Detailed clinical, physiological and pathological phenotyping can impact access to disease-modifying treatments in ATTR carriers.

BACKGROUND: Hereditary transthyretin amyloidosis is a life-threatening autosomal dominant systemic disease due to pathogenic TTR variants (ATTRv), mostly affecting the peripheral nerves and heart. The disease is characterised by a combination of symptoms, organ involvement and histological amyloid deposition. The available disease-modifying ATTRv treatments (DMTs) are more effective if initiated early. Pathological nerve conduction studies (NCS) results are the cornerstone of large-fibre polyneuropathy diagnosis, but this anomaly occurs late in the disease. We investigated the utility of a multimodal neurological and cardiac evaluation for detecting early disease onset in ATTRv carriers. METHODS: We retrospectively analysed a cohort of ATTRv carriers with normal NCS results regardless of symptoms. Multimodal denervation and infiltration evaluations included a clinical questionnaire (Lauria and New York Heart Association (NYHA)) and examination, intra-epidermal nerve fibre density assessment, autonomic assessment based on heart rate variability, Sudoscan, meta-iodo-benzyl-guanidine scintigraphy, cardiac biomarkers, echocardiography, MRI and searches for amyloidosis on skin biopsy and bone scintigraphy. RESULTS: We included 130 ATTRv carriers (40.8% men, age: 43.6±13.5 years), with 18 amyloidogenic TTR gene mutations, the majority of which was the late-onset Val30Met variant (42.3%). Amyloidosis was detected in 16.9% of mutation carriers, including 9 (6.9%) with overt disease (Lauria>2 or NYHA>1) and 13 asymptomatic carriers (10%) with organ involvement (small-fibre neuropathy or cardiomyopathy). Most of these patients received DMT. Abnormal test results of unknown significance were obtained for 105 carriers (80.8%). Investigations were normal in only three carriers (2.3%). CONCLUSIONS: Multimodal neurological and cardiac investigation of TTRv carriers is crucial for the early detection of ATTRv amyloidosis and initiation of DMT.

Effects of Patisiran, an RNA Interference Therapeutic, on Cardiac Parameters in Patients With Hereditary Transthyretin-Mediated Amyloidosis.

BACKGROUND: Hereditary transthyretin-mediated (hATTR) amyloidosis is a rapidly progressive, multisystem disease that presents with cardiomyopathy or polyneuropathy. The APOLLO study assessed the efficacy and tolerability of patisiran in patients with hATTR amyloidosis. The effects of patisiran on cardiac structure and function in a prespecified subpopulation of patients with evidence of cardiac amyloid involvement at baseline were assessed. METHODS: APOLLO was an international, randomized, double-blind, placebo-controlled phase 3 trial in patients with hATTR amyloidosis. Patients were randomized 2:1 to receive 0.3 mg/kg patisiran or placebo via intravenous infusion once every 3 weeks for 18 months. The prespecified cardiac subpopulation comprised patients with a baseline left ventricular wall thickness ≥13 mm and no history of hypertension or aortic valve disease. Prespecified exploratory cardiac end points included mean left ventricular wall thickness, global longitudinal strain, and N-terminal prohormone of brain natriuretic peptide. Cardiac parameters in the overall APOLLO patient population were also evaluated. A composite end point of cardiac hospitalizations and all-cause mortality was assessed in a post hoc analysis. RESULTS: In the cardiac subpopulation (n=126; 56% of total population), patisiran reduced mean left ventricular wall thickness (least-squares mean difference ± SEM: -0.9±0.4 mm, P=0.017), interventricular septal wall thickness, posterior wall thickness, and relative wall thickness at month 18 compared with placebo. Patisiran also led to increased end-diastolic volume (8.3±3.9 mL, P=0.036), decreased global longitudinal strain (-1.4±0.6%, P=0.015), and increased cardiac output (0.38±0.19 L/min, P=0.044) compared with placebo at month 18. Patisiran lowered N-terminal prohormone of brain natriuretic peptide at 9 and 18 months (at 18 months, ratio of fold-change patisiran/placebo 0.45, P<0.001). A consistent effect on N-terminal prohormone of brain natriuretic peptide at 18 months was observed in the overall APOLLO patient population (n=225). Median follow-up duration was 18.7 months. The exposure-adjusted rates of cardiac hospitalizations and all-cause death were 18.7 and 10.1 per 100 patient-years in the placebo and patisiran groups, respectively (Andersen-Gill hazard ratio, 0.54; 95% CI, 0.28-1.01). CONCLUSIONS: Patisiran decreased mean left ventricular wall thickness, global longitudinal strain, N-terminal prohormone of brain natriuretic peptide, and adverse cardiac outcomes compared with placebo at month 18, suggesting that patisiran may halt or reverse the progression of the cardiac manifestations of hATTR amyloidosis. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01960348.

