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Myocardial collagen in cardiac hypertrophy resulting from chronic aortic regurgitation
S M Goldfine1, M Peña, N M Magid
1Division of Cardiovascular Pathophysiology, Cornell University Medical College, New York, NY USA.
Insights
Unlike pressure overload, aortic regurgitation-induced cardiac fibrosis in rabbits does not involve increased collagen. This suggests different therapeutic strategies may be needed for volume overload versus pressure overload heart conditions.
Area of Science:
- Cardiology
- Pathology
- Biochemistry
Background:
- Myocardial fibrosis and abnormal collagen content are hallmarks of pathological cardiac hypertrophy.
- Pressure overload cardiac hypertrophy is associated with increased myocardial collagen.
- Chronic aortic regurgitation (AR) can lead to congestive heart failure, with fibrosis observed in animal models.
Purpose of the Study:
- To determine if fibrotic lesions in volume overload (AR) are collagen-based, similar to pressure overload.
- To compare the fibrotic response in AR to that seen in pressure overload.
- To inform the development of targeted therapies for cardiac fibrosis in different types of heart disease.
Main Methods:
- Moderate to severe AR induced in 19 rabbits via aortic valve perforation.
- Animals studied at three time points: onset of systolic dysfunction, 1 month post-AR, and >3 years post-AR.
- Left ventricular collagen content assessed biochemically (hydroxyproline) and histologically (Mason's trichrome, Picro-Sirius Red).
Main Results:
- An age-related increase in left ventricular collagen concentration was observed in rabbits.
- No specific increase in collagen was found in animals exhibiting fibrosis after AR.
- Fibrotic lesions in AR were not predominantly composed of excess collagen.
Conclusions:
- Volume overload (AR) induces fibrotic lesions in the heart that differ chemically from those in pressure overload.
- The fibrotic process in AR may not primarily involve collagen accumulation.
- Therapeutic strategies to prevent cardiac fibrosis may need to be distinct for volume and pressure overload conditions.
Abstract:
Myocardial fibrosis and abnormal myocardial collagen content are common in many forms of pathological cardiac hypertrophy, including that mediated by pressure overload. Recently, in an experimental animal model of chronic aortic regurgitation (AR), we found a strong relation between myocardial fibrosis and congestive heart failure development. To determine if these fibrotic lesions are composed of collagen, as they are in pressure overload, and to determine if potential preventive therapies should be developed similarly in both diseases, we assessed left ventricular collagen content at three time points after AR induction. Moderate to severe AR was induced in 19 New Zealand White rabbits by inserting a catheter through the carotid artery to perforate the aortic valve leaflets. Animals were killed (1) when they showed echocardiographically discernible systolic dysfunction or (2) if normal cardiac function continued, either early (1 month) or late (>3 years) after operation. Fourteen age-matched, sham-operated controls and seven normal unoperated rabbits also were studied. Collagen concentrations were determined biochemically by hydroxyproline measurement. Fibrosis was measured histologically using Mason's trichrome stain and the fibrous collagen-specific stain, Picro-Sirius Red. Our results show an age-related increase in left ventricular collagen concentration with no specific increase among animals with evidence of fibrosis. We conclude that, unlike pressure overload, volume overload produces fibrotic lesions not composed predominantly of excess collagen and that the therapy needed to prevent fibrosis may be different in these conditions. Further study is needed to define the chemical characteristics of the fibrous lesions and the pathophysiological importance of this finding.