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Old spontaneously hypertensive rats gather together typical features of human chronic left-ventricular dysfunction with preserved ejection fraction

Marzak, Halima; Ayme-Dietrich, Estellea; Lawson, Rolanda; Mokni, Walida; Combe, Royb; Becker, Julienb; Fertak, Lahcen Elb; Champy, Marie-Franceb; Monassier, Laurenta,b

doi: 10.1097/HJH.0000000000000159

Objective: Heart failure with preserved left-ventricular ejection fraction (HF-PEF) is an entity leading to pulmonary congestion because of impaired diastolic filling. This syndrome usually strikes those who have experienced a long history of hypertension or metabolic risk factors. Pathophysiological mechanisms are not fully understood, and standard therapy is not established. Relevant preclinical models are still lacking. The aim of this work was to evaluate aging spontaneously hypertensive rats (SHRs) as a model of HF-PEF.

Methods: Serial echocardiographic and blood pressure (BP) measurements were performed in 28, 36, 43, 47 and 51-week-old SHRs and their normotensive controls (Wistar–Kyoto rats). In 52–53-week-old animals, final investigations included ECG, invasive left-ventricular (LV) and aortic catheterization, brain natriuretic peptide (BNP) plasma concentrations, ventricular reverse transcription-qPCR evaluations (β-myosin heavy chain, atrial natriuretic peptide, BNP, sarco/endoplasmic reticulum calcium ATPase 2a and collagens 1a, 3a and 2a) and cardiac histology.

Results: SHRs develop a progressive alteration of the early diastole, some of the echocardiographic parameters being not sensitive to BP reduction by the calcium blocker, nicardipine. The systolic function evaluated by echocardiography and invasive catheterization was preserved. When the observation period was over, an increase in collagen synthesis and deposits were identified in subendocardial layers. This attested a probable myocardial ischemia that was confirmed by ECG changes of the ST segment. BNP increased in the blood and at the mRNA level in the myocardium.

Conclusion: When aging, SHRs progressively develop HF-PEF showed by impaired LV relaxation and hypertrophy, BNP increase but preserved contractility and fibrosis. This model seems pertinent for further pharmacological preclinical studies in the field.

aLaboratoire de Neurobiologie et Pharmacologie Cardiovasculaire, Faculté de Médecine, Fédération de Médecine translationnelle, Université et Centre Hospitalier de Strasbourg, Strasbourg

bMouse Clinical Institute, Illkirch-Graffenstaden, France

Correspondence to Laurent Monassier, MD, PhD, Laboratoire de Neurobiologie et Pharmacologie Cardiovasculaire, Faculté de Médecine, 11 rue Humann, 67085, Strasbourg Cedex, France. Tel: +33368853392; fax: +33368853388; e-mail:

Abbreviations: β-MHC, myosin heavy chain β; ANP, atrial natriuretic peptide; BNP, brain natriuretic peptide; BP, blood pressure; DAP, diastolic arterial pressure; EDLVD, left-ventricular end diastolic diameter; ESLVD, left-ventricular end systolic diameter; HF-PEF, heart failure with preserved ejection fraction; HR, heart rate; IVRT, isovolumetric relaxation time; LV, left-ventricle; LVSP, left-ventricular systolic pressure; LVW, left-ventricular weight; PW, posterior wall; SAP, systolic arterial pressure; SERCA, sarco/endoplasmic reticulum calcium ATPase; SF, shortening fraction; SHRs, spontaneously hypertensive rats; SW, septal wall; WKYs, Wistar–Kyoto rats

Received 30 September, 2013

Revised 28 January, 2014

Accepted 1 February, 2014

© 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins