Immunosuppression Versus Medical Therapy for UN-explained Low Ejection Fraction and VT

Ventricular arrhythmia (VT) is a well-established consequence in patients with non-ischemic cardiomyopathy (NICM). NICM is a broad category that includes a wide spectrum of causes, which may include: bacterial, viral toxin mediated and immune mediated and "unexplained" when coronary disease has been excluded. The pathophysiology of NICM is not well understood but inflammatory responses with macrophage recruitment during remodeling have been described. On the other hand, an infectious trigger i.e. myocarditis may be the inciting event for the development of cardiomyopathy. A previous study by Tung et al showed that nearly 50% of patients with unexplained cardiomyopathy and ventricular arrhythmias presented ongoing focal myocardial inflammation on PET. To date, targeting inflammation as a substrate in order to reduce burden of ventricular tachycardia has not been investigated in randomized prospective fashion.

The TIMIC trial was one of the few randomized studies to examine long-term benefit of immunosuppressive therapies in patients with virus-negative NICM. A moderate improvement in Left Ventricular Ejection Fraction (LVEF) over 6 months after initiation of immunosuppressive therapy was demonstrated in this study but current guidelines do not routinely recommend anti-inflammatory therapies for NICM. While considered to be gold standard, endomyocardial biopsy can often times be incorrect due to sampling error and typically is not performed multiple times in patient with chronic non-ischemic cardiomyopathy. Fasting Fluorodeoxyglucose (FDG)-positron emission tomography (PET) is an emerging imaging modality to identify and monitor abnormal metabolic patterns of the myocardium. By exploiting the metabolic demand of inflammatory tissue with macrophage recruitment, PET imaging is emerging as the preferred modality to diagnose and measure response to therapy for patients with myocarditis and sarcoidosis. A recent study by Kandolin et al in Finland showed that the incidence of cardiac sarcoidosis has increased by 20-fold over the past two decades.

FDG-PET may reveal inflammation as a central pathophysiologic mechanism in a significant proportion of patients with unexplained cardiomyopathy and VT. Potential innovative insights from the trial will be to identify the underlying pathogenesis of idiopathic cardiomyopathy and assess whether immunosuppression changes the clinical course of patients with identified arrhythmogenic cardiomyopathy. Aside from guideline-direct medical therapy (GDMT), antiarrhythmic agents, and catheter ablation, there are no disease-specific therapies for patients with VT and NICM. Prospective studies that evaluate the incidence of occult inflammation and clinical response to anti-inflammatory and immunosuppressive therapy have not been performed to date and are warranted for the emerging NICM population referred for advanced heart failure and arrhythmia management.