menopause, myocardial infarction rates equalize between sexes.

Conclusion: Sex Matters

Watson concluded with key take-home messages for the audience of internal medicine specialists:

• Sex differences in cardiovascular disease are clinically significant and impact all aspects of care
• Heart disease remains the number one killer of women, with presentations that often differ from men
• Some heart diseases are more common in women
• Certain risk factors carry greater weight for women, particularly those related to reproductive history
• Understanding these sex-specific features is essential to effectively combat the leading cause of mortality in women

Her overall message was clear: effective cardiovascular prevention in women requires moving beyond one-size-fits-all approaches to embrace a more nuanced, sex-specific paradigm of care.