Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Schwarzl, M.
Haemodynamic and molecular mechanisms of acute and chronic heart failure with preserved ejection fraction
[ Dissertation ] Medical University of Graz; 2013. pp. 149
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- Autor*innen der Med Uni Graz:
- Schwarzl Michael
- Betreuer*innen:
- Pieske Burkert Mathias
- Post Heiner
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- Abstract:
- Heart failure with preserved ejection fraction (HF-PEF) is of increasing importance in the aging population and accounts for almost half of clinical heart failure cases. However, no therapeutic strategy has been established so far to improve the prognosis in HF-PEF patients. This failure in part relates to insufficient understanding of haemodynamic and molecular alterations and their complex interplay in HF-PEF as well as to a lack of suitable animal models for this disease. Left ventricular (LV) diastolic dysfunction in HF-PEF comprises slowed relaxation and a loss of LV end-diastolic capacitance. In a first set of experiments, the interplay between these mechanisms was studied in healthy, anaesthetised, closed-chest pigs by use of pressure-volume analysis. Measurements were performed a) during normal relaxation at regular body temperature (38 °C) and b) during hypothermia (33 °C) induced prolongation of the isovolumic relaxation constant ¿. At both temperatures, the LV end-diastolic pressure-volume relationship (EDPVR) was shifted leftwards, when the ratio of diastolic duration (t-dia) to ¿ fell below a certain threshold. This threshold was higher than in previous studies and therefore emphasizes the need to measure LV volume next to LV pressure and time-intervals to adequately characterize incomplete relaxation. This concept was used in further experiments in anaesthetised, closed-chest pigs to study the role of incomplete relaxation in acute and chronic HF-PEF. Acute HF-PEF was induced by coronary microembolisation, which resulted in major cardiac failure with decreased mixed venous oxygen saturation. This was associated with a progressive leftward-shift of the EDPVR. This loss of LV end-diastolic capacitance was not caused by incomplete relaxation, but solely by increased passive stiffness. Of note, LV ejection fraction remained unchanged compared to baseline. The induction of mild hypothermia (MH, 33 °C) improved mixed venous oxygen saturation and mean aortic pressure. Moreover, the progressive leftward-shift of the EDPVR was attenuated during MH, potentially by preventing ischaemic cardiomyocyte contracture. MH may thus be a treatment option for cardiogenic shock. Chronic HF-PEF is associated with the accumulation of cardiovascular risk factors and a lack of physical exercise. To establish a large animal model of chronic HF-PEF, risk factors were mimicked in pigs. Hypertension was induced by implantation of a subcutaneous DOCA-depot and combined with a western-diet containing high amounts of salt, sugar, fat and cholesterol for 90 days. DOCA/western-diet pigs developed a HF-PEF phenotype including LV concentric hypertrophy, a leftward-shift of the EDPVR, a loss of cardiac output reserve and reduced LV diastolic suction. However, parameters of active relaxation were not different compared to control animals and relaxation was complete at the end of diastole. The loss of LV end-diastolic capacitance in DOCA/western-diet was associated with titin hypophosphorylation and a titin isoform shift towards the stiff N2B isoform in LV myocardial tissue samples. Increased superoxide production due to nitric oxide (NO) synthase uncoupling was found in DOCA/western-diet, which might have contributed to titin hypophosphorylation via reduced NO bioavailability and subsequent low protein kinase G (PKG) activity. In final experiments, increasing PKG activity in healthy pigs by acute pharmacological stimulation of the soluble guanylate cyclase, however, did not influence LV systolic and diastolic function. The effects of PKG enhancing strategies on LV structure and function remain to be determined in this large animal model of chronic HF-PEF.