Sex differences among young individuals with myocardial infarction

This editorial refers to ‘Women who experience a myocardial infarction at a young age have worse outcomes compared with men: the Partners YOUNG-MI Registry Brief’^†, by E.M. DeFilippis et al., on page 4127.

Despite great strides in the prevention and treatment of cardiovascular disease, it remains the leading cause of mortality across the world.^{1  ,  2} Mortality rates due to cardiovascular disease have been declining, but less so for young adults, especially women.³ The incidence of acute myocardial infarction (AMI) has plateaued among individuals <55 years of age,⁴ with a concerning increase in AMI hospitalization rates in young women.^3–5 Studies such as the Variation in Recovery: Role of Gender on Outcomes of Young AMI Patients (VIRGO) and the GENdEr and Sex determInantS of cardiovascular disease: from bench to beyond-Premature Acute Coronary SYndrome (GENESIS-PRAXY) have been instrumental in determining the differences that exist among young men and women in regards to AMI presentation, treatment, and outcomes.^{3  ,  6} Such sex differences were also observed within the contemporary cohort of AMI patients in the Partners YOUNG-MI Registry (Figure 1), as described by DeFilippis, Collins et al. in this issue of the European Heart Journal.⁷

Figure 1.

Recent AMI trends, summary of the Partners YOUNG-MI Registry findings, and suggestions for future action.

This retrospective cohort included 404 women and 1693 men who presented with a first AMI at or before 50 years of age from 2000 to 2016 at two academic medical centres. A key strength of this study was that it included all consecutive patients presenting with AMI, allowing for a wide spectrum of illness severity. The median time to follow-up was 11.2 years which permitted comparison of long-term mortality in a young group of AMI patients, as compared to the 1-year follow-up in the VIRGO and GENESIS-PRAXY studies. Consistent with other observations, the Partners YOUNG-MI Registry study found that young women with AMI were less likely to undergo coronary angiography or coronary revascularization, or be treated with guideline-directed medical therapy as compared with men. Women were also less likely to have ST-elevation myocardial infarction (STEMI) and more likely to have non-obstructive coronary disease, single-vessel disease, lower plaque burden, and coronary artery dissection.

Women and men had similar rates of in-hospital mortality, in contrast to studies which have shown a two-fold excess in-hospital mortality among young women with AMI^{3  ,  6  ,  8  ,  9} and perhaps is related to sample size or burden of comorbidities. Long-term cardiovascular mortality was also no different between the sexes, although the adjusted all-cause mortality was 1.63 times higher among women as compared with men. Prior studies including AMI patients of all ages have shown an increased unadjusted long-term mortality among women with AMI, but these sex differences were less apparent after adjustment for covariates and age.¹⁰ The authors of this study propose that this higher all-cause mortality among young women with AMI may reflect an excess of risk which supersedes the cardioprotective effects of oestrogen. Supporting that hypothesis, the women in this study were more likely to have diabetes (more likely to be a long-standing diagnosis and on insulin), rheumatological conditions, depression, lower median income, and public insurance, whereas men more often had dyslipidaemia, and alcohol and illicit substance use. Although the composite score of atherosclerotic risk factors was similar between both sexes in this study, factors such as diabetes, smoking, and depression may confer/represent a greater relative risk in women.^{3  ,  11  ,  12}

Women were less likely than men to undergo invasive coronary angiography on multivariable analysis. When the analysis was stratified according to AMI, this difference remained among patients with non-ST elevation myocardial infarction (NSTEMI) but not among patients with STEMI. Women were less likely than men to undergo percutaneous coronary intervention (PCI) for both STEMI and NSTEMI. These differences may reflect persistent sex or gender disparities in clinical care and decision-making, but may also in part be due to the differing aetiologies of AMI among men and women. For instance, in this cohort, women more frequently had spontaneous coronary artery dissection (SCAD) for which conservative treatment is preferred over PCI whenever possible.^{13  ,  14} In addition, women more often had myocardial infarction with non-obstructive coronary arteries (MINOCA) for which PCI would not be an appropriate treatment. In total, 17.4% of women had SCAD or MINOCA as compared with 4.4% of men.

The women in this study were less often discharged on guideline-directed medical therapy. This apparent disparity has been observed in other studies^{3  ,  5} and may reflect sex differences in disease pathogenesis or aetiology of AMI, perceived medication effectiveness or tolerance, cost, access to care, or effects of conscious or unconscious biases. Race and ethnicity was not a focus of this study, but 27% of the patients were not white. The impact that race and ethnicity may have had on the study findings is uncertain, although notable racial and ethnic disparities have been previously observed in young women with AMI.³ The aetiology of AMI may also affect medication decision-making; for example, high-intensity statin therapy is not considered standard of care for SCAD patients with a normal lipid profile by consensus, since, to date, no secondary prevention benefit has been observed.^{13  ,  14} Statins are also usually avoided during pregnancy and lactation. However, these exceptions are likely to reflect a small proportion of young women with AMI in this study, particularly since 93.7% of women had plaque or stenosis at the time of AMI and a similar composite score of atherosclerotic risk factors as compared with men.

Therefore, it is essential to aggressively address traditional cardiovascular risk factors in young AMI patients, especially among young women with AMI and a high burden of comorbidities.³ Assessing clinical risk and implementing primary prevention is imperative, and non-traditional risk factors require attention, although not always addressed. For instance, female-specific risk factors such as history of pre-eclampsia, hypertension in pregnancy, gestational diabetes, or oophorectomy were not accounted for in this study, nor are they included in commonly used risk profile calculators. Depression was twice as prevalent among the women in this study compared with men. Depression impacts adherence to healthy lifestyle recommendations and medications, and on a mechanistic level depression contributes to increases in serotonin, stress hormones, and inflammatory cytokines.¹⁵ Young women with depression are six times more likely to have coronary heart disease than women without depression.¹⁵Psychological distress (depression, post-traumatic stress, anxiety, anger, hostility, and perceived stress) has been associated with future cardiovascular events in women, but not in men.¹² Women are twice as likely to have mental stress-induced ischaemia after AMI as compared with men, despite similar measures of psychosocial risk and clinical comorbidities.¹⁶ These findings highlight the relevance of paying attention to and addressing depression and other aspects of psychological distress, and socioeconomic and psychosocial stressors.

In summary, this study by the Partners YOUNG-MI Registry investigators demonstrates the continued need—and obligation—to study and improve the incidence and mortality trajectory of cardiovascular disease in the young, especially women. We can each work towards this goal by increasing awareness of heart disease and ‘heart healthy’ lifestyles within our communities; engaging with local policy makers; promoting primary or secondary prevention efforts within our clinical practices; designing studies that account for sex differences; facilitating recruitment of women into clinical trials; requesting sex-based data when reviewing manuscripts; and reporting sex differences in published research.

 

The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.