Importance: There is growing awareness of sex-related differences in cardiovascular risk profiles, but less is known about whether these extend to pre-menopausal females experiencing an early-onset myocardial infarction (MI), who may benefit from the protective effects of estrogen exposure.Methods: A nationwide study involving 125 Italian Coronary Care Units recruited 2,000 patients between 1998 and 2002 hospitalized for a type I myocardial infarction before the age of 45 years (male, n = 1,778 (88.9%). Patients were followed up for a median of 19.9 years (IQR 18.1–22.6). The primary composite endpoint was the occurrence of cardiovascular death, non-fatal myocardial re-infarction or non-fatal stroke, and the secondary endpoint of hospitalization for revascularisation by means of a percutaneous coronary intervention (PCI) or coronary artery bypass surgery (CABG).Results: ST-elevation MI was the most frequent presentation among both men and women (85.1 vs. 87.4%, p = ns), but the men had a greater baseline coronary atherosclerotic burden (median Duke Coronary Artery Disease Index: 48 vs. 23; median Syntax score 9 vs. 7; both p < 0.001). The primary composite endpoint occurred less frequently among women (25.7% vs. 37.0%; adjusted hazard ratio: 0.69, 95% CI 0.52–0.91; p = 0.01) despite being less likely to receive treatment with most secondary prevention medications during follow up.Conclusions: There are significant sex-related differences in baseline risk factors and outcomes among patients with early-onset MI: women present with a lower atherosclerotic disease burden and, although they are less frequently prescribed secondary prevention measures, experience better long-term outcomes.Trial Registration: 4272/98 Ospedale Niguarda, Ca' Granda 03/09/1998.

BACKGROUND: Myocardial infarction (MI) is a complex disease caused by both lifestyle and genetic factors. This study aims to investigate the predictive value of genetic risk, in addition to traditional cardiovascular risk factors, for recurrent events following early-onset MI. METHODS: The Italian Genetic Study of Early-Onset Myocardial Infarction is a cohort study enrolling patients with MI before 45 years. Monogenic variants causing familial hypercholesterolemia were identified, and a coronary artery disease polygenic score (PGS) was calculated. Ten-fold cross-validated Cox proportional hazards models were fitted sequentially including all clinical variables, the PGS, and monogenic variants on the composite outcome of cardiovascular death, recurrent MI, stroke, or revascularization. RESULTS: During a 19.9-year follow-up, 847 (50.7%) patients experienced recurrent events. Each 1-SD higher PGS was associated with a 21% higher hazard of recurrent events (hazard ratio, 1.21 [95% CI, 1.13–1.31]; P =4.04×10 ⁻⁶ ). Except for secondary prevention, PGS was the strongest determinant of recurrent event risk (C index, 0.56 [95% CI, 0.54–0.58]) compared with clinical risk factors. Overall, predictive performance of clinical risk factors (C index, 0.69 [95% CI, 0.67–0.71]) improved after adding the PGS (C index, 0.69 [95% CI, 0.68–0.71]; P =0.006). When dividing the population by PGS quintiles, the highest fifth had a 57% higher hazard of recurrent events than the lowest fifth (hazard ratio, 1.57 [95% CI, 1.26–1.96]; P =5.57×10 ⁻⁵ ). CONCLUSIONS: When compared with other clinical risk factors, PGS was the strongest predictor of event recurrence among patients with an early-onset MI. Though the discriminative power of recurrent event prediction in this cohort was modest, the addition of PGS significantly improved discrimination.

Despite evidence-based therapies, patients presenting with atherosclerosis involving more than one vascular bed, such as those with peripheral artery disease (PAD) and concomitant coronary artery disease (CAD), constitute a particular vulnerable group characterized by enhanced residual long-term risk for major adverse cardiac events (MACE), as well as major adverse limb events (MALE). The latter are progressively emerging as a hard outcome to be targeted, being correlated with increased mortality. Antithrombotic therapy is the mainstay of secondary prevention in both patients with PAD or CAD however, the optimal intensity of such therapy is still topic of debate, particularly in the post-acute and long-term setting. Recent well powered randomized clinical trials (RCTs) have provided data in favor of a more intense antithrombotic therapy, such as prolonged dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 inhibitor or a therapy with aspirin combined with an anticoagulant drug. Both approaches increase bleeding and patients selection is a key issue. The aim of this review is therefore to discuss and summarize the most updated available evidences for different strategies of anti-thrombotic therapies in patients with chronic PAD and CAD, particularly focusing on studies enrolling patients with both type of atherosclerotic disease and comparing a higher versus a lower intensity antithrombotic strategy. The final objective is to identify the optimal tailored approach in this setting, to achieve the greatest cardiovascular benefit and improving precision medicine.

Heart failure represents a complex clinical syndrome characterized by progressive ventricular dysfunction, systemic congestion, and high mortality despite significant advances in pharmacological and device-based therapy. This review explores recent developments across the heart failure continuum, with a focus on therapeutic advances across the continuum of care, with emphasis on both established and emerging strategies. In patients with reduced ejection fraction, early initiation of the four pillars markedly lowers cardiovascular events, yet real-world implementation remains limited by therapeutic inertia and underdosing. Novel agents such as finerenone provide cardiorenal benefits in patients with diabetes and chronic kidney disease, while glucagon-like peptide-1 receptor agonists show promise in preserved or mildly reduced ejection fraction, particularly with obesity. Tricuspid regurgitation, once considered a secondary phenomenon, is now recognized as a modifiable contributor to disease progression, with transcatheter interventions offering new therapeutic avenues. In advanced disease, innovations including donation after circulatory death and the development of total artificial heart systems offer promising solutions to overcome organ shortages and improve access to transplantation. Together, these advances highlight a shift toward precision-guided, multidisciplinary heart failure care.

Ischemia with non-obstructive coronary arteries (INOCA) is a chronic coronary condition associated with poor prognosis and reduced quality of life. The increasing use of invasive assessments of microcirculatory function and provocative spasm testing has significantly advanced the understanding of INOCA’s pathophysiology, which ranges from coronary microvascular dysfunction to vasomotor disorders. However, the optimal management and therapeutic approach for INOCA remain to be determined. Significant sex-based differences in the pathophysiology of INOCA have been reported, resulting in variations in prevalence, phenotype, and natural history between male and female patients. The aim of this narrative review is to provide a comprehensive overview of the sex-specific pathophysiological mechanisms underlying INOCA and to summarize the differences in INOCA phenotype and prognosis. Additionally, we will explore the current knowledge on management and therapy, with the goal of advancing towards sex-based personalized treatment strategies for INOCA.