Sex and the Biology of Sudden Cardiac Death

Article, see p 1012 D espite meaningful advances in prevention and resuscitation, sudden cardiac death (SCD) continues to extact a major toll on society.SCD accounts for approximately 350 000 deaths in the United States annually, and this condition accounts for more years of potential life lost than any individual cancer affecting women or men. 1 Published observations regarding manifestations of SCD suggest that the pathophysiology of SCD is likely to be sex-specific.For example, women are significantly less likely to have the classical precursors for SCD, 2 with half the likelihood of severe left ventricular systolic dysfunction (OR 0.51 [0.31-0.84]versus men) and a one-third the likelihood of an established diagnosis of coronary artery disease (CAD; OR 0.34 [0.20-0.60]versus men).3 If we are going to make a real impact on the major public health burden of this condition, identification of sex-specific pathways to SCD is of paramount importance.In this issue of Circulation, Haukilahti and colleagues examined sex differences in autopsy findings as well as archived ECGs available for a subset of patients, from the established Fingesture Study. 4 Among >5800 subjects who presented with SCD between 1998 and 2017, approximately 80% were men and 20% were women.There were several sex-related differences identified on pathological examination.Women were less likely to have coronary artery disease (72% versus 76%, P=0.005), and more likely to have primary myocardial fibrosis (5% versus 3%, P<0.001), valve disease (2% versus 1%, P=0.049), myocarditis (2% versus 1%, P=0.020) and a structurally normal heart (0.6% versus 0.2%, P=0.015).Body mass index and abdominal fat were slightly higher in women.Following a comprehensive analysis of the available antemortem ECGs, a few sex differences were observed.Women were more likely to have left ventricular hypertrophy by ECG criteria (18% versus 11%, P=0.001), lower mean QRS complex duration (94 ms versus 102 ms, P<0.001) and lower prevalence of Q-waves (8% versus 16%, P<0.002).How does this large, carefully-conducted autopsy series advance our quest to identify sex-specific mechanisms of SCD?While several statistically significant sex-dependent differences were observed on pathological examination, the absolute magnitude of these differences was small.In fact, what is most striking about their findings is the relatively similar prevalence of abnormal cardiac structural findings in women and men.The >70% prevalence of coronary artery disease in women who suffered SCD is significantly higher than reported in previously published autopsy series 5 as well as the antemortem findings recently reported from the WISE study (Women's Ischemia Syndrome Evaluation).6 The latter study reported lower rates of SCD among women with obstructive CAD (27%) compared with those with no or minimal CAD (57%; information missing in 17%).