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Transthyretin Cardiac Amyloidosis in Western Europe
Study Questions:
What are the different phenotypes and genotypes associated with transthyretin amyloidosis (ATTR) among patients enrolled in a large multinational registry in Western Europe?
Methods:
Included patients were enrolled in THAOS (Transthyretin Amyloidosis Outcomes Survey), which is the largest ongoing, worldwide, longitudinal, observational registry of symptomatic patients with confirmed wild-type ATTR (ATTRwt) or hereditary ATTR (ATTRm). Follow-up data were collected at scheduled visits 6 months apart. Patients were stratified based on phenotype by clinical presentation at the time of enrollment including mainly neurologic, mainly cardiac or mixed neurologic, and cardiac manifestations. Genotypic stratification was based on ATTRwt, mutations associated with cardiac disease, pathogenic TTR mutation Val30Met with onset of disease <50 years, Val30Met mutation with onset of disease >50 years of age, and all other mutations.
Results:
Between 2007 and 2016, 1,417 patients with symptomatic ATTR were enrolled in THAOS from nine countries in western Europe. Overall, 125 (8.8%) patients had ATTRwt and 1,286 (91.2%) had ATTRm. There were 54 different TTR mutations observed. Among ATTRm patients, the commonest mutation was Val30Met (73.6% patients). The type of mutations and age of onset of disease with these mutations differed highly between countries. The majority of Val30Met subjects from Portugal had early onset at age <50 years and the majority of Val30Met subjects from Sweden had late-onset disease. ATTRwt patients and patients with cardiac disease were more likely to be older, male with history of palpitations or heart failure, on treatment for heart disease, and have higher B-type natriuretic peptide (BNP) and N-terminal proBNP, troponin I and T, and creatinine. These patients were more likely to have abnormal electrocardiograms and symmetric left ventricular (LV) hypertrophy with mildly depressed LV ejection fraction, suggesting diagnosis at an advanced stage. All genotypes were associated with thickened interventricular septum except early-onset cardiac disease with Val30Met mutations.
Cardiac presentation was noted in 210 patients (14.9%), mixed cardiac and neurologic in 298 patients (21.1%), with the rest having neurologic manifestations. For patients with only cardiac presentation first, echo abnormalities were more common compared to patients with mixed cardiac and neurologic presentation.
Survival data were available on 1,375 (97%) patients. Those with cardiac mutations or ATTRwt genotype had a lower survival than patients with all other genotypes. Patients with only neurologic manifestations at presentation had a better survival than those with only cardiac or mixed disease.
Conclusions:
In this large prospective registry of patients with ATTR in Europe, wide geographic variation in disease genotype and phenotype was notable. Cardiac symptoms were seen in one third of the patients, and prognosis of ATTR was driven by extent of cardiac involvement. Patients with cardiac disease had notable echocardiographic abnormalities with clinical manifestations of heart failure at enrollment suggesting diagnosis later in the disease.
Perspective:
ATTR is a relatively rare disease and registries such as THAOS offer important insights into the natural history of this disease. The most important findings include presence of 54 different TTR genotype abnormalities within this cohort with geographical variations in genotype and phenotype. This highlights difficulty in diagnosis of ATTR with some patients presenting at a younger age being misdiagnosed as hypertrophic cardiomyopathy and older patients being misdiagnosed as ATTRwt. Hence, genetic testing should be offered to all suspected ATTR patients irrespective of age of disease onset. Furthermore, one third of the cohort had cardiac manifestations upon enrollment in the registry with clinical and echocardiographic abnormalities highlighting delays in diagnosis. Importantly, cardiac manifestations correlated inversely with survival.
Limitations of this study include reliance on participating sites for data collection with lack of core data collection labs. Accordingly, neurological symptoms may have been under-reported by cardiologists and vice versa. Nonetheless, data from such registries provide much needed insights into rare diseases such as ATTR.
Clinical Topics: Anticoagulation Management, Cardiovascular Care Team, Heart Failure and Cardiomyopathies, Noninvasive Imaging, Acute Heart Failure, Heart Failure and Cardiac Biomarkers, Echocardiography/Ultrasound
Keywords: Amyloid Neuropathies, Familial, Amyloidosis, Amyloidosis, Familial, Cardiomyopathies, Creatinine, Echocardiography, Electrocardiography, Genetic Testing, Genotype, Heart Diseases, Heart Failure, Hypertrophy, Mutation, Natriuretic Peptide, Brain, Peptide Fragments, Phenotype, Stroke Volume, Troponin I, Troponin T
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