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Observational Study
. 2022 Jul 14;43(27):2622-2632.
doi: 10.1093/eurheartj/ehac259.

Characteristics and natural history of early-stage cardiac transthyretin amyloidosis

Steven Law  1 , Melanie Bezard  2 , Aviva Petrie  3 , Liza Chacko  1 , Oliver C Cohen  1 , Sriram Ravichandran  1 , Olabisi Ogunbiyi  1 , Mounira Kharoubi  3 , Sashiananthan Ganeshananthan  1 , Sharmananthan Ganeshananthan  1 , Janet A Gilbertson  1 , Dorota Rowczenio  1 , Ashutosh Wechalekar  1 , Ana Martinez-Naharro  1 , Helen J Lachmann  1 , Carol J Whelan  1 , David F Hutt  1 , Philip N Hawkins  1 , Thibaud Damy  2 , Marianna Fontana  1 , Julian D Gillmore  1
Affiliations
Observational Study

Characteristics and natural history of early-stage cardiac transthyretin amyloidosis

Steven Law et al. Eur Heart J. .

Abstract

Aims: Transthyretin amyloid cardiomyopathy (ATTR-CM) is increasingly diagnosed at an early stage of the disease natural history, defined as National Amyloidosis Centre (NAC) ATTR Stage I. The natural history of early-stage ATTR-CM remains poorly characterized.

Methods and results: A retrospective multi-centre observational study of 879 patients with ATTR-CM, either wild-type TTR genotype or carrying the p.V142I TTR variant, and NAC ATTR Stage I biomarkers at the time of diagnosis who did not receive disease-modifying therapy for amyloidosis. Disease characteristics at diagnosis that were independently associated with mortality by Cox regression analysis were N-terminal pro-B-type natriuretic peptide (NT-proBNP), TTR genotype, and troponin T. Patients were categorized into NAC ATTR Stage Ia, defined as a furosemide equivalent diuretic requirement of <0.75 mg/kg and an NT-proBNP ≤500 ng/L or ≤1000 ng/L in the presence of atrial fibrillation, and NAC ATTR Stage Ib comprising all remaining Stage I patients. Median estimated survival among the 88% NAC ATTR Stage Ib patients was 75 (95% CI 57-93) months compared with >100 months in the 12% with Stage Ia disease [hazard ratio for death 5.06 (95% confidence interval 1.23-20.87); P = 0.025] despite significant cardiovascular morbidity at the time of diagnosis which increased during follow-up, including among patients diagnosed in NAC ATTR Stage Ia. Estimated survival among UK NAC ATTR Stage Ia patients was comparable to UK general population controls (P = 0.297).

Conclusion: Patients with NAC ATTR Stage I ATTR-CM can be further stratified according to NT-proBNP concentration and diuretic requirement at diagnosis. Patients with Stage Ia ATTR-CM have significant cardiovascular morbidity despite good short- and mid-term survival.

Keywords: Amyloid; Amyloidosis; Cardiomyopathy; Staging; TTR; Transthyretin.

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Figures

Structured Graphical Abstract
Structured Graphical Abstract
Patients diagnosed with NAC ATTR Stage Ia amyloidosis have an estimated median survival in excess of 100 months in the absence of disease-modifying therapy despite significant cardiovascular morbidity which increases further during follow up.
Figure 1
Figure 1
(A) Kaplan–Meier survival curves stratified by National Amyloidosis Centre transthyretin amyloid stage for the whole cohort. Median estimated survival among patients with Stage Ia was not met at 100 months and was 75 months (95% CI: 57–93) in patients with Stage Ib (P = 0.0002). (B) Survival of the UK National Amyloidosis Centre cohort with Stage Ia compared with matched UK general population controls. Median estimated survival was not met in either group at 100 months; there was no evidence of a difference in survival between the two groups (P = 0.297). (C) Survival of the UK National Amyloidosis Centre cohort with Stage Ib compared with matched UK general population controls. Median estimated survival among patients with Stage Ib was 85 months (95% CI: undefined), and was not met at 100 months in a matched UK general population control group; patient survival was reduced in the Stage Ib group compared with UK general population controls (P < 0.0001).
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