Cardiac denervation evidenced by MIBG occurs earlier than amyloid deposits detection by diphosphonate scintigraphy in TTR mutation carriers.

PURPOSE: Cardiac involvement in familial transthyretin (TTR) amyloidosis is of major prognostic value, and the development of early-diagnostic tools that could trigger the use of new disease-modifying treatments is crucial. The aim of our study was to compare the respective contributions of 99mTc-diphosphonate scintigraphy (DPD, detecting amyloid deposits) and 123I-MIBG (MIBG, assessing cardiac sympathetic denervation) in patients with genetically proven TTR mutation referred for the assessment of cardiac involvement. METHODS: We prospectively studied 75 consecutive patients (classified as symptomatic or asymptomatic carriers), using clinical evaluation, biomarkers (troponin and BNP), echocardiography, and nuclear imaging. Patients were classified as having normal heart-to-mediastinum (HMR) MIBG uptake ratio 4 h after injection (defined by HM4 ≥ 1.85) or abnormal HM4 < 1.85, and positive DPD uptake (grade ≥ 1 of Perugini classification) or negative DPD uptake. RESULTS: Among 75 patients, 49 (65%) presented with scintigraphic sympathetic cardiac denervation and 29 (39%) with myocardial diphosphonate uptake. When MIBG was normal, DPD was negative except for two patients. Age was an independent predictor of abnormal scintigraphic result of both MIBG and DPD (HR 1.08 and 1.15 respectively), whereas echocardiographic-derived indicators of increased left ventricular filling pressure (E/e' ratio) was an independent predictor of abnormal MIBG (HR 1.33) and global longitudinal strain of positive DPD (HR 1.45). In asymptomatic patients (n = 31), MIBG was abnormal in 48% (n = 15) among whom 50% had a normal DPD; all those with a normal MIBG (n = 16) had a normal DPD. CONCLUSIONS: In TTR mutation carriers, cardiac sympathetic denervation evidenced by decreased MIBG uptake is detected earlier than amyloid burden evidenced by DPD. These results raise the possibility of a diagnostic role for MIBG scintigraphy at an early stage of cardiac involvement in TTR-mutated carriers, in addition to its well-established prognostic value.

Can Nuclear Imaging Techniques Predict Patient Outcome and Guide Medical Management in Hereditary Transthyretin Cardiac Amyloidosis?

PURPOSE OF REVIEW: Nuclear imaging recently gained a key role in the diagnosis and prognostic assessment of transthyretin (TTR)-related cardiac amyloidosis. This review aims at summarizing the state-of-the art regarding the implementation of nuclear imaging in the management of hereditary mutated TTR-cardiac amyloidosis (mTTR-CA). RECENT FINDINGS: Although cardiac uptake of bone tracers is acknowledged as a specific marker of TTR amyloid cardiac burden, recent studies validated the implementation of bone scan in the flow chart for non-invasive diagnosis and follow-up of CA in multicenter trials. Simultaneously, cardiac denervation evidenced by MIBG scintigraphy proved to be a strong and independent prognostic marker of poor outcome in mTTR-CA. By its unique ability to assess both amyloid burden and cardiac denervation, nuclear imaging may prove useful as part of multimodality imaging tools to trigger treatment initiation and monitoring in patients with mTTR-CA.

