Cardiac amyloidosis prevalence and 1-year outcome in patients with aortic stenosis undergoing transaortic valve implantation: Findings from the CAMPOS-TAVI study.

BACKGROUND: Transthyretin amyloid cardiomyopathy (ATTR-CM) can manifest as rhythm disorders, heart failure, but also valvular degeneration. Despite aortic stenosis (AS) being prevalent among the elderly, data on ATTR-CM prevalence and outcome in patients with AS undergoing transaortic valve implantation (TAVI) remain scarce. AIM: To determine ATTR-CM prevalence and evaluate 1-year survival in patients undergoing TAVI. METHODS: Between December 2020 and September 2021, 100 consecutive patients underwent TAVI and were screened prospectively for ATTR-CM using bone scintigraphy (BS). Monoclonal gammopathy was ruled out in case of cardiac uptake on BS. All patients were followed prospectively for 1year after TAVI. RESULTS: The proportion of patients aged≥75years or with a EuroSCORE II>8% and possible femoral access was 99%. The abnormal cardiac uptake rate on BS was 7% (95% confidence interval: 2-12%); 86% of these patients were male. The RAISE (remodelling, age, injury, system and electrical) score, indicative of ATTR-CM risk, was higher in case of positive BS (P=0.04). Patients with positive BS were older and exhibited wider QRS complexes on electrocardiography (P=0.003), a higher frequency of reduced LVEF (57% vs. 17%), impaired basal LV strain (P=0.02) and a lower voltage/mass ratio (P=0.01). History of pacemaker implantation before TAVI was higher in the positive BS group (P=0.0004) and remained the only statistically significant factor after adjustment using the Holm-Bonferroni method. One-year survival of patients with positive BS did not differ from that of patients with isolated AS. CONCLUSIONS: Prevalence of ATTR-CM in patients treated with TAVI, underscoring the need for continued surveillance for potential development of ATTR-CM after TAVI. Caution is warranted regarding the 1-year survival because of the lack of study power. Further investigations are needed to define long-term prognosis of AS with ATTR-CM.

Substrate Characterization and Outcomes of Ventricular Tachycardia Ablation in Amyloid Cardiomyopathy: A Multicenter Study.

BACKGROUND: Sustained ventricular tachycardia (VT) in cardiac amyloidosis is uncommon, and the substrate and outcomes of catheter ablation are not defined. METHODS: We included 22 consecutive patients (mean age, 68±10 years; male sex, 91%) with cardiac amyloidosis (ATTR [transthyretin], n=16; light chain, n=6) undergoing catheter ablation for VT/ventricular fibrillation (VF) between 2013 and 2023 in a retrospective, observational, international study. The primary efficacy outcome was recurrent VT/VF during follow-up, while the primary safety end point included major procedure-related adverse events. RESULTS: The indication for ablation was drug-refractory VT in 17 patients (77%), and premature ventricular complex-initiated polymorphic VT/VF in 5 patients (23%). Catheter ablation was performed using endocardial (n=17.77%) or endo-epicardial approaches (n=5.23%). Complete endocardial electroanatomical voltage maps of the left and right ventricles were obtained in 17 (77%) and 10 (45%) patients, respectively. Each patient had evidence of low-voltage areas, most commonly involving the interventricular septum (n=16); late potentials were recorded in 16 patients (73%). A median of 1 (1-2) VT was inducible per patient; 12 of the 26 mappable VTs (46%) originated from the interventricular septum. Complete procedural success was achieved in 16 patients (73%), with 4 (18%) major procedure-related adverse events. After a median follow-up of 32 (14-42) months, sustained VT/VF recurrence was observed in 9 patients (41%); survival free from VT/VF recurrence was 56% (95% CI, 36%-86%) at 36-month follow-up, and most patients remained on antiarrhythmic drugs. A significant reduction in per patient implantable cardioverter defibrillator therapies was noted in the 6-month period after ablation (before: 6 [4-9] versus after: 0 [0-0]; P<0.001). In multivariable analysis, complete procedural success was associated with reduced risk of recurrent VT/VF (hazard ratio, 0.002; P=0.034). CONCLUSIONS: Catheter ablation can achieve control of recurrent VT/VF in more than half of patients with cardiac amyloidosis, and the reduction in VT/VF burden post-ablation may be relevant for quality of life. Septal substrate and risk of procedure-related complications challenge successful management of patients with cardiac amyloidosis and VT/VF.

