Author + information
- Vincent Algalarrondo, MD, PhD∗ (, )
- Teresa Antonini, MD,
- Marie Théaudin, MD, PhD,
- Béatrice Ducot, PhD,
- Pierre Lozeron, MD, PhD,
- Denis Chemla, MD, PhD,
- Anouar Benmalek, PhD,
- Catherine Lacroix, MD,
- Daniel Azoulay, MD, PhD,
- Denis Castaing, MD,
- Cécile Cauquil, MD,
- François Rouzet, MD, PhD,
- Sylvie Dinanian, MD,
- Ludivine Eliahou, MD,
- Dominique Le Guludec, MD,
- Didier Samuel, MD, PhD,
- Michel S. Slama, MD and
- David Adams, MD, PhD
- ↵∗French Reference Center for FAP and Other Rare Peripheral Neuropathies (NNERf), Service de Cardiologie, Hôpital Antoine Béclère, 157 Rue de la Porte de Trivaux, Clamart 92140, France
Familial transthyretin amyloidosis (ATTR) is a rare, life-threatening, autosomal dominant disease involving mainly the heart and the peripheral nervous system due to a point mutation of the transthyretin (TTR) gene. By removing the main source of the mutated TTR, liver transplantation (LT) has become the standard treatment for ATTR (1). Because the demand for liver grafts exceeds the number of available organs and because new treatments have recently emerged, screening patients at high risk of death after LT is critical (2).
We identified 215 consecutive patients who underwent LT between 1993 and 2011. The diagnosis was made by the observation of both amyloid deposits in biopsy specimens and a TTR mutation. The pre-operative evaluation included physical examination, electrocardiography, echocardiography, autonomic dysfunction score, and polyneuropathy disability score (PND) calculation. The primary study endpoint was all-cause mortality after LT. The prognostic model predicting the individual probability of death within the first 5 years after LT was developed from the Cox proportional hazards model and was internally validated using bootstrapping.
At the time of LT, patients' median age was 43 years, 61% were men, and 69% carried the Val30Met mutation. There were 81% patients in New York Heart Association (NYHA) functional class I, 40% had conduction disorders, 36% had a ≥12-mm interventricular septum on the echocardiograms, and the median left ventricular ejection fraction was 65%. All patients presented with neurological manifestations of ATTR: isolated sensory disturbances (PND I: 61%), difficulties with walking (PND II: 22%), and the need for cane(s) to walk (PND III: 17%). The vegetative score was abnormal in 82%, and 59% had orthostatic hypotension.
Over a median follow-up of 5.9 years after LT, 84 patients died, and cardiac events were the leading cause of death (38% of all deaths). The significant pejorative factors were PND score ≥III (hazard ratio [HR]: 1.75; 95% confidence interval [CI]: 1.04 to 2.96; p = 0.036), orthostatic hypotension (HR: 2.26; 95% CI: 1.39 to 4.22; p = 0.001), NYHA functional class >I (HR: 2.25; 95% CI: 1.18 to 4.27; p = 0.014), QRS duration ≥120 ms (HR: 1.90; 95% CI: 1.05 to 3.43; p = 0.035), thickened interventricular septum (for each millimeter: HR: 1.12; 95% CI: 1.04 to 1.20; p = 0.002).
The individual probability of death at 5 years was calculated as Pdeath at 5 years = 1 − 0.735e(coeff sum − 1.27810), where coeff sum = (0.57423 × PND score ≥III) + (0.77339 × orthostatic hypotension) + (0.91192 × NYHA functional class >I) + (0.60378 × QRS ≥120 ms) + (0.14589 × [interventricular septum thickness − 6]). Risk can be computed using the online calculator. The calibration slope was 0.89 (95% CI: 0.64 to 1.15), the C-index of Harrel was 0.68 (95% CI: 0.45 to 0.88), and the concordance probability estimate was 0.71 (95% CI: 0.67 to 0.75). The area under the receiver-operating characteristic curve for the 5-year survival was 0.80, and significant differences of survival were found according to the 5-year death risk (Figure 1). Pre-operative identification of a high-risk profile (risk >50%) was retrospectively documented in 40 of 215 patients (19%).
The risk score was built from variables that measured the cardiac and neurological status regardless of mutation type. Therefore, our proposed score should be useful to gauge the risk of patients with rare variants of TTR and to take into account the phenotypic variability encountered among patients with a similar mutation. The study population was representative of a region where ATTR is not endemic and the 74% 5-year survival of our patients in line with the 77% previously reported (3). Previous reports suggested that septum thickness could be associated with a worse prognosis in ATTR patients with a liver transplant (4). Wide QRS complexes on electrocardiography were associated with an independent increased risk of death in our study, and this was consistent with the high frequency of conduction disorders in transthyretin cardiac amyloidosis.
The predictive model was internally validated by the bootstrap method, but further prospective studies will be required to confirm its external validity. Application of new imaging techniques and biomarkers may improve the risk stratification of patients with ATTR in further studies.
The risk prediction model proposed in this study accurately estimated the individual risk of death after liver transplantation for patients with familial transthyretin amyloidosis. The identification of high-risk patients should prompt the choice of liver transplantation with extreme caution, and alternate therapeutic strategies (e.g., combined heart and liver transplantations, new antiamyloid treatments) should be considered.
Please note: Funded by the French Ministry of Health. Dr. Algalarrondo has received research grants from Biotronik, Sorin, Medtronic, Boston Scientific, and St. Jude Medical. Dr. Adams is a consultant for Alnylam Pharmaceuticals and Pfizer. Dr. Lozeron has received consulting fees from CSL Behring; and travel support from Laboratoire français du Fractionnement et des Biotechnologies, CSL Behring, and Pfizer. Dr. Cauquil has received honoraria from Pfizer. Dr. Samuel has received consulting fees from Astellas, Novartis, Laboratoire français du Fractionnement et des Biotechnologies, Biotest, Gilead Sciences, Bristol-Myers Squibb, and Abbvie. Dr. Slama has received consulting fees from Fold Rx/Pfizer and Alnylam Pharmaceuticals. Dr. Théaudin has received travel support from Pfizer. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- American College of Cardiology Foundation