First European consensus for diagnosis, management, and treatment of transthyretin familial amyloid polyneuropathy.

PURPOSE OF REVIEW: Early and accurate diagnosis of transthyretin familial amyloid polyneuropathy (TTR-FAP) represents one of the major challenges faced by physicians when caring for patients with idiopathic progressive neuropathy. There is little consensus in diagnostic and management approaches across Europe. RECENT FINDINGS: The low prevalence of TTR-FAP across Europe and the high variation in both genotype and phenotypic expression of the disease means that recognizing symptoms can be difficult outside of a specialized diagnostic environment. The resulting delay in diagnosis and the possibility of misdiagnosis can misguide clinical decision-making and negatively impact subsequent treatment approaches and outcomes. SUMMARY: This review summarizes the findings from two meetings of the European Network for TTR-FAP (ATTReuNET). This is an emerging group comprising representatives from 10 European countries with expertise in the diagnosis and management of TTR-FAP, including nine National Reference Centres. The current review presents management strategies and a consensus on the gold standard for diagnosis of TTR-FAP as well as a structured approach to ongoing multidisciplinary care for the patient. Greater communication, not just between members of an individual patient's treatment team, but also between regional and national centres of expertise, is the key to the effective management of TTR-FAP.

Genotype-phenotype correlation and course of transthyretin familial amyloid polyneuropathies in France.

OBJECTIVE: To compare the natural history of familial transthyretin amyloid polyneuropathies (FAP) due to the Val30Met, Ser77Tyr, and Ile107Val mutations in France with the classical Portuguese Val30Met FAP. METHODS: We compared 84 French patients with a control group of 110 Portuguese patients carrying the Val30Met mutation also living in France, all referred to and followed at the French National FAP Reference Center from 1988 to 2010. Clinical examination, functional and walking disability scores, nerve conduction studies, and muscle biopsies are reported. We also conducted a comprehensive literature review to further determine the range of phenotypic expression. RESULTS: By comparison with Portuguese Val30Met FAP, French Ile107Val, Ser77Tyr, and LateVal30Met FAP showed more rapid and severe disease progression; onset of gait disorders was 3 times more rapid (p < 0.0001) and the rate of modified Norris test decline was up to 40 times faster in Ile107Val patients (p < 0.0001). Median survival was much shorter in Ile107Val and in Val30Met mutation with late onset (>50 years; LateMet30) FAP (p = 0.0005). Other distinctive features relative to the Portuguese patients included atypical clinical presentations, demyelination on nerve conduction studies (p = 0.0005), and difficult identification of amyloid deposits in nerve and muscle biopsies. INTERPRETATION: Ile107Val and LateMet30 mutations are associated with the most debilitating and severe FAP ever described, with rapid onset of tetraparesis and shorter median survival. It could be explained by frequent large-fiber involvement and associated demyelination and more severe axonal loss. These findings have major implications for genetic counseling and patient management as new therapeutic options are being assessed in clinical trials (TTR gene silencing).

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.

Expert opinion on monitoring symptomatic hereditary transthyretin-mediated amyloidosis and assessment of disease progression.

