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Experimental Cardiology

Diseases of the heart muscles

Cardiomyopathies

Cardiomyopathies comprise various structural diseases of the heart muscle. Despite their different origins, these changes manifest themselves in common pathophysiological pathways, characterized by myocardial hypertrophy, dilatation of the ventricle, increased fibrosis and loss of myocardial pumping function. Currently available pharmacological therapies increase the survival time of patients with the disease, but cannot stop the pathophysiological changes in the heart, such as hypertrophy or fibrosis of the myocardium and the associated remodeling. Targeted molecular therapy has recently become possible by inhibiting specific micro-RNAs (miRs), which are highly elevated upton certain cardiovascular diseases in the affected cell types and/or tissues, by means of antagomiRs (antimiRs). We have investigated this therapeutic strategy in pigs as preclinical large animal models.

 

Ischemic cardiomyopathy

In a first study, regional inhibition of a specific miR, miR-21, in the affected working myocardium reduced fibrosis development and the associated loss of function in the ischemic cardiomyopathy model. MiR-21 is a key regulator of cardiac fibrosis, and its inhibition has already been shown to be an effective anti-fibrotic strategy in various organs, including the heart, in small animal models. In the pre-clinical study in pigs, we demonstrated that intracoronary infusion of antimiR-21 is feasible and therapeutically effective. The catheter-based regional application of antimiR-21 could represent a novel therapeutic option to prevent the development of heart failure after myocardial infarction.

 

Hypertrophic cardiomyopathies

Another entity of cardiomyopathy is cardiac hypertrophy. Pathologic cardiac hypertrophy is a consequence of diseases that increase afterload, such as untreated hypertension and aortic stenosis. It is characterized by negative remodeling, capillary rarefaction and fibrosis, which often lead to heart failure. In a translational study in pigs, we first established a model for cardiac hypertrophy by stent implantation in the aorta.

 

 

 

 

While control animals developed cardiomyocyte growth with increased afterload, which led to massive hypertrophy, this effect was significantly attenuated by the intracoronary application of inhibition of m-132 (antimiR-132). In addition, interstitial fibrosis and negative remodeling were significantly reduced, resulting in a marked improvement in function. 
In addition to other results from the cooperation partners from the MHH Hannover (Prof. Thomas Thum), this knowledge contributed to clinical translation and testing in the form of clinical studies, which are currently underway.

Genetic cardiomyopathies

In addition to disease-related changes in heart structure and function, there are also congenital genetic changes that cause heart muscle weakness. These can be treated using traditional gene therapy, in which the faulty protein is replaced with a correct one. However, this approach is limited by the size of the protein to be replaced. Novel therapeutic approaches therefore aim to directly correct the faulty sequence of the protein produced (in vivo genome editing). Our research group is pursuing approaches in which adeno-associated viral vectors transport recombinases (enzymes) into the affected cells, which are able to repair the gene sequences.

 

Diabetic cardiomyopathy

Diabetes mellitus is a common and serious metabolic disease that affected 422 million people worldwide in 2014, with the incidence increasing in industrialized countries in particular. The search is on for new treatment options to treat diabetes itself and the various secondary symptoms of diabetes mellitus. Diabetes mellitus affects many organ systems, including blood vessels. As the most common secondary disease, diabetes mellitus affects the cardiovascular system. Particularly the function of the coronary arteries and, hence the blood flow to the heart. Heart attacks and the resulting heart failure are the most common causes of death in diabetics. Unfortunately, for reasons still unknown, cardiovascular mortality in diabetics is barely affected by modern antidiabetic treatments, including insulin. Therefore, there is a great need for better understanding and treatments of diabetic cardiomyopathy. 

 

Current research projects on diabetic cardiomyopathy are predominantly based on animal models, which, in addition to obvious advantages such as genetics that can be traced over generations and the directly measurable influence of nutritional regimens, also have limitations that should not be underestimated. For example, many studies are based on transgenic rodent models, which are only partially symptomatically comparable with humans due to their genetically modified backgrounds. Moreover, they are also under debated discussion with regard to their clinical relevance for translation of biomedical therapeutic approaches. We have therefore set up a range of models (cell culture, ex-vivo studies and animal models (mouse and pig)) in order to have a rather comprehensive understanding of the pathophysiological changes in diabetes and to enable the development and testing of new therapeutic approaches.

In our studies on pigs with a genetic diabetes mellitus caused by a mutated insulin, we were able to show that hyperglycemia itself leads to pathophysiological changes in the heart (e.g. capillarization, fibrosis) at a very early stage and thus to a deterioration in cardiac function.

Gene therapy with a pro-angiogenic factor using an adeno-associated viral vector coding for Thymosin ß4 showeds a significant growth of micro- and macro- vessels in diabetic animals in a model of chronic myocardial ischemia, associated with a reduction in fibrosis, as well as improvement in cardiac function, however not to the same level as in non-diabetic animals.