A multi-modality, multi-parametric phenotyping study of transthyretin amyloid cardiomyopathy associated with the p.V142I TTR variant
Authors: Razvi Y , Ioannou A , Chacko L , Patel R , Ganesananthan S , Kaza N , Blakeney I , Porcari A , Masi A , Venneri L , Rauf M U , Martinez-Naharro A , Hawkins P N , Fontana M , Gillmore J 
Published: October 2022

Abstract

Introduction
Transthyretin amyloid cardiomyopathy (ATTR-CM) is an increasingly recognised cause of heart failure. 3–4% of individuals of African descent carry a transthyretin gene mutation encoding the p.V142I variant, a powerful risk factor for development of variant ATTR-CM. This equates to 1.6 million potential carriers in the USA alone. We report findings from a multi-parametric, multi-modality phenotyping study of p.V142I ATTR-CM.

Hypothesis
The phenotype of p.V142I variant ATTR-CM is an aggressive form of ATTR CM.

Methods
A retrospective phenotyping study of 395 patients with p.V142I-ATTR-CM at our national referral centre was conducted. Patients underwent evaluation at the centre at time of diagnosis, including clinical and functional assessment, echocardiography, biomarker analysis; a subgroup had cardiac magnetic resonance imaging. 395 wild type ATTR-CM patients matched for independent predictors of prognosis (NAC Disease Stage, age, decade of first presentation) were used as a comparator group.

Results
Average age of pV142I ATTR-CM patients was 75.8 years. There was significant functional impairment (38.2% of cases NHYA ≥ III, mean 6 minute walk test distance 272m). Significant impairment of echocardiographic parameters was seen; mean LVEF 43%, global longitudinal strain −9.1%, TAPSE 14.2mm, E/E prime 17.4, E/A ratio 2.47 with high frequency of at least moderate mitral (44%) and tricuspid regurgitation (51%). Median NT-proBNP was 3165 ng/L (IQR 4224). Arrhythmias were common with 17.4% of patients having a bradyarrhythmia, 26.1% having atrial fibrillation/flutter, and 5.6% having a pacemaker at presentation. Uni and multivariate cox regression analysis identified serum troponin, tricuspid regurgitation, LVEF, TAPSE and lower systolic blood pressure as independent predictors of prognosis. Prognostic parameters were statistically significantly worse and five year survival by Kaplan Meier analysis was significantly reduced when compared to matched WT ATTR-CM patients (p&lt;0.05) (Figure 1).
Mean serum high sensitivity troponin T and extracellular volume (ECV) by cardiac magnetic resonance (CMR) was higher in p.V142I ATTR-CM than WT ATTR-CM cases (94 ng/L vs 74.2 ng/L, p&lt;0.05, 58% vs 55%, p&lt;0.05). Interventricular wall thickness however was lower in p.V142I ATTR-CM than matched WT cases (17.2 mm vs 16.8 mm).

Conclusion
p.V142I ATTR-CM is an aggressive phenotype, with significant functional impairment, burden of regurgitant valvular disease and systolic impairment resulting in poor survival.
Patients with p.V142I ATTR-CM had a higher burden of amyloid infiltration as measured as shown by ECV measurements on CMR, higher serum troponin and lower wall thickness when compared to a matched cohort of WT ATTR-CM patients. This novel observation suggests a unique disease mechanism that is more cardiotoxic which results in myocyte loss and myocardial thinning as opposed to myocyte hypertrophy.

Funding Acknowledgement
Type of funding sources: None.