Inflammatory and Genetic Cardiomyopathies: Metabolic Phenotyping to Guide Diagnosis and Therapy

University Of Washington, Seattle WA

Investigators

Abstract

Cardiac sarcoidosis (CS) is both under- and over-diagnosed. While vigilance has increased, diagnosis of isolated CS (ICS) remains challenging as detecting granulomatous inflammation on endomyocardial biopsy (EMB) is low yield. Thus, ICS is often presumed based on positron emission tomography (PET), the use of which has been proliferating. Thus, in an attempt not to under-diagnose CS, we are: 1) mis-diagnosing patients with “ICS” who actually have genetic CMP (36% in our prior work), with major clinical implications including unnecessary immunosuppression and failure to screen family members 2) identifying a growing group of “idiopathic 18FDG-avidity” patients” (64%) who have neither CS nor genetic CMP in whom identifying mechanism of 18FDG-avidity will guide future therapeutic options In this “bedside to bench” translational proposal, we perform “deep phenotyping” with genetic testing, PET imaging, metabolomic studies, voltage-guided EMB (with advanced inflammation histology methods) to: 1) help clinicians decide in which patients to order genetic testing and PET scans 2) develop minimally invasive diagnostic tests to determine mechanism of 18FDG-avidity and therapeutic options in patients with “idiopathic” or genetically-driven 18FDG-avidity In Aim 1, a total 200 patients will systematically undergo PET and genetic testing to help determine revalence and predictors of true CS, genetic CMP and “idiopathic 18FDG avidity”, and we will develop a prediction model to guide clinicians when to order genetic testing and PET scans. In Aim 2.1, we will metabolically phenotype these patients by simultaneously sampling radial artery and coronary sinus blood and using mass spectrometry to quantify myocardial fuel use, testing our hypothesis that the 18FDG-avidity in genetic CMP and idiopathic 18FDG-avid patients is due to a “metabolic switch” from fatty acid (normal) to glucose metabolism, and not due to inflammatory cell infiltrate. We will also measure and correlate inflammatory cytokines and oxygen consumption rate and extracellular acidification rate with metabolic data to help develop a “non-invasive signature” of true inflammation versus metabolic switch. To test the inflammatory counter-hypothesis, in Aim 2.2 we will process EMBs of “idiopathic 18FDG-avidity” patients and positive (true CS) and negative (18FDG-negative) controls using multi-spectral immunostaining, spatial transcriptomics, and imaging cytometry, which historically differentiate CS from its mimicking conditions. In Aim 3, cardiomyopathy mouse models will be utilized on our 18FDG-PET scan protocol to allow us to further study this phenomenon with even greater anatomic detail and control than in humans, and eventually to allow testing of novel therapies for this condition. In addition to providing predictive tools and novel diagnostic tests, elucidating the mechanism of 18FDG-avidity will enable future animal and human studies of immunosuppression and/or metabolic therapies for this growing group of patients and their families.