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Contractile systolic and diastolic dysfunction in renin-induced hypertensive cardiomyopathy
1Klinik III für Innere Medizin der Universität zu Köln, Cologne, Germany. markus.flesch@medizin.uni-koeln.de
Insights
Early cardiac changes in compensated hypertensive hypertrophy, including myosin shifts and reduced SR proteins, precede heart failure. These alterations, linked to the renin-angiotensin system, may accelerate disease progression.
Area of Science:
- Cardiovascular Physiology
- Molecular Cardiology
- Biochemistry
Background:
- Chronic heart failure involves functional, molecular, and biochemical changes.
- Hypertensive cardiac hypertrophy is a precursor to heart failure.
Purpose of the Study:
- To investigate early alterations in compensated hypertensive cardiac hypertrophy.
- To determine if these changes precede chronic heart failure.
Main Methods:
- Studied isolated papillary muscle strips for contraction and relaxation.
- Analyzed sarcoplasmic reticulum (SR) protein and myosin heavy chain isoform expression.
- Quantified myocardial fibrosis, renin mRNA, angiotensin II, and aldosterone levels.
Main Results:
- Reduced contraction and relaxation velocities observed.
- Increased beta-/alpha-myosin heavy chain ratio and decreased SR Ca2+-ATPase (SERCA 2a) and phospholamban levels.
- Elevated myocardial renin mRNA, angiotensin II, and plasma aldosterone concentrations without increased fibrosis.
Conclusions:
- Myosin heavy chain shift and reduced SR proteins correlate with systolic and diastolic dysfunction in hypertrophy.
- These molecular changes precede fibrosis and may accelerate the transition to heart failure.
- An activated tissue renin-angiotensin system might contribute to these early alterations, suggesting potential therapeutic targets.
Abstract:
The present study investigated whether functional, molecular, and biochemical alterations occurring in chronic heart failure can already be detected in compensated hypertensive cardiac hypertrophy. Force of contraction (isolated papillary muscle strip preparations), sarcoplasmic reticulum (SR) protein and myosin heavy chain isoform expression (Northern and Western blot analysis), myocardial fibrosis (collagen stains, hydroxyproline quantification), myocardial renin mRNA (RT-PCR), and angiotensin II levels and plasma aldosterone concentrations (radioimmunoassay) were studied in hypertrophied myocardium from transgenic rats harboring the mouse Ren-2d gene. Contraction and relaxation velocities of isolated papillary muscle strips were significantly reduced in cardiac hypertrophy. The beta-/alpha-myosin heavy chain ratio was significantly increased in the hypertrophied left ventricles, whereas SR Ca2+-ATPase (SERCA 2a) and phospholamban mRNA and protein levels were significantly decreased. The decrease in SERCA 2a was more pronounced than the decrease in phospholamban levels. There was no increased myocardial fibrosis. Left ventricular myocardial renin mRNA and angiotensin II concentrations, as well as plasma aldosterone levels, were higher in transgenic than in control rats. In hypertensive cardiac hypertrophy, myosin heavy chain isoform shift and reduction of SR protein levels are related to systolic and diastolic dysfunction, respectively. These alterations precede the development of myocardial fibrosis. Increased myocardial renin mRNA and angiotensin II concentrations suggest that an activated tissue renin-angiotensin system might contribute to these alterations. Since the alterations in compensated cardiac hypertrophy apparently precede those in chronic heart failure, they might accelerate the transition from hypertrophy to failure and could therefore be targets for pharmacological interventions.