Soluble Neprilysin in ST-elevation Myocardial Infarction

Background and hypotheses In our research project entitled Soluble Neprilysin in ST-elevation Myocardial Infarction, we will investigate the role of neprilysin in patients suffering from acute myocardial infarction (AMI). Neprilysin is a membrane-bound zinc-dependent protein which can be found in most organs, especially in specific kidney cells. Besides this membrane-bound form a soluble form is known, which circulates in the blood and regulates the degradation of a diversity of proteins strongly influencing hemodynamics. Due to the essential effects of soluble neprilysin in the cardiovascular system, neprilysin has moved into focus of clinical research in the past years. In patients with chronic heart failure, neprilysin has been revealed as independent predictor of worse clinical outcome. Moreover, the pharmacological blockade of neprilysin with so-called angiotensin-receptor-neprilysin inhibitors (ArNI) has been proven to reduce the risk of morbidity and mortality in chronic heart failure. These convincing data even led to the implementation of this therapeutic approach into the recent guidelines of the European Society of Cardiology (ESC). Since myocardial infarction is one of the most important determinants of heart failure, we hypothesize that neprilysin may have a comparable clinical impact also in AMI patients. Aim of this project is to investigate the association of soluble neprilysin with markers of cardiac injury as well as clinical outcome after AMI. Methods We aim to include 700 consecutive AMI patients treated with primary percutaneous coronary intervention (PPCI). Analysis of release kinetics of soluble neprilysin will be performed at predefined time points within the first days after PPCI and will be repeated 4 months thereafter. Additionally, patients will undergo magnetic resonance imaging of the heart within the first week after infarction as well as 4 months after the index event to assess acute and chronic markers of cardiac injury and dysfunction. Evaluation of potential clinical complications in the course of the disease will be performed at 18 months after infarction. Aims and perspectives The named research project could become the cornerstone of neprilysin research in myocardial infarction. We will, for the first time, illuminate the prognostic significance of the promising new cardiac biomarker neprilysin in AMI patients, potentially revealing a novel clinical marker for risk stratification of this patient population. Out data could provide a basis for future randomized clinical trials to investigate on the effect of ArNI in patients suffering from AMI.

Neprilysin is a zinc-dependent enzyme found in mammals, notably in the kidneys. Neprilysin is essential to break down various peptides that significantly influence cardiovascular health, including those that regulate blood vessel behaviour and heart structure. The importance of neprilysin in cardiovascular diseases, particularly heart failure, has made it a focus of recent research. Studies have shown that high levels of neprilysin in the blood can predict worse outcomes in patients with chronic and acute heart failure, suggesting it could serve as a valuable marker for assessing the risk of heart-related deaths or hospitalization. This enzyme has not only proven to be an important predictor of health outcomes but has also emerged as a potential target for treatment. In PRADIGM-HF trial, a drug that inhibits neprilysin and a receptor involved in blood pressure regulation was found to be more effective than traditional treatments in reducing death and hospitalizations related to heart failure. This is believed to be due to the drug's ability to restore a balance in the body's natural systems that control blood pressure and heart function. However, while the role of neprilysin is well-documented in heart failure, its implications in patients with acute myocardial infarction (MI) are not yet fully understood. Current studies have not explored into how neprilysin levels change after MI or how they relate to the severity of the overall heart function. This gap in research highlights a significant opportunity to explore neprilysin as a new biomarker for predicting and managing complications after MI. Cardiac magnetic resonance (CMR) imaging provides detailed insights into the structure and function of the heart, particularly after MI. In Particular, advanced techniques in CMR have improved our understanding of the pathophysiological processes in post-MI patients. In this study involving 663 patients with acute STEMI, we measured neprilysin levels post-MI at two timepoints and evaluated myocardial tissue damage and global cardiac function using CMR. We found no association between neprilysin levels and markers of myocardial tissue injury, including infarct size, microvascular obstruction, and intramyocardial haemorrhage. Additionally, while adverse remodelling was observed in 21% of patients, there was no association with neprilysin levels. During the follow-up period, which averaged 27 months, 10% of the patients suffered major adverse cardiac events, such as new congestive heart failure, MI or death. However, neprilysin levels were not significantly different between those who did and did not experience these events. This study underscores the complex role of neprilysin in heart disease and highlights the need for further research to understand its potential as a therapeutic target, especially in the context of MI.