Image Biomarker-Piloted Neurohumoral Reparative Intervention after Myocardial Infarction

• Applicant: Professor Dr. Rudolf Werner
• Subject Area: Radiology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 507803309

It is increasingly recognized that myocardial ischemia (MI) can initiate a fatal cascade of neurohumoral dysregulation leading to heart failure. Such neurohumoral alterations comprise multiple pathophysiological pathways, including sympathetic nervous system overactivity and continuous upregulation of the renin angiotensin-aldosterone system (RAAS). On a subcellular level, heart failure is characterized by an excess of the physiological norepinephrine, which is not sufficiently removed by the norepinephrine transporter (NET) from the nerve terminal at the presynapse. Such neurohumoral hyperactivity after MI also has detrimental effects on the kidneys, which can lead to cardiac and renal remodeling. Incidences of acute and chronic kidney injury as a comorbidity after MI are associated with renal replacement therapies and increased all-cause mortality. Thus, there is a need for novel treatment regimens to improve the patients’ outcome. As proposed in the current project, a highly innovative image biomarker assay will meet this urgent need to assess the heart-kidney interaction on a (sub)cellular level. Whole-body positron emission tomography (PET) imaging using 18F-labeled radiotracers targeting the NET and the RAAS will be combined with a rat model of MI leading to heart failure and subsequent chronic renal impairment. Specific aims of the project are as follows: First, we will serially explore the extent and severity of persistent NET and RAAS overactivity in the heart (target) and kidneys (remote organ) by using our 18F-labeled NET and RAAS-targeting image biomarker assay. Secondly, we will assess the predictive capability of the serially obtained PET signal for cardiorenal outcome by correlating our PET data with multiple functional endpoints (e.g., decline of left ventricular ejection fraction or glomerular filtration rate during follow-up). Finally, guided by the PET signal, the ideal time-point for initiation of neurohumoral overactivation inhibiting therapies will be determined. We hypothesize that such an image-piloted treatment strategy will maximize regeneration of the heart and reduce the negative impact on the kidneys as a secondary affected organ after MI. Ultimately, we aim to optimize bilateral heart-kidney functional outcome by implementing PET-based reparative strategies in the clinic – to identify the optimal treatment at the right time for the right patient.

• DFG Programme: Research Grants
• International Connection: USA
• Cooperation Partner: Professor Steven Rowe, Ph.D.