Descriptive study of the clinical and myocardial status of a population with anatomopathological aortic valve amyloidosis.

BACKGROUND: Aortic stenosis (AS) and transthyretin (ATTR) cardiac amyloidosis (CA) share the same clinical profiles and cardiac phenotype. Amyloid deposits have been frequently reported in aortic valves of patients with severe AS referred for surgical aortic valve replacement (SAVR). The aim of this study was to determine the clinical and myocardial status of patients with aortic valve amyloidosis after aortic valve surgery. METHODS AND RESULTS: We performed a retrospective descriptive study of 46 patients who underwent SAVR for severe AS with amyloid deposits upon histological analysis. All patients were screened for cardiac involvement. Amyloid deposits typing was successful in 35 (76%) patients and 28 (80%) were ATTR. Two (4%) had positive bone scintigraphy and among the 5 myocardial biopsies performed during surgery, 80% were positive for ATTR deposits. CONCLUSION: ATTR is the predominant type in the presence of amyloid deposits on the aortic valve after surgery for severe AS but is only rarely accompanied by cardiac uptake on bone scintigraphy. Early stages of myocardial involvement are frequent and myocardial biopsy is more sensitive for detection of mild amyloid deposits than bone scintigraphy.

Clinical outcomes of catheter ablation for atrial fibrillation, atrial flutter, and atrial tachycardia in wild-type transthyretin amyloid cardiomyopathy: a proposed treatment strategy for catheter ablation in each arrhythmia.

AIMS: Wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM) is often accompanied by atrial fibrillation (AF), atrial flutter (AFL), and atrial tachycardia (AT), which are difficult to control because beta-blockers and antiarrhythmic drugs can worsen heart failure (HF). This study aimed to investigate the outcomes of catheter ablation (CA) for AF/AFL/AT in patients with ATTRwt-CM and propose a treatment strategy for CA. METHODS AND RESULTS: A cohort study was conducted on 233 patients diagnosed with ATTRwt-CM, including 54 who underwent CA for AF/AFL/AT. The background of each arrhythmia and the details of the CA and its outcomes were investigated. The recurrence-free rate of AF/AFL/AT overall in ATTRwt-CM patients with multiple CA was 70.1% at 1-year, 57.6% at 2-year, and 44.0% at 5-year follow-up, but CA significantly reduced all-cause mortality [hazard ratio (HR): 0.342, 95% confidence interval (CI): 0.133-0.876, P = 0.025], cardiovascular mortality (HR: 0.378, 95% CI: 0.146-0.981, P = 0.045), and HF hospitalization (HR: 0.488, 95% CI: 0.269-0.889, P = 0.019) compared with those without CA. There was no recurrence of the cavotricuspid isthmus (CTI)-dependent AFL, non-CTI-dependent simple AFL terminated by one linear ablation, and focal AT originating from the atrioventricular (AV) annulus or crista terminalis eventually. Twelve of 13 patients with paroxysmal AF and 27 of 29 patients with persistent AF did not have recurrence as AF. However, all three patients with non-CTI-dependent complex AFL not terminated by a single linear ablation and 10 of 13 cases with focal AT or multiple focal ATs originating beyond the AV annulus or crista terminalis recurred even after multiple CA. CONCLUSION: The outcomes of CA for ATTRwt-CM were acceptable, except for multiple focal AT and complex AFL. Catheter ablation may be aggressively considered as a treatment strategy with the expectation of improving mortality and hospitalization for HF.

Efficacy of Computed Tomography-Based Evaluation of Myocardial Extracellular Volume Combined With Red Flags for Early Screening of Concealed Cardiac Amyloidosis in Patients With Atrial Fibrillation.

