Clinicians can encounter sex and gender disparities in diagnostic and therapeutic responses. These disparities are noted in epidemiology, pathophysiology, clinical manifestations, disease progression, and response to treatment. This Review discusses the fundamental influences of sex and gender as modifiers of the major causes of death and morbidity. We articulate how the genetic, epigenetic, and hormonal influences of biological sex influence physiology and disease, and how the social constructs of gender affect the behaviour of the community, clinicians, and patients in the health-care system and interact with pathobiology. We aim to guide clinicians and researchers to consider sex and gender in their approach to diagnosis, prevention, and treatment of diseases as a necessary and fundamental step towards precision medicine, which will benefit men's and women's health.

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Background: Myocardial infarction with non-obstructive coronary arteries (MINOCA) occurs in 6-15% of MI and disproportionately affects women. Scientific statements recommend multi-modality imaging in MINOCA to define the underlying cause. We performed coronary optical coherence tomography (OCT) and cardiac magnetic resonance imaging (CMR) to assess mechanisms of MINOCA. Methods: In this prospective, multicenter, international, observational study, we enrolled women with a clinical diagnosis of MI. If invasive coronary angiography revealed <50% stenosis in all major arteries, multi-vessel OCT was performed, followed by CMR (cine imaging, late gadolinium enhancement, and T2-weighted imaging and/or T1 mapping). Angiography, OCT, and CMR were evaluated at blinded, independent core laboratories. Culprit lesions identified by OCT were classified as definite or possible. The CMR core laboratory identified ischemia-related and non-ischemic myocardial injury. Imaging results were combined to determine the mechanism of MINOCA, when possible. Results: Among 301 women enrolled at 16 sites, 170 were diagnosed with MINOCA, of whom 145 had adequate OCT image quality for analysis; 116 of these underwent CMR. A definite or possible culprit lesion was identified by OCT in 46.2% (67/145) of participants, most commonly plaque rupture, intra-plaque cavity or layered plaque. CMR was abnormal in 74.1% (86/116) of participants. An ischemic pattern of CMR abnormalities (infarction or myocardial edema in a coronary territory) was present in 53.4% of participants undergoing CMR (62/116). A non-ischemic pattern of CMR abnormalities (myocarditis, takotsubo syndrome or non-ischemic cardiomyopathy) was present in 20.7% (24/116). A cause of MINOCA was identified in 84.5% of the women with multi-modality imaging (98/116), higher than with OCT alone (p<0.001) or CMR alone (p=0.001). An ischemic etiology was identified in 63.8% of women with MINOCA (74/116), a non-ischemic etiology was identified in 20.7% (24/116), and no mechanism was identified in 15.5% (18/116). Conclusions: Multi-modality imaging with coronary OCT and CMR identified potential mechanisms in 84.5% of women with a diagnosis of MINOCA, three-quarters of which were ischemic and one-quarter of which were non-ischemic, alternate diagnoses to MI. Identification of the etiology of MINOCA is feasible and has the potential to guide medical therapy for secondary prevention. Clinical Trial Registration: URL: https://clinicaltrials.gov Unique Identifier: NCT02905357

Background Angina, in the absence of obstructive CAD is more common in women, is associated with adverse cardiovascular morbidity and mortality, and is a major burden to the healthcare system. While advancements have been made to understand the mechanistic underpinning of this disease, the functional consequence remains unclear. Methods and Results Cardiac magnetic resonance imaging was performed to assess left ventricular (LV) function in 20 women with signs and symptoms of ischemia, but no obstructive CAD (cases), and 15 age and body mass index-matched reference controls. Functional imaging included standard cinematic imaging to assess LV morphology and global function, along with tissue tagging to assess LV tissue deformation. Systolic function was preserved in both cases and controls, with no differences in ejection fraction (mean ± SE: 63.1 ± 8% vs. 65 ± 2%), circumferential strain (−20.7±0.6 vs. −21.9±0.5%) or systolic circumferential strain rate (−105.9±6.1 vs. −109.0±3.8%/s), respectively. In contrast, we observed significant differences between cases and controls in diastolic function, as demonstrated by reductions in both diastolic circumferential strain rate (153.8 ± 8.9 vs. 191.4 ± 8.9 %/s, P < 0.05) and the peak rate of left ventricular untwisting (−99.4 ± 8.0 vs. −129.4 ± 12.8 °/s, P < 0.05), respectively. Conclusions Diastolic function is impaired in women with signs and symptoms of ischemia in the absence of CAD, as assessed by cardiac magnetic resonance tissue tagging. These results are hypothesis generating—larger studies are needed in order to define the exact mechanism(s) responsible, and to establish viable treatment strategies.