Reducing the mortality rate of patients after Aortic-Valve Implantation by Anti-Fibrotic Treatment

A subpopulation of patients with a very high risk to die in only one year after an aortic valve implantation (AVI) was identified. A novel, anti-fibrotic treatment was developed, which adresses the most important factor for the survival rate of patients and is being tested in a phase 3 clinical trial.

Challenge

27000 Heart valve implantations were performed in Germany in 2019 and this number is increasing at an average rate of 4% every year. Also the age group undergoing such surgeries is reducing every year. In 2008 it was mainly for age 90 and above while in 2019 it has shifted to the age group of 70-80. Although the survival rate after surgery is very high, many patients die within one year after surgery. These patients contribute to almost 29% of total deaths within 1 year of surgery. A successful surgery therefore does not always lead to a healthy outcome and higher survival rate. Currently it is not completely known, which factors decide if you are in a high risk group and thus there is also no efficient after treatment.

Our Solution

Scientists at the university Göttingen identified a sub-population of patients having a very high risk after an aortic valve implantation. The most important factor was the level of myocardial fibrosis and not neccessarily the  functioning of the heart. It was found, that patients with more than 11% myocardial fibrotic tissue have a 1:4 risk to die within one year after the transplantation, while patients with less than 11% have a risk of 1:50 (Fig.1). 

Fig. 1: Analysis of endomyocardial biopsies from 100 patients with Aortic Stenosis after Transcatheter Aortic Valve Implantation (TAVI)

The high risk patients can be treated with a novel anti-fibrotic treatment, namely with low-dose Hydralazin and Spironolactone. This treatment can significantly reduce the progression of heart fibrosis (Fig.2) and will stabilize heart functioning.

Fig. 2: Treatment with low-doses of hydralazin reduces progression of myocardial fibrosis in the Angiotensin-cardiac-fibrosis mouse model.

Hydralazin and Spironolactone are both FDA approved drugs, which means, that there is much clinical data available and the use of Hydralazine in very low doses will reduce side effects. Taking a look on the mechanisms of action, this therapeutic approach seems to be very promising, since they are complementary to each other. While Spironolactone inhibts progression of fibrosis by blocking the expression of pro-fibrotic genes, Hydralazine activates an anti-fibrotic cellular response (Fig.3).

Fig. 3: The modes of action of Hydralazine and Spironolactone are complementary. Spironolactone inhibits pro-fibrotic genes by blocking the Aldosterone receptors. Low-dose Dihydralazine reactivates anti-fibrotic genes by reversing aberrant DNA-methylation.

Advantages

• Myocardial fibrosis is identified as marker for a subpopulation with a very high mortality
• The level of myocardial fibrosis is easy to diagnose
• An individual low dose of Hydralazine together with Spironolactone can be used as a novel anti-fibrotic treatment
• Both Spironolactone and Hydralazine are FDA approved drugs
• Low dose also corresponds to lower side effect risks
• A synergistic effect of Spironolactone and Hydralazine can be anticipated
  

Development Status

The clinical trial (ClinicalTrials.gov ID NCT05230901) has started in 2022 and the results are expected to be published in early 2026.

Patent Situation

The European unitary patent is in the process of being granted.

Contact

Dr. Vanessa Jensen
Patent Manager Life Sciences
E-Mail: This email address is being protected from spambots. You need JavaScript enabled to view it.
Tel.: +49 551 30724 149
Referenz: BioT-2207-UMG

Tags: Therapy, Life science