MINOCA syndrome and obstructive coronary artery disease: does sex matter?

Introduction Myocardial infarction with non-obstructive coronary arteries (MINOCA) represents a heterogeneous entity involving microvascular dysfunction, thrombosis, and genetic susceptibility. Although women are more frequently affected, sex-specific genetic determinants and cardiometabolic profiles remain insufficiently characterised. Objective To stratify MINOCA by sex and evaluate its association with traditional cardiovascular risk factors and CAD-related genetic variants in a Southern European population. Methods This prospective single-centre cohort included 1,633 consecutive patients admitted with myocardial infarction between 2000 and 2019. Coronary angiography was independently assessed by two interventional cardiologists using the Leaman Score; a score of 0 defined MINOCA. MINOCA patients were stratified by sex and compared with those with obstructive MI (MI-CAD). Thirty-three SNPs previously associated with CAD were genotyped using TaqMan assays. Associations between genetic variants, clinical risk factors, and MI phenotype were evaluated using bivariate and multivariate logistic regression analyses, Results MINOCA was diagnosed in 87 patients (5.3%): 29 women and 58 men. Women with MINOCA showed lower prevalence of type 2 diabetes (p=0.005) and metabolic syndrome (p=0.003) and reported higher physical activity (p<0.0001) compared with MI-CAD women. Genetic variants PON1 rs854560 (p=0.040) and CDKN2B rs4977574 (p=0.036) showed significance, but after multivariate adjustment, only CDKN2B GG remained independently associated with MINOCA women (p=0.020), together with type 2 diabetes (p=0.025), age (p=0.012), and sedentary lifestyle (p=0.008). Men with MINOCA showed lower rates of hypertension (p=0.033), diabetes (p=0.021), and metabolic syndrome (p=0.042) versus MI-CAD men. Significant SNP associations included TCF21 rs12190287 (p<0.0001), FTO rs9939609 (p=0.048), and PCSK9 rs562556 (p=0.038) in MINOCA men. When adjusted in multivariate logistic regression, TCF21 GC+CC (p<0.0001) and PCSK9 GA+AA (p=0.042) remained independently associated with MINOCA men, along with age (p<0.0001). Conclusion MINOCA patients exhibit a more favourable cardiometabolic profile compared with obstructive MI-CAD, irrespective of sex. However, distinct sex-specific genetic associations were identified: CDKN2B in women and TCF21/PCSK9 in men. These findings suggest divergent biological pathways underlying MINOCA and support the need for sex-specific risk-stratification strategies.