BACKGROUND: The prevalence of transthyretin amyloid cardiomyopathy (ATTR-CM) in atrial fibrillation (AF) patients remains unclear. We explored the efficacy of computed tomography-based myocardial extracellular volume (CT-ECV) combined with red flags for the early screening of concealed ATTR-CM in AF patients undergoing catheter ablation. METHODS AND RESULTS: Patients referred for AF ablation at Oita University Hospital were prescreened using the red-flag signs defined by echocardiographic or electrocardiographic findings, medical history, symptoms, and blood biochemical findings. Myocardial CT-ECV was quantified in red flag-positive patients using routine pre-AF ablation planning cardiac CT with the addition of delayed-phase cardiac CT scans. Patients with high (>35%) ECV were evaluated using technetium pyrophosphate (99 mTc-PYP) scintigraphy. A cardiac biopsy was performed during the planned AF ablation procedure if 99 mTc-PYP scintigraphy was positive. Between June 2022 and June 2023, 342 patients were referred for AF ablation. Sixty-seven (19.6%) patients had at least one of the red-flag signs. Myocardial CT-ECV was evaluated in 57 patients because of contraindications to contrast media, revealing that 16 patients had high CT-ECV. Of these, 6 patients showed a positive 99 mTc-PYP study, and 6 patients were subsequently diagnosed with wild-type ATTR-CM via cardiac biopsy and genetic testing. CONCLUSIONS: CT-ECV combined with red flags could contribute to the systematic early screening of concealed ATTR-CM in AF patients undergoing catheter ablation.

Transthyretin cardiac amyloidosis in patients with severe aortic stenosis undergoing transcatheter aortic valve replacement: experience of a single center.

BACKGROUND: Even if prevalent among patients with severe aortic stenosis (AS), the clinical suspicion for transthyretin cardiac amyloidosis (ATTR-CA) remains difficult in this subset. We report our single center experience on ATTR-CA detection among TAVR candidates to provide insights on the prevalence and clinical features of dual pathology as compared to lone AS. METHODS: Consecutive severe AS patients undergoing transcatheter aortic valve replacement (TAVR) evaluation at a single center were prospectively included. Those with suspected ATTR-CA based on clinical assessment underwent 99m Tc-3,3-diphosphono-1,2-propanodicarboxylic acid (DPD) bone scintigraphy. The RAISE score, a novel screening tool with high sensitivity for ATTR-CA in AS, was retrospectively calculated to rule-out ATTR-CA in the remaining patients. Patients were categorized as follow: "ATTR-CA+": patients with confirmed ATTR-CA at DPD bone scintigraphy; "ATTR-CA-": patients with negative DPD bone scintigraphy or a negative RAISE score; "ATTR-CA indeterminate": patients not undergoing ATTR-CA assessment with a positive RAISE score. The characteristics of ATTR-CA+ and ATTR-CA- patients were compared. RESULTS: Of 107 included patients, ATTR-CA suspicion was posed in 13 patients and confirmed in six. Patients were categorized as follow: 6 (5.6%) ATTR-CA+, 79 (73.8%) ATTR-CA-, 22 (20.6%) ATTR-CA indeterminate. Excluding ATTR-CA indeterminate patients, the prevalence of ATTR-CA was 7.1% (95% CI 2.6-14.7%). As compared to ATTR-CA - patients, ATTR-CA + patients were older, had higher procedural risk and more extensive myocardial and renal damage. They had higher left ventricle mass index and lower ECG voltages, translating into a lower voltage to mass ratio. Moreover, we describe for the first time bifascicular block as an ECG feature highly specific of patients with dual pathology (50.0% vs. 2.7%, P<0.001). Of note, pericardial effusion was rarely found in patients with lone AS (16.7% vs. 1.2%, P=0.027). No difference in procedural outcomes was observed between groups. CONCLUSIONS: Among severe AS patients, ATTR-CA is prevalent and presents with phenotypic features that may aid to differentiate it from lone AS. A clinical approach based on routine search of amyloidosis features might lead to selective DPD bone scintigraphy with a satisfactory positive predictive value.

Long-term surgical results of trabeculectomy for secondary glaucoma in Val30Met hereditary transthyretin amyloidosis.