BACKGROUND: Hereditary transthyretin-mediated amyloidosis, also known as ATTRv amyloidosis (v for variant), is a rare, autosomal dominant, fatal disease, in which systemic amyloid progressively impairs multiple organs, leading to disability and death. The recent approval of disease-modifying therapies offers the hope of stabilization or eventual reversal of disease progression, and yet highlights a lack of disease-management guidance. A multidisciplinary panel of expert clinicians from France and the US came to consensus on monitoring the disease and identifying progression through a clinical opinion questionnaire, a roundtable meeting, and multiple rounds of feedback. MONITORING DISEASE AND PROGRESSION: A multidisciplinary team should monitor ATTRv amyloidosis disease course by assessing potential target organs at baseline and during follow-up for signs and symptoms of somatic and autonomic neuropathy, cardiac dysfunction and restrictive cardiomyopathy, and other manifestations. Variability in penetrance, symptoms, and course of ATTRv amyloidosis requires that all patients, regardless of variant status, undergo regular and standardized assessment in all these categories. Progression in ATTRv amyloidosis may be indicated by: worsening of several existing quantifiable symptoms or signs; the appearance of a new symptom; or the worsening of a single symptom that results in a meaningful functional impairment. CONCLUSIONS: We suggest that a multisystem approach to monitoring the signs and symptoms of ATTRv amyloidosis best captures the course of the disease. We hope this work will help form the basis of further, consensus-based guidance for the treatment of ATTRv amyloidosis.

Long-term safety and efficacy of patisiran for hereditary transthyretin-mediated amyloidosis with polyneuropathy: 12-month results of an open-label extension study.

BACKGROUND: Hereditary transthyretin-mediated amyloidosis is a rare, inherited, progressive disease caused by mutations in the transthyretin (TTR) gene. We assessed the safety and efficacy of long-term treatment with patisiran, an RNA interference therapeutic that inhibits TTR production, in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy. METHODS: This multicentre, open-label extension (OLE) trial enrolled patients at 43 hospitals or clinical centres in 19 countries as of Sept 24, 2018. Patients were eligible if they had completed the phase 3 APOLLO or phase 2 OLE parent studies and tolerated the study drug. Eligible patients from APOLLO (patisiran and placebo groups) and the phase 2 OLE (patisiran group) studies enrolled in this global OLE trial and received patisiran 0·3 mg/kg by intravenous infusion every 3 weeks with plans to continue to do so for up to 5 years. Efficacy assessments included measures of polyneuropathy (modified Neuropathy Impairment Score +7 [mNIS+7]), quality of life, autonomic symptoms, nutritional status, disability, ambulation status, motor function, and cardiac stress, with analysis by study groups (APOLLO-placebo, APOLLO-patisiran, phase 2 OLE patisiran) based on allocation in the parent trial. The global OLE is ongoing with no new enrolment, and current findings are based on the interim analysis of the patients who had completed 12-month efficacy assessments as of the data cutoff. Safety analyses included all patients who received one or more dose of patisiran up to the data cutoff. This study is registered with ClinicalTrials.gov, NCT02510261. FINDINGS: Between July 13, 2015, and Aug 21, 2017, of 212 eligible patients, 211 were enrolled: 137 patients from the APOLLO-patisiran group, 49 from the APOLLO-placebo group, and 25 from the phase 2 OLE patisiran group. At the data cutoff on Sept 24, 2018, 126 (92%) of 137 patients from the APOLLO-patisiran group, 38 (78%) of 49 from the APOLLO-placebo group, and 25 (100%) of 25 from the phase 2 OLE patisiran group had completed 12-month assessments. At 12 months, improvements in mNIS+7 with patisiran were sustained from parent study baseline with treatment in the global OLE (APOLLO-patisiran mean change -4·0, 95 % CI -7·7 to -0·3; phase 2 OLE patisiran -4·7, -11·9 to 2·4). Mean mNIS+7 score improved from global OLE enrolment in the APOLLO-placebo group (mean change from global OLE enrolment -1·4, 95% CI -6·2 to 3·5). Overall, 204 (97%) of 211 patients reported adverse events, 82 (39%) reported serious adverse events, and there were 23 (11%) deaths. Serious adverse events were more frequent in the APOLLO-placebo group (28 [57%] of 49) than in the APOLLO-patisiran (48 [35%] of 137) or phase 2 OLE patisiran (six [24%] of 25) groups. The most common treatment-related adverse event was mild or moderate infusion-related reactions. The frequency of deaths in the global OLE was higher in the APOLLO-placebo group (13 [27%] of 49), who had a higher disease burden than the APOLLO-patisiran (ten [7%] of 137) and phase 2 OLE patisiran (0 of 25) groups. INTERPRETATION: In this interim 12-month analysis of the ongoing global OLE study, patisiran appeared to maintain efficacy with an acceptable safety profile in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy. Continued long-term follow-up will be important for the overall assessment of safety and efficacy with patisiran. FUNDING: Alnylam Pharmaceuticals.

