Nitric oxide-sensitive guanylyl cyclase stimulation improves experimental heart failure with preserved ejection fraction

Item Type:	Article
Title:	Nitric oxide-sensitive guanylyl cyclase stimulation improves experimental heart failure with preserved ejection fraction
Creators Name:	Wilck, N. and Markó, L. and Balogh, A. and Kräker, K. and Herse, F. and Bartolomaeus, H. and Szijártó, I.A. and Gollasch, M. and Reichhart, N. and Strauss, O. and Heuser, A. and Brockschnieder, D. and Kretschmer, A. and Lesche, R. and Sohler, F. and Stasch, J.P. and Sandner, P. and Luft, F. and Müller, D.N. and Dechend, R. and Haase, N.
Abstract:	Heart failure with preserved ejection fraction (HFpEF) can arise from cardiac and vascular remodeling processes following long-lasting hypertension. Efficacy of common HF therapeutics is unsatisfactory in HFpEF. Evidence suggests that stimulators of the nitric oxide-sensitive soluble guanylyl cyclase (NOsGC) could be of use here. We aimed to characterize the complex cardiovascular effects of NOsGC stimulation using NO-independent stimulator BAY 41-8543 in a double-transgenic rat (dTGR) model of HFpEF. We show a drastically improved survival rate of treated dTGR. We observed less cardiac fibrosis, macrophage infiltration, and gap junction remodeling in treated dTGR. Microarray analysis revealed that treatment of dTGR corrected the dysregulateion of cardiac genes associated with fibrosis, inflammation, apoptosis, oxidative stress, and ion channel function toward an expression profile similar to healthy controls. Treatment reduced systemic blood pressure levels and improved endothelium-dependent vasorelaxation of resistance vessels. Further comprehensive in vivo phenotyping showed an improved diastolic cardiac function, improved hemodynamics, and less susceptibility to ventricular arrhythmias. Short-term BAY 41-8543 application in isolated untreated transgenic hearts with structural remodeling significantly reduced the occurrence of ventricular arrhythmias, suggesting a direct nongenomic role of NOsGC stimulation on excitation. Thus, NOsGC stimulation was highly effective in improving several HFpEF facets in this animal model, underscoring its potential value for patients.
Keywords:	Angiotensinogen, Animal Disease Models, Blood Pressure, Cardiac Arrhythmias, Chronic Disease, Echocardiography, Heart Failure, Heart Ventricles, Isolated Heart Preparation, Morpholines, Oral Administration, Preclinical Drug Evaluation, Pyrimidines, Renin, Soluble Guanylyl Cyclase, Stroke Volume, Survival Rate, Transgenic Rats, Treatment Outcome, Animals, Rats
Source:	JCI Insight
ISSN:	2379-3708
Publisher:	American Society for Clinical Investigation
Volume:	3
Number:	4
Page Range:	e96006
Date:	22 February 2018
Official Publication:	https://doi.org/10.1172/jci.insight.96006
External Fulltext:	View full text on PubMed Central
PubMed:	View item in PubMed

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