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

Objective: Heart failure with preserved left-ventricularejection fraction (HF-PEF) is an entity leading to pulmonarycongestion because of impaired diastolic filling. Thissyndrome usually strikes those who have experienceda long history of hypertension or metabolic risk factors.Pathophysiological mechanisms are not fully understood,and standard therapy is not established. Relevantpreclinical models are still lacking. The aim of this workwas 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 and51-week-old SHRs and their normotensive controls(Wistar–Kyoto rats). In 52–53-week-old animals, finalinvestigations included ECG, invasive left-ventricular (LV)and aortic catheterization, brain natriuretic peptide (BNP)plasma concentrations, ventricular reverse transcription-qPCR evaluations (b-myosin heavy chain, atrial natriureticpeptide, BNP, sarco/endoplasmic reticulum calcium ATPase2a and collagens 1a, 3a and 2a) and cardiac histology.Results: SHRs develop a progressive alteration of theearly diastole, some of the echocardiographic parametersbeing not sensitive to BP reduction by the calcium blocker,nicardipine. The systolic function evaluated byechocardiography and invasive catheterization waspreserved. When the observation period was over,an increase in collagen synthesis and deposits wereidentified in subendocardial layers. This attested a probablemyocardial ischemia that was confirmed by ECG changesof the ST segment. BNP increased in the blood and at themRNA level in the myocardium.Conclusion: When aging, SHRs progressively developHF-PEF showed by impaired LV relaxation and hypertrophy,BNP increase but preserved contractility and fibrosis. Thismodel seems pertinent for further pharmacologicalpreclinical studies in the field.Keywords: cardiac hypertrophy, diastole, ejection fraction,hypertension, ischemia, nicardipine, spontaneouslyhypertensive ratAbbreviations: b-MHC, myosin heavy chain b; ANP, atrialnatriuretic 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 withpreserved 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