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Cardiovascular Molecular Imaging for Personalized Tailored Treatment

Periodic Reporting for period 2 - Neuroheart (Cardiovascular Molecular Imaging for Personalized Tailored Treatment)

Reporting period: 2019-01-01 to 2019-12-31

Problem being addressed. Causing 4 million deaths in Europe annually, the Heart Failure (HF) epidemic caused by inflammation of the heart continues to rise, while long-term prognosis of this devastating disease remains poor. Alterations of hormonal cardiac conditions play a crucial role in HF development. Drugs targeting those underlying mechanism have opened the door for promising therapeutic approaches in HF treatment, but it remains unclear which patient may benefit the most. Why is it important for society? Costs attributable to HF are expected to triple within the next decade. Despite promising efforts in recent years, mortality and morbidity remain high. Thus, novel non-invasive strategies for the reliable assessment of altered hormonal conditions in HF have intensively been sought for and ideally, such novel biomarkers may pave the way for personalized treatment. As a novel imaging modality, molecular imaging allows for precise assessment of the current hormonal status of the heart. During this research project, we aimed to elucidate if such molecular imaging techniques can differentiate between different inflammation states of the heart and thereby allow for imaging-guided treatment optimization in HF patients. For this purpose a set of different molecular imaging probes (radiotracers) were studied in a small animal model of cardiac inflammation. Overall objectives. For a molecular imaging PET scan, a radioactive substance is injected and the patient is passed through the imaging device to detect energy emission of the radioactive substance within the body (e.g. to assess treatment response for an anti-cancer drug). Notably, as a counterpart to human PET scanners, small-animal molecular imaging PET systems have recently been introduced. Such systems allow for serial in-vivo imaging in rodents and facilitate translation of new imaging strategies from bench to bedside. In the present project, we established a rodent model of cardiac inflammation, which led to a broad range of immune cell activation. Thereafter, a set of radiotracers, which target alterations of hormonal cardiac conditions and activated macrophages, were investigated. First, we could prove that these radiotracers for imaging the cardiac hormonal status indeed mimic the physiological neuronal cell-cell interaction. Second, we were able to show that using these tracers, molecular imaging can differentiate between active and chronic inflammation in the heart. Notably, these PET-based imaging results were also further corroborated by histological analyses at each disease stage serving as reference standard. After completing these experiments at the American host institution, an extensive knowledge exchange to the German home institution has been conducted and thus, the European Research Area has been strengthened. Conclusions and Outlook. The obtained results of the current preclinical project are encouraging and demonstrate that molecular imaging could potentially be applied for risk stratification, e.g. by monitoring treatment response using anti-inflammatory medications. Nonetheless, further research is warranted to investigate the benefit of such a molecular cardiac imaging approach and to finally transfer it into a human setting.
Main results. First, molecular imaging enables for visualizing cell-cell communication between cardiac nerve cells, the so-called neurotransmission: Physiological neurotransmitters are stored in nerve terminals of the heart, and once a firing impulse has arrived, such neuronal hormones are released from the cardiac nerve cell to enable further neurotransmission. After completing its primary task of signal transmission, such hormonal neurotransmitters undergo a recycling mechanism, i.e. they are transported back into the releasing nerve cell and are stored for the next firing impulse. Forming the backbone of cardiac sympathetic nervous system imaging, radiolabeled molecular imaging neurotransmitters for PET use the identical mechanism to enter the cardiac nerve cell. If the recycling mechanism is hampered (e.g. due to cardiac inflammation or in HF), the impaired cell-cell communication can be visualized by a decreased PET signal. However, if the clinician aims to interpret those imaging results in a human scan, a precise understanding of the molecular mechanism of those PET radiotracers at a cellular level is indispensable. Thus, by using a dedicated PET device for rodents, radiotracers for targeting humoral neurotransmission have been tested. We could prove that those radiolabeled neurotransmitters indeed mimic the physiological neurotransmission in a manner similar to the human heart. Second, we aimed to explore if molecular imaging could identify patients most at risk of suffering from chronic cardiac inflammation. In an inflammatory heart setup using rats, we observed a maximum PET signal 3 weeks after inducing inflammation in the rodent heart, which was followed by a rapid decline thereafter. Thus, guided by longitudinal molecular imaging, PET differentiates between acute and chronic inflammation in the heart, which allows monitoring of the cardiac inflammatory cascade in humans. Applying this imaging strategy in the clinic can guide the referring cardiologist into initiating the appropriate treatment at the right time. Exploitation and dissemination. Exploitation and dissemination of the results will be ensured by an application for a follow-up grant. Based on the herein presented high accuracy of PET to monitor disease course of cardiac inflammation non-invasively, a project proposal will be composed: The aim is to investigate the currently tested radiotracers in myocardial infarction patients and to monitor treatment response to anti-inflammatory medication.
Progress beyond the state of the art. HF patients suffering from inflammation of the myocardium, e.g. caused by myocardial infarction, should be monitored closely and high-risk patients should be identified, preferably at an early stage of disease. As a novel diagnostic biomarker, the results of this fellowship achieved indicate that PET allows for differentiation between acute vs. post-inflammatory cardiac reactions. Thus, PET may play an incremental role for diagnosis and treatment of cardiac inflammation: The appropriate time-point to escalate treatment regimen in HF patients can be identified using PET. Potential impacts. An implementation of PET-guided diagnosis and treatment in management of patients suffering from cardiac inflammation may contribute to precision cardiology, which in turn pave the way for a significant cost-reduction of hospitalization and therapy within the EU. In addition, earlier improvement in heart function may significantly contribute to an increased reemployment rate of patients after hospitalization. Thus, improvement in symptoms based on imaging-based personalized treatment may be an essential factor for successful occupational reintegration of HF patients and may contribute to reduce health-related productivity loss.
Translational Molecular Imaging