Reduced pulsatility induces periarteritis in kidney: role of the local renin-angiotensin system

Abstract

Objective: The need for pulsatility in the circulation during long-term mechanical support has been a subject of debate. We compared histologic changes in calf renal arteries subjected to various degrees of pulsatile circulation in vivo. We addressed the hypothesis that the local renin-angiotensin system may be implicated in these histologic changes.

Methods and results: Sixteen calves were implanted with devices giving differing degrees of pulsatile circulation: 6 had a continuous flow left ventricular assist device (LVAD); 6 had a continuous flow right ventricular assist device (RVAD); and 4 had a pulsatile total artificial heart (TAH). Six other calves were histologic and immunohistochemical controls. In the LVAD group, the pulsatility index was significantly lower (0.28 +/- 0.07 LVAD vs 0.56 +/- 0.08 RVAD, vs 0.53 +/- 0.10 TAH; P < 0.01), and we observed severe periarteritis in all cases in the LVAD group. The number of angiotensin II type 1 receptor-positive cells and angiotensin converting enzyme-positive cells in periarterial areas was significantly higher in the LVAD group (angiotensin II type 1 receptor: 350 +/- 139 LVAD vs 8 +/- 6 RVAD, vs 3 +/- 2 TAH, vs 3 +/- 2 control; P < .001; angiotensin-converting enzyme: 325 +/- 59 LVAD vs 6 +/- 4 RVAD, vs 6 +/- 5 TAH, vs 3 +/- 1 control; P < .001).

Conclusions: The reduced pulsatility produced by a continuous flow LVAD implantation induced severe periarteritis in the kidneys. The local renin-angiotensin system was up-regulated in the inflammatory cells only in the continuous flow LVAD group.

Fig. 1

Hematoxylin-eosin (HE) staining of renal arteries in the corticomedullary junction area (magnification x40). (A) Continuous flow left ventricular assist device (LVAD) implanted calf. Extensive hyperplasia of the intima, media, and adventitia of the arteries is evident, along with mononuclear inflammatory cell infiltrates. (B) Continuous flow right ventricular assist device (RVAD) implanted calf. (C) Pulsatile total artificial heart (TAH) implanted calf. (D) Control normal calf. There are no morphological changes, suggesting that periarteritis exists in the other groups (B, C, D).

Fig. 2

HE staining of kidney in continuous flow LVAD implanted calf. (A) The corticomedullary junction area (magnification x40). The medium-size arteries, such as the arcuate artery and interlobular arteries, showed wall thickening and the presence of inflammatory cells. (B) The arcuate artery: expanded view of area encircled with yellow line in A (magnification x100), showing abundant mononuclear cells accumulating in the periarterial area. The artery structure is relatively conserved and has few inflammatory cells in the vascular wall. There is extensive hyperplasia of the smooth muscle layer of the media of the vessels.

Fig. 3

Histopathology and immunohistochemistry of serial sections of renal arteries from a calf implanted with a continuous flow LVAD (magnification x200). HE staining of the interlobular artery (A) and cortical interstitial area (B). Immunohistochemical staining for angiotensin II type 1 receptor (AT1R) (C, D) and angiotensin-converting enzyme (ACE) (E, F). AT1R is observed in the endothelial cells and inflammatory cells that infiltrated the periarterial area (C) and cortical interstitial area (D). ACE is observed in renal tubuli, endothelial cells, the smooth muscle layer and in inflammatory cells that had infiltrated the periarterial area (E) and cortical interstitial area (F).

Fig. 4

The number of inflammatory cells in periarterial areas from the continuous flow LVAD group was significantly higher than in the other groups. † p < 0.01.

Fig. 5

The number of AT1R-positive cells in periarterial areas from the continuous flow LVAD group was significantly higher than in the other groups. * p < 0.001.

Fig. 6

The number of ACE-positive cells in periarterial areas from the continuous flow LVAD group was significantly higher than in the other groups. * p < 0.001.

Fig. 7

Immunohistochemical staining for endothelial nitric oxide synthase (eNOS) (magnification x200). (A) Continuous flow LVAD implanted calf. The immunohistochemical study showed a prominent expression of eNOS in the endothelium of renal arteries that appeared more prominent in LVAD group than other group. (B) Continuous flow RVAD implanted calf. (C) Pulsatile TAH implanted calf. (D) Control normal calf.