Prognostic impact of intensified risk stratification with extended immunohistochemical analysis of cardiac remodelling in patients at risk for sudden cardiac death due to non-ischemic cardiomyopathy

I. Toskas (Tübingen)¹, L. Baas (Tübingen)¹, P. Krumm (Tübingen)², C. S. Meyer-Zürn (Basel)³, S. Greulich (Tübingen)¹, K.-P. Kreisselmeier (Tübingen)¹, T. Harm (Tübingen)¹, D. Rath (Tübingen)⁴, M. Gawaz (Tübingen)⁴, J. Schreieck (Tübingen)⁴, L. Schöllmann (Friedrichshafen)⁵, K. A. L. Müller (Tübingen)^4
1Universitätsklinikum Tübingen Innere Medizin III, Kardiologie und Angiologie Tübingen, Deutschland; ²Universitätsklinikum Tübingen Radiologie Tübingen, Deutschland; ³Universitätsspital Basel Abt. für Kardiologie Basel, Schweiz; ⁴Universitätsklinikum Tübingen Innere Medizin III, Kardiologie und Kreislauferkrankungen Tübingen, Deutschland; ⁵Medizin Campus Bodensee Klinik für Kardiologie, Pneumologie und Intensivmedizin Friedrichshafen, Deutschland

Background: Patients with non-ischemic cardiomyopathy undergo an extensive clinical risk stratification that includes laboratory parameters, echocardiography, myocardial biopsy, monitoring of arrhythmias, and contrast-enhanced CMRI to assess their risk of sudden cardiac death. We previously found that the additional immunohistochemical analysis of myocardial Gremlin-1 (Grem1) expression, is associated with left ventricular dysfunction, cardiac remodeling and adverse prognosis in patients with non-ischemic heart failure. Here, we aimed to assess if endomyocardial Grem1 expression correlates with the non-invasive visualization of fibrosis by contrast-enhanced CMRI and if the analysis of Gremlin-1 expression provides additional value to identify patients at risk for sudden cardiac death.
Methods: 198 patients with non-ischemic heart failure underwent endomyocardial biopsy with additional Gremlin-1 staining and contrast-enhanced CMRI. The follow-up of patients was performed over 8 years after first diagnosis of non-ischemic heart failure. The primary study endpoint was defined as all-cause mortality. The secondary composite clinical endpoint was determined as all-cause mortality and/or survived sudden cardiac death defined as adequate ICD-shock due to hemodynamically relevant sustained ventricular tachycardia or ventricular fibrillation.
Results: 117 patients showed positive LGE patterns on CMRI. Grem1 positive patients revealed a significantly higher rate of positive LGE detection on CMRI and a higher degree of myocardial fibrosis detected by trichrome staining of myocardial tissue. Out of the 81 patients without pathological LGE on CMRI, 49 patients showed high myocardial Grem1 expression in immunohistochemistry. Those patients presented with a significantly lower LVEF and showed lower serum levels of BNP. During the follow-up period, 17 patients died, while 45 patients suffered the composite secondary endpoint. To further evaluate the subgroup of patients without evidence of LGE in CMRI, we performed Cox regression and Kaplan-Meier analysis. Kaplan-Meier curves illustrate worst survival rates in LGE positive and Gremlin-1 positive patients. However, LGE negative but Grem1 positive patients showed a significantly higher frequency of the secondary endpoint during follow-up. Cox regression analysis revealed that BNP levels, LVEF and positive Grem1 expression were independent predictors for the primary endpoint in patients with presence of LGE and positive Grem1 expression among other parameters tested including age, gender, and RV function. Cox regression analysis of the subgroup without LGE in CMRI revealed that BNP levels, LVEF and positive Grem1 expression were independent predictors for the occurrence of the secondary endpoint.
Conclusions: Risk stratification of patients with non-ischemic heart failure is insufficient to identify all patients at risk for sudden cardiac death. Our results indicate that in particular patients without presence of pathological LGE patterns in CMRI may benefit from an additional immunohistochemical analysis of myocardial tissue to detect advancing and/or irreversible cardiac remodelling associated with poor prognosis. Therefore, additional Grem1 staining may help to identify patients at risk sudden cardiac death and may therefore be analysed in histological and immunohistochemical staining of myocardial tissue.