Einc, Elastic incremental modulus; eple, eplerenone; ESV, end-systolic ..... the Weigert's orcein-fuchsin method to determine the medial cross sectional ... measuring the percent of fibrotic area (evidenced in magenta staining) of whole heart.
Preventive and chronic mineralocorticoid receptor antagonism is highly beneficial in obese SHHF rats Short running title: Chronic MRA effects on obesity and HF development
G Youcef1,2,3,4, A Olivier1,2,3,5, N Nicot4, A Muller4, C Deng2,3,6, C Labat1,2,3, R Fay5,7, R-M Rodriguez-Guéant 2,3,5,8, C Leroy1,7, F Jaisser5,7, F Zannad1,2,3,5,7, P Lacolley1,2,3,5, L Vallar4 and A Pizard1,2,3,5,7 1
UMRS U1116 Inserm, Nancy, France,
Lorraine, Nancy, France,
4
2
Fédération de Recherche 3209, Nancy, France,
3
Université de
Genomics Research Unit, Luxembourg Institute of Health, Luxembourg,
6
5
CHU
7
Nancy, Nancy, France, UMR 7365 CNRS, Nancy, France, CIC 1433 Inserm, Pierre Drouin, Nancy, France, 8 U954 Inserm, Nancy, France.
BJP editorial To view the IUPHAR/BPS Guide to PHARMACOLOGY visit (http://onlinelibrary.wiley.com/doi/10.1111/bph.13112/epdf) Correspondence Anne Pizard, Inserm U1116, CHRU Nancy, rue du Morvan, Vandoeuvre-lès-Nancy 54500 France Email: anne.pizard @inserm.fr Phone: 00 33(0)3-83-15-52-97 Fax: 00 33(0)3-83-15-73-24
Authorship contribution statement:
GY, AO, NN, AM, CD, RMRG, CLe and AP performed the research AP, FZ and LV designed the research study RMRG, CL, RF and AM contributed essential tools AP, GY, AO, CL, RF, FZ and PL analysed the data AP, GY, AO, FJ, FZ, PL and LV wrote the paper This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/bph.13479 This article is protected by copyright. All rights reserved.
Abbreviations aldo, aldosterone; BMI, body mass index; BNP, brain natriuretic peptide; cp, mutant cp allele of the leptin receptor; CSAA, cross sectional adipocyte area; d, diastole; DBP, diastolic blood pressure; EDT, E wave deceleration time; EDV, end-diastolic volume; EF, ejection fraction; Einc, Elastic incremental modulus; eple, eplerenone; ESV, end-systolic volume; FFA, free fatty acids; Fn1, fibronectin 1; HDL, high density lipoproteins; HF, heart failure; HW, heart weight; IR, insulin resistance; IVRT, isovolumetric relaxation time; LDL, low density lipoproteins; Lepr, leptin receptor; LV, left ventricle; LVID, Left ventricle internal diameter; MBP, mean blood pressure; MCSA, medial cross sectional area; MR, mineralocorticoid receptor; MRA, mineralocorticoid receptor antagonist; Nox4, NADPH oxidase 4; PP, pulse pressure; PWT, posterior wall thickness; RAAS, renin-angiotensin aldosterone system; s, systole; SBP, systolic blood pressure; SEM, standard error of the mean.; SHHF, spontaneously hypertensive heart failure; SWT, septum wall thickness; TDI, tissue doppler imaging; TG, triglycerides; TGF, transforming growth factor; TL, tibia length; TTE, transthoracic echocardiography; VAT, visceral adipose tissue; Vim, vimentin; WS, wall stress
BACKGROUND AND PURPOSE Mineralocorticoid receptor (MR) activation contributes to heart failure (HF) progression. Its over-activation in obesity is suggested to accelerate cardiac remodelling and HF development. Given that MR antagonists (MRA) are beneficial in chronic HF patients, we hypothesised that early MRA treatment may target obesity-related disorders and consequently delay the development of HF. EXPERIMENTAL APPROACH Twenty spontaneously hypertensive HF dyslipidemic obese SHHFcp/cp rats and eighteen nondyslipidemic lean SHHF+/+ controls underwent regular monitoring for their metabolic and cardiovascular phenotypes with or without MRA (eplerenone (eple), 100 mg.kg-1.day-1) from 1.5 to 12.5 months of age. KEY RESULTS Eleven-months eple treatment in obese rats (SHHFcp/cpeple) reduced obesity-related metabolic disorders observed in untreated SHHFcp/cp rats by minimising weight gain (563±43 vs. 634±27 g), triglycerides (8.29±1.93 vs. 20.50±2.60 g.L-1) and total cholesterol levels (2.67±0.24 vs. 4.25±0.33 g.L-1) and by preserving adiponectinemia (22.7±1.6 vs. 11.9±0.7
This article is protected by copyright. All rights reserved.
µg. mL-1). MRA treatment predominantly preserved diastolic and systolic functions in obese rats by alleviating eccentric cardiac hypertrophy observed in untreated SHHFcp/cp animals (left ventricular mass 1760±72 vs. 2195±73 mg) and preserving ejection fraction (70±1 vs. 59±1 %). MRA also improved survival independently of pressure effects. CONCLUSION AND IMPLICATIONS Early chronic eple treatment resulted in a delay in cardiac remodelling and HF onset in both SHHF+/+ and SHHFcp/cp rats whereas SHHFcp/cp rats further benefited from MRA treatment through reduction of their obesity and dyslipidemia. These findings suggest that preventive MRA therapy may provide greater derived benefits in obese patients with cumulating risk factors of developing cardiovascular complications. Key Words: aldosterone, adipocyte, heart failure, mineralocorticoid receptor antagonism, and prevention Introduction Over 23 million patients are diagnosed with heart failure (HF) worldwide (McMurray et al., 1998) among whom 32% to 49% are obese (body mass index, BMI≥30kg.m-2) and 31% to
40% are overweight (25≤BMI
