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A chicken and egg conundrum: coronary microvascular dysfunction and heart failure with preserved ejection fraction.

Vahagn Ohanyan,H. Sisakian,Punita Peketi,Ankur A. Parikh,W. Chilian

Published 2018 in American Journal of Physiology. Heart and Circulatory Physiology

ABSTRACT

Heart failure (HF) with preserved ejection fraction (HFpEF) is a type of HF characterized by poor diastolic ventricular function and is associated with several cardiovascular and noncardiovascular comorbidities. All types of HF, including HFpEF, are a leading cause of hospital admission in elderly patients (9, 11). It is important to add that HFpEF is predicted to be the one of the leading causes of HF within a decade (9, 11). The prevalence of HFpEF is higher in women and is associated with arterial hypertension, obesity, and diabetes mellitus, although its pathophysiology remains incompletely understood (1, 19). HFpEF is a challenging medical need because most clinical trials have been unsuccessful in devising a therapy, and the cause of the condition is unknown (3, 4, 15). In a recent article published in the American Journal of Physiology-Heart and Circulatory Physiology, Dryer et al. (7a) reported coronary microvascular dysfunction (CMD) in patients with HFpEF. The authors found that coronary flow reserve (CFR) was decreased and an index of microvascular resistance (IMR) was increased in patients with HFpEF compared with control patients without HFpEF. The goal of Dryer et al. was to connect coronary hemodynamics and echocardiographic indexes of cardiac diastolic function to CMD to diastolic dysfunction in patients with HFpEF. Based on the results, CMD was clearly associated with HFpEF. A potential consequence of such microvascular dysfunction would be ischemia, if flow reserve is compromised to the point where flow cannot meet metabolic demands. In the event of ischemia, there would be subsequent inflammation leading to the generation of reactive oxygen species. Such a series of events could lead to a positive feedback situation with the initial inflammation begetting further inflammation and worsening a proinflammatory state. This inflammation may contribute to CMD and myocardial fibrosis. An analysis of 124 hearts of patients with HFpEF demonstrated an inverse relationship between microvascular density and myocardial fibrosis, further suggesting a role of the coronary microcirculation in fibrosis and the pathophysiological mechanism of HFpEF (12). Clinical cardiac MRI studies found that patients with HFpEF also show diffuse interstitial myocardial fibrosis with abnormal extracellular volume and increased stiffness (18). The conundrum regarding HFpEF remains a “which came first, the chicken or the egg” dilemma. For example, does CMD lead to perfusion abnormalities (deficiencies) that lead to microareas of ischemia, myocyte death, fibroblast activation, fibrosis, and diastolic dysfunction? Or does one of the myriad comorbidities lead to inflammation and oxidative stress that induce CMD? This conundrum is further challenged by a third option, that both causes are correct. Systemic inflammation in associated comorbid conditions may lead to reduced nitric oxide bioavailability (16), which is an important factor for the regulation of coronary blood flow (5– 8). On the other hand, systemic inflammation associated with comorbidities of HFpEF lead to expression of transforming growth factorand activation of cardiac fibroblasts into myofibroblasts, increasing collagen type 1 formation. The consequential interstitial fibrosis contributes to high diastolic left ventricular stiffness and could lead to HFpEF (16, 18). As shown by the authors and many other groups (10), there are multiple comorbidities associated with the development of HFpEF. One of the manifestations of HFpEF is myocardial remodeling with elevated left atrial pressure, which leads to left atrial hypertension with clinical symptoms of HF. This may be the pathophysiological explanation of the NH2-terminal pro-B-type natriuretic peptide elevation in patients with HFpEF. We suppose that the pathogenic background for HFpEF development is the left atrial remodeling with an increase in left atrial pressure. Such changes were evident in the Dryer et al. study, vis-à-vis, patients with HFpEF had higher left ventricular end-diastolic pressure, mitral valve inflow E velocity, and E/e=, although left ventricular and left atrial volumes were similar to control subjects. Despite the similar left atrial volumes (between patients with HFpEF and control subjects), mean pulmonary capillary wedge pressure as an indicator of left atrial pressure was higher in patients with HFpEF. The critical aspect of this preceding discussion relates to the defining characteristics of HFpEF. The authors used a set of criteria to define HFpEF, whereas other groups may define this disorder as occurring only with an increase in left atrial volume. The reason we are pointing this out is that differences among clinical studies may pertain to the defining characteristics of the patients. Although the study of Dryer et al. made an important observation (linking CMD to HFpEF), this result needs to be interpreted in the context of the perspective of the population and associated comorbidities. Specifically, the patient number was small (total of 44 patients: 30 patients with HFpEF and 14 Address for reprint requests and other correspondence: V. Ohanyan, Dept. of Integrative Medical Sciences, Northeast Ohio Medical Univ., Rootstown, OH 44272 (e-mail: vohanyan@neomed.edu). Am J Physiol Heart Circ Physiol 314: H1262–H1263, 2018; First published March 16, 2018; doi:10.1152/ajpheart.00154.2018.

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