tafamidis and Arrhythmias--Cardiac

Cardiac amyloidosis (CA) is an infiltrative and restrictive cardiomyopathy that leads to heart failure, reduced quality of life, and death. The disease has two main subtypes, transthyretin cardiac amyloidosis (ATTR-CA) and immunoglobulin light chain cardiac amyloidosis (AL-CA), characterized by the nature of the infiltrating protein. ATTR-CA is further subdivided into wild-type (ATTRwt-CA) and variant (ATTRv-CA) based on the presence or absence of a mutation in the transthyretin gene. CA is significantly underdiagnosed and increasingly recognized as a cause of heart failure with preserved ejection fraction. Advances in diagnosis that employ nuclear scintigraphy to diagnose ATTR-CA without a biopsy and the emergence of effective treatments, including transthyretin stabilizers and silencers, have changed the landscape of this field and render early and accurate diagnosis critical. This review summarizes the epidemiology, pathophysiology, diagnosis, prognosis, and management of CA with an emphasis on the significance of recent developments and suggested future directions.

Topics: Amyloid Neuropathies, Familial; Amyloidosis; Arrhythmias, Cardiac; Benzoates; Benzoxazoles; Biopsy; Cardiac Pacing, Artificial; Cardiomyopathies; Diflunisal; Disease Progression; Early Diagnosis; Early Medical Intervention; Echocardiography; Electrocardiography; Heart Failure; Humans; Immunoglobulin Light-chain Amyloidosis; Immunologic Factors; Magnetic Resonance Imaging; Oligonucleotides; Prealbumin; Prognosis; Proteasome Inhibitors; Pyrazoles; Radionuclide Imaging; RNA, Small Interfering

In the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT), tafamidis significantly reduced mortality and cardiovascular (CV)-related hospitalizations compared with placebo in patients with transthyretin amyloid cardiomyopathy (ATTR-CM). This analysis aimed to assess the causes of CV-related death and hospitalization in ATTR-ACT to provide further insight into the progression of ATTR-CM and efficacy of tafamidis. ATTR-ACT was an international, double-blind, placebo-controlled, and randomized study. Patients with hereditary or wild-type ATTR-CM were randomized to tafamidis (n = 264) or placebo (n = 177) for 30 months. The independent Endpoint Adjudication Committee determined whether certain investigator-reported events met the definition of disease-related efficacy endpoints using predefined criteria. Cause-specific reasons for CV-related deaths (heart failure [HF], arrhythmia, myocardial infarction, sudden death, stroke, and other CV causes) and hospitalizations (HF, arrhythmia, myocardial infarction, transient ischemic attack/stroke, and other CV causes) were assessed. Total CV-related deaths was 53 (20.1%) with tafamidis and 50 (28.2%) with placebo, with HF (15.5% tafamidis, 22.6% placebo), followed by sudden death (2.7% tafamidis, 5.1% placebo), the most common causes. The number of patients with a CV-related hospitalization was 138 (52.3%) with tafamidis and 107 (60.5%) with placebo; with HF the most common cause (43.2% tafamidis, 50.3% placebo). All predefined causes of CV-related death or hospitalization were less frequent with tafamidis than placebo. In conclusion, these data provide further insight into CV disease progression in patients with ATTR-CM, with HF the most common adjudicated cause of CV-related hospitalization or death in ATTR-ACT. Clinical trial registration ClinicalTrials.gov: NCT01994889.

Topics: Aged; Amyloid Neuropathies, Familial; Amyloidosis; Arrhythmias, Cardiac; Benzoxazoles; Cardiomyopathies; Cardiovascular Diseases; Cause of Death; Death, Sudden, Cardiac; Double-Blind Method; Female; Heart Failure; Hospitalization; Humans; Ischemic Attack, Transient; Male; Myocardial Infarction; Prealbumin; Proportional Hazards Models; Stroke

The treatment of familial amyloid polyneuropathies (FAP) is complex and requires a neurological and cardiological multidisciplinary coverage. It includes specific treatments to control the progression of the systemic amyloidogenesis, the symptomatic treatment of the peripheral and autonomic neuropathy (digestive, urinary, sexual, postural hypotension) and the treatment of organs severely involved by amyloidosis (heart, eyes, kidneys). First line specific treatment of met30 TTR-FAP is liver transplantation (LT) which allows to suppress the main source of mutant TTR, to stop the progression of the neuropathy in 70 % of cases at long-term (with an experience of 18 years) and to double the median survival. In case of severe renal or cardiac insufficiency, a double transplant kidney-liver or heart-liver can be discussed. The tafamidis (in temporary authorization of use in France) is a stabilizing medicine of the tetrameric TTR which showed in very early stages of met30 TTR-FAP short-term capacities to stop the progress of the peripheral neuropathy in 60 % of the cases versus 38 % with placebo. It should be proposed in case of contraindication of TH (age>70 years [20 % of the cases]), of very early stages (very low NIS-LL score), or for the period of wait of LT. Other innovative medicines issued from biopharmaceutical companies have been developed to block the hepatic production of both mutant and wild TTR which are noxious in the late forms NAH (>50 years old) (RNAi [RNA interference] therapeutics, AntiSens oligonucleotids), for removing the amyloid deposits (monoclonal antibody anti-SAP), or to slow down the formation of deposits of TTR and amyloidosis (combination of doxycycline-TUDCA). Clinical trials should be first addressed to the patients with a late onset of FAP or non-met30 TTR-FAP who are less responding to LT and patients with contraindications in the LT. Initial cardiac assessment and periodic cardiac investigations are important for the FAP according to the frequency of cardiac impairment which is responsible of high rate of mortality. Conduction disorders (atrio-ventricular blocks) require the implantation of a pacemaker in about one third of the cases during the evolution of the disease. A myocardial infiltration is detected in two third of the cases and is for a long time latent; it remains often limited to a diastolic dysfunction which can be responsible for hemodynamical difficulties during the LT; it evolves sometimes, late, towards a systol

Topics: Amyloid; Amyloid Neuropathies, Familial; Arrhythmias, Cardiac; Benzoxazoles; Early Diagnosis; Follow-Up Studies; Heart Transplantation; Humans; Kidney Transplantation; Liver Transplantation; Mutation; Prealbumin; Quality of Life; RNA Interference; RNA, Small Interfering