Why Cardiovascular Medicine Must Be Rebuilt Around Women's Biology

Cardiovascular disease is the leading cause of death in women. Women also live longer than men but are more likely to develop chronic conditions and live with long-term disability. Even so, diagnostic, risk-prediction and treatment paradigms rest mainly on studies in which men are over-represented. This Nature Medicine Perspective, from teams in Utrecht, Paris and UCLA, argues that closing this gap requires understanding sex-biased biology, not only enrolling more women in trials.

The authors describe a self-reinforcing cycle of inequity. Women present more often with atypical symptoms such as nausea, fatigue and pain between the shoulder blades. They more often have diffuse atherosclerosis and plaque erosion, which conventional imaging detects poorly. Baseline troponin is lower in women, so uniform cutoffs can hide injury. Sex-specific thresholds reclassify roughly five times more women than men, yet treatment and outcome gaps persist. Women are under-represented in trials relative to disease prevalence and discontinue more often, frequently in the context of adverse drug reactions. This leaves trials underpowered for sex-stratified conclusions.

Physiology differs too. Women have about 26% lower heart mass and about 34% lower left ventricular mass, and an ejection fraction about 2–7% higher. They also have a QRS duration 4–10 ms shorter, a longer QT interval and smaller epicardial coronary arteries even after adjusting for body size. Higher resting myocardial blood flow lowers measured coronary flow reserve without worse microvascular resistance. The authors propose that higher shear stress may favor diffuse, fibrous, erosion-prone plaques. They note this hypothesis is not yet established. Pregnancy complications and menopause add life-course risk.

Female-predominant conditions illustrate the evidence gap. Spontaneous coronary artery dissection accounts for 1–4% of acute coronary syndromes but up to 35% of heart attacks in women under 50, with recurrence near 10%. Takotsubo syndrome affects women in up to 90% of cases, with 2–5% in-hospital mortality and 5–10% recurrence. About 30–50% of people with angina lack obstructive coronary disease, and invasive testing finds vasomotor disorders in 70–90% of them. Treatments for these conditions are largely extrapolated from obstructive disease.

Treatment responses also appear to differ by sex. Women may benefit from lower ACE inhibitor and ARB doses. In REBOOT, beta-blockers were linked to a 45% higher risk of death, reinfarction or heart-failure hospitalization in women with preserved ejection fraction after myocardial infarction. Subgroup analyses suggest sacubitril–valsartan may benefit women with HFpEF more than men on composite heart-failure outcomes, though this is hypothesis-generating. Cardiac resynchronization therapy helps women at shorter QRS durations (130–149 ms) than men. Women receive only about 20–25% of left ventricular assist devices, and they have more bleeding and stroke complications.

The proposed roadmap covers several areas. Preclinical work should include both sexes and use models such as the Four Core Genotypes. It should use phenol-red-free media and karyotype iPSC lines. Multi-omics should be used to find sex-specific mechanisms; for example, a large share of circulating proteins (reported at about 70%) differ in abundance between women and men, and TGF-β signaling is a candidate pathway. Biomarker thresholds should be sex-aware, and devices should be repurposed or redesigned for female anatomy, such as the coronary sinus reducer and SCAD scaffolds. Trials need sex-informed enrollment and prespecified sex-stratified analyses, with target trial emulation for existing therapies. As a Perspective, this is a narrative synthesis, not a systematic review, and several mechanisms remain hypotheses.