Cardiac Dysautonomia Predicts Long-Term Survival in Hereditary Transthyretin Amyloidosis After Liver Transplantation

Algalarrondo, Vincent; Antonini, Térésa; Théaudin, Marie; Chemla, Denis; Benmalek, Anouar; Lacroix, Catherine; Castaing, Denis; Cauquil, Cécile; Dinanian, S.; Eliahou, Ludivine; Samuel, Didier; Adams, David H.; Guludec, Dominique Le; Slama, Michel; Rouzet, François

doi:10.1016/j.jcmg.2016.07.008

Cited by 45 publications

(38 citation statements)

References 35 publications

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“…The principle of autonomic dysfunction and interpretation of 123 I-MIBG scintigraphy in ATTRm patients is rather difficult to understand. 40,41 Sympathetic denervation and heart failure seem to coincide and contribute to each other, especially in advanced stages of the disease. 42 However, a recent study of Piekarski et al showed that 48% of asymptomatic patients show abnormal 123 I-MIBG findings whereas no cardiac uptake on 99m Tc-DPD scintigraphy is visible.…”

Section: Discussionmentioning

confidence: 99%

Imaging cardiac innervation in hereditary transthyretin (ATTRm) amyloidosis: A marker for neuropathy or cardiomyopathy in case of heart failure?

Jonker

Hazenberg

Nienhuis

et al. 2020

Journal of Nuclear Cardiology

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Background. Nuclear imaging modalities using 123 Iodine-metaiodobenzylguanidine (123 I-MIBG) and bone seeking tracers identify early cardiac involvement in ATTRm amyloidosis patients. However, little is known whether results from 123 I-MIBG scintigraphy actually correlate to markers for either cardiac autonomic neuropathy or cardiomyopathy. Methods. All TTR mutation carriers and ATTRm patients who underwent both 123 I-MIBG and 99m Technetium-hydroxymethylene diphosphonate (99m Tc-HDP) scintigraphy were included. Cardiomyopathy was defined as NT-proBNP > 365 ng/L, and cardiac autonomic neuropathy as abnormal cardiovascular reflexes at autonomic function tests. Late 123 I-MIBG heart-to-mediastinum ratio (HMR) < 2.0 or wash-out > 20%, and any cardiac 99m Tc-HDP uptake were considered as abnormal. Results. 39 patients (13 carriers and 26 ATTRm patients) were included in this study. Patients with cardiomyopathy, with or without cardiac autonomic neuropathy, had lower late HMR than similar patients without cardiomyopathy [median 1.1 (range 1.0-1.5) and 1.5(1.2-2.6) vs 2.4 (1.4-3.8) and 2.5 (1.5-3.7), respectively, P < 0.001]. Late HMR and wash-out (inversely) correlated with NT-proBNP r = 2 0.652 (P < 0.001) and r = 0.756 (P < 0.001), respectively. Furthermore, late HMR and wash-out (inversely) correlated with cardiac 99m Tc-HDP uptake r = 2 0.663 (P < 0.001) and r = 0.617 (P < 0.001), respectively. Conclusion. In case of heart failure, 123 I-MIBG scintigraphy reflects cardiomyopathy rather than cardiac autonomic neuropathy in ATTRm patients and TTR mutation carriers. 123 I-MIBG scintigraphy may already be abnormal before any cardiac bone tracer uptake is visible.

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Section: Discussionmentioning

confidence: 99%

Imaging cardiac innervation in hereditary transthyretin (ATTRm) amyloidosis: A marker for neuropathy or cardiomyopathy in case of heart failure?

Jonker

Hazenberg

Nienhuis

et al. 2020

Journal of Nuclear Cardiology

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“…75 In a monocentric cohort study of 215 ATTRm amyloidosis patients, predictors of death were PND score > II, orthostatic hypotension, NYHA stage > I, QRS duration >120 ms, and thickened interventricular septum. 91 In a study of 116 patients with ATTRwt amyloidosis, reduced serum TTR values were associated with short survival. 91 In a study of 116 patients with ATTRwt amyloidosis, reduced serum TTR values were associated with short survival.…”

Section: Predictors Of Survivalmentioning

confidence: 99%

“…90 Survival was reduced if there was cardiac dysautonomia after LTX, or on MIBG-SPECT and no response to atropine. 91 In a study of 116 patients with ATTRwt amyloidosis, reduced serum TTR values were associated with short survival. 44 Low TTR serum levels were an independent predictor of the outcome in these patients.…”