Ventricular tachycardia reveals cardiac infiltration due to mediastinal lymphoma.

A 61-year-old man was referred to us for palpitations and ventricular tachycardia. After being treated by chemotherapy for a mediastinum lymphoplasmocytic lymphoma, a ventricular tachycardia (VT) occurred. It was well tolerated. Several imaging techniques showed that this VT was related to a tumoural infiltration of the anterior part of the right ventricle by the lymphoma. Ventricular arrhythmias were controlled under antiarrhythmic drugs and chemotherapy was continued, with close cardiac follow-up. Complete remission was reached with restoration of a normal right ventricular function and resolution of the ventricular arrhythmias.

Sirolimus-eluting versus uncoated stents in acute myocardial infarction.

BACKGROUND: Sirolimus-eluting stents reduce rates of restenosis and reintervention, as compared with uncoated stents. Data are limited regarding the safety and efficacy of such stents in primary percutaneous coronary intervention (PCI) for acute myocardial infarction with ST-segment elevation. METHODS: We performed a single-blind, multicenter, prospectively randomized trial to compare sirolimus-eluting stents with uncoated stents in primary PCI for acute myocardial infarction with ST-segment elevation. The trial included 712 patients at 48 medical centers. The primary end point was target-vessel failure at 1 year after the procedure, defined as target-vessel-related death, recurrent myocardial infarction, or target-vessel revascularization. A follow-up angiographic substudy was performed at 8 months among 174 patients from selected centers. RESULTS: The rate of the primary end point was significantly lower in the sirolimus-stent group than in the uncoated-stent group (7.3% vs. 14.3%, P=0.004). This reduction was driven by a decrease in the rate of target-vessel revascularization (5.6% and 13.4%, respectively; P<0.001). There was no significant difference between the two groups in the rate of death (2.3% and 2.2%, respectively; P=1.00), reinfarction (1.1% and 1.4%, respectively; P=1.00), or stent thrombosis (3.4% and 3.6%, respectively; P=1.00). The degree of neointimal proliferation, as assessed by the mean (+/-SD) in-stent late luminal loss, was significantly lower in the sirolimus-stent group (0.14+/-0.49 mm, vs. 0.83+/-0.52 mm in the uncoated stent group; P<0.001). CONCLUSIONS: Among selected patients with acute myocardial infarction, the use of sirolimus-eluting stents significantly reduced the rate of target-vessel revascularization at 1 year. (ClinicalTrials.gov number, NCT00232830 [ClinicalTrials.gov].).

Major ischaemic and bleeding risks following current drug-eluting stent implantation: Are there differences across current drug-eluting stent types in real life?

