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[New aspects of the pathophysiology of heart failure]
1Abteilung für Kardiologie und Pneumologie, Zentrums Innere Medizin, Georg-August-Universität Göttingen, Deutschand.
Insights
Neuroendocrine hormone systems activate in heart failure, causing ventricular remodeling and impaired myocyte function. Key issues include disturbed intracellular calcium handling and reduced cAMP signaling, impacting cardiac contractility.
Area of Science:
- Cardiology
- Molecular Biology
- Physiology
Context:
- Heart failure progression involves neuroendocrine system activation.
- This leads to myocardial hypertrophy, dilation, and ventricular remodeling.
- Vascular and skeletal muscle alterations contribute to patient symptoms.
Purpose:
- To elucidate subcellular mechanisms underlying heart failure progression.
- To investigate the role of intracellular calcium handling and signaling pathways.
- To understand the impact on myocardial contractility and excitation-contraction coupling.
Summary:
- Neuroendocrine activation in heart failure alters myocyte function through disturbed intracellular calcium (Ca2+) handling, affecting excitation-contraction coupling.
- Reduced sarcoplasmic reticulum Ca2+ re-uptake and enhanced Na+/Ca2+ exchange impair systolic and diastolic function.
- Decreased myocardial beta-adrenoceptors and cAMP levels reduce protein phosphorylation, further impacting Ca2+ handling and contractility.
Impact:
- Findings highlight critical molecular targets for heart failure therapies.
- Understanding these mechanisms can lead to improved treatment strategies for cardiac dysfunction.
- Provides insights into the pathophysiology of failing human myocardium.
Abstract:
The progression of heart failure is related to activation of neuroendocrine hormone systems. On the level of the myocardium, they contribute to hypertrophy, dilation and remodeling of the ventricles. In addition, vascular alterations with endothelial dysfunction and alterations of skeletal muscle contribute to clinical symptoms of heart failure patients. Changes in ventricular geometry during the progression of cardiac diseases are associated with specific subcellular alterations on the level of the myocytes. Especially, disturbed intracellular Ca2+ handling resulting in altered excitation contraction coupling may lead to impaired systolic and diastolic function. Disturbed Ca2+ homeostasis has been associated with reduced re-uptake capacity of the sarcoplasmic reticulum for Ca2+ and an enhanced activity of the sarcolemmal Na+/Ca2+ exchange. In consequence, alterations in force-frequency behavior were attributed to a decline in intracellular Ca2+ transients at higher stimulation rates. The reduced expression of myocardial beta-adrenoceptors and alterations on the level of the G-proteins result in a reduced activity of adenylate cyclase and reduction in intracellular cAMP content of the myocytes. In consequence, reduced phosphorylation of intracellular functional proteins in the failing human heart contributes to altered Ca2+ handling. The Frank-Starling-mechanism seems to be unaltered in failing isolated human myocardium. Endothelin and angiotensin may contribute to the regulation of myocardial contractility in the human heart, but their functional relevance in the regulation of myocardial contractility under clinical conditions remains to be evaluated.