Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Scharer, K.
Epigenetic modification of cardiac function
Humanmedizin; [ Diplomarbeit ] Medizinische Universität Graz; 2023. pp. 74
[OPEN ACCESS]
FullText
- Autor*innen der Med Uni Graz:
- Betreuer*innen:
- Kolesnik Ewald
- Wallner Markus
- Altmetrics:
- Abstract:
- Background: Heart failure (HF) is a major public health issue and is combined with high morbidity and mortality. In Europe, 14 million patients living with HF. In Austria 1-2% of the adult population suffers from chronic HF, and almost 14,000 patients die of this every year. HF with preserved ejection fraction (HFpEF) represents about 50% of all HF cases. Typical features of HFpEF are left ventricular hypertrophy (LVH), elevated left ventricular end-diastolic pressure (LVEDP), left atrial enlargement, and elevated NT-proBNP plasma levels, despite a persevered left ventricular ejection fraction. These alterations result in impaired exercise capacity, fatigue, dyspnea, and edema. While there are several pharmacological strategies for treating heart failure with reduced ejection fraction (HFrEF) there are no detected effective therapies to improve outcomes in HFpEF, except for the use of sodium–glucose cotransporter 2 (SGLT-2) inhibitors. Thus, there is an unmet clinical need to develop new therapeutic options. Histone deacetylases (HDAC) are enzymes that play an important role in controlling gene expression via posttranslational modification. HDAC inhibitors (HDACi) are clinically used for treating t-cell lymphoma. In preclinical studies the use of HDACi revealed positive effects related to myofibril relaxation. (1) However, the underlying pathophysiological mechanisms remain poorly understood, and HDACi has never been tested in human myocardium. Furthermore, non-specific, pan-HDAC inhibition can cause adverse effects such as myelosuppression, limiting its use in clinical practice. Thus, novel isoform-selective HDACi may be effective and reduce adverse effects. Aim: The aim of this research was to assess the effects of isoform-selective HDACi on human myocardium. Methods: Human atrial trabeculae were isolated from right appendages with microsurgical instruments. Then trabeculae were transferred into an organ bath, fixed with hooks and connected to an electric stimulator and a force transducer. Afterward, Ca2+ was added, and the trabeculae were electrically stimulated at 1 Hz. Subsequently, the trabeculae were stretched to a length with the best strain. Finally, the trabeculae were incubated with two different isoform-selective HDACi or a pan-HDACi for 2 hours. Untreated trabeculae served as a control. Functional parameters like systolic and diastolic force, as well as twitch kinetics were continuously recorded and analyzed. Conclusion: The use of selective HDACi led to a significant, acute increase in developed force without altering diastolic tension compared with the control group. Furthermore, the selective HDACi increased systolic and diastolic kinetic parameters, reflected in an improvement of dp/dtmax and dp/dtmin. In conclusion, isoform-selective HDACi increased systolic and diastolic functional parameters in human atrial myocardium. Therefore, isoform-selective HDAC inhibition, that enable the direct control diastolic and systolic function, may be a promising therapeutic option for treating patients with HF across the entire spectrum of the ejection fraction.