Volume 16 Supplement 1
The sGC stimulator BAY 41-8543 in a rat model of hypertension-induced heart failure
© Haase et al. 2015
Published: 2 September 2015
Hypertension with left ventricular hypertrophy is a major cause of diastolic heart failure (DHF). Due to its high prevalence and high rate of mortality, DHF represents a major challenge in today's cardiovascular medicine; with limited therapeutic options. Soluble guanylate cyclase (sGC) stimulation is emerging as a promising treatment option in DHF, and is currently under investigation in preclinical and clinical studies. The present study investigates the effect of the sGC stimulator BAY 41-8543 in a transgenic rat model of hypertension-induced heart failure.
We used 4 week-old male double transgenic rats expression both human renin and angiotensinogen genes (dTGRs). At 7 weeks of age, dTGRs exhibit striking cardiac hypertrophy with fibrosis and inflammation, ventricular arrhythmias and heart failure, which is accompanied with high mortality. We compared vehicle-treated dTGR (receiving 10% transcutol, 20% cremophor, 70% water) to those receiving 3 mg/kg/d BAY 41-8543, and vehicle-treated SD control rats (single oral dose per day for 3 weeks). We performed in vivo echocardiography, hemodynamic monitoring, cardiac electrophysiology studies and blood pressure measurements. Endothelial function was measured in isolated mesenteric arteries. Transcriptional analyses in cardiac tissue were performed using qRT-PCR and gene-microarray. Cardiac tissue was analyzed using histology.
Treatment of dTGRs with BAY 41-8543 resulted in 100% survival at week 7, whereas only 24% of vehicle-treated dTGRs survived. Mean arterial pressure in dTGRs was significantly by BAY 41-8543 reduced (197 ± 11 mmHg vehicle vs 133 ± 4 mmHg BAY 41-8543). In addition, BAY 41-8543 significantly decreased in vivo total peripheral resistance and improved endothelium-dependent vasorelaxation of isolated mesenteric arteries. Furthermore BAY 41-8543 prevented fibrosis and inflammation of cardiac tissue. Echocardiography and invasive hemodynamic monitoring revealed BAY 41-8543 significantly increased ejection fraction and cardiac output in dTGR, whereas vehicle-treated had preserved systolic function but reduced diastolic function. In addition, diastolic compliance was significantly enhanced by BAY 41-8543, as shown by myocardial strain analysis and end-diastolic pressure volume relationship (EDPVR); indicative of an improved diastolic function. In vivo programmed electrical stimulation revealed a high ventricular tachycardia induction rate in vehicle-treated dTGRs (46%), which was significantly reduced in BAY 41-8543-treated dTGR (11%). Myocardial gene-microarray analysis showed a reversal of dysregulated genes in dTGR by BAY 41-8543 treatment.
Our data demonstrate that BAY 41-8543 improves survival and cardiac performance in a transgenic rat model of hypertension-induced DHF. We postulate that treatment of DHF with sGC stimulators offers a novel therapeutic potential for humans.
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.