The primary aim of this observational registry is to evaluate the efficacy of CCM in patients with heart failure with mid-range or reduced EF and diagnosis of TTR amyloidosis. The efficacy will be evaluated in terms of composite of occurrence of heart failure-related hospitalizations and/or acute intravenous interventions (IVI) at 12-month follow up compared to those reported 12 months before CCM implantation. Among the secondary endpoints, clinical functional status, quality of life, drug changes and Echocardiographic parameters will be evaluated and compared from baseline to follow up.

Amyloidosis represents a group of human degenerative diseases characterized by the deposition of aggregates of abnormally folded proteins in single or multi-organs. Cardiac amyloidosis is primarily associated with the systemic production and release of a number of amyloidogenic proteins, notably immunoglobulin light chain proteins (also known as amyloid light chain or AL) or transthyretin proteins (TTR). Notably, although myocardial dysfunction is generally understood as a result of infiltration by extracellular amyloid deposits, there is experimental evidence of direct cytotoxic effect, possibly due to oxidative stress.

Since neither HF optimal medical therapy nor HF devices seems to have a clear benefit in amyloid cardiomyopathy, this clinical setting needs to test other therapeutic options.

Randomized clinical trials have shown that Cardiac contractility modulation (CCM) may be considered as a concrete therapeutic option in patients with symptomatic Heart Failure (HF) despite optimal medical therapy (OMT), with Left Ventricular Ejection Fraction (LVEF) between 25% and 45%, with narrow QRS complex (<130ms).

CCM signal treatment reverses the cardiac maladaptive fetal gene program and normalizes expression of key sarcoplasmic reticulum Ca2+ cycling and stretch response genes. Specifically, 3-month on CCM therapy resulted in decreased expression of A- and B-type natriuretic peptides, p38 mitogen activated protein kinase (MAPK) and p21 Ras and increased expression of α-MHC, SERCA-2a, phospholamban, and ryanodine receptors. Notably, pre-clinical data suggest that triggering p38α MAPK autophosphorylation plays a crucial role in amyloidogenic light-chain mediated cellular oxidative stress, dysfunction and ultimately cell death in cardiomyocytes. Therefore CCM mechanism of action could be beneficial in cardiac amyloidosis but there are no data in this specific clinical setting.

Inclusion Criteria:

• Age 18 years or older
• Male or a nonpregnant female
• All of the following: Established diagnosis of amyloid TTR Cardiomyopathy; baseline ejection fraction ≥25% and ≤45%; at least one hospitalization due to worsening heart failure over the year before entry into the registry.
• ICD if indicated
• PM if indicated
• Willing and able to return for all follow-up visits

Exclusion Criteria:

• AL amyloid cardiomyopathy
• Subjects who have a potentially correctible cause of heart failure (eg, Ischemic or valvular or congenital heart disease).
• Scheduled for CABG or PCI or has undergone a CABG within 90 d or PCI within 30 d.
• Myocardial infarction within 90 days
• Mechanical tricuspid valve
• Prior heart transplant
• Chronic haemodialysis
• Familial TTR amyloidotic cardiomyopathy with significant polyneuropathy potentially eligible for Patirisan or Inotersen17
• Unable to provide informed consent

This Registry includes patients with chronic, symptomatic heart failure with moderately-to-severely reduced left ventricular systolic function despite optimal pharmacological and electrical therapy, who have been diagnosed with TTR Cardiac Amyloidosis. The clinical trial study (prospective registry) will be conducted in accordance with the protocol, with the Helsinki Declaration and with the favorable opinion of the local Ethics Committee of the participating Centers.