Less myocardial scar but greater propensity for heart failure: another gender paradox in myocardial infarction

This editorial refers to ‘Infarct size, left ventricular function, and prognosis in women compared with men after primary percutaneous coronary intervention in ST-segment elevation myocardial infarction: result from an individual patient-level pooled analysis of 10 randomized clinical trials’†, by I. Kosmidou et al., on page 1656. Across most European countries, cardiovascular diseases remain the leading cause of death, accounting for nearly every second fatality.1 Numerous studies exploring gender-related differences in outcomes after myocardial infarction (MI) report higher crude mortality among women compared with men, which is attenuated after adjustments for gender-related differences in baseline risk profile and clinical presentation.2 , 3 Women presenting with MI are usually older, suffer more frequently from co-morbidities such as diabetes and chronic renal failure, have longer delays in seeking care, and more often present haemodynamically unstable compared with men. Paradoxically, severity of coronary artery disease (CAD) in women is less pronounced compared with men.3 A large variety of biological differences among both genders in pathophysiology, clinical presentation, diagnosis, and response to therapy in the setting of MI have been described. However, their contribution in addition to the biases introduced by baseline risk remains a matter of debate.4 In this issue of the journal, Ioanna Kosmidou and colleagues make a valid contribution to our understanding of the ventricular response in women and men with ST-segment elevation myocardial infarction (STEMI) undergoing primary PCI (PPCI) in terms of infarct size and its impact on clinical outcome. They pooled individual patient data from 10 randomized controlled trials (587 women and 2045 men) in which infarct size was measured either by cardiac magnetic resonance imaging (CMRI, 72%) or by 99mTc-single-photon emission computed tomography (99mTc-SPECT, 28%) and expressed as a percentage of left ventricular myocardial mass (LVMM). Compared with men, women had numerically smaller infarct size: 15.8% (6.8–26.3%) of LVMM vs. 18% (8.3–29.1%) of LVMM, P = 0.10, at a median of 4 days after PPCI.5 This finding is in contradiction to the worse final coronary blood flow and a 34 min longer symptom onset to reperfusion time interval among women. There is evidence that in STEMI patients undergoing PPCI within 12 h from symptom onset, the indexed myocardial salvage is less dependent on the time to treatment interval.6 In addition, better hypoxia tolerance of female myocardium has been hypothesized as one potential mechanism to explain the differential response to acute cardiac ischaemia.7 Pre-clinical studies have shown better protection of female hearts from apoptosis and necrosis presumably driven by oestrogen receptors (e.g. protection from calcium overload, inhibitory effects on endothelin-1) and higher levels of the survival-associated proteins. Other putative mechanisms include differences in ischaemic pre-conditioning further supported by more frequent pre-infarct angina in women. Whether better developed collateral circulation in women plays a role can only be speculated on since this information was lacking in this meta-analysis. This finding suggests either more benefit from PPCI or a smaller amount of jeopardized myocardium among women compared with men. The proportion of men with a history of MI was twice as high compared with women in this meta-analysis, while information about the amount of jeopardized myocardium is lacking. However, in a study of 202 women and 561 men undergoing PPCI for acute MI, despite no gender-related difference in the amount of initial area at risk as assessed by 99mTc-SPECT, a greater amount of the jeopardized myocardium was salvaged among women: 64% (35–95%) of the left ventricle vs. 50% (26–77%) of the left ventricle among men (P < 0.001), leading to a smaller final infarct size [6% (0.71–18.7%) vs. 10% (3.9–21.8%), respectively, P = 0.001].8 Compared with SPECT, CMRI has been found to have higher spatial resolution and to be less prone to attenuation artefacts, thus better detecting small subendocardial infarcts (Figure 1). In this regard, a CMRI study of 45 women and 245 men with STEMI also confirmed smaller infarcts and higher myocardial salvage after PPCI.9 Cardiac magnetic resonance images of a patient with acute lateral wall myocardial infarction 5 days after primary percutaneous coronary intervention (Department of Radiology and Nuclear Medicine, German Heart Center Munich). Upper left: T2-weighted turbo spin echo visualizes acute inflammation/cell oedema in the area at risk. Upper right: late gadolinium enhancement, bright signal of the necrotic tissue; the dark core indicates microvascular obstruction (infarct size). Lower left: T1-map during the same examination showing an area at risk similar to T2-weighted turbo spin echo. Lower right: T2*-map showing intramyocardial haemorrhage (dark area). Compared with men, women have smaller infarct size and greater left ventricular ejection fraction, although they more frequently experience rehospitalization due to heart failure in the long term. Another important and clinically relevant finding of this meta-analysis was that although women derive at least comparable if not disproportionately more benefit from PPCI in terms of infarct size, this advantage did not translate into better clinical outcome, i.e. the composite of death or heart failure (HF) at 1 year. While the excess mortality risk in women was attenuated after adjustment in the multivariate analysis, the risk for HF remained increased. The discrepancy between objective measures of cardiac function [ΔLVEF (left ventricular ejection fraction) 1.5, 95% confidence interval (CI) 0.38–2.64, P = 0.02, in favour of women]5 on the one hand and increased HF symptoms on the other suggests a higher rate of HF with preserved ejection fraction (HFpEF) caused by diastolic dysfunction in women. In line with this, a recent analysis of the VALIANT trial of patients with MI suggested a higher risk for HF in women independent of systolic function.10 The hypothesis is further supported by the fact that the prevalence of HFpEF in women in the general population is twice as high as in men. There is a growing body of basic and clinical research showing profound gender-related differences in cardiac remodelling after MI. In a mouse model of MI, female hearts showed faster healing, less neutrophil infiltration, and less matrix metalloproteinase (MMP) activity in the acute phase, while male hearts had significantly poorer left ventricular function and dilatation.11 After chronic volume overload, women are more likely to develop concentric remodelling while men are more prone to eccentric remodelling. The fact that ageing in general has been shown to be associated with more concentric remodelling, diastolic dysfunction, and vascular stiffness, and the fact that women with MI usually present at an older age may also add to the higher incidence of HFpEF in women.7 In addition to HFpEF, the contribution of other co-morbidities (e.g. atrial fibrillation, valvular dysfunction, or uncontrolled hypertension), differences in medication and drug compliance, and other confounders to the reported HF hospitalization cannot be excluded. While the value of PPCI in both women and men with STEMI is indisputable, Kosmidou and colleagues in the current individual patient-level analysis identify another gender paradox in MI—despite a smaller infarct size, women are at higher risk for HF rehospitalization compared with men. The reasons and therapeuticy consequences of this finding are largely unexplored and should be subject to further research. Conflict of interest: none declared.