Section: Predictors Of Survivalmentioning

confidence: 99%

Hereditary transthyretin-related amyloidosis

et al. 2018

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Hereditary transthyretin(TTR)-related amyloidosis (ATTRm amyloidosis) is an endemic/non-endemic, autosomal-dominant, early-and late-onset, rare, progressive disorder, predominantly manifesting as length-dependent, small fiber dominant, axonal polyneuropathy and frequently associated with cardiac disorders and other multisystem diseases. ATTRm amyloidosis is due to variants in the TTR gene, with the substitution Val30Met as the most frequent mutation. TTR mutations lead to destabilization and dissociation of TTR tetramers into variant TTR monomers, and formation of amyloid fibrils, which are consecutively deposited extracellularly in various tissues, such as nerves, heart, brain, eyes, intestines, kidneys, or the skin. Neuropathy may not only include large nerve fibers but also small fibers, and not only sensory and motor fibers but also autonomic fibers. Types of TTR variants, age at onset, penetrance, and clinical presentation vary between geographical areas. Suggestive of a ATTRm amyloidosis are a sensorimotor polyneuropathy, positive family history, autonomic dysfunction, cardiomyopathy, carpal tunnel syndrome, unexplained weight loss, and resistance to immunotherapy. If only sensory A-delta or C fibers are affected, small fiber neuropathy ensues. Diagnostic tests for small fiber neuropathy include determination of intraepidermal nerve fiber density, laser-evoked potentials, heat-and cold-detection thresholds, and measurement of the electrochemical skin conductance. Therapy currently relies on liver transplantation and TTR-stabilizers (tafamidis, diflunisal). K E Y W O R D Samyloid, neuropathy, small fiber, tafamidis, transplantation, transthyretin | 93 FINSTERER ET al. eyes, the gastrointestinal tract, the kidneys, and the skin. ATTRm amyloidosis is resistant to immunotherapy. Though ATTRm-related polyneuropathy or TTR-CA may occur without affection of another tissue, a variable combination of organ affection (multiorgan involvement) is the most frequent phenotype. This review aims at summarizing and discussing previous and recent findings concerning the clinical presentation, genetic background, pathogenesis, diagnosis, treatment, and outcome of ATTRm-related polyneuropathy. | ME THODSData for this review were identified by searches of MEDLINE for references of relevant articles. Search terms applied were "transthyretin," "gene," "TTR-FAP," or "mutation," combined with "neuropathy," "hereditary," "autonomic," "small fiber neuropathy," and "polyneuropathy." Results of the search were screened for potentially relevant studies by application of inclusion and exclusion criteria for the full texts of the relevant studies. Included were randomized controlled trials (RCTs), observational studies with controls, case series, and case reports. Only original articles about humans, and published between 1966 and 2018 were included. Reviews, editorials, and letters were not considered. Reference lists of retrieved studies were checked for reports of additional studies. Websites checked for additional, particularly geneti...

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“…As a result, insoluble amyloid fibrils accumulate in the peripheral and autonomic nerves, heart, gastrointestinal tract, kidneys, eyes, and connective tissues [1,2]. Three phenotypes predominate in ATTRv amyloidosis: one is almost exclusively characterized by restrictive cardiomyopathy, another predominantly by polyneuropathy (ATTR-PN), and the third is a mixed phenotype [3][4][5].…”

Section: Introductionmentioning

confidence: 99%

“…Among persons with the classic disease phenotype, death has been reported to occur within 10-15 years of symptom onset, often from cachexia and malnutrition due to gastrointestinal complications [11,12]. Prognostic survival factors include cardiac dysautonomia [3] and the presence of a mutation other than the more common Val30Met (also referred to as p.Val50Me) tgenotype [11,13]; both of which are associated with poorer survival.…”

Section: Introductionmentioning

confidence: 99%

Impact of Non-Cardiac Clinicopathologic Characteristics on Survival in Transthyretin Amyloid Polyneuropathy

et al. 2020

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Introduction: Hereditary (variant) transthyretin amyloidosis (ATTRv) with polyneuropathy (ATTR-PN) is a rare genetic disorder that causes progressive autonomic and sensorimotor neuropathy, severe disability, and death within 10 years of onset. Previous studies have primarily focused on how baseline cardiac characteristics affect mortality, but the impact of non-cardiac baseline characteristics is less defined. Methods: We systematically searched PubMed/ Medline (1990-2019) to identify studies that assessed the impact of baseline ATTR-PN characteristics on survival. Outcomes were first summarized descriptively. Extracted survival data were then disaggregated, and parametric mixture models were used to assess survival differences among patient groups defined by factors known to affect survival. Results: The search yielded 1193 records, of which 35 were retained for analysis. Median survival ranged from 0.5 to [ 25 years. The largest survival differences were between cohorts who underwent liver transplantation (LTx) versus those who did not. Among LTx cohorts, pre-LTx ATTR-PN disease duration C 7 years, poor nutritional status, and late disease onset reduced median survival by 13, 12, and 10 years, respectively. Other prognostic survival factors included non-Val30Met genotype and baseline presence of urinary incontinence, erectile dysfunction, or muscle weakness. Conclusion: Survival in patients with ATTR-PN is highly variable and affected by non-cardiac baseline characteristics, such as autonomic dysfunction, large fiber involvement, late-onset disease, and non-Val30Met mutation. Careful interpretation of these findings is warranted Enhanced digital features To view enhanced digital features for this article go to https://doi.org/10.6084/ m9.figshare.11891175.

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Cardiac Dysautonomia Predicts Long-Term Survival in Hereditary Transthyretin Amyloidosis After Liver Transplantation

Cited by 45 publications

References 35 publications

Imaging cardiac innervation in hereditary transthyretin (ATTRm) amyloidosis: A marker for neuropathy or cardiomyopathy in case of heart failure?

Imaging cardiac innervation in hereditary transthyretin (ATTRm) amyloidosis: A marker for neuropathy or cardiomyopathy in case of heart failure?

Hereditary transthyretin-related amyloidosis

Impact of Non-Cardiac Clinicopathologic Characteristics on Survival in Transthyretin Amyloid Polyneuropathy

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