Myocardial Responses to Eplontersen in Transthyretin Amyloid Cardiomyopathy: The CARDIO-TTRansform CMR study

Background: Transthyretin-lowering therapies target the underlying cause of transthyretin amyloid cardiomyopathy (ATTR-CM), but their effects on myocardial amyloid burden and cardiac remodelling remain incompletely characterized. We evaluated the myocardial effects of sustained transthyretin suppression with eplontersen using serial multiparametric cardiovascular magnetic resonance (CMR). Methods: This CMR study was a pre-specified, international, prospective study embedded within the randomized, placebo-controlled phase 3 CARDIO-TTRansform trial. Participants underwent CMR at baseline and planned assessments at weeks 25, 49, 97, and 140. The primary imaging analysis evaluated longitudinal changes in CMR parameters using mixed models for repeated measures. Myocardial amyloid regression and progression were defined as ≥5 percentage-point decreases and increases in extracellular volume (ECV), respectively. All other patients were considered stable. Results: We enrolled 120 participants with baseline and ≥1 follow-up CMR assessment (eplontersen, n=58; placebo, n=62; mean age, 76.7±6.5 years; 95% male; baseline stabilizer, 12.5%). At week 140 eplontersen resulted in lower ECV, compared with placebo (least-squares mean difference [95% CI], –6.7 percentage points [ –8.7 to –4.7]; P<0.001) and lower native T1 ( –25.9ms [–41.7 to –10.2 ]; P=0.002) and left ventricular mass (–19.1g [–28.0 to –10.2]; P<0.001). Eplontersen also increased left ventricular ejection fraction (+5.1% [1.8–8.3]; P=0.002), right ventricular ejection fraction (+4.6% [0.6–8.7]; P=0.03), and left ventricular global longitudinal, circumferential, and radial strain and right ventricular longitudinal strain (all P<0.05), compared to placebo. At week-140, myocardial amyloid regression occurred in 12.5% receiving eplontersen versus 0% receiving placebo, whereas progression occurred in 12.5% versus 76%, respectively. Conclusions: Sustained transthyretin suppression with eplontersen resulted in substantially lower myocardial ECV and favorable changes in cardiac structure, biventricular systolic function, and myocardial deformation compared with placebo in a cohort of patients mostly not on background stabilizer at baseline. These findings provide randomized evidence that lowering circulating transthyretin modifies myocardial disease progression in ATTR-CM and support serial multiparametric CMR for characterizing myocardial treatment response.