Mechanical work and energetic analysis of eccentric cardiac remodeling in a volume overload heart failure in rats

Abstract

Eccentric cardiac remodeling seen in dilated cardiomyopathy or regurgitant valvular disease is a well-known process of heart failure progression, but its mechanoenergetic profile has not been yet established. We made a volume overload (VO) heart failure model in rats and for the first time investigated left ventricular (LV) mechanical work and energetics in cross-circulated whole heart preparations. Laparotomy was performed in 14 Wistar male rats, and abdominal aortic-inferior vena caval shunt was created in seven rats (VO group). Another seven rats underwent a sham operation without functional shunt (Sham group). LV dimensions changes were followed with weekly transthoracic echocardiography. Three months after surgery, we measured LV pressure and volume and myocardial O(2) consumption in isolated heart cross circulation. LV internal dimensions in both systolic and diastolic phases were significantly increased in the VO group versus the Sham group (P < 0.05). LV pressure was markedly decreased in the VO group versus in the Sham group (P < 0.05). LV end-systolic pressure-volume relation shifted downward, and myocardial O(2) consumption related to Ca(2+) handling significantly decreased. The contractile response to Ca(2+) infusion was attenuated. Nevertheless, the increase in Ca(2+) handling-related O(2) consumption per unit change in LV contractility in the VO group was significantly higher than that in the Sham group (P < 0.05). The levels of sarco(endo)plasmic reticulum Ca(2+)-ATPase 2a protein were reduced in the VO group (P < 0.01). In conclusion, VO failing rat hearts had a character of marked contractile dysfunction accompanied with less efficient energy utilization in the Ca(2+) handling processes. These results suggest that restoring Ca(2+) handling in excitation-contraction coupling would improve the contractility of the myocardium after eccentric cardiac remodeling.

Fig. 1.

Representative M-mode echocardiograms in both volume overloading (VO) and Sham rats 10 wk after aortocaval shunt creation. Left ventricular (LV) internal dimensions at both diastole and systole (LVIDd and LVIDs, respectively) were markedly increased in VO rats compared with those in Sham rats.

Fig. 2.

Serial changes in echocardiographic parameters in VO and Sham rats. The LVIDd, LVIDs, percentage of LV ejection fraction (EF), percentage of LV fractional shortening, and interventricular septal dimensions in diastole (IVSd) are shown. *P < 0.05 vs. Sham. As early as 2 wk after the surgery, LVIDd significantly increased in VO compared with Sham rats. This trend continued up to 12 wk where VO rats exhibited chamber dilatation in diastole that reached 140% of that in Sham rats. The LVIDs in the VO group was significantly increased from 3 wk after shunt compared with that in the Sham group, then continued to increase gradually, and reached 150% of that in Sham rats after 9 wk. The EF in the VO group was increased at first 2 wk after arteriovenous shunt but then decreased gradually to become less than Sham group at 6 wk. The IVSd in the VO group was slightly thinner compared with that in the Sham group. Post Op, postoperation of shunt creation or sham procedure.

Fig. 3.

Whole hearts 3 mo after aortocaval shunt surgery in both VO and Sham rats. The heart in the VO group was markedly enlarged compared with that in the Sham group.

Fig. 4.

Representative LV pressure-volume data and the best-fit curves [LV end-systolic pressure (ESP)-volume relation (ESPVR), LV end-diastolic pressure-volume relation (EDPVR)] in each heart for both VO and Sham groups. The LV ESP was markedly decreased in the VO compared with the Sham heart. The LV ESPVR shifted downward but the EDPVR did not shift upward in the VO heart.

Fig. 5.

Representative LV pressure-volume data and ESPVRs under Ca²⁺ infusion at a rate of 6 ml/h in both hearts from Sham and VO groups. The contractile response to Ca²⁺ infusion was smaller in the VO heart than that in the Sham heart.

Fig. 6.

Representative V̇o₂-pressure-volume area (PVA) data and best-fit linear regression lines (the V̇o₂-PVA linear relations). The V̇o₂ intercept was smaller in the VO heart than in the Sham heart, but the slopes were similar in both VO and Sham hearts.

Fig. 7.

Representative PVA-independent V̇o₂-equivalent maximal elastance (eE_max) midrange LV volume data and best-fit regression line (the PVA-independent V̇o₂-eE_max linear relation; the slope of the relation is the O₂ cost of LV contractility). The O₂ cost of LV contractility in this VO heart was higher than that in the Sham heart.

Fig. 8.

Immunoblotting of sarco(endo)plasmic reticulum Ca²⁺-ATPase 2a (SERCA2a) normalized to GAPDH. The mean protein level of SERCA2a in VO rat hearts was significantly lower (P < 0.01) than that in Sham rat hearts.

Fig. 9.

Immunoblotting of sodium-calcium exchanger (NCX) normalized to GAPDH. The mean protein level of NCX1 in VO rat hearts was significantly higher than that in Sham rat hearts.