Coronary Microvascular Dysfunction and Heart Failure with Preserved Ejection Fraction - implications for Chronic Inflammatory Mechanisms.

Coronary Microvascular Dysfunction (CMD) is now considered one of the key underlying pathologies responsible for the development of both acute and chronic cardiac complications. It has been long recognized that CMD contributes to coronary no-reflow, which occurs as an acute complication during percutaneous coronary interventions. More recently, CMD was proposed to play a mechanistic role in the development of left ventricle diastolic dysfunction in heart failure with preserved ejection fraction (HFpEF). Emerging evidence indicates that a chronic low-grade pro-inflammatory activation predisposes patients to both acute and chronic cardiovascular complications raising the possibility that pro-inflammatory mediators serve as a mechanistic link in HFpEF. Few recent studies have evaluated the role of the hyaluronan-CD44 axis in inflammation-related cardiovascular pathologies, thus warranting further investigations. This review article summarizes current evidence for the role of CMD in the development of HFpEF, focusing on molecular mediators of chronic proinflammatory as well as oxidative stress mechanisms and possible therapeutic approaches to consider for treatment and prevention.

Role of Adipose Tissue Endothelial ADAM17 in Age-Related Coronary Microvascular Dysfunction.

OBJECTIVE: A disintegrin and metalloproteinase ADAM17 (tumor necrosis factor-α [TNF]-converting enzyme) regulates soluble TNF levels. We tested the hypothesis that aging-induced activation in adipose tissue (AT)-expressed ADAM17 contributes to the development of remote coronary microvascular dysfunction in obesity. APPROACH AND RESULTS: Coronary arterioles (CAs, ≈90 µm) from right atrial appendages and mediastinal AT were examined in patients (aged: 69±11 years, BMI: 30.2±5.6 kg/m2) who underwent open heart surgery. CA and AT were also studied in 6-month and 24-month lean and obese mice fed a normal or high-fat diet. We found that obesity elicited impaired endothelium-dependent CA dilations only in older patients and in aged high-fat diet mice. Transplantation of AT from aged obese, but not from young or aged, mice increased serum cytokine levels, including TNF, and impaired CA dilation in the young recipient mice. In patients and mice, obesity was accompanied by age-related activation of ADAM17, which was attributed to vascular endothelium-expressed ADAM17. Excess, ADAM17-shed TNF from AT arteries in older obese patients was sufficient to impair CA dilation in a bioassay in which the AT artery was serially connected to a CA. Moreover, we found that the increased activity of endothelial ADAM17 is mediated by a diminished inhibitory interaction with caveolin-1, owing to age-related decline in caveolin-1 expression in obese patients and mice or to genetic deletion of caveolin-1. CONCLUSIONS: The present study indicates that aging and obesity cooperatively reduce caveolin-1 expression and increase vascular endothelial ADAM17 activity and soluble TNF release in AT, which may contribute to the development of remote coronary microvascular dysfunction in older obese patients.