Background— Most studies of amyloidotic cardiomyopathy consider as a single entity the 3 main systemic cardiac amyloidoses: acquired monoclonal immunoglobulin light-chain (AL); hereditary, mutated transthyretin-related (ATTRm); and wild-type transthyretin-related (ATTRwt). In this study, we compared the diagnostic/clinical profiles of these 3 types of systemic cardiac amyloidosis. Methods and Results— We conducted a longitudinal study of 233 patients with clear-cut diagnosis by type of cardiac amyloidosis (AL, n=157; ATTRm, n=61; ATTRwt, n=15) at 2 large Italian centers providing coordinated amyloidosis diagnosis/management facilities since 1990. Average age at diagnosis was higher in AL than in ATTRm patients; all ATTRwt patients except 1 were elderly men. At diagnosis, mean left ventricular wall thickness was higher in ATTRwt than in ATTRm and AL. Left ventricular ejection fraction was moderately depressed in ATTRwt but not in AL or ATTRm. ATTRm patients less often displayed low QRS voltage (25% versus 60% in AL; P <0.0001) or low voltage-to-mass ratio (1.1±0.5 versus 0.9±0.5; P <0.0001). AL patients appeared to have greater hemodynamic impairment. On multivariate analysis, ATTRm was a strongly favorable predictor of survival, and ATTRwt predicted freedom from major cardiac events. Conclusions— AL, ATTRm, and ATTRwt should be considered 3 different cardiac diseases, probably characterized by different pathophysiological substrates and courses. Awareness of the diversity underlying the cardiac amyloidosis label is important on several levels, ranging from disease classification to diagnosis and clinical management.

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Background Heart failure due to wild-type transthyretin amyloidosis (ATTRwt) is an under-appreciated cause of morbidity and mortality in the aging population. The aims of this study were to examine features of disease and characterize outcomes in a large ATTRwt cohort. Methods and Results Over 20 years, 121 patients with ATTRwt were enrolled in a prospective observational study. Median age at enrollment was 75.6 years (range, 62.6–87.8); 97% of patients were Caucasian. The median survival, measured from biopsy diagnosis, was 46.69 months (95% CI, 41.95–56.77); 78% of deaths were due to cardiac causes. By Kaplan-Meier analysis, 5-year survival was 35.7% (95% CI, 25–46). Impaired functional capacity (mean VO2 max of 13.5 mL/kg/min) and atrial fibrillation (67%) were common clinical features. Multivariate predictors of reduced survival were elevated serum brain natriuretic peptide (BNP, 482 ± 337 pg/mL) and uric acid (8.2 ± 2.6 mg/dL), decreased left ventricular ejection fraction (LVEF, 50% median ranging 10-70%), and increased relative wall thickness (RWT, 0.75 ± 0.19). Conclusions In this series of patients with biopsy-proven ATTRwt amyloidosis, poor functional capacity and atrial arrhythmias were common clinical features. Elevated BNP and uric acid, decreased LVEF, and increased RWT were associated with limited survival of only 35.7% at 5 years for the group as a whole. These data establish the natural history of ATTRwt, provide statistical basis for the design of future interventional clinical trials, and highlight the need for more sensitive diagnostic tests and disease-specific treatments for this disease.