Mehta, Puja K.

Platelets are central to hemostasis and thrombosis. Excessive platelet activation contributes to arterial thrombotic events, including myocardial infarction, ischemic stroke, and complications of peripheral artery disease, whereas excessive platelet inhibition increases bleeding risk. Antiplatelet therapy remains a cornerstone of secondary prevention in atherosclerotic and thrombotic cardiovascular diseases, yet current treatment paradigms do not fully account for biological heterogeneity in platelet function, including differences related to sex, age, hormonal status, and disease context. This state-of-the-art review examines current antiplatelet strategies, fundamental mechanisms of signal transduction, clinical indications, and limitations of preclinical and clinical studies, with a focus on sex-specific considerations and opportunities for personalized antiplatelet therapy. Aspirin and P2Y 12 receptor antagonists are widely used for secondary prevention. However, women have been underrepresented in many pivotal clinical trials, limiting the precision of sex-specific estimates of efficacy and bleeding risk. In parallel, commonly used preclinical models often fail to recapitulate the physiological conditions in which platelets interact with the vasculature, leukocytes, and soluble factors. Emerging therapeutic approaches seek to refine platelet inhibition by targeting pathways that reduce thrombotic risk while preserving hemostasis. Advancing antiplatelet therapy will require integration of mechanistic platelet biology with diverse clinical trial populations, standardized platelet phenotyping, and disease-specific approaches that account for how platelet function is altered across health and vascular disease.

Background Although there has been a decrease in the incidence of ST‐segment–elevation myocardial infarction (STEMI) in the United States, this trend might be stagnant or increasing in young women. We assessed the trends, characteristics, and outcomes of STEMI in women aged 18 to 55 years. Methods and Results We identified 177 602 women aged 18 to 55 with the primary diagnosis of STEMI from the National Inpatient Sample during years 2008 to 2019. We performed trend analyses to assess hospitalization rates, cardiovascular disease (CVD) risk factor profile, and in‐hospital outcomes stratified by three age subgroups (18–34, 35–44, and 45–55 years). We found STEMI hospitalization rates were decreased in the overall study cohort from 52 per 100 000 hospitalizations in 2008 to 36 per 100 000 in 2019. This was driven by decreased proportion of hospitalizations in women aged 45 to 55 years (74.2% to–71.7%; P <0.001). Proportion of STEMI hospitalizationincreased in women aged 18–34 (4.7%–5.5%; P <0.001) and 35–44 years (21.2%–22.7%; P <0.001). The prevalence of traditional and non‐traditional female‐specific or female‐predominant CVD risk factors increased in all age subgroups. The adjusted odds of in‐hospital mortality in the overall study cohort and age subgroups were unchanged throughout the study period. Additionally, we observed an increase in the adjusted odds of cardiogenic shock, acute stroke, and acute kidney injury in the overall cohort over the study period. Conclusions STEMI hospitalizations are increasing among women aged <45 years, and in‐hospital mortality has not changed over the past 12 years in women aged <55 years. Future studies on the optimization of risk assessment and management of STEMI in young women are urgently needed.

Background: Microvascular dysfunction is known to play a key role in patients with angina and nonobstructive coronary artery disease. We investigated the impact of ranolazine among patients with angina and nonobstructive coronary artery disease. Methods: In this randomized, double-blinded, placebo-controlled pilot trial, 26 patients with angina once weekly or more, abnormal stress test, and nonobstructive coronary artery disease (<50% stenosis by angiography and fractional flow reserve >0.80) were randomized 1:1 to ranolazine or placebo for 12 weeks. Primary end point was ΔSeattle Angina Questionnaire (SAQ) angina frequency score. Baseline and 3 months follow-up SAQ, Duke Activity Status Index scores along with invasive fractional flow reserve, coronary flow reserve (CFR), hyperemic myocardial resistance, and cardiopulmonary exercise testing measurements were performed. Results: No significant differences in ΔSAQ angina frequency scores ( P =0.53) or Duke Activity Status Index ( P =0.76) were observed between ranolazine versus placebo, although patients on ranolazine had lesser improvement in SAQ physical limitation scores ( P =0.02) compared with placebo at 3 months. There were no significant differences in ΔCFR or Δhyperemic myocardial resistance between ranolazine and placebo groups. Patients treated with ranolazine, compared with placebo, had no significant improvement in maximum rate of oxygen consumption measured during incremental exercise (VO 2 max) and peak metabolic equivalents of task. Interestingly, in the ranolazine group, patients with baseline CFR<2.0 demonstrated greater gain in CFR compared with those with baseline CFR≥2.0 ( P =0.02). Conclusions: Ranolazine did not demonstrate improvement in SAQ angina frequency score, invasive microvascular function, or peak metabolic equivalent compared with placebo at 3 months. Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02147067.