Sex Differences in Congenital Heart Disease

Abstract

S ex differences in the clinical presentation, diagnosis, and treatment outcomes of cardiac disease have long been recognized. Since the mid-1980s, the total number of deaths from cardiovascular disease has been higher for women than for men. A greater proportion of women (52%) than men (42%) with myocardial infarction die of sudden cardiac death before reaching the hospital, perhaps in part because women tend to have nonspecific prodromal symptoms rather than chest pain and these symptoms are not recognized as being cardiac in origin. 1 Even after acute myocardial infarction, women are 46% less likely to undergo coronary angiography than men, despite accounting for confounders. 2 Two-thirds of women who suffer a myocardial infarction never completely recover, 3,4 and those who do survive have a 2-fold recurrence of myocardial infarction and mortality during the first year compared with their male counterparts. 5 Article p 26 Women with stable angina have higher in-hospital mortality rates 6 and worse outcomes after coronary interventions, both percutaneous and surgical. Following percutaneous coronary interventions women have higher rates of short-and long-term mortality, cardiac events, and the need for emergency coronary artery bypass grafting. This may relate to the comparatively smaller coronary artery size of women, 7 although this is unproven. 8 Higher mortality and complication rates of coronary artery bypass grafting also occur, with women obtaining less functional relief, more frequent hospital readmissions, and lower functional gains than their male counterparts. 9 Whether some of these sex disparities relate to an autoimmune precursor for atherosclerotic disease remains speculative. Sex-specific differences in C-reactive protein, as an inflammatory marker, are consistent with the 10-fold increased frequency of inflammatory-mediated autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythe-matosus, and thyroiditis in women compared with men. 4,10 Recent studies report atherosclerotic plaque in both the carotid and coronary arteries to be significantly increased in women with systemic lupus erythematosus. Sex differences may also extend to cardiac electrophysiol-ogy. Women have higher resting heart rates and longer corrected QT intervals compared with men. 11 Variations in arrhythmia frequency in relation to the menstrual cycle have also been observed. Sudden cardiac death with coronary artery disease has a male-to-female ratio of 1.4:1. 12 Now, in the current issue of Circulation, the article by Verheugt et al 13 from the CONgenital CORvitia (CONCOR) Dutch national registry reports sex differences in outcomes of congenital heart disease. This database comprises over 7000 adult patients with congenital heart disease with a median age of 35 years; half of them are women. No sex differences in mortality were found but 4 specific cardiac outcomes appeared to be different in men and women. Pulmonary Hypertension Pulmonary arterial hypertension was defined as a systolic pulmonary pressure above 40 mm Hg. Women had a 35%-higher risk of pulmonary hypertension with an odds ratio of 1.33, an observation which has been noted previously. Atrial and ventricular septal defects were the 2 most frequent defects in this whole series and these defects were associated with pulmonary hypertension more commonly than any other lesion. The association of pulmonary hypertension with female sex is intriguing. Idiopathic pulmonary arterial hypertension is also much more common in women with a ratio of approximately 2.5:1, and although various genetic mutations and polymorphisms have been found to be associated with idiopathic pulmonary arterial hypertension, none appear to be sex-linked. In the study by Verheugt et al, 13 no sex difference was found in patients with irreversible pulmonary vascular disease but perhaps secundum atrial septal defect (ASD) deserves special examination. In our adult congenital heart disease clinic at Mayo Clinic, comprising over 4000 patients, the frequency of isolated secundum ASD with Eisenmenger syndrome in women exceeds that in males by 28:1. Some authors have even speculated that the ASD in this situation is really an "innocent bystander" and that the underlying pathology is really that of idiopathic pulmonary arterial hyper-tension. Nonetheless the female vulnerability to the development of pulmonary hypertension in this setting is striking, perhaps suggesting that a "two-hit hypothesis" is necessary (ie, a genetic susceptibility exists) and then the trigger of a secundum ASD initiates the vascular injury in the lungs which, in turn, leads to endothelial and vascular smooth muscle dysfunction and subsequent pulmonary vascular re-modeling. The explanation that hormonal differences and pregnancy account for these sex disparities appears somewhat simplistic.