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Published on: December 2, 2016
Reduction of cardiac fibrosis decreases systolic performance without affecting diastolic function in hypertensive
Oscar H Cingolani1, Xiao-Ping Yang, Yun-He Liu
1Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Health System, Detroit, Mich, USA.
Insights
Reducing cardiac fibrosis with N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) in hypertensive rats did not improve diastolic function. Instead, it decreased systolic performance, suggesting collagen reduction alone is insufficient for treating hypertensive heart disease.
Area of Science:
- Cardiovascular Research
- Pharmacology
- Fibrosis Research
Background:
- Pressure-overload left ventricular hypertrophy (LVH) involves myocyte size increase and fibrosis, key factors in hypertensive heart disease (HHD).
- The specific impact of fibrosis reduction on HHD progression remains unclear.
- N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is an endogenous antifibrotic peptide with potential therapeutic applications.
Purpose of the Study:
- To investigate the effects of Ac-SDKP-mediated fibrosis inhibition on cardiac function in a rat model of HHD.
- To determine if reducing collagen deposition improves systolic and diastolic function in hypertensive hearts.
- To assess the role of fibrosis as a therapeutic target in HHD.
Main Methods:
- Spontaneously hypertensive rats (SHR) and normotensive WKY rats were treated with Ac-SDKP or vehicle.
- In vivo pressure-volume (PV) analysis was used to assess cardiac systolic and diastolic function.
- Ex vivo assessment of left ventricle passive compliance was performed.
Main Results:
- Ac-SDKP normalized collagen content in SHR without altering myocyte diameter or left ventricle mass.
- Diastolic function remained unaffected by Ac-SDKP treatment in both SHR and WKY rats.
- Systolic function significantly decreased in Ac-SDKP-treated SHR, while remaining unchanged in WKY rats.
Conclusions:
- Reducing left ventricle collagen deposition with Ac-SDKP does not improve diastolic function in adult SHR and impairs systolic performance.
- These findings indicate that solely reducing collagen quantity may not benefit cardiac function in HHD.
- Targeting other factors like myocyte hypertrophy or collagen characteristics may be crucial for improving cardiac function in HHD.
Abstract:
Pressure-overload left ventricular hypertrophy (LVH) is characterized by an increase in myocyte size and fibrosis. However, it is not clear how each of these components affects hypertensive heart disease (HHD). We have shown in 2 different rat models of hypertension that cardiac fibrosis can be reduced with N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP), an antifibrotic peptide normally present in mammals. To assess how inhibition of fibrosis affects HHD, spontaneously hypertensive rats (SHR) and normotensive controls (WKY) were treated with Ac-SDKP or vehicle. Cardiac systolic and diastolic function were assessed using in vivo pressure-volume (PV) analysis. Left ventricle passive compliance was also determined ex vivo. We found that in SHR, Ac-SDKP normalized left ventricle total collagen content and interstitial collagen fraction without changing myocyte diameter or left ventricle mass. In WKY, collagen did not change significantly after treatment. Ac-SDKP did not affect left ventricle diastolic function, determined in vivo and ex vivo in SHR and WKY, whereas systolic function was significantly decreased in SHR treated with Ac-SDKP and unchanged in treated WKY. We concluded that in adult SHR, reducing left ventricle collagen deposition with Ac-SDKP does not improve diastolic function, whereas it decreases systolic performance. These findings suggest that total left ventricle collagen reduction per se does not necessarily benefit cardiac function. In HHD, other factors besides collagen quantity, such as myocyte hypertrophy and/or collagen type or cross-link, might be targeted to improve cardiac function.
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