CBS 2019
CBSMD教育中心
中 文

充血性心力衰竭

Abstract

Recommended Article

Proteomics to Improve Phenotyping in Obese Patients with Heart Failure with Preserved Ejection Fraction Lateral Wall Dysfunction Signals Onset of Progressive Heart Failure in Left Bundle Branch Block Haemodynamic-guided management of heart failure (GUIDE-HF): a randomised controlled trial Clinical Phenogroups in Heart Failure With Preserved Ejection Fraction: Detailed Phenotypes, Prognosis, and Response to Spironolactone 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure Criteria for Iron Deficiency in Patients With Heart Failure 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines Impact of epicardial adipose tissue on cardiovascular haemodynamics, metabolic profile, and prognosis in heart failure

Original Research2019 Apr 10. [Epub ahead of print]

JOURNAL:Nature. Article Link

Nitrosative stress drives heart failure with preserved ejection fraction

Schiattarella GG, Altamirano F, Hill JA et al. Keywords: HFpEF; iNOS-driven dysregulation; IRE1α-XBP1 pathway; mechanism of cardiomyocyte dysfunction

ABSTRACT


Heart failure with preserved ejection fraction (HFpEF) is a common syndrome with high morbidity and mortality 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 and inhibition of constitutive nitric oxide synthase using Nω-nitro-L-arginine methyl ester (L-NAME)-recapitulates the numerous systemic and cardiovascular features of HFpEF in humans. Expression of one of the unfolded protein response effectors, the spliced form of X-box-binding protein 1 (XBP1s), was reduced in the myocardium of our rodent model and in humans with HFpEF. Mechanistically, the decrease in XBP1s resulted from increased activity of inducible nitric oxide synthase (iNOS) and S-nitrosylation of the 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 report that iNOS-driven dysregulation of the IRE1α-XBP1 pathway is a crucial mechanism of cardiomyocyte dysfunction in HFpEF.