Clin Res Cardiol (2021). 10.1007/s00392-021-01933-9

LCZ696 improves post-infarction survival and cardiac function through Notch-1-dependent de-novo angiogenesis
E. Klapproth1, A. Shukla1, S. Künzel1, K. Lorenz2, K. Guan1, A. El-Armouche1
1Institut für Pharmakologie und Toxikologie, Medizinische Fakultät Carl Gustav Carus der TU Dresden, Dresden; 2Institut für Pharmakologie und Toxikologie, Universitätsklinikum Würzburg, Würzburg;

Background and Aim. Despite substantial advances in the management of heart failure (HF) upon myocardial infarction (MI), prognosis remains poor with many patients suffering from life-long symptoms. The development of the angiotensin/neprilysin inhibitor LCZ696 accounts as major milestone in the treatment of cardiovascular diseases. The induction of angiogenic responses to enhance vascular development is a promising treatment approach to restore oxygen and nutrition supply after MI and decelerate the development to HF. Here we evaluate the value of post-infarction LCZ696 treatment to induce angiogenesis for cardioprotection.

Methods and Results. In mice subjected to LAD ligation, LCZ696 treatment resulted in a significantly improved overall survival, augmented cardiac function, and reduced infarct size compared to DMSO controls. This functional improvement was accompanied by enhanced VEGFR2 expression and phosphorylation. Quantitative real-time PCR (qPCR) on a panel of pro-angiogenic and pro-arteriogenic factors in heart tissue of LCZ696-treated mice showed elevated expression of the pro-angiogenic genes NRP1, NOTCH1 and DLL4 compared to DMSO-treated animals while pro-arteriogenic genes were not significantly regulated. Similarly, qPCR analysis on primary HUVEC cultures validated the significant upregulation of NOTCH1 and DLL4 in response to LCZ696 treatment.  Further, immunofluorescence analysis of histological sections and light sheet microscopy of whole hearts revealed a significantly higher CD31 count in LCZ696-treated mice when compared to controls.

Conclusion. Our data suggest that LCZ696 is highly efficient for improving post-infarction cardiac function and survival. Mechanistically, LCZ696 induces NOTCH1 and DLL4-dependend VEGFR2 signaling to induce de-novo angiogenesis after MI. Due to its beneficial effects in the PARAGON-HF and PARADISE-MI trial, LCZ696 treatment following MI might represent a potential therapeutic strategy to improve patient outcome.


https://dgk.org/kongress_programme/ht2021/V304.htm