Hyperphosphatemia aggravates cardiac fibrosis and microvascular disease in experimental uremia

Abstract

Background: Hyperphosphatemia is a known predictor of cardiovascular death and specifically of cardiac death in hemodialysis patients. The pathomechanisms involved have not been completely clarified. While a number of observations suggest an important role of hyperphosphatemia and positive calcium balance on atherosclerosis and calcification of the coronary conduit arteries, independent effects on postcoronary microvessels and on cardiac fibrosis have not been excluded.

Methods: Male Sprague-Dawley rats were sham operated (N = 14) or subtotally nephrectomized (SNX, N = 17) and subsequently placed on low phosphorus (0.08% w/w) and high phosphorus (1.2% w/w) diet under pair-feeding conditions. After 8 weeks, serum chemistry and inhibitory parathyroid hormone (iPTH) were measured, and the hearts were harvested using perfusion fixation. Arteriolar thickness and volume density of the interstitium (excluding vessels) were quantitated using stereologic techniques.

Results: In SNX animals with moderate renal failure serum phosphorus concentrations were higher than in sham-operated controls on low phosphorus diet (1.7 +/- 0.37 mmol/L) and were significantly higher in SNX + high phosphorus diet (2.33 +/- 0.23 mmol/L) compared to SNX + low phosphorus diet (1.95 +/- 0.32 mmol/L; P < 0.05). In sham-operated controls, dietary phosphorus content had no effect on cardiac morphologic indices. In contrast, in SNX + high phosphorus diet the index of interstitial cardiac fibrosis was significantly higher (3.22 +/- 0.44%) than in SNX + low phosphorus (2.75 +/- 0.46%) or in sham-operated controls (2.5 +/- 0.05% on high phosphorus and 2.4 +/- 0.89 on low phosphorus, respectively). In SNX + high phosphorus (14.0 +/- 9.0 microm), but not in SNX + low phosphorus (9.2 +/- 4.5 microm), arterial wall thickness was significantly higher compared to sham-operated controls (10.2 +/- 5.1 on high phosphorus and 9.8 +/- 5.0 micro;m on low phosphorus, respectively). The data were confirmed in an independent repeat experiment.

Conclusion: 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.