ABSTRACT
Background: Cardiomyopathy is a major cause of death in patients with systemic transthyretin amyloidosis. Long term effect of therapy designed to inhibit hepatic production of the amyloid precursor has not been established in cardiomyopathy. The purpose of this study was to evaluate the long term safety and efficacy of transthyretin specific antisense oligonucleotide therapy, inotersen, in transthyretin cardiomyopathy.Methods: Patients with hereditary or wildtype transthyretin cardiomyopathy (NYHA I-III) with an LV wall thickness [Formula: see text]1.3 cm and clinical evidence of congestive heart failure were eligible for this single centre, open label protocol. Safety and cardiac structural and functional parameters were prospectively studied.Results: As of October 2018, 33 subjects have entered the study. Twenty have completed 1 year, 16 have completed 2 years, and 14 have completed three years. At the 2 year time point, mean LV mass decreased by 8.4% as measured by MRI, and exercise tolerance increased by 20.2 metres as measured by 6 minute walk test. Further positive indicators were noted at 3 years, with LV mass decreasing by 11.4% and 6MWT increasing by 16.2 metres.Conclusion: Long term treatment of amyloid cardiomyopathy with inotersen is safe and effective in inhibiting progression and potentially reversing amyloid burden.
Subject(s)
Amyloid Neuropathies, Familial/drug therapy , Cardiomyopathies/drug therapy , Oligonucleotides/administration & dosage , Aged , Amyloid Neuropathies, Familial/complications , Amyloid Neuropathies, Familial/diagnostic imaging , Cardiomyopathies/diagnostic imaging , Cardiomyopathies/etiology , Female , Humans , Male , Middle Aged , Oligonucleotides/adverse effectsABSTRACT
OBJECTIVES: Cardiomyopathy is a major cause of death in both the hereditary form of transthyretin (TTR) amyloidosis and the sporadic late-age-onset transthyretin amyloidosis (ATTR wild-type (ATTRwt)). Clinically disease progression from time of diagnosis to death is usually quoted as 5- to 15-years. In prior studies, significant progression of cardiac parameters in patients with moderate to severe cardiomyopathy has been noted within a 12-month time span. METHODS: The present study was designed to prospectively monitor changes in cardiac parameters, both structural and functional, in patients with ATTR cardiomyopathy while treated with a TTR specific antisense oligonucleotide (ASO; IONIS-TTRâ) designed to lower blood levels of the amyloid fibril precursor protein. To date 22 patients have been admitted to the study, 15 have completed 12 months on the drug and are the subject of this report. RESULTS: Eight patients with hereditary ATTR amyloidosis and 7 patients with wild-type ATTR amyloidosis with moderate to severely advanced restrictive cardiomyopathy showed stabilization of disease as measured by left ventricular wall thickness, left ventricular mass (LVM), 6-min walk test (6MWT), and echocardiographic global systolic strain. IONIS-TTRâ was well tolerated by all 15 subjects and showed a good safety profile. CONCLUSIONS: ASO treatment of patients with moderate to advanced ATTR cardiomyopathy shows indication of stabilization of disease progression and may therefore contribute to enhanced life expectancy.
Subject(s)
Amyloid Neuropathies, Familial , Cardiomyopathies , Echocardiography , Oligonucleotides, Antisense/administration & dosage , Prealbumin/antagonists & inhibitors , RNA, Messenger/antagonists & inhibitors , Aged , Aged, 80 and over , Amyloid Neuropathies, Familial/diagnostic imaging , Amyloid Neuropathies, Familial/drug therapy , Amyloid Neuropathies, Familial/genetics , Amyloid Neuropathies, Familial/physiopathology , Cardiomyopathies/diagnostic imaging , Cardiomyopathies/drug therapy , Cardiomyopathies/genetics , Cardiomyopathies/physiopathology , Humans , Male , Middle Aged , Oligonucleotides, Antisense/adverse effects , Prealbumin/genetics , Prealbumin/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolismSubject(s)
Career Choice , Personnel Selection , Physicians, Women , Radiology , Female , Humans , United States , WorkforceABSTRACT
BACKGROUND: Atrial fibrillation (AF) may be the cause or sequela of left atrial abnormalities and variants. PURPOSE: To determine the prevalence of left atrial (LA) abnormalities in AF patients compared to normal sinus rhythm (NSR) patients. MATERIAL AND METHODS: We retrospectively reviewed 281 cardiac CT examinations from 2010 to 2012, excluding patients with prior pulmonary vein ablation, known coronary artery disease, prior coronary stent placement, or coronary artery bypass grafts. The first group consisted of 159 AF patients undergoing cardiac CT prior to pulmonary vein ablation and the second group consisted of 122 NSR patients evaluated with coronary CT angiography. Demographic data were collected. LA abnormalities were analyzed. Left atrial diameter was measured on an axial view. RESULTS: A total of 281 patients were included. The male gender has significantly higher prevalence of AF than female gender, P value <0.001. Patients with AF were significantly older (mean age, 57.4 years; standard deviation [SD], 11.8 years) than NSR patients (mean age, 53.4 years; SD, 13.6 years), P value, 0.01. The left atrial diameter was greater in the AF patients (mean diameter, 4.3 cm; SD, 0.82 cm) versus the NSR patients (3.4 cm; SD, 0.58 cm), P value, <0.0001. LA diverticulum was the most prevalent variant, occurring in 28.4% of the entire patient population followed by LA pouch, occurring in 24%. There was no significant between group differences in the prevalence of these or the remainder of the LA variants. CONCLUSION: AF patients differed significantly from NSR patients in LA size, gender, and mean age. There was no statistical significance between the two groups with regard to the LA morphologic abnormalities other than size.
