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      Coronary microvascular dysfunction in hypertrophy and heart failure

      1 , 2 , 3 , 4 , 5 , 6 , 7 , 1 , 8 , 2 , 3
      Cardiovascular Research
      Oxford University Press (OUP)

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          Abstract

          Left ventricular (LV) hypertrophy (LVH) is a growth in left myocardial mass mainly caused by increased cardiomyocyte size. LVH can be a physiological adaptation to physical exercise or a pathological condition either primary, i.e. genetic, or secondary to LV overload. Patients with both primary and secondary LVH have evidence of coronary microvascular dysfunction (CMD). The latter is mainly due to capillary rarefaction and adverse remodelling of intramural coronary arterioles due to medial wall thickening with an increased wall/lumen ratio. An important feature of this phenomenon is the diffuse nature of this remodelling, which generally affects the coronary microvessels in the whole of the left ventricle. Patients with LVH secondary to arterial hypertension can develop both heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF). These patients can develop HFrEF via a ‘direct pathway’ with an interval myocardial infarction and also in its absence. On the other hand, patients can develop HFpEF that can then progress to HFrEF with or without interval myocardial infarction. A similar evolution towards LV dysfunction and both HFpEF and HFrEF can occur in patients with hypertrophic cardiomyopathy, the most common genetic cardiomyopathy with a phenotype characterized by massive LVH. In this review article, we will discuss both the experimental and clinical studies explaining the mechanisms responsible for CMD in LVH as well as the evidence linking CMD with HFpEF and HFrEF.

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          Most cited references107

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          Effect of phosphodiesterase-5 inhibition on exercise capacity and clinical status in heart failure with preserved ejection fraction: a randomized clinical trial.

          Studies in experimental and human heart failure suggest that phosphodiesterase-5 inhibitors may enhance cardiovascular function and thus exercise capacity in heart failure with preserved ejection fraction (HFPEF). To determine the effect of the phosphodiesterase-5 inhibitor sildenafil compared with placebo on exercise capacity and clinical status in HFPEF. Multicenter, double-blind, placebo-controlled, parallel-group, randomized clinical trial of 216 stable outpatients with HF, ejection fraction ≥50%, elevated N-terminal brain-type natriuretic peptide or elevated invasively measured filling pressures, and reduced exercise capacity. Participants were randomized from October 2008 through February 2012 at 26 centers in North America. Follow-up was through August 30, 2012. Sildenafil (n = 113) or placebo (n = 103) administered orally at 20 mg, 3 times daily for 12 weeks, followed by 60 mg, 3 times daily for 12 weeks. Primary end point was change in peak oxygen consumption after 24 weeks of therapy. Secondary end points included change in 6-minute walk distance and a hierarchical composite clinical status score (range, 1-n, a higher value indicates better status; expected value with no treatment effect, 95) based on time to death, time to cardiovascular or cardiorenal hospitalization, and change in quality of life for participants without cardiovascular or cardiorenal hospitalization at 24 weeks. Median age was 69 years, and 48% of patients were women. At baseline, median peak oxygen consumption (11.7 mL/kg/min) and 6-minute walk distance (308 m) were reduced. The median E/e' (16), left atrial volume index (44 mL/m2), and pulmonary artery systolic pressure (41 mm Hg) were consistent with chronically elevated left ventricular filling pressures. At 24 weeks, median (IQR) changes in peak oxygen consumption (mL/kg/min) in patients who received placebo (-0.20 [IQR, -0.70 to 1.00]) or sildenafil (-0.20 [IQR, -1.70 to 1.11]) were not significantly different (P = .90) in analyses in which patients with missing week-24 data were excluded, and in sensitivity analysis based on intention to treat with multiple imputation for missing values (mean between-group difference, 0.01 mL/kg/min, [95% CI, -0.60 to 0.61]). The mean clinical status rank score was not significantly different at 24 weeks between placebo (95.8) and sildenafil (94.2) (P = .85). Changes in 6-minute walk distance at 24 weeks in patients who received placebo (15.0 m [IQR, -26.0 to 45.0]) or sildenafil (5.0 m [IQR, -37.0 to 55.0]; P = .92) were also not significantly different. Adverse events occurred in 78 placebo patients (76%) and 90 sildenafil patients (80%). Serious adverse events occurred in 16 placebo patients (16%) and 25 sildenafil patients (22%). Among patients with HFPEF, phosphodiesterase-5 inhibition with administration of sildenafil for 24 weeks, compared with placebo, did not result in significant improvement in exercise capacity or clinical status. clinicaltrials.gov Identifier: NCT00763867.
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            Coronary microvascular rarefaction and myocardial fibrosis in heart failure with preserved ejection fraction.

            Characterization of myocardial structural changes in heart failure with preserved ejection fraction (HFpEF) has been hindered by the limited availability of human cardiac tissue. Cardiac hypertrophy, coronary artery disease (CAD), coronary microvascular rarefaction, and myocardial fibrosis may contribute to HFpEF pathophysiology.
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              Nitrosative stress drives heart failure with preserved ejection fraction

              Heart failure with preserved ejection fraction (HFpEF) is a common, morbid, and mortal syndrome for which there are no evidence-based therapies. Here, we report that concomitant metabolic and hypertensive stress in mice elicited by a combination of high fat diet (HFD) and constitutive nitric oxide (NO) synthase inhibition by N [w] -nitro-l-arginine methyl ester (L-NAME) recapitulates the numerous systemic and cardiovascular features of human HFpEF. One of the unfolded protein response (UPR) effectors, the spliced form of X-box binding protein 1 (Xbp1s), was reduced in the myocardium of both experimental and human HFpEF. Mechanistically, the decrease in Xbp1s resulted from increased inducible NO synthase (iNOS) activity and S-nitrosylation of endonuclease inositol-requiring protein 1α (IRE1α), culminating in defective Xbp1 splicing. Pharmacological or genetic suppression of iNOS, or cardiomyocyte-restricted overexpression of Xbp1s, each ameliorated the HFpEF phenotype. We have unveiled iNOS-driven dysregulation of IRE1α-Xbp1s as a crucial mechanism of cardiomyocyte dysfunction in HFpEF.
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                Author and article information

                Journal
                Cardiovascular Research
                Oxford University Press (OUP)
                0008-6363
                1755-3245
                March 15 2020
                March 01 2020
                January 30 2020
                March 15 2020
                March 01 2020
                January 30 2020
                : 116
                : 4
                : 806-816
                Affiliations
                [1 ]Vita Salute University and San Raffaele Hospital, Milano, Italy
                [2 ]Berlin Institute of Health Center for Regenerative Therapies (BCRT), Charité—Universitätsmedizin Berlin, Berlin, Germany
                [3 ]German Center for Cardiovascular Research (DZHK), Partner Site Berlin, Berlin, Germany
                [4 ]Department of Cardiology, Charité—Universitätsmedizin Berlin, Campus Virchow Klinikum, Berlin, Germany
                [5 ]Cardiovascular Imaging Program, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
                [6 ]Department of Radiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
                [7 ]Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
                [8 ]CNR IBFM, Segrate, Italy
                Article
                10.1093/cvr/cvaa023
                31999329
                38a10b3c-def5-452d-9568-d61844b81434
                © 2020

                https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model

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