This study reports the long-term results of trabeculectomy (LEC) for secondary glaucoma in hereditary transthyretin (ATTRv) amyloidosis patients and its correlation with prior vitrectomy. A retrospective case series was conducted involving 31 consecutive eyes of 20 ATTRv amyloidosis patients who underwent LEC between 2007 and 2020. The mean follow-up period was 73.2 ± 37.0 months (range: 20-181 months). Postoperative intraocular pressures (IOPs) were evaluated based on the following criteria: (a) IOP between 6 and 21 mmHg without additional glaucoma surgeries, except for laser suture lysis, (b) IOP between 6 and 15 mmHg without additional glaucoma surgeries, except for laser suture lysis, and (c) IOP between 6 and 21 mmHg without additional glaucoma surgeries, except for needling and laser suture lysis. Kaplan-Meier analysis revealed survival rates after LEC of 0.52 at 36 months, 0.42 at 60 months, and 0.25 at 84 months under criterion (a); 0.49 at 36 months, 0.27 at 60 months, and 0.11 at 84 months under criterion (b); and 0.76 at 36 months, 0.71 at 60 months, and 0.65 at 84 months under criterion (c). Eyes with a history of small gauge transconjunctival vitrectomy (SGTV) exhibited a tendency towards lower survival rates, although no statistically significant difference was observed (log-rank test; p = 0.193 under criterion (a) and p = 0.0553 under criterion (b)). Our findings suggest that LEC and additional needling procedures can provide some control over IOP; however, the overall postoperative outcomes of LEC for ATTRv amyloidosis remain unsatisfactory, even in the era of SGTV with reduced conjunctival scarring.

Comparison between tafamidis and liver transplantation as first-line therapy for hereditary transthyretin amyloidosis.

BACKGROUND: By stabilizing transthyretin, tafamidis delays progression of amyloidosis due to transthyretin variant (ATTRv) and replaced liver transplantation (LT) as the first-line therapy. No study compared these two therapeutic strategies. METHODS: In a monocentric retrospective cohort analysis, patients with ATTRv amyloidosis treated with either tafamidis or LT were compared using a propensity score and a competing risk analysis for three endpoints: all-cause mortality, cardiac worsening (heart failure or cardiovascular death) and neurological worsening (worsening in PolyNeuropathy Disability score). RESULTS: 345 patients treated with tafamidis (n = 129) or LT (n = 216) were analyzed, and 144 patients were matched (72 patients in each group, median age 54 years, 60% carrying the V30M mutation, 81% of stage I, 69% with cardiac involvement, median follow-up: 68 months). Patients treated with tafamidis had longer survival than LT patients (HR: 0.35; p = .032). Conversely, they also presented a 3.0-fold higher risk of cardiac worsening and a 7.1-fold higher risk of neurological worsening (p = .0071 and p < .0001 respectively). CONCLUSIONS: ATTRv amyloidosis patients treated with tafamidis would present a better survival but also a faster deterioration of their cardiac and neurological statuses as compared with LT. Further studies are needed to clarify the therapeutic strategy in ATTRv amyloidosis.

Predictors of cognitive dysfunction in hereditary transthyretin amyloidosis with liver transplant.

BACKGROUND: Cognitive dysfunction is part of the broad spectrum of clinical manifestations in older untreated hereditary transthyretin amyloidosis patients with peripheral polyneuropathy. OBJECTIVE: The objective of this study is to systematically explore cognitive dysfunction in ATTRV30M amyloidosis patients whose disease course was modified by liver transplant (LT). METHODS: A series of 269 carriers of TTRVal30Met mutation treated with LT underwent a neuropsychological assessment. Clinical charts were reviewed to identify focal neurological episodes (FNEs), cognitive complaints and laboratory results. Chi-square and Mann-Whitney tests explored potential predictors of cognitive dysfunction. RESULTS: Cognitive dysfunction was identified in 35 patients (13%)-14 (5%) had mild and 21 (8%) had moderate dysfunction. In comparison to normal cognition, both mild and moderate cognitive dysfunction patients had older age, higher mPND score and elevated NT-proBNP and Cystatin C values. Mild cognitive dysfunction was associated with longer disease duration and history of FNEs, whereas moderate dysfunction was related to older age at disease onset and more cognitive complaints and depression symptoms. CONCLUSIONS: Consistent with the natural history of the disease, older age and higher severity of the disease are significantly associated and potentially predictors of cognitive dysfunction in ATTRV30M patients treated with LT. The level of cognitive dysfunction may depend on some clinical variables.

