Exercise Training and Rehabilitation In Cardiac Amyloidosis

Among Systemic amyloidosis, the peculiar deposition of beta-amyloid fibrils agglomerates localized in the interstitial space between the cardiomyocytes characterizes the spectrum of cardiac amyloidosis (AC). All AC phenotypes culminate in a progressive deterioration of cardiac compliance up to a true infiltrative cardiomyopathy with restrictive physiology. Clinical presentation may vary from mildly symptomatic Heart Failure (HF), usually labeled, and mistakenly confused as a classic Heart Failure with preserved ejection fraction (HFpEF) up to a severe scenario of severe cardiac decompensation with fluid overload, marked shortness of breath, fatigue and orthostatic hypotension. Syncope may also appear due to infiltration in the conduction system leading to sinoatrial disease and atrioventricular block. To date, more than 30 proteins responsible for the deposition of fibrils have been identified and of these 9 have been identified as responsible for the cardiac involvement of the disease. AC is determined in 98% of cases by the accumulation of monoclonal light chains of immunoglobulins (AL) or transthyretin (ATTR); the latter can occur either in its hereditary form (ATTRv) or in the wild-type variant (ATTRwt). Although AC is perceived as a rare disease, standing a reported prevalence of around 1/100,000 inhabitants, a recent metanalysis reported AC as underlying HF cause in 13.7% of cases, varying from 15.1% of Heart Failure (HF) with preserved ejection fraction (HFpEF) and 11.3% in reduced fraction phenotype (HFrEF). This mismatch begets the hypothesis that AC is often underdiagnosed, probably due to its challenging diagnosis, the diverse spectrum of clinical presentation ranging from severely compromised clinical cases to rather silent manifestations, and the absence of specific therapies for this condition making until a few years ago AC a true orphan disease. This paradigm has been subverted in recent years, by the emergence of tafamidis, a targeted drug from amyloidosis that binds transthyretin, preventing tetramer dissociation and production of amyloid. Tafamidis has been successfully tested for ATTRwt-AC in a relatively large multicenter, international, double-blind, placebo-controlled, phase 3 trial, the Transthyretin Amyloidosis Cardiomyopathy Clinical Trial (ATTR-ACT), showing a remarkable improvement of the composite outcome of all-cause mortality and hospitalizations due to cardiovascular causes. Apart from Tafamidis, there are no evidence supporting the use of guideline-directed medical therapy (GDMT) used in classical forms of HF in ATTR-ACT. On top of GDMT, exercise training (ET) remains largely uninvestigated in AC. ET consists of a multidisciplinary approach, including a medical evaluation with modification of cardiovascular risk factors, prescription of a physical exercise program and psychosocial evaluation and is currently recommended with the highest degree of recommendation (in class I, type A level) in current guidelines on HF. To date, there are no data about the efficacy and safety of ET in AC, specifically in the ATTRwt-AC. We hereby present the outlines and the study protocol of the Exercise Rehabilitation and training in Cardiac Amyloidosis (ERICA) study, whose aim is to investigate and analyze the safety and the efficacy of cardiac rehabilitation on patients with AC, specifically those affected by the ATTR-wt form. The present study aims to investigate and analyze, through an interventional longitudinal, controlled, randomized, design, the effects of a structured program of Exercise training in patients with ATTRwt-AC.