The role of inflammation in the pathogenesis of cardiovascular changes in apolipoprotein E knockout mice with chronic renal failure

Abstract

In previous studies on experimental renal failure, hypertrophy of cardiomyocytes, diminished capillarization, and increased intercapillary distances had been observed, abnormalities that will expose the heart to reduced ischemia tolerance. It has not been established, however, whether such structural alteraitons are unique for the heart (eg, as a consequence of left ventricular hypertrophy) or are demonstrable in other tissues as well. Clarification of this point is important to test hypotheses on some potential mechanisms for cardiac undercapillarization. To address this issue further, we compared capillary length density (by stereologic techniques) in perfusion-fixed skeletal muscle (m. psoas) and hearts of subtotally nephrectomized (SNX) rats with moderate renal failure to those in sham-operated pair-fed controls. The duration of renal failure was 8 weeks. SNX rats had significantly higher mean systolic blood pressure (128 mm Hg v 109 mm Hg), serum creatinine, and urea levels. Despite pair feeding, the mean body weight was significantly lower in the SNX rats (409 g v 471 g), but the left ventricular weight to body weight ratio tended to be higher than in the sham-operated controls (2.39 mg/g v 2.13 mg/g). In the heart, myocyte mean cross-sectional area (675 ± 112 μm2v 545 ± 111 μm2) and volume density of nonvascular interstitial tissue (3.47 ± 1.04 v 1.33 ± 0.22) were significantly higher in the SNX rats than in the controls. In parallel, myocardial capillary length density was significantly reduced after subtotal nephrectomy (3,036 ± 535 mm/mm3v 3,916 ± 615 mm/mm3). In contrast, in skeletal muscle, myocyte cross-sectional rea (3,109 ± 783 μm2v 3,042 ± 639 μm2), capillary length density (718 ± 248 mm/mm3v 717 ± 184 mm/mm3), and three-dimensional capillary fiber ratio (2.10 ± 0.26 v 2.13 ± 0.4) were similar in SNX and control rats. These data document a selective defect of capillarization in the heart of animals with moderate renal failure, pointing to tissue-specific abnormalities of cardiac capillarogenesis.