Comparison of phenotype and prognosis of hereditary Val122Ile and wild type transthyretin cardiomyopathy

Abstract Background Transthyretin cardiac amyloidosis (ATTR-CA) is an under-recognized cause of congestive heart failure, caused by either the wild-type (ATTRwt) or hereditary (ATTRv) form. The most common hereditary mutation is Val122Ile with a high prevalence among Afro-Caribbean individuals. However, data regarding the phenotypic and prognostic differences between these two forms remain limited and conflicting. Methods Using the Healthcare European Amyloidosis Registry (HEAR), we included 3,666 patients, of whom 3,153 (86.0%) were ATTRwt and 513 (14.0%) were symptomatic ATTRv Val122Ile. The majority of patients (n = 3,213; 87.6%) were treated by specific drug at baseline, Tafamidis 61 mg (88.7%), Tafamidis 20 mg (0.5%), or Tafamidis combined with an RNA-interfering drug (0.8%). We assessed differences in cardiac and extracardiac phenotype at diagnosis, overall survival, and treatment effects in ATTRwt versus ATTR Val122Ile patients, adjusting for potential confounders using Inverse Probability of Treatment Weighting (IPTW). Results ATTRv Val122Ile patients were younger at diagnosis than those with ATTRwt (78 ± 9 vs. 83 ± 7 years, p 0.001) and had more severe cardiac involvement, with increased posterior wall thickness (15.0 12.7, 17.0 vs. 15.5 13.2, 18.0 mm), lower left ventricular ejection fraction (55 46, 62 vs. 50 40, 58%, p 0.001), reduced global longitudinal strain (-12.0 -9.0, -14.5 vs. -10.0 -7.8, -12.6%, p 0.001) and higher troponin (hs-Tnt) (52 34, 80 ng/L vs. 70 47, 104 ng/L, p = 0.001).There was no significant difference in NT-proBNP levels. ATTRv patients have more joint involvement and symptoms related to neuropathy. During a mean follow-up of 48 months, 916 deaths were recorded, and Kaplan-Meier analysis showed no significant survival difference between overall (treated and untreated) ATTRv Val122Ile and ATTRwt (73.7% vs. 72.8%, unadjusted HR = 1.07, 95% CI: 0.91 – 1.27). Untreated patients had have significantly higher risk of mortality than treated patients, (unadjusted HR = 3.33, 95% CI: 2.86 - 3.85, p 0.001). The treatment survival benefit was similar between ATTR subgroups (ATTRv Val122Ile and ATTRwt), HR= 0.30, 95% CI: 0.26 – 0.35. After IPTW adjustment, tafamidis treatment showed a survival benefit compared to no treatment in the overall cohort (IPTW HR = 1.45, 95% CI: 1.29 – 1.63, p 0.01) and in both ATTRv Val122Ile (IPTW: HR = 1.55, 95% CI: 1.29 – 1.85, p = 0.02) and ATTRwt , (IPTW: HR = 1.38, 95% CI: 1.14 – 1.69, p = 0.003) without interaction between the two genotypes = 0.07 for interaction. Conclusion ATTRv Val122Ile were younger and had more severe cardiac amyloidosis than ATTRwt. Tafamidis improved survival in both ATTRv Val122Ile and ATTRwt after weighted adjustment between treated and untreated patients. All these results suggested that cardiac amyloidosis process is more aggressive in ATTRv Val122Ile than in ATTRwt and these patients should be manage carefully.