Smooth muscle cell hypertrophy of renal cortex arteries with chronic continuous flow left ventricular assist

doi:10.1016/S0003-4975(02)04087-0

The Annals of Thoracic Surgery

Volume 75, Issue 1, January 2003, Pages 178-183

https://doi.org/10.1016/S0003-4975(02)04087-0 Get rights and content

Abstract

Background

Pathophysiology of long-term continuous flow left ventricular assist is not well described. With many of these devices becoming available, it is important to examine for possible pathologic effects. In this study we examined the relationship between diminished pulsatility and pathologic changes in renal cortical arteries.

Methods

Twenty-nine calves were implanted with various continuous flow left ventricular assist systems in a left ventricle-descending thoracic aorta bypass configuration. Pulsatility was quantified by pulse pressure and pulsatility index. Pathologic changes of the renal cortex arteries were described and evaluated by medial thickness, medial/vascular cross-sectional area ratio, and smooth muscle cell count, to quantify hypertrophy or hyperplasia. Seven calves, which underwent a sham-implant, were used as controls.

Results

Systolic arterial pressure, pulse pressure, and pulsatility index were significantly lower and diastolic pressure was significantly higher than before implant in pump-implanted animals. Twenty-three of 29 pump-implanted calves (79.3%) had medial smooth muscle cell hypertrophy in renal cortex arteries, whereas none of sham-implanted calves had any abnormal lesions. When the pump-implanted calves were grouped according to the presence of smooth muscle cell hypertrophy, there was a clear trend toward lower pump flow rate in calves with lesions. Renal function was within the normal range in all calves.

Conclusions

There appears to be a relationship between smooth muscle cell hypertrophy in renal cortex arteries and continuous flow left ventricular assist. Furthermore, although the pathologic changes are likely multifactorial, these lesions appear to be related to lower pump assist rates.

Section snippets

Animals and device description

Twenty-nine male Jersey breed calves (55 to 87 kg) were implanted with a continuous flow LVAS through a left thoracotomy in left ventricle-descending thoracic aorta bypass fashion (implant). There were five pump types, both axial and centrifugal. Seven calves, which underwent a sham implant, were used as controls to exclude the effects of operation and postsurgical responses (control).

Implant procedure

Anesthesia induction was with methohexital (10 mg/kg intravenously) after atropine premedication (30 to 45 mg

Pump and hemodynamic data

At operation, there was no difference in hemodynamic variables between groups. Hemodynamic characteristics after operation are shown in Table 1. In implant animals, systolic arterial pressure was significantly lower and diastolic pressure was significantly higher than control animals, but there was no difference in mean arterial pressure. Pulse pressure and pulsatility index were also lower in implant animals.

Pathologic study

There were two major pathologic changes in the renal cortex arteries in implant

Comment

Although clinical use of the continuous flow LVAS has started, few reports discuss long-term pathophysiologic consequence of continuous flow circulatory support 1, 2, 3. In this study, we found SMC hypertrophy of the renal arteries with long-term continuous flow LVAS assistance. Pathologic changes of the aortic wall properties with continuous flow LVAS have been reported, suggesting that there is SMC atrophy in the tunica media of the aortic wall caused by diminished pulsatility, decreased

Acknowledgements

This work was supported in part by a grant from the National Institutes of Health, 1R01 HL64950–01. We express our gratitude to Dr Kristine Krotec, Mary J. Watach, and Lisa Gordon for their excellent technical assistance.

References (19)

R.A. Sinclair et al.
Renal proliferative arteriopathies and associated glomerular changesa light and electron microscopic study
Hum Pathol
(1976)
P. Ruggenenti et al.
Malignant vascular disease of the kidneynature of the lesions, mediators of disease progression, and the case for bilateral nephrectomy
Am J Kidney Dis
(1996)
L.D. Truong et al.
Experimental chronic renal ischemiamorphologic and immunologic studies
Kidney Int
(1992)
G.M. Wieselthaler et al.
First experiences with outpatient care of patients with implanted axial flow pumps
Artif Organs
(2001)
T.R. Maher et al.
Heartmate left ventricular assist devicesa multigeneration of implanted blood pumps
Artif Organs
(2001)
Frazier OH, Myers TJ, Jarvik RK, et al. Research and development of an implantable, axial-flow left ventricular assist...
T. Nishimura et al.
Diminished vasoconstrictive function caused by long-term nonpulsatile left heart bypass
Artif Organs
(1999)
T. Nishimura et al.
Effects of long-term nonpulsatile left heart bypass on the mechanical properties of the aortic wall
Asaio J
(1999)
T. Nishinaka et al.
Cardiac autonomic nervous function during long-term nonpulsatile left heart bypass
Artif Organs
(1999)

There are more references available in the full text version of this article.

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Original article: cardiovascularSmooth muscle cell hypertrophy of renal cortex arteries with chronic continuous flow left ventricular assist

Abstract

Background

Methods

Results

Conclusions

Section snippets

Animals and device description

Implant procedure

Pump and hemodynamic data

Pathologic study

Comment

Acknowledgements

Hum Pathol

Am J Kidney Dis

Kidney Int

First experiences with outpatient care of patients with implanted axial flow pumps

Artif Organs

Heartmate left ventricular assist devicesa multigeneration of implanted blood pumps

Artif Organs

Diminished vasoconstrictive function caused by long-term nonpulsatile left heart bypass

Artif Organs

Effects of long-term nonpulsatile left heart bypass on the mechanical properties of the aortic wall

Asaio J

Cardiac autonomic nervous function during long-term nonpulsatile left heart bypass

Artif Organs

Original article: cardiovascular
Smooth muscle cell hypertrophy of renal cortex arteries with chronic continuous flow left ventricular assist