BACKGROUND: Current drug-eluting stents (c-DESs) reduce the occurrence of ischaemic events, but expose recipients to stent thrombosis and bleeding secondary to preventive antiplatelet therapy. To date, comparative data on the relative effectiveness and safety of the various c-DESs in real life are limited. AIM: To compare ischaemic and bleeding risks across the major c-DESs used in France. METHODS: French national health insurance reimbursement and hospitalization databases were used. Patients implanted with a c-DES in 2014 were followed for 1 year. The risks of ischaemic events (revascularization, myocardial infarction and/or stroke), major bleeding events and death were compared across six c-DESs (XIENCE®, PROMUS®, RESOLUTE®, BIOMATRIX®, NOBORI® and ORSIRO®), using multilevel Cox models adjusted for baseline individual and hospital characteristics. RESULTS: A total of 52,891 subjects were included: 34.4% with XIENCE®; 27.6% with PROMUS®; 24.0% with RESOLUTE®; 8.0% with BIOMATRIX®; 5.0% with NOBORI®; and 1.0% with ORSIRO®. Among them, 9378 had at least one event (ischaemic, 6064; major bleeding, 1968; death, 2411), resulting in an overall incidence rate of 19 per 100 person-years. In the multivariable analysis, the risk of ischaemic events, major bleeding events or death did not differ between the c-DESs overall (adjusted hazard ratios between 0.85 [95% confidence interval 0.68-1.07] and 1.04 [95% confidence interval 0.98-1.10] compared with XIENCE® used as the reference) and when each outcome was considered separately. CONCLUSIONS: In real life, major ischaemic and bleeding risks do not differ across the various c-DESs over the first year following implantation. Future studies are needed to assess comparative c-DES effectiveness and safety longer term.

Association of Patisiran, an RNA Interference Therapeutic, With Regional Left Ventricular Myocardial Strain in Hereditary Transthyretin Amyloidosis: The APOLLO Study.

Importance: Patients with cardiac amyloidosis demonstrate reduced myocardial strain with associated sparing of the cardiac apex. In the APOLLO randomized clinical trial, patisiran, an RNA interference therapeutic that inhibits transthyretin synthesis, improved left ventricular (LV) global longitudinal strain (LV GLS) compared with placebo in patients with hereditary transthyretin-mediated (hATTR) amyloidosis with polyneuropathy and evidence of cardiac involvement. Objective: To evaluate the treatment association of patisiran with regional LV myocardial strain in cardiac manifestation in hATTR amyloidosis. Design, Setting, and Participants: This exploratory analysis of APOLLO, a randomized, double-blind, placebo-controlled, phase 3, multicenter international clinical trial that was conducted from December 2013 to January 2016, included patients with hATTR amyloidosis with polyneuropathy who were randomized 2:1 to receive patisiran or placebo. The prespecified cardiac subpopulation (126 of 225 [56%]) comprised patients with a baseline LV wall thickness of 13 mm or more and no history of hypertension or aortic valve disease. This post hoc data analysis was performed between September 2018 and January 2019. Intervention: Placebo or patisiran, 0.3 mg/kg, via intravenous infusion once every 3 weeks for 18 months. Main Outcomes and Measures: The association of patisiran with LV regional longitudinal strain at 18 months. Results: Of the 126 patients included in the prespecified cardiac subpopulation, 36 patients (28.6%) received placebo (median [interquartile range] age, 62 [57-72] years) and 90 patients (71.4%) received patisiran (median [interquartile range] age, 60 [54-66] years); 98 (77.8%) were men, 28 (22.2%) were from North America, and 43 (34.1%) were from Western Europe. At baseline, LV GLS was impaired and regional longitudinal strains were lowest in the basal segments with apical sparing. There were no differences in regional longitudinal strains between the treatment groups at baseline. Patisiran improved the absolute GLS (least-squares mean [SE] difference, 1.4% [0.6%]; 95% CI, 0.3%-2.5%; P = .02) compared with placebo at 18 months, with the greatest differential increase observed in the basal region (overall least-squares mean [SE] difference, 2.1% [0.8%]; 95% CI, 0.6%-3.6%; P = .006) and no significant differences in the mid and apical regions among groups. Conclusions and Relevance: Patisiran prevented the deterioration of LV GLS over 18 months, driven primarily by attenuating disease progression in the basal region, suggesting that basal longitudinal strain may be a more sensitive marker of treatment associations with the cardiac manifestation in hATTR amyloidosis and that basal region may be influenced by disease-modifying therapies more than other ventricular regions. Trial Registration: ClinicalTrials.gov identifier: NCT01960348.

Early detection of right ventricular functional abnormalities in patients with complex right premature ventricular contractions.

