Dual ACE-inhibition and AT1 receptor antagonism improves ventricular lusitropy without affecting cardiac fibrosis in the congenic mRen2.Lewis rat

Abstract

Background: Hypertension and left ventricular (LV) hypertrophy often precede diastolic dysfunction and are risk factors for diastolic heart failure. Although pharmacologic inhibition of the renin-angiotensin system (RAS) improves diastolic function and functional capacity in hypertensive patients with LV hypertrophy, the effects of combination therapy with an angiotensin converting enzyme inhibitor (ACEi) and an angiotensin receptor blocker (ARB) are unclear. Method: We assessed the effects of the combined 10-week administration of lisinopril (10 mg/kg/ day, p.o.) and losartan (10 mg/kg/day, p.o.) (LIS/LOS) on diastolic function and LV structure in seven young (5 weeks), prehypertensive congenic mRen2.Lewis male rat, a model of tissue renin overexpression and angiotensin II (Ang II)-dependent hypertension compared to vehicle (VEH) treated (n = 7), age-matched rats. Results: Systolic blood pressures were 64% lower with the combination therapy (p < 0.001), but there were no differences in heart rate or systolic function between groups. RAS inhibition increased myocardial relaxation, defined by tissue Doppler mitral annular descent (e') by 2.2 fold (p < 0.001). The preserved lusitropy in the LIS/LOS-treated rats was accompanied by a reduction in phospholamban-to-SERCA2 ratio (p < 0.001). Despite lower relative wall thicknesses (VEH: 1.56±0.17 versus LIS/LOS: 0.78±0.05) and filling pressures, defined by the transmitral Doppler-to-mitral annular descent ratio (E/e', VEH: 28.7±1.9 versus LIS/LOS: 17.96±1.5), no differences in cardiac collagen were observed. Conclusion: We conclude that the lusitropic benefit of early dual RAS blockade may be due to improved vascular hemodynamics and/or cardiac calcium handling rather than effects on extracellular matrix reduction.