Ventricular structure and function in aged dogs with renal hypertension: a model of experimental diastolic heart failure

Abstract

Background: Heart failure (HF) with normal ejection fraction (diastolic HF [DHF]) usually occurs in elderly patients with hypertension. The presence and significance of altered systolic and diastolic ventricular function in DHF is increasingly controversial. Our objective was to develop a clinically relevant large-animal model to better understand the pathophysiology of DHF.

Methods and results: Ventricular structure and function were characterized in young control (YC group; n=6), old control (OC group; n=7), and old dogs made hypertensive by renal wrapping (experimental DHF [ExDHF] group; n=8). The ExDHF group was associated with normal left ventricular (LV) volume, increased LV mass, and myocardial fibrosis. LV relaxation was impaired in ExDHF (tau=53+/-6 ms) compared with OC (tau=35+/-3 ms; P<0.05) and YC (tau=33+/-6 ms; P<0.05) dogs. The percent diastole at which relaxation is complete was increased in ExDHF (116+/-30%) compared with OC (69+/-8%; P<0.05) and YC (35+/-5%; P<0.05) dogs. The coefficient of LV diastolic stiffness was similar in OC, YC, and ExDHF dogs. Diastolic pressures increased dramatically in response to increases in blood pressure. End-systolic LV stiffness was enhanced in ExDHF dogs and after load enhancement of myocardial performance was maintained. Arterial stiffness was increased in ExDHF dogs.

Conclusions: Aged dogs with chronic hypertension exhibit LV hypertrophy and fibrosis with impaired LV relaxation but no increase in the coefficient of LV diastolic stiffness. LV systolic and arterial stiffness are increased, which may exacerbate load-dependent impairment of relaxation and contribute to increased filling pressures with hypertensive episodes. This model mimics many of the structural and functional characteristics described in the limited studies of human DHF and provides insight into the pathogenesis of DHF.

Figure 1

Systolic (SBP), diastolic (DBP), and mean (MAP) arterial BPs and pulse pressure (PP) measured in conscious dogs after renal wrapping (ExDHF) or sham procedure in YC and OC dogs. Inset shows MAP over time in ExDHF, YC, and OC dogs.

Figure 2

LV end-diastolic volume (LVEDV), LV mass to body weight ratio, collagen volume fraction (% fibrosis), and representative picrosirius red stained–LV sections in YC, OC, and ExDHF dogs.

Figure 3

τ calculated assuming a zero (left) or non-zero (right) asymptote in YC and OC dogs and in ExDHF dogs before (ExDHF_nlBP) and after (ExDHF_↑BP) phenylephrine.

Figure 4

Top, Representative LV pressure tracings (end-systole to end-systole) from YC (left), OC (middle), and ExDHF (left) groups before (black) and after (red) phenylephrine infusion. The point at which relaxation is complete (end-systole+3.5×τ) is shown. Bottom, Percent diastole at which relaxation is complete in YC and OC dogs and in ExDHF dogs before (ExDHF_nlBP) and after (ExDHF_↑BP) phenylephrine.

Figure 5

Coefficient of passive LV diastolic stiffness (β; top) and curve-fitting constant (α; middle) in YC, OC, and ExDHF dogs. Bottom, Representative end-diastolic pressure-volume relationships in YC (black), OC (blue), and ExDHF (red) dogs.

Figure 6

End-systolic elastance (Ees) (A), Ees indexed to LV mass/body weight (B), and preload recruitable stroke work (PRSW) (C) in YC, OC, and ExDHF dogs. D, Representative end-systolic pressure-volume relationships in YC (black), OC (blue), and ExDHF (red) dogs. E, Correlation between Ees and collagen volume fraction (CVF). F, Correlation between Ees and LV mass index.

Figure 7

Representative examples of afterload enhancement of LV performance observed in OC and ExDHF dogs with a leftward shift in the end-systolic pressure-volume relationships observed after phenylephrine (PE) infusion. BL indicates baseline; IVC, inferior vena cava.

Figure 8

Arterial elastance (Ea) in YC, OC, and ExDHF (left) and in OC and ExDHF dogs after volume expansion (right).