The heart after transplant: long-term cardiovascular outcomes in hereditary ATTRv Amyloidosis

Introduction

Hereditary transthyretin amyloidosis (ATTRv) is an autosomal dominant disease caused by mutations in the TTR gene, leading to misfolded protein deposition, particularly in the heart and peripheral nervous system. This multisystem involvement results in cardiomyopathy, neuropathy, significant morbidity, and poor survival. As the liver is the main source of mutated transthyretin, orthotopic liver transplantation (LT) emerged in the 1990s as the first disease-modifying therapy, improving outcomes and survival. Despite recent advances in TTR-stabilizing and gene-silencing therapies, cardiac involvement remains a key prognostic factor.

Methods

We conducted a single-center observational study including patients with a diagnosis of hereditary ATTR amyloidosis (V30M mutation) who underwent liver transplantation between 1992 and 2020. Clinical, laboratory, and echocardiographic data were collected at baseline and during follow-up.

Results

A total of 114 hATTR V30M patients were included (56% male; mean age at LT 38 ± 0.9 years), with a mean follow-up of 13.6 ± 0.6 years. Most patients received tacrolimus (74%), cyclosporine (11%), or mycophenolate (9%). During follow-up, chronotropic incompetence increased from 14% to 40% (p = 0.10). Echocardiography showed progression of interventricular septal thickness (10 ± 0.2 vs 11 ± 0.3 mm, p = 0.01), posterior wall thickness (9 ± 0.2 vs 10 ± 0.2 mm, p = 0.01), left ventricular mass (92 ± 2.8 vs 101 ± 3 g, p = 0.04), and NT-proBNP levels (101 [58–218] to 193 [109–373] pg/mL, p = 0.003).

Pacemakers were implanted in 86 patients (75%). Age at liver transplantation independently predicted pacemaker implantation (OR 1.043; 95% CI 1.012–1.075; p = 0.006), corresponding to a 4.3% increase in risk per additional year. Cardiovascular hospitalization occurred in 6 patients (5%). Higher follow-up E/E′ was an independent predictor of cardiovascular hospitalization after adjustment for age at liver transplantation (OR 1.30; 95% CI 1.04–1.63; p = 0.023), indicating a 30% increase in risk per unit increase.

30 patients (26%) died during follow-up. Mortality was not associated with pacemaker implantation or cardiovascular hospitalization. In multivariable analysis, cyclosporine use (OR 5.06; 95% CI 1.41–18.12; p = 0.013) and older age at liver transplantation (OR 1.05 per year; 95% CI 1.00–1.10; p = 0.036) were independent predictors of mortality. Kaplan–Meier analysis showed a trend toward lower survival among patients receiving cyclosporine (HR 2.04; p = 0.105).

Conclusion

In this long-term cohort of hATTR V30M patients after liver transplantation, older age at transplantation was associated with higher risks of pacemaker implantation and mortality, while elevated follow-up E/E′ independently predicted cardiovascular hospitalization. These findings highlight persistent cardiac vulnerability in hATTR despite liver transplantation and reinforce the need for sustained, targeted cardiac monitoring.For image description, please refer to the figure legend and surrounding text.