BACKGROUND: Right ventricular (RV) premature contractions, although generally benign, may represent the first manifestation of arrhythmogenic RV cardiomyopathy. The diagnostic and prognostic value of RV functional abnormalities evidenced by equilibrium radionuclide angiocardiography (ERNA) with multiharmonic Fourier analysis has been validated in patients with severe RV arrhythmias suspected of being affected by arrhythmogenic RV cardiomyopathy. The aim of this study was to assess the prevalence of the same RV functional abnormalities in patients with frequent left bundle branch block pattern premature ventricular contractions (PVCs), without known heart disease, using ERNA as a screening tool. METHODS: The study included 377 consecutive patients (mean age: 40+/-15 years, males: 58%) presenting with complex PVCs. Cine mode and multiharmonic analysis were used to define global enlargement and areas of dyskinesia of both ventricles. Studies were classified as: normal, right and/or left ventricular abnormalities either localized or diffuse. RESULTS: ERNA was normal in 302 patients (80%) and evidenced RV functional abnormalities in 75 patients (20%). Patients with RV outflow tract PVCs (n=276) were affected to the same extent as patients with right or left axis PVCs. CONCLUSION: In a specific population with complex left bundle branch block pattern PVCs, RV functional abnormalities were detected by ERNA in 20% of patients. Consequently, ERNA may serve as a screening tool by selecting patients who may require a specific management.

Cause of death analysis and temporal trends in survival after liver transplantation for transthyretin familial amyloid polyneuropathy.

BACKGROUND: Hereditary transthyretin amyloidosis (ATTR) is a multisystemic disease involving mainly the peripheral nervous system and the heart. Liver transplantation (LT) is the reference treatment for ATTR neuropathy and preoperative detection of high risk patients is crucial. We aimed to document the causes of death of ATTR patients after LT, their temporal trends, and to evaluate whether the available preoperative tools that predict the risk of death after LT for hereditary ATTR amyloidosis matched with these trends. METHODS: A retrospective longitudinal cohort study was performed on 215 consecutive ATTR patients who underwent LT between January 1993 and January 2011. Each patient's death cause and timing were classified. RESULTS: Over a median follow up of 5.9 years, 84 patients died. The rate of death was higher in the first year following LT than thereafter (13.0 vs. 4.3 ± 1.8%/year; p = .004). Cardiac events ranked as the leading cause of death (C: 38%), followed by infections (I: 24%), graft complications (G: 17%), end stage amyloidosis, stroke and others (ASO: 7% each). Deaths due to graft complications and infections (GI) occurred earlier than those due to end stage amyloidosis and stroke. Death prediction was less accurate for GI-related mortality than for other causes, which blunted the accuracy of the early-term risk prediction scores. Conclusions In ATTR amyloidosis, cardiac events were the leading cause of death after liver transplantation. Close preoperative evaluation allowed for accurate mid-term prediction of mortality, but the high rate of graft complications and infections blunted the early-term risk prediction.

Impact of liver transplantation on cardiac autonomic denervation in familial amyloid polyneuropathy.

