PSEN1 and NUP98 as Diagnostic Biomarkers for Human Myocarditis

Abstract

BackgroundMyocarditis, inflammation of the myocardium not associated with ischemia, is a spectrum of conditions causing considerable morbidity and mortality. The etiologies known to drive such inflammation are diverse and include autoimmunity and drug hypersensitivity, but are most commonly attributed to cardiotropic viral infections. Clinical symptoms are also variable, ranging from life threatening acute illness to chronic disease, while others never come to clinical attention. Moreover, these factors make the frequency of myocarditis difficult to ascertain, however, an estimated 9% of adult autopsies show myocarditis on histologic examination. Given the tools presently available, clinical, etiologic and hitstologic variability make diagnosis, and therefore treatment, exceedingly difficult. The current gold standard of diagnosis is inflammation shown on endomyocardial biopsy with (“active”) or without (“borderline”) myocyte damage. However, under these criteria, myocarditis diagnostic sensitivity is estimated as low as 30%. To improve upon this, we examined several markers implicated in the pathogenesis of viral myocarditis in animal models as possible adjunct diagnostic biomarkers in human myocarditis. PSEN1, a cellular protease implicated in heart failure and NUP98, a nuclear pore protein with inducible cardioprotective and antiviral gene transcription capabilities, have emerged as promising candidates.DesignTwo groups were examined for PSEN1 and NUP98 immunohistochemical (IHC) staining: a development set of 50 cases (18 lymphocytic active or healing myocarditis, 4 eosinophilic myocarditis, 4 idiopathic dilated cardiomyopathy, 3 hypertrophic cardiomyopathy, 4 sarcoidosis, 3 transplant rejection, 1 toxoplasmosis, 4 arrhythmogenic right ventricular cardiomyopathy (ARVC), 4 coronary artery disease (CAD) and 5 normal controls) and a validation set of all (62) cardiac biopsies performed at SPH from January 2015–June 2016, irrespective of diagnosis. Staining intensity was assessed by computer aided image analysis. Statistical analysis was performed using Mann Whitney U test and receiver operating characteristic (ROC) curves. All protocols were approved by the UBC/PHCRI Research Ethics Board.ResultsPSEN1 distinguished myocarditis from all other diagnoses in the development set (p=0.0001). NUP98 could distinguish inflammatory myocarditides as well as viral from non‐viral from most other diagnoses in the development set (p=0.001). ROC values comparing myocarditis to all other cardiomyopathies was 0.85 for PSEN1 and 0.80 for NUP98. These findings appear hold true in preliminary analyses of the validation set.ConclusionPSEN1 and NUP98 appear to be valuable biomarkers, particularly in combination, for improving sensitivity of endomyocardial biopsy for diagnosing myocarditis, and may provide greater ability to deduce etiologic information from such biopsies. Moreover, PSEN1 and NUP98 are detectable even in regions even without inflammation and in tissue long after initial insult. These insights will aid in personalization of treatment and significantly improve clinical outcomes.Support or Funding InformationThis research is funded by the Providence Health Care Research Institute and through donations made to the St. Paul's Hospital Foundation.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.