Treatment of acquired transthyretin amyloidosis in domino liver transplantation.

BACKGROUND: Domino liver transplantation (DLT) has been commonly used during the last two decades to partly meet the high need for liver transplants. However, the recipients of grafts from patients with noncirrhotic inherited metabolic disorders may ultimately develop metabolic syndrome, and management is usually intricate, being complicated by the underlying initial disorder, other comorbidities, and post-transplantation conditions. CASE: We report here the management and the outcome in a patient with acquired transthyretin amyloidosis after DLT and significant comorbidities. Final treatment with a transthyretin gene silencing agent, patisiran, was well tolerated and resulted in remission of the aggravating neurological deficits in a follow-up period of 2 years. CONCLUSIONS: The case presented here supports the concept that patisiran can target the hepatocytes producing the mutated transthyretin in acquired transthyretin amyloidosis, as efficiently as in hereditary transthyretin amyloidosis (hATTR), and can be used to treat patients with transthyretin amyloidosis after DLT.

Suture trabeculotomy ab interno for secondary glaucoma in Japanese patients with Val30Met hereditary transthyretin amyloidosis.

We retrospectively evaluated surgical outcomes of suture trabeculotomy (SLOT) ab interno for secondary glaucoma in 18 eyes of 12 patients with hereditary transthyretin (ATTRv) amyloidosis with Val30Met mutation. SLOT ab interno was performed between May 2015 and January 2020. All the participants were followed up for at least 12 months. The primary outcome measure was Kaplan-Meier survival. Failure of this treatment was defined as an intraocular pressure (IOP) of ≥ 22 mmHg and a < 20% IOP reduction with or without medication or as additional operations needed to reduce IOP. The mean postoperative follow-up period was 3.5 years (1.2-6.1 years). The SLOT ab interno procedure alone was performed in 17 eyes (94%). Fifteen eyes (83%) had a 360° incision made in Schlemm's canal and 3 eyes (17%) had a 180° incision performed. Cumulative survival values were 0.83, 0.63, and 0.22 at 1, 2, and 3 years, respectively. Ten eyes (56%) needed additional surgery, such as repeated SLOT ab interno, Ahmed glaucoma valve implantation, or MicroPulse transscleral cyclophotocoagulation. Our results here, as well as our previous results with trabeculectomy, suggest that SLOT ab interno may not have a sufficiently long-term effect on secondary glaucoma because of ATTRv amyloidosis.

Screening for Cardiac Amyloidosis 5 to 15 Years After Surgery for Bilateral Carpal Tunnel Syndrome.

BACKGROUND: Bilateral carpal tunnel syndrome (CTS) is a common extracardiac manifestation of amyloidosis and usually predates overt cardiac amyloidosis (CA) by several years. Screening studies on patients undergoing CTS surgery have shown a low yield of CA (2.0%), but high prevalence of amyloid in the carpal ligament. The proportion of patients with amyloid in the carpal ligament who later develop CA is unknown. OBJECTIVES: The authors sought to investigate the prevalence of undiagnosed CA 5 to 15 years after surgery for bilateral CTS. METHODS: Using national registries, the authors identified subjects aged 60 to 85 years with prior CTS surgery, where the first procedure on the second wrist was performed 5 to 15 years earlier. Invitations to participate in the study were sent by mail. Per international recommendations, the initial cardiac evaluation included echocardiography, 99mtechnetium-pyrophosphate scintigraphy, and assessment of monoclonal proteins in serum and urine. RESULTS: A total of 250 subjects (35.7% of those invited) participated in the study. The median age was 70.4 years, and 50% were female. CA was diagnosed in 12 patients (4.8%; 95% CI: 2.5%-8.2%), and all cases were wild-type transthyretin amyloidosis (ATTRwt). The prevalence of ATTRwt in men was 8.8% (95% CI: 4.5%-15.2%; n = 11), and 21.2% (95% CI: 11.1%-34.7%) in male subjects ≥70 years with a BMI <30 kg/m2. All but 2 patients diagnosed with ATTRwt were in the lowest disease severity score (Mayo score). CONCLUSIONS: Screening for CA in patients with prior surgery for bilateral CTS finds approximately 5% with early-stage transthyretin CA. The clinical yield was higher (>1 in 5) when focusing on nonobese men ≥70 years, showing potential for systematic screening.

