Genotype-phenotype correlation of transthyretin cardiomyopathy in patients with stage C/D heart failure: atrial and myocardial mechanics and fibrosis

Abstract Objectives We sought to investigate: (1) the relationship between transthyretin (TTR) pathogenic variants and their corresponding echocardiographic atrial and ventricular strains in patients with TTR cardiomyopathy (TTR-CM) and clinical evidence of heart failure (HF), and (2) the relationship between TTR pathogenic variants and atrial fibrosis assessed by cardiac MRI. Methods and results Fifty Asian patients with biopsy or scintigraphy proven TTR-CM and stage C or D (C/D) HF were identified from an advanced HF clinic in a tertiary-care university hospital. Genetic testing for the pathogenic variants in the TTR genes associated with hereditary TTR-CM (hTTR-CM) was available in 22 patients (67 ±13 years; 77% were male). Of these, 3 different mutations were identified. The most prevalent pathogenic variant was Ala97Ser (67%) followed by Val30Met (27%), and Gly67Glu (6%). Wild-type TTR-CM was diagnosed in 32% of the cohort. Strain analysis was performed using the TomTec Arena 2D-cardiac performance analysis (CPA) software. Atrial and left ventricular (LV) late gadolinium enhancement (LGE) was quantified using a 9-segment and a 17-segment model, respectively. Patients with hTTR-CM had less impaired longitudinal strain (LS) (more negative strain values) than those with wild-type TTR-CM in the regional basal right ventricular free wall (RV-FW) (-21 ± -8.3 % vs.-12.6 ± -8.1%, p = 0.048) and LV basal inferoseptum (-7.3 ± -4.1 % vs.-3.1 ± -3.0 %, p = 0.045). In univariate analysis, more negative LS values in the basal LV inferoseptum and basal RV-FW were significant predictors of hTTR-CM (OR 5.1 and 2.3; p <0.05, respectively). However, MRI findings revealed similar regional LGE extent involving basal inferolateral segments between hTTR-CM and wild-type TTR-CM (38.3 ± 7.9 vs. 52.5 ± 34.5%, p =0.314). Left atrial (LA) and right atrial (RA) LGE was present in 90% and 81% of patients, respectively. Patients with hTTR-CM had reduced RA LGE when compared to those with wild-type TTR-CM (41% vs 67%, p =0.039). Conclusions In patients with TTR-CM and stage C/D HF, a reduced RA LGE extent and/or more preserved myocardial deformation in specific regions of basal LV and RV segments (basal LV inferoseptum and basal RV free wall) assessed by 2-D speckle tracking echocardiography were significantly more prevalent in patients with hTTR-CM than in wild-type TTR-CM. These echocardiographic and/or MRI findings may facilitate genotype testing in patients with TTR-CM, particularly in resource-limited settings. Further validation of these novel findings in patients with TTR-CM with HF is needed.