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Selected Publication:
Alogna, A.
Mechanisms of heart failure with preserved ejection fraction
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Graz Medical University; 2016. pp.
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- Authors Med Uni Graz:
- Alogna Alessio
- Advisor:
- Marsche Gunther
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- Abstract:
- Heart failure with preserved ejection fraction (HFpEF) is a highly prevalent clinical syndrome that is reaching epidemic proportions in western societies. The hemodynamic and molecular mechanisms behind this disease are still incompletely understood, and no treatment so far has shown to impact on its natural history. The classical hallmark of the disease is left ventricular (LV) diastolic dysfunction, deriving from a combination of impaired isovolumic active relaxation, reduced mid-diastolic suction and decreased end-diastolic capacitance, i.e. passive elastic proprieties of the myocardium. Temperature is a major determinant of cardiac function, and we have previously shown that mild hypothermia (33 °C, MH) induces acute LV diastolic dysfunction by incomplete relaxation, while substantially increasing LV contractility. However, a direct comparison with hyperthermia (40.5°C, HT) has never been performed in vivo. We therefore set up a first study to investigate the effect of temperature on myocardial function in healthy closed-chest pigs by pressure-volume analysis. At each temperature step, we further characterized the effect of temperature on myocardial function by comparison with a standard inotropic drug, i.e. dobutamine. While cooling from HT to normothermia (38°C, NT) and from NT to MH increased LV contractility to the same magnitude as a clinically relevant dose of dobutamine, the end-diastolic pressure-volume relationship (EDPVR) was progressively shifted leftwards, indicating opposite effects of HT and MH on LV compliance. This shift was reversed by dobutamine infusion during MH. These findings address the effect of high and low temperatures on cardiac function, and underline the possible synergistic role of ß-adrenergic stimulation and cooling in a condition of impaired contractile function, i.e. cardiogenic shock. As mentioned above, an increased LV stiffness at rest is characteristic of the disease. However, most patients become symptomatic preferably during exercise, and a limited myocardial perfusion and contractility reserve may play a role. We therefore set up a cardiac magnetic resonance (CMR) imaging study to investigate LV function and perfusion during dobutamine stress in a previously established porcine model of early-stage HFpEF, induced by deoxycorticosteroneacetate (DOCA) pellets, combined with high-salt and high-sugar diet. The protocol consisted of two CMR imaging sessions, one at rest and one during stress. Aside numerous functional alterations at rest, such as altered myocardial muscle mechanics and left ventricular filling characteristics, an impaired increase of cardiac index during dobutamine stress was paralleled by a reduced myocardial perfusion reserve. Exercise induced myocardial ischemia may therefore be a contributor to LV dysfunction in HFpEF. HFpEF evolves from the accumulation of a multitude of cardiovascular comorbidities, leading to increased systemic inflammation, oxidative stress and coronary microvascular endothelial inflammation. Nitric oxide (NO) bioavailability is therefore reduced, and the NO-cyclic GMP (cGMP)-protein kinase G (PKG) pathway is affected, leading to a stiffer LV through its impact on the phosphorylation state and on the function of the major myofilament protein titin. Enhancement of PKG activity has emerged in the past years as a possible therapeutic approach. In our study, enhancing PKG activity via acute pharmacological stimulation of the soluble guanylate cyclase (sGC) in healthy pigs did not exert any beneficial effect on LV compliance, as confirmed by the unchanged phosphorylation state of titin, but rather exerted a slightly negative inotropic effect. In a series using the previously established porcine model of early stage HFpEF, only phosphodiesterase V inhibition via sildenafil, but not sGC stimulation or their combination, increased LV compliance, while both treatments clearly decreased LV contractility.