Klinik für Kardiologie
Klinik für Kardiologie / Forschung
Research group of Dr. rer. nat. Petra Büttner
Members of the group

Tina Fischer (MTA)
Sarah Werner (MTA)
Angela Kricke (MTA)
Thanh Nguyen (doctoral student)
Paulien Vinke-Schr├Âter (doctoral student)
Scientific projects
1. Molecular alterations elicited by heart failure in the diaphragm - impact of exercise training

Patients with chronic heart failure (CHF) present symptoms of breathlessness and muscle weakness, which exacerbate exercise limitation leading to a reduced prognosis. The pathophysiology underlying these symptoms is complex and remains poorly understood - an issue largely complicated by the fact that central hemodynamics are poorly associated with exercise limitation in CHF. In contrast, limb skeletal muscle and ventilatory impairments have been shown to be strong predictors of the former. While diaphragm muscle weakness is likely a key mediator in the overall pathogenesis of CHF, little is still known about its temporal progression and underlying molecular mechanisms.
The goals of our investigations in this area are to answer the following questions:
  1. Does the development of chronic heart failure is associated with a reduction of diaphragm contractility
  2. How fast do we see a force reduction in the diaphragm after an MI-induced chronic heart failure?
  3. What molecular mechanisms are responsible for the CHF-induced loss of diaphragmatic muscle?
  4. Can we influence the loss of muscle function and the related molecular changes by exercise training? If yes, what is the optimal training modality?
To answer all these questions we are using mice and rat models of chronic heart failure (LAD ligation model). To follow-up the questions of exercise training the animals are trained for different time periods at different intensity levels on a treadmill specifically designed for rats and mice. To measure muscle force of diaphragmatic muscle, a strip of the diaphragm is prepared and hooked up to a force transducer in an organ bath as shown on the left side. For the molecular work up parts of the diaphragm are frozen in liquid nitrogen and stored at -80┬░C for subsequent molecular analysis by RT-PCR or Western Blot.
The first results clearly showed that already 72h after a myocardial infarction diaphragmatic force is reduced by around 20% and that this reduction is probably due to modifications (carbonylation) of proteins involved in contraction. The force reduction is also evident in the animals with stable chronic heart failure. Further studies are performed at the moment to study the impact of exercise training on these modifications.

2. Molecular alterations in the skeletal muscle and endothelium in heart failure with preserved ejection fraction - impact of exercise training.

More than 14 million Europeans are affected by heart failure (HF) whereof at least 50% are considered to have Heart Failure with preserved Ejection Fraction (HFpEF).1 Besides advanced age and female gender, prevalent modifiable risk factors for HFpEF also include hypertension, diabetes, obesity, and inactive lifestyle.2,3 The ageing populations explains in part why HFpEF is the only cardiovascular disease with increasing prevalence and incidence, affecting 10-20% of the elderly and contributing substantially to hospitalizations of elderly HF patients. The poor clinical outcome in patients with HFpEF is not explained by age, gender, nor the high prevalence of cardiovascular risk factors and co-morbidities4, and the underlying mechanisms and therefore treatment options are incompletely understood. The pharmacological therapy of HFpEF to improve outcome and symptoms has been particularly disappointing.
As part of the OptimEx trail (a study supported by the EU) we will investigate the molecular changes in the skeletal muscle, the diaphragm and the endothelium in HFpEF and the impact of different training regimes. The studies are performed in an animal model of HFpEF (Dahl salt sensitive rats). Experiments will study the function of isolated organ in an in-vitro system (see figure below) and relate these alterations with the molecular changes observed. These investigations will show us if the development of HFpEF alters the function of these peripheral organs and which molecular mechanisms may be responsible. In addition we can clarify if exercise training is a therapeutic option to treat HFpEF.
This is a collaborative study between the University of Trondheim (Norway), Munich, Leipzig (Germany), Antwerp (Belgium) and Graz (Austria).

3. Impaired HDL function in obese children and patients with chronic heart failure.

HDL is a very complex organized particle inversely related to the risk of a myocardial infarction or even death, as demonstrated by epidemiological studies. Unfortunately up to now, all efforts to increase HDL concentration by pharmaceutical interventions have failed to result in the anticipated changes in cardiovascular risk of atherosclerosis plaque load or recurrent cardiovascular events. In recent years it has become more and more evident that in addition to the concentration of HDL, the functional capacity of HDL may also play a key role in its atheroprotective effects. Besides promotion of reverse cholesterol transport, HDL has been shown to exert beneficial antiatherogenic effects, which include: stimulation of nitric oxide (NO) via activating endothelial nitric oxide synthase (eNOS), endothelial repair, anti-inflammatory and anti-oxidative properties. Unfortunately, these anti-atherogenic effects of HDL are reversed in patients with coronary artery disease, where HDL appears to be for example a pro-oxidant and pro-inflammatory molecule. Therefore, simple measurements of HDL levels seem to inadequately assess the impact of HDL on the cardiovascular system, and thus improving HDL function may represent a better therapeutic target than simply raising HDL levels.
In recent studies our group could demonstrate that the functional capacity of HDL to activate eNOS was significantly impaired in patients with chronic heart failure (Adams et al.; Circ Res 2013) and in severely obese children (Matsuo et al.; Obesity 2013). In addition exercise training over a period of 12 weeks could partially reverse the functional impairment in CHF patients. Future experiments will be performed to analyze the molecular changes in the HDL particle responsible for these functional changes and the beneficial effect of exercise training.

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