Abstract. Rodents do not develop spontaneous atherosclerosis. Currently, there is no good animal model to study the effect of uremia on atherosclerosis. This study evaluated whether apolipoprotein E knockout (ApoeϪ/Ϫ) mice are useful to study the effect of renal dysfunction on cardiovascular risk. ApoeϪ/Ϫ mice have decreased serum apolipoprotein E and exhibit lipid abnormalities and atherosclerosis even on a lowcholesterol diet. Ten-wk-old ApoeϪ/Ϫ mice were subtotally nephrectomised (SNX ApoeϪ/Ϫ; n ϭ 8), uninephrectomised (UNX ApoeϪ/Ϫ; n ϭ 5), or sham-operated (sham ApoeϪ/Ϫ; n ϭ 5) and compared with their genetic controls (SNX C57/ BL6; UNX C57/BL6; sham C57/BL6). After 12 wk, BP was measured intraarterially, blood samples were taken, and the experiment was terminated by perfusion fixation. The heart weight was determined, and quantitative morphologic analysis of intramyocardial arteries and aortic changes was performed. At the end of the experiment, heart weight and relative left ventricular weight were comparable in all groups. Intraarterial BP was somewhat higher in ApoeϪ/Ϫ mice compared with controls. Baseline serum cholesterol and triglyceride levels were higher in ApoeϪ/Ϫ mice than in C57/BL6. Atherosclerotic plaques were not present in sham or UNX C57/BL6, but minor plaque formation was noted in some SNX control animals. In contrast, beginning plaques were seen even in untouched ApoeϪ/Ϫ mice, and strikingly increased plaque formation was noted in UNX and SNX ApoeϪ/Ϫ mice. Maximal plaque diameter (cross-section) was 37 Ϯ 74 m in SNX C57/BL6, 191 Ϯ 90 m in sham ApoeϪ/Ϫ, 323 Ϯ 66 m in UNX ApoeϪ/Ϫ, and 457 Ϯ 17 m in SNX ApoeϪ/Ϫ. The plaque morphology corresponded with that of early plaques characterized by foam cells and virtual absence of lymphocytes or smooth muscle cell infiltration. In conclusion, even mild renal dysfunction, i.e., after uninephrectomy, causes a dramatic increase in plaque size and aggressive morphology (foam cell rich soft plaques) in the animal model of the ApoeϪ/Ϫ mouse.After the seminal communication of Lindner et al. (1), the high prevalence and possibly accelerated development of atherosclerosis have been well documented in patients with renal failure. Because of the multitude of classical and non-classical atherosclerosis risk factors, e.g., hypertension, dyslipidemia, hyperhomocysteinemia, increased oxidative stress, it has remained controversial whether the high burden of atherosclerosis in uremia can be explained by classical risk factors or whether uremia per se aggravates or accelerates atherosclerosis.With the exception of diabetic patients with renal failure (2), there has been little documentation that atherosclerotic complications evolve more rapidly in patients with renal failure, and it has generally been difficult to reproduce atherosclerosis in animal models of renal failure.The apolipoprotein E knockout mouse (ApoeϪ/Ϫ) is a wellestablished model to study atherogenesis (3,4). We reasoned that it might also constitute a suitable model to address the issue whether athero...

High dietary phosphorus and hyperphosphatemia have significant effects on cardiac fibrosis and arterial wall thickening. Such abnormalities of cardiac architecture may be relevant for the increased cardiac risk in hyperphosphatemic uremic patients.

Abstract. In patients with renal failure, myocardial infarction (MI) is more frequent and the rate of death from acute MI is very high. It has been argued that ischemia tolerance of the heart is reduced in uremia, but direct evidence for this hypothesis has not been provided. It was the purpose of this study (1) to ligate the left coronary artery and to measure the nonperfused area (risk area: total infarction plus penumbra) as well as the area of total infarction in subtotally nephrectomized (SNX) rats compared with sham-operated pair-fed control rats and (2) to examine the effects of potential confounders such as BP, sympathetic overactivity, and salt retention. The left coronary artery was ligated for 60 min, followed by reperfusion for 90 min. For visualizing perfused myocardium, lissamine green ink was injected. The nonperfused area (lissamine exclusion) and the area of total infarction (triphenyltetrazolium chloride stain) were assessed in sections of the left ventricle using image analysis. Groups of SNX rats also received: antihypertensive treatment (nadolol plus hydralazine); moxonidine; high salt diet or low salt diet (1.58% versus 0.015%). In surviving animals, the nonperfused area at risk (as the proportion of total left ventricular area), presumably determined by the geometry of vascular supply, was similar in sham-operated and SNX animals (0.38 Ϯ 0.13 versus 0.45 Ϯ 0.09; NS). In contrast, the infarcted area, given as a proportion of the nonperfused risk area, was significantly (P Ͻ 0.003) higher in SNX (0.68 Ϯ 0.09) compared with sham-operated (0.51 Ϯ 0.11) rats and was not altered by any of the above interventions. The finding that a greater proportion of nonperfused myocardium undergoes total necrosis is consistent with the hypothesis of reduced ischemia tolerance of the heart in renal failure. The findings could explain the high rate of death from MI in patients with impaired renal function.The high cardiovascular mortality of renal patients has been widely appreciated since the seminal communication of Lindner (1). This is undoubtedly, at least in part, the consequence of premature and more severe atherosclerosis of the coronary arteries (2,3). Such accelerated atherogenesis recently also was documented in experimental models (4).Not only is the frequency of myocardial infarction (MI) increased in renal patients, there is also convincing evidence that the rate of death from acute MI is dramatically increased. In the observation of Shlipak et al. (5), even moderate renal insufficiency was associated with a substantially elevated risk of death during the first months of follow-up after MI. In a retrospective cohort study on patients with acute MI, Wright et al. (6) found a graded increase of in-hospital mortality with decreasing renal function. Mortality was 2% in patients with normal renal function and 30% in patients with ESRD. Although the authors commented on the "association between reduced use of acute perfusion therapy in these patients and poor survival" (6), there is little doubt that ...

(i) Despite comparable reduction in systolic blood pressure, different classes of antihypertensive agents had diverse effects on renal damage in subtotally nephrectomized rat. This observation is consistent with specific, non-hemodynamic actions of anti-hypertensives. (ii) Glomerular and tubulointerstitial damage are prevented by treatment with ACE inhibitors and antisympathotonic agents, but not with the calcium antagonist nifedipine. In contrast, renal vascular changes were also prevented by nifedipine. (iii) Only ACE inhibitors effectively inhibited podocyte hypertrophy and mesangial cell hyperplasia. Whether the superior effect of ACE inhibitors on glomerulosclerosis is related to inhibition of glomerular growth and podocyte hypertrophy as well as preservation of podocyte structure, or whether these findings are merely a passive reflection of greater efficacy, remains unresolved.

(i) Despite comparable reduction in systolic blood pressure, different classes of antihypertensive agents had diverse effects on renal damage in subtotally nephrectomized rat. This observation is consistent with specific, non-hemodynamic actions of anti-hypertensives. (ii) Glomerular and tubulointerstitial damage are prevented by treatment with ACE inhibitors and antisympathotonic agents, but not with the calcium antagonist nifedipine. In contrast, renal vascular changes were also prevented by nifedipine. (iii) Only ACE inhibitors effectively inhibited podocyte hypertrophy and mesangial cell hyperplasia. Whether the superior effect of ACE inhibitors on glomerulosclerosis is related to inhibition of glomerular growth and podocyte hypertrophy as well as preservation of podocyte structure, or whether these findings are merely a passive reflection of greater efficacy, remains unresolved.