Emergence of Nonobstructive Coronary Artery Disease

Pepine, Carl J.; Ferdinand, Keith C.; Shaw, Leslee J.; Light-McGroary, Kelly Ann; Shah, Rashmee U.; Gulati, Martha; Duvernoy, Claire S.; Walsh, Mary Norine; Merz, C. Noel Bairey

doi:10.1016/j.jacc.2015.08.876

Cited by 262 publications

(129 citation statements)

References 111 publications

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“…Future studies directly exploring sex differences in mechanisms of coronary microvessel dysfunction in response to obesity could have particular clinical importance. Indeed, women with cardiovascular ischemia are more likely than men to have coronary microvascular dysfunction than large vessel coronary disease,58 but the mechanisms are not clear and no treatments are available. Consequently, these women are particularly difficult to treat, so enhanced mechanistic understanding could lead to novel treatment strategies for this unmet medical need.…”

Section: Discussionmentioning

confidence: 99%

Sex‐Specific Mechanisms of Resistance Vessel Endothelial Dysfunction Induced by Cardiometabolic Risk Factors

Davel

Lü

Moss

et al. 2018

JAHA

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BackgroundThe incidence of obesity is rising, particularly among women. Microvascular dysfunction is more common with female sex, obesity, and hyperlipidemia and predicts adverse cardiovascular outcomes, but the molecular mechanisms are unclear. Because obesity is associated with mineralocorticoid receptor (MR) activation, we tested the hypothesis that MR in endothelial cells contribute to sex differences in resistance vessel dysfunction in response to cardiometabolic risk factors.Methods and ResultsMale and female endothelial cell–specific MR knockout mice and MR‐intact littermates were randomized to high‐fat‐diet–induced obesity or obesity with hyperlipidemia induced by adeno‐associated virus–based vector targeting transfer of the mutant stable form (DY mutation) of the human PCSK9 (proprotein convertase subtilisin/kexin type 9) gene and compared with control diet. Female but not male mice were sensitive to obesity‐induced endothelial dysfunction, whereas endothelial function was impaired in obese hyperlipidemic males and females. In males, obesity or hyperlipidemia decreased the nitric oxide component of vasodilation without altering superoxide production or endothelial nitric oxide synthase expression or phosphorylation. Decreased nitric oxide content in obese males was overcome by enhanced endothelium‐derived hyperpolarization–mediated relaxation along with increased SK3 expression. Conversely, in females, endothelium‐derived hyperpolarization was significantly impaired by obesity with lower IK1 expression and by hyperlipidemia with lower IK1 and SK3 expression, loss of H2O2‐mediated vasodilation, and increased superoxide production. Endothelial cell–MR deletion prevented endothelial dysfunction induced by risk factors only in females. Rather than restoring endothelium‐derived hyperpolarization in females, endothelial cell–MR deletion enhanced nitric oxide and prevented hyperlipidemia‐induced oxidative stress.ConclusionsThese data reveal distinct mechanisms driving resistance vessel dysfunction in males versus females and suggest that personalized treatments are needed to prevent the progression of vascular disease in the setting of obesity, depending on both the sex and the metabolic profile of each patient.

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Section: Discussionmentioning

confidence: 99%

Sex‐Specific Mechanisms of Resistance Vessel Endothelial Dysfunction Induced by Cardiometabolic Risk Factors

Davel

Lü

Moss

et al. 2018

JAHA

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“…Although there is likely overlap between INOCA and myocardial infarction (MI) with no obstructive coronary arteries, which appears to be increasingly described, our primary focus is INOCA, the non‐MI syndromes. These stable patients typically have symptoms of chest pain suspected to be angina and/or abnormal stress testing, in the setting of no obstructive CAD at coronary angiography 1, 2. The definition of obstructive CAD varies between different guidelines or studies 3, 4, 5, 6, 7, 8, 9, 10.…”

Section: Inoca—prevalencementioning

confidence: 99%

Ischemia and No Obstructive Coronary Artery Disease (INOCA): What Is the Risk?

Herscovici

Sedlak

Wei

et al. 2018

JAHA

Self Cite

140

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“…4,15,29,30 Emerging data have significantly contributed to our understanding of the full spectrum of IHD in women, which includes obstructive epicardial disease, microvascular disease, coronary spasm, and spontaneous coronary artery dissection. The role of microvascular dysfunction, vascular inflammation, coronary reactivity, endothelial function, hormonal influences, oxidative stress, and coronary size on the development of IHD in women is being increasingly recognized.…”

Section: Pathophysiologymentioning

confidence: 99%

“…34 The higher burden of nonobstructive atherosclerosis in women may result in negative stress tests and obscure the diagnosis of IHD, underscoring the need for additional diagnostic imaging that reveals the nonobstructive pathophysiological mechanisms of IHD. 30,35 Consequently, the 2014 AHA consensus statement for noninvasive evaluation of woman at risk for IHD recommends testing for the full spectrum of IHD ( Figure 3). 35 Contemporary cardiac imaging techniques Many traditional risk factors for ischemic heart disease in women impart a differential risk for women compared with men.…”

Section: 31-33mentioning

confidence: 99%

Sex Differences in Ischemic Heart Disease

Aggarwal

Patel

Mehta

et al. 2018

Circ: Cardiovascular Quality and Outcomes

240

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Evolving knowledge of sex-specific presentations, improved recognition of conventional and novel risk factors, and expanded understanding of the sex-specific pathophysiology of ischemic heart disease have resulted in improved clinical outcomes in women. Yet, ischemic heart disease continues to be the leading cause of morbidity and mortality in women in the United States. The important publication by the Institute of Medicine titled "Women's Health Research-Progress, Pitfalls, and Promise," highlights the persistent disparities in cardiovascular disease burden among subgroups of women, particularly women who are socially disadvantaged because of race, ethnicity, income level, and educational attainment. These important health disparities reflect underrepresentation of women in research, with the resultant unfavorable impact on diagnosis, prevention, and treatment strategies in women at risk for cardiovascular disease. Causes of disparities are multifactorial and related to differences in risk factor prevalence, access to care, use of evidence-based guidelines, and social and environmental factors. Lack of awareness in both the public and medical community, as well as existing knowledge gap regarding sex-specific differences in presentation, risk factors, pathophysiology, and response to treatment for ischemic heart disease, further contribute to outcome disparities. There is a critical need for implementation of sex-and gender-specific strategies to improve cardiovascular outcomes. This review is tailored to meet the needs of a busy clinician and summarizes the contemporary trends, characterizes current sex-specific outcome disparities, delineates challenges, and proposes transformative solutions for improvement of the full spectrum of ischemic heart disease clinical care and research in women.by guest on May 7, 2018

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Emergence of Nonobstructive Coronary Artery Disease

Cited by 262 publications

References 111 publications

Sex‐Specific Mechanisms of Resistance Vessel Endothelial Dysfunction Induced by Cardiometabolic Risk Factors

Sex‐Specific Mechanisms of Resistance Vessel Endothelial Dysfunction Induced by Cardiometabolic Risk Factors

Ischemia and No Obstructive Coronary Artery Disease (INOCA): What Is the Risk?

Sex Differences in Ischemic Heart Disease

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