What is the clinical evidence from this study?

Study design: Other. Population: Experimental Uremic Cardiomyopathy (n=73). Intervention: Enalapril vs. Untreated or Furosemide/dihydralazine. Primary outcome: Volume density of cardiac interstitial tissue (myocardial fibrosis) (p=<0.05).

January 27, 2011Open Access

High-Dose Enalapril Treatment Reverses Myocardial Fibrosis in Experimental Uremic Cardiomyopathy

Q: What are the key findings of this study?

High-dose enalapril treatment significantly reversed myocardial fibrosis in subtotally nephrectomized rats compared to untreated controls (1.63% vs 2.57%, p<0.05).

Key Result

High-dose enalapril treatment significantly reversed myocardial fibrosis in subtotally nephrectomized rats compared to untreated controls (1.63% vs 2.57%, p<0.05).

Structured PICO

Does high-dose enalapril reverse myocardial fibrosis and cardiovascular alterations in experimental uremic cardiomyopathy?

Population

Male Sprague Dawley rats (n=73) undergoing subtotal nephrectomy (SNX, n=34) or sham operation (sham, n=39) to model moderate chronic renal failure and uremic cardiomyopathy.

Intervention

Enalapril 48 mg/kg body weight per day in drinking water for 4 weeks (from week 8 to 12 after surgery).

Comparator

Furosemide + dihydralazine (15+20 mg/kg body weight) or untreated (solvent).

Outcome

Reversal of cardiovascular alterations including myocardial fibrosis, capillary density, and aortic wall changes.surrogate

High-dose ACE inhibitor treatment causes partial, but not complete, reversal of cardiovascular changes such as myocardial fibrosis in a rat model of uremic cardiomyopathy.

Main Result

Absolute Event Rate: 1.63% vs 2.57%

p-value: p=<0.05

Limitations

Animal model may not fully replicate human chronic kidney disease
Short treatment duration of 4 weeks
Potential confounding by blood pressure differences before the start of treatment
Kidney AT1 receptors were not knocked out, leaving some Ang II signaling intact

Abstract

AIMS: Patients with renal failure develop cardiovascular alterations which contribute to the higher rate of cardiac death. Blockade of the renin angiotensin system ameliorates the development of such changes. It is unclear, however, to what extent ACE-inhibitors can also reverse existing cardiovascular alterations. Therefore, we investigated the effect of high dose enalapril treatment on these alterations. METHODS: Male Sprague Dawley rats underwent subtotal nephrectomy (SNX, n = 34) or sham operation (sham, n = 39). Eight weeks after surgery, rats were sacrificed or allocated to treatment with either high-dose enalapril, combination of furosemide/dihydralazine or solvent for 4 weeks. Heart and aorta were evaluated using morphometry, stereological techniques and TaqMan PCR. RESULTS: After 8 and 12 weeks systolic blood pressure, albumin excretion, and left ventricular weight were significantly higher in untreated SNX compared to sham. Twelve weeks after SNX a significantly higher volume density of cardiac interstitial tissue (2.57±0.43% in SNX vs 1.50±0.43% in sham, p<0.05) and a significantly lower capillary length density (4532±355 mm/mm(3) in SNX vs 5023±624 mm/mm(3) in sham, p<0.05) were found. Treatment of SNX with enalapril from week 8-12 significantly improved myocardial fibrosis (1.63±0.25%, p<0.05), but not capillary reduction (3908±486 mm/mm(3)) or increased intercapillary distance. In contrast, alternative antihypertensive treatment showed no such effect. Significantly increased media thickness together with decreased vascular smooth muscles cell number and a disarray of elastic fibres were found in the aorta of SNX animals compared to sham. Both antihypertensive treatments failed to cause complete regression of these alterations. CONCLUSIONS: The study indicates that high dose ACE-I treatment causes partial, but not complete, reversal of cardiovascular changes in SNX.

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