Heart transplantation in Val142Ile mutation in the modern era: A single center experience.

Little is known about the post heart transplantation management of extra cardiac manifestations in patients with hereditary transthyretin amyloid cardiomyopathy (hATTR-CM) in the new era of disease modifying treatment for ATTR amyloidosis. This is a retrospective study of all patients with hATTR-CM associated with the Val142Ile variant who underwent heart transplantation (HT) from January 2014 to February 2022. All 10 patients with the Val142Ile mutation were successfully transplanted, with a 1 year survival post heart transplantation (HT) of 90%, comparable to an age, sex, and race matched cohort of patients transplanted for non-amyloid indications. However, 4 (40%) of these patients developed progressive extracardiac manifestations requiring initiation of TTR silencer therapy with the small interfering RNA (siRNA) drug patisiran, which was well tolerated with no significant side effects in this population. We recommend formal neurologic evaluation and assessment of extracardiac manifestations annually as part of routine post-transplant care, and disease modifying therapy, aimed at TTR stabilization or silencing, should be initiated in the context of previously untreated extracardiac manifestations or evidence of subclinical neuropathy to prevent progression.

Reverse Remodeling Following Valve Replacement in Coexisting Aortic Stenosis and Transthyretin Cardiac Amyloidosis.

BACKGROUND: Dual pathology of severe aortic stenosis (AS) and transthyretin cardiac amyloidosis (ATTR) is increasingly recognized. Evolution of symptoms, biomarkers, and myocardial mechanics in AS-ATTR following valve replacement is unknown. We aimed to characterize reverse remodeling in AS-ATTR and compared with lone AS. METHODS: Consecutive patients referred for transcatheter aortic valve replacement (TAVR) underwent ATTR screening by blinded 99mTc-DPD bone scintigraphy (Perugini Grade-0 negative, 1-3 increasingly positive) before intervention. ATTR was diagnosed by DPD and absence of monoclonal protein. Reverse remodeling was assessed by comprehensive evaluation before TAVR and at 1 year. RESULTS: One hundred twenty patients (81.8±6.3 years, 51.7% male, 95 lone AS, 25 AS-ATTR) with complete follow-up were studied. At 12 months (interquartile range, 7-17) after TAVR, both groups experienced significant symptomatic improvement by New York Heart Association functional class (both P<0.001). Yet, AS-ATTR remained more symptomatic (New York Heart Association ≥III: 36.0% versus 13.8; P=0.01) with higher residual NT-proBNP (N-terminal pro-brain natriuretic peptide) levels (P<0.001). Remodeling by echocardiography showed left ventricular mass regression only for lone AS (P=0.002) but not AS-ATTR (P=0.5). Global longitudinal strains improved similarly in both groups. Conversely, improvement of regional longitudinal strain showed a base-to-apex gradient in AS-ATTR, whereas all but apical segments improved in lone AS. This led to the development of an apical sparing pattern in AS-ATTR only after TAVR. CONCLUSIONS: Patterns of reverse remodeling differ from lone AS to AS-ATTR, with both groups experiencing symptomatic improvement by TAVR. After AS treatment, AS-ATTR transfers into a lone ATTR cardiomyopathy phenotype.

[de novo hATTR amyloidosis after domino transplantation of a donor's liver: a case report for the use of Patisiran]. / de novo hATTR Amyloidose nach Domino-Lebertransplantation: Ein Fallbeispiel für den Einsatz von Patisiran.

