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Cardiomyocyte loss in experimental renal failure: prevention by ramipril
Kerstin Amann1, Karin Tyralla, Marie-Luise Gross
1Department of Pathology, University of Erlangen, Erlangen, Germany. kerstin.amann@path.imed.uni-erlangen.de
Insights
Renal failure causes left ventricular hypertrophy (LVH) through increased cardiomyocyte size and number loss. Ramipril treatment, an angiotensin-converting enzyme (ACE) inhibitor, reversed these cardiac changes in experimental renal failure.
Area of Science:
- Cardiology
- Nephrology
- Experimental Medicine
Background:
- Left ventricular hypertrophy (LVH) is a key cardiac abnormality in renal failure, contributing to cardiac mortality.
- The impact of renal failure on cardiomyocyte volume and number in LVH development remains uninvestigated.
- The renin-angiotensin system (RAS) is a suspected contributor to LVH in renal failure.
Purpose of the Study:
- To characterize cardiomyocyte volume and number in short-term experimental renal failure.
- To investigate the effect of the angiotensin-converting enzyme (ACE) inhibitor ramipril on these cardiac parameters.
Main Methods:
- Subtotal nephrectomy (SNX) or sham operation was performed on rats, with one SNX group receiving ramipril.
- Hearts were analyzed using stereologic techniques after 8 weeks.
- Cardiomyocyte morphology, volume, and number were assessed.
Main Results:
- SNX rats showed significantly increased left ventricular (LV) weight and cardiomyocyte volume, along with decreased cardiomyocyte number.
- These LVH-associated changes were accompanied by an increase in TUNEL-positive myocytes.
- Ramipril treatment abrogated cardiomyocyte hypertrophy and loss, and prevented the increase in LV weight.
Conclusions:
- LVH in renal failure involves both cardiomyocyte hypertrophy and cell loss.
- The beneficial effects of ramipril suggest a role for the RAS in LVH pathogenesis, independent of blood pressure changes.
- ACE inhibition may be a therapeutic strategy for mitigating cardiac remodeling in renal failure.
Background:
The development of left ventricular hypertrophy (LVH) and of structural abnormalities of the heart is a key abnormality in renal failure that potentially contributes to the high rate of cardiac death. In renal failure, the behavior of cardiomyocyte volume and number in the development of LVH has so far not been investigated. A potential role of the (local) renin-angiotensin system (RAS) in the genesis of LVH has been suspected. It was the aim of the present study in short-term experimental renal failure (1) to characterize cardiomyocyte volume and number and (2) to study whether they are affected by the angiotensin-converting enzyme (ACE) inhibitor ramipril.
Methods:
Sprague-Dawley rats (N = 8 to 10 per group) had a subtotal nephrectomy (SNX) or sham operation and followed for 8 weeks. One SNX group received the ACE inhibitor ramipril (0.5 mg/kg body weight) in the drinking fluid. After perfusion fixation, the morphology of the heart was investigated using stereologic techniques.
Results:
Systolic blood pressure was slightly, but not significantly, higher in untreated SNX, but the left ventricular (LV) weight and LV weight/body weight ratio (2.32 +/- 0.20 mg/g) were significantly higher in SNX than in sham-operated animals (1.90 +/- 0.16 mg/g). Sarcomeric length was not significantly different between SNX and sham-operated animals. There was an increase in the number of terminal deoxynucleotidyl transferase-mediated uridine triphosphate nick end labeling (TUNEL)-positive myocytes in SNX compared to sham-operated animals and a significant increase in cardiomyocyte volume (15,713 +/- 4557 microm3 vs. 10,067 +/- 2242 microm3, P < 0.01) as well as a decrease of cardiomyocyte numbers per unit myocardial volume (61.2 +/- 16.2 vs. 92.2 +/- 20.9 x 103/mm3) and per left ventricle (70.9 +/- 16.5 x 106 vs. 94.8 +/- 18.1 x 106, P < 0.05). Both abnormalities were abrogated by treatment with ramipril (6347 +/- 972.4 microm3 and 106 +/- 18.9 103/mm3 or 118 +/- 39.5 x 106, respectively), which also completely prevented the increase in LV weight/body weight ratio (1.83 +/- 0.14 mg/g).
Conclusion:
LVH in renal failure is characterized by cardiomyocyte hypertrophy, but also cardiomyocyte drop out. A role of the RAS is suggested by the beneficial effect of ramipril treatment that is not accounted for by differences in blood pressure.