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[Functional genomics of pressure-loaded cardiomyocytes: etomoxir in heart failure?]
1Klinik für Innere Medizin-Kardiologie, Philipps-Universität Marburg. Rupp@mailer.uni-marburg.de
Insights
Metabolic modulators like etomoxir may improve heart failure by enhancing SERCA2 expression, crucial for cardiomyocyte function. This approach targets ventricular diastolic dysfunction and offers promise for various cardiomyopathies.
Area of Science:
- Cardiology
- Molecular Biology
- Pharmacology
Background:
- Heart failure treatment faces challenges in preventing adverse cardiac remodeling.
- Ventricular diastolic dysfunction indicates early heart failure progression.
- Neuroendocrine activation contributes to heart failure pathophysiology.
Purpose of the Study:
- To investigate the potential of metabolic modulators to enhance SERCA2 expression in heart failure.
- To evaluate the effects of etomoxir on cardiac function in pressure-overloaded hearts.
- To explore etomoxir as a therapeutic strategy for cardiomyopathies with impaired SERCA2 function.
Main Methods:
- Assessed the impact of CPT-1 inhibitors/PPARalpha activators on glucose oxidation and SERCA2 expression.
- Administered etomoxir to pressure-overloaded heart models.
- Correlated functional cardiac parameters with alpha-myosin heavy chain proportions.
Main Results:
- Drugs increasing glucose oxidation, like etomoxir, enhance SERCA2 expression.
- Etomoxir selectively improved contraction and relaxation rates in overloaded hearts.
- Fetal gene programming in cardiac injury suggests metabolic modulators' broad applicability.
Conclusions:
- Metabolic modulators targeting glucose oxidation represent a promising therapeutic avenue for heart failure.
- Etomoxir demonstrates potential in improving cardiac function by addressing SERCA2 deficiency.
- This approach may be beneficial for cardiomyopathies characterized by inadequate SERCA2 expression.
Background:
Drugs for counteracting the neuroendocrine activation in heart failure can reduce the adverse remodelling of the extracellular matrix of the heart. Progression of heart failure can, however, often not be prevented and the question arises whether important pharmacological targets remain unidentified. Promising are drugs targeted at ventricular diastolic dysfunction which is a marker of early progression of heart failure.
Pathophysiology:
Left ventricular dysfunction is characteristic of overloaded hypertrophied hearts with molecular structures that are not adapted to the increased Ca2+ diffusion distances. Thus, the Ca(2+)-pump (SERCA2) of sarcoplasmic reticulum is inadequately expressed leading to a reduced force development and relaxation of hypertrophied cardiomyocytes.
Etomoxir:
Drugs in development (CPT-1 inhibitor/PPARalpha activator) that increase glucose oxidation can enhance SERCA2 expression. The lead compound etomoxir had a selective influence on the contraction and relaxation rate of pressure-overloaded hearts. The functional parameters were correlated with the proportion of alpha-myosin heavy chains. Since viral or inflammatory injury of the heart can also induce a fetal phenotype, metabolic modulators such as etomoxir represent a promising therapeutic approach also for cardiomyopathies with inadequate SERCA2 expression.