Acute aortocaval fistula: role of low perfusion pressure and subendocardial remodeling on left ventricular function

Abstract

The experimental model of aortocaval fistula is a useful model of cardiac hypertrophy in response to volume overload. In the present study it has been used to investigate the pathologic subendocardial remodeling associated with the development of heart failure during the early phases (day 1, 3, and 7) following volume overload. Compared with sham treated rats, aortocaval fistula rats showed lower systemic blood pressure and higher left ventricular end-diastolic pressure This resulted in lower coronary driving pressure and left ventricular systolic and diastolic dysfunction. Signs of myocyte necrosis, leukocyte cell infiltration, fibroplasia and collagen deposition appeared sequentially in the subendocardium where remodeling was more prominent than in the non-subendocardium. Accordingly, increased levels of TNF-alpha, IL-1 beta, and IL-6, and enhanced MMP-2 activity were all found in the subendocardium of rats with coronary driving pressure ≤ 60 mmHg. The coronary driving pressure was inversely correlated with MMP-2 activity in subendocardium in all time-points studied, and blood flow in this region showed positive correlation with systolic and diastolic function at day 7. Thus the predominant subendocardial remodeling that occurs in response to low myocardial perfusion pressure during the acute phases of aortocaval fistula contributes to early left ventricular dysfunction.

Figure 1

Photomicrographs of the subendocardial layer of the left ventricle of rats with aortocaval fistula in HE, Sirius red and smooth muscle alpha-actin immunohistochemistry-stained tissue sections. Panels a depicts intense cytoplasmatic vacuolization of myocytes, as necrosis signs at day 1; in panel b, inflammatory cell infiltration stained with HE at day 3; in panel c, fibroplasia evidenced by myofibroblasts positively marked for smooth muscle alpha-actin in brown at day 7; and in panel d, Sirius red-stained patch of collagen fibres indicative of fibrosis repair at day 7.

Figure 2

Myocardial blood flow of subendocardial (SE, in black bar) and non-subendocardial (non-SE, in white bar) layers of the left ventricle at day 7. ACF, aortocaval fistula. Statistical analysis: one-way repeated-measure anova complemented by Bonferroni′s test; *P < 0.05 vs. SHAM SE; ^#P < 0.05 vs. SHAM non-SE; ^$P < 0.05 vs. ACF non-SE.

Figure 3

The relationships found between coronary perfusion pressure and blood flow and between coronary blood flow and left ventricular function of rats with aortocaval fistula at day 7. Graphs represent the relationships of coronary driving pressure (CDP) with subendocardial (SE) and non-subendocardial (non-SE) blood flow (panels a and b); and of SE blood flow with +dP/dt and –dP/dt (panels c and d). Statistical analysis: linear regression.

Figure 4

Myeloperoxidase activity (MPO) (panel a), interleukin levels (IL-1β and IL-6; panels b and d respectively) and tumour necrosis factor-alpha level (TNF-α; panel c) measured in the subendocardial (SE) and non-subendocardial (non-SE) layers of the left ventricle of rats with aortocaval fistula (ACF) and coronary driving pressure ≤60 mmHg at days 1, 3 and 7. Statistical analysis: one-way repeated-measure anova complemented by Bonferroni′s test; *P < 0.05 vs. control SE; †P < 0.05 vs. control non-SE.

Figure 5

In the upper panels are represented MMP-2 activity measured in the subendocardial (SE) layer and in the non-subendocardial (non-SE) layer of the left ventricle of rats with aortocaval fistula accordingly to coronary driving pressure (CDP) at days 1, 3 and 7 (panels a, b, and c). In the bottom panels are represented the graphs of the relationships found between CDP and MMP-2 activity in the SE layer at days 1, 3 and 7 (panels d, e and f). Statistical analysis: from a to c, one-way repeated-measure anova complemented by Bonferroni′s test. From d to j, Linear regression analysis; †P < 0.05 vs. >60 mmHg SE; #P < 0.05 vs. >60 mmHg non-SE; *P < 0.05 vs. ≤60 mmHg non-SE.