Myocardial interstitial fibrosis in experimental uremia—Implications for cardiac compliance

Abstract

Experimental uremia is known to cause cardiac hypertrophy. In the present study we examined the effect of uremia with or without concomitant treatment of hypertension by the converting enzyme Ramipril (125 micrograms/day) on micromorphometric indices of cardiac interstitium at the light microscopical and ultrastructural level. In male SD rats, 21 days of uremia caused an increase of total heart weight (1040 +/- 73 mg wet wt vs. 871 +/- 81 in controls, P less than 0.05) with an increase of both right and left ventricular weight. This was accompanied by reduction of capillary cross-sectional area despite unchanged capillary length. The volume density (cm3/cm3) of cardiomyocytes was unchanged (0.881 +/- 0.01 vs. 0.871 +/- 0.016 in controls), but volume density of interstitial tissue (excluding capillary lumen) was significantly increased (0.042 +/- 0.011 cm3 interstitial tissue/cm3 total heart tissue vs. 0.019 +/- 0.007 in controls). This was associated with signs of activation of interstitial cells, that is, increased volume of interstitial cell nuclei and interstitial cell cytoplasm. Concomitantly, a significant increase of volume density of non-cellular interstitial ground substance was found which was not normalized by antihypertensive treatment using Ramipril. After three months of uremia, electron microscopy showed collagen fiber deposition in the interstitium. Comparable interstitial fibrosis was not observed in hearts of rats with renovascular (one clip-two kidney) hypertension. It is concluded that uremia increases myocardial interstitial ground substance by mechanisms independent of hypertension. The data may be relevant for recent findings of diastolic heart malfunction secondary to impaired compliance in uremic patients.

Mineralocorticoid Receptor Antagonism Attenuates Cardiac Hypertrophy and Prevents Oxidative Stress in Uremic Rats

“…6,11,29,30 However, whether MR is involved in heart hypertrophy of chronic renal failure has not been established. [2][3][4] In the present study, we detected concentric ventricular hypertrophy. Accordingly, morphometric studies confirmed increased cardiomyocyte size.…”

“…Although some studies have shown that correction of hypertension and/or anemia in dialysis patients significantly decreased LVH, other studies have shown that LVH did not change or that it can even progress, in spite of adequate blood pressure control in uremic patients. 1 Experimental studies evidenced similar cardiovascular abnormalities in models of chronic uremia, 2,3 and correction of anemia or treatments with several antihypertensive agents did not prevent hypertrophy in uremic rats. [3][4][5] These findings are in favor of a blood pressureindependent effect of uremia that could function as a prohypertrophic factor.…”

Echocardiographic evaluation of epicardial adipose tissue in non-diabetic, non-hypertensive hemodialysis patients

“…24 Uremia causes an increase in myocardial interstitial tissue regardless of HT. 25 The HD treatment itself may affect cardiac functions. Increased levels of myocardial calcium are closely related with the myocardial dysfunction in HD patients.…”

Uremic Cardiomyopathy and Insulin Resistance

“…80 -84 It is of the reactive type, a consequence of endothelial-to-mesenchymal transition 85 followed by activation and proliferation of new interstitial fibroblasts. 82,83,86 Compared with control hearts with a similar degree of hypertension and LVH, the uremic cardiac interstitium demonstrates increased expression of proinflammatory mediators, such as PDGF, with correspondingly increased fibrosis, suggesting renal disease enhances myocardial fibrosis. 80,87 This interstitial fibrosis contributes to ventricular stiffness and diastolic dysfunction and cardiac dysrhythmias and may further compromise molecular exchange between cardiomyocytes and capillary bed.…”