Hereditary transthyretin-mediated (hATTR) amyloidosis is a rare, rapidly progressing, and potentially life-threatening disease caused by one of more than 120 mutations in the transthyretin (TTR) gene. As a result of the cumulative amyloid deposits, especially in the peripheral nerves and the heart, the majority of patients develop progressive, peripheral sensorimotor polyneuropathy and biventricular cardiomyopathy over time.Since TTR - and its amyloidogenic variants too - is predominantly synthesized in the liver, early, orthotopic liver transplantation (LTx) is a treatment option that can be used to potentially stop the progression of hATTR amyloidosis.The actual case shows a patient with hepatocellular carcinoma who received the organ of a patient with hATTR as part of a domino liver transplantation. After approximately 10 years, the patient started to develop the characteristic symptoms of the metabolic disorder. Because of a further progression of the amyloidosis, therapy with the RNA interference therapeutic patisiran was initiated, which temporarily halted the progression.

Deterioration after Liver Transplantation and Transthyretin Stabilizer Administration in a Patient with ATTRv Amyloidosis with a Leu58Arg (p.Leu78Arg) TTR Variant.

We herein report a 44-year-old Japanese man with hereditary transthyretin amyloidosis (ATTRv amyloidosis) harboring the variant Leu58Arg (p.Leu78Arg) in TTR in whom we conducted an observational study with liver transplantation (LT) and transthyretin (TTR) stabilizers (tafamidis and diflunisal) for 9 years. This patient showed gradual deterioration of sensory, motor, and autonomic neuropathy symptoms after LT. Furthermore, cardiac amyloidosis gradually developed. Although the present case showed deterioration of the symptoms after disease-modifying treatments, LT might be suitable in patients with the same variant if they are young and in good condition due to a long survival after LT.

Patisiran treatment in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy after liver transplantation.

Hereditary transthyretin-mediated (hATTR) amyloidosis, or ATTRv amyloidosis, is a progressive disease, for which liver transplantation (LT) has been a long-standing treatment. However, disease progression continues post-LT. This Phase 3b, open-label trial evaluated efficacy and safety of patisiran in patients with ATTRv amyloidosis with polyneuropathy progression post-LT. Primary endpoint was median transthyretin (TTR) reduction from baseline. Twenty-three patients received patisiran for 12 months alongside immunosuppression regimens. Patisiran elicited a rapid, sustained TTR reduction (median reduction [Months 6 and 12 average], 91.0%; 95% CI: 86.1%-92.3%); improved neuropathy, quality of life, and autonomic symptoms from baseline to Month 12 (mean change [SEM], Neuropathy Impairment Score, -3.7 [2.7]; Norfolk Quality of Life-Diabetic Neuropathy questionnaire, -6.5 [4.9]; least-squares mean [SEM], Composite Autonomic Symptom Score-31, -5.0 [2.6]); and stabilized disability (Rasch-built Overall Disability Scale) and nutritional status (modified body mass index). Adverse events were mild or moderate; five patients experienced ≥1 serious adverse event. Most patients had normal liver function tests. One patient experienced transplant rejection consistent with inadequate immunosuppression, remained on patisiran, and completed the study. In conclusion, patisiran reduced serum TTR, was well tolerated, and improved or stabilized key disease impairment measures in patients with ATTRv amyloidosis with polyneuropathy progression post-LT (www.clinicaltrials.gov NCT03862807).

Progressive Multiple Mononeuropathy in a Patient With Familial Transthyretin Amyloidosis After Liver Transplantation.

ABSTRACT: Valine 122 isoleucine (V122I) is the most common mutation associated with familial transthyretin-related amyloidosis (fATTR) in the metropolitan United States. V122I-related fATTR usually presents with cardiomyopathy. When polyneuropathy is encountered, it is usually mild, distal, and axonal in nature. Although liver transplantation improves survival for fATTR neuropathy patients, neuropathy may progress post liver transplantation because of the deposition of wild-type transthyretin. We report a patient with homozygous V122I mutation who presented with asymmetrical, upper limb predominant neuropathy rather early in his disease course, which progressed for a period of 5 years after liver transplantation before stabilization with the initiation of patisiran.