Improvement of cardiac function in heart failure


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Title Improvement of cardiac function in heart failure
Period 11 / 2003 - unknown
Status Completed
Research number OND1295569


In myocardial infarction, optimal treatment with thrombolytic therapy, prevention of re-occlusion and reduction of the inflammatory reaction following coronary occlusion will lead to further reduction of infarct size and thus the development of heart failure. Viable tissue is an unstable substrate after infarction and can be quantified in terms of energy metabolism. Hormonal status is another important aspect in relation to heart failure. This is studied at the molecular level and in aging women. More knowledge of the immunological response could provide a model for immunological intervention in patients. The relation between contractility, cross-bridge and calcium cycling, and energy turnover under different pathological conditions, especially heart failure are studied intensively. The effects of bioactive food supplements on the energy status of cardiomyocytes in heart failure are also studied. The study of the relationship between the metabolic properties of muscle and its function under normal and pathological conditions form a major program. The pathological process of mitochondrial damage (permeability transition) and induction of apoptosis in hypertrophy is analyzed at the molecular level. The goal of the research on cardiac energy metabolism is understanding the molecular processes of cardiac metabolism in vivo in the intact heart. This is accomplished by working in the 'four corners region' between physiology, biophysics, biochemistry, and molecular biology. The main emphasis continues to be on the heterogeneity of metabolism and cardiac perfusion. The studies of mitochondrial function also make use of intracellular imaging of cardiomyocytes and trabeculae. The mitochondrial energy status is also the subject of study and not only the regulation processes, but given the sensitivity of heart muscle function to mitochondrial capacity, in particular the processes leading to loss of mitochondria will be addressed. The implementation of multi-photon laser scanning microscopy greatly increases the reach of our analyses. Using a mouse model which allows determination of the activation time of oxidative phosphorylation in transgenics, we are investigating the role of phosphotransfer enzymes such as mitochondrial and cytoplasmic CK isoforms in transcytoplasmic energy signaling. Isolated vessels remain an important research topic in the studies of the coronary circulation. Especially since we have the newly developed NO micro-electrode available we can study time responses to mechanical and chemical factors. The emphasis of the studies now turns to the intracellular signaling pathways. The studies of the effects of mechanical factors such as (axial) stretch on the cytoskeleton of the endothelial cell give new information. In hypertension and failure the mutual effects between coronary vasculature and cardiac muscle are investigated in different ways. To get better insight into the process of hypertension and failure we have chosen for the Dahl salt sensitive rat and its control. The (reoxygenated) coronary effluent from the isolated rat heart is used to superfuse papillary muscle thereby making it possible to investigate what factors are released that affect cardiac function. Preconditioning (short, 5 minute, period of ischemia) protects the heart against a long lasting (one hour) of ischemia. The contribution of the coronary vasculature in this process is investigated. Clinical studies on heart function and the role of the endothelium are carried out. Myocardial relaxation in the working human heart is affected by variations in the load and non-uniformity of the heart muscle, we therefore study the effects of NO on diastolic function. Cardiac perfusion after by-pass surgery is studied. Stenosis quantification by the measurement of coronary flows and pressures is carried out. The wealth of information obtainable on coronary perfusion in combination with cardiac function is of great scientific interest and one of our major goals is to make it possible to accurately quantify therapeutic interventions. The combination of MR Imaging, MR spectroscopy, and PET imaging is a long-term goal that will be pursued intensively. The goal is to contribute to our understanding how to cure diseases of the heart muscle, particularly hypertrophy culminating in heart failure.

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Related people

Project leader Prof.dr. A.C. van Rossum
Project leader Dr. D. Simonides


D21700 Physiology
D23220 Internal medicine

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