Familial amyloid polyneuropathy (FAP) is a rare and severe hereditary form of amyloidosis, due to the deposition of a genetic variant transthyretin essentially produced by the liver, and characterized by both sensorimotor and autonomic neuropathy. Liver transplantation (LT) is the most effective treatment to stop the progression of the disease. Cardiac amyloid infiltration is usually associated with cardiac denervation, restrictive cardiomyopathy, conduction disturbances, and sometimes sudden death. Whether the cardiac involvement related to amyloid deposition may be altered after LT remains unclear. We conducted the present study to define the outcome of cardiac involvement after LT in 31 patients with FAP (age, 39 +/- 12 yr). Patients were evaluated before and after LT (24 +/- 15 mo). Cardiac sympathetic denervation was assessed by both iodine-123 metaiodobenzylguanidine (MIBG) scintigraphy and heart rate variability (HRV) analysis. The scintigraphic importance of sympathetic denervation was evaluated globally on planar imaging using heart-to-mediastinum activity ratio (H/M) measured 4 hours after injection, and regionally using single-photon emission tomography (SPET) imaging. Amyloid myocardial infiltration was assessed by echocardiography. Diffuse sympathetic denervation was found when using cardiac MIBG planar imaging in patients evaluated before LT and compared with 12 control subjects (H/M: 1.45 +/- 0.29 vs. 1.98 +/- 0.35, p < 0.001). On SPET images, defects were diffuse in 12 patients and focal in 19 patients, with predominance at the inferior and apical segments. No change in sympathetic innervation was found in patients after LT as assessed either with planar imaging (H/M after LT: 1.46 +/- 0.28, p = not significant vs. H/M before LT) or with SPET imaging. HRV nonspectral indexes showed that the standard deviation of all cycles was significantly lower in patients compared with control subjects, and remained unchanged after LT. Conduction disturbances and ventricular arrhythmias were associated with low cardiac MIBG uptake, and progressed after LT. The left ventricular wall was slightly thickened in patients, and a further increase was observed after LT (posterior wall from 9.2 +/- 1.8 to 10.1 +/- 2.3 mm, p = 0.02; septal wall from 10.6 +/- 2.7 to 12.1 +/- 4, p = 0.046). Neurologic status stabilized in 26 patients, but worsened in the 5 patients who had the most severe cardiac sympathetic denervation before LT as measured by MIBG imaging. The magnitude of the cardiac sympathetic denervation remained stable 2 years after LT in patients with FAP, whereas the cardiac amyloid infiltration progressed. The importance of cardiac sympathetic denervation found in FAP patients before LT was associated with a neurologic worsening after LT.

Myocardial Fractional Flow Reserve Measurement Using Contrast Media as a First-Line Assessment of Coronary Lesions in Current Practice.

BACKGROUND: Fractional flow reserve (FFR) measurement requires adenosine injection. However, adenosine can induce conductive and rhythmic complications, or be contraindicated in some patients. Contrast-induced hyperemia could provide a simple first-line method (contrast-enhanced FFR; cFFR) to assess coronary lesions. In this study we evaluated the accuracy of cFFR to predict lesion significance. METHODS: This prospective study included 104 patients with 138 coronary lesions. Each stenosis was evaluated using resting distal coronary pressure to aortic pressure ratio (Pd/Pa) measurements using intracoronary iodixanol (cFFR) and adenosine (FFR) injection. An FFR value ≤ 0.8 defined a significant lesion. RESULTS: Dose-ranging analysis (n = 12 lesions) showed that 10 mL iodixanol was required to obtain the lowest cFFR value. Intermeasurement reproducibility of cFFR (n = 18 lesions) showed limited variability and small mean estimated bias (0.001 ± 0.014). Values of cFFR and FFR were highly correlated in a first series of n = 36 lesions (r = 0.9; P < 0.001). Receiver-operating characteristic curve analysis showed an excellent accuracy of cFFR cutoff value of ≤ 0.85 in predicting FFR value ≤ 0.80 (area under the curve, 0.94; 95% confidence interval, 0.90-0.98; sensitivity, 95%; specificity, 73%). This threshold was then tested prospectively in an independent cohort of n = 72 lesions. A cFFR value ≤ 0.85 correctly identified hemodynamically significant lesions with a sensitivity of 100%, specificity of 78%, positive predictive value of 78%, and negative predictive value of 100%. CONCLUSIONS: cFFR is reproducible and can be achieved with usual volumes of contrast. A cFFR threshold value of 0.85 provides excellent sensitivity and negative predictive value in coronary artery stenosis.

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

OBJECTIVES: This study sought to compare techniques evaluating cardiac dysautonomia and predicting the risk of death of patients with hereditary transthyretin amyloidosis (mATTR) after liver transplantation (LT). BACKGROUND: mATTR is a multisystemic disease involving mainly the heart and the peripheral nervous system. LT is the reference treatment, and pre-operative detection of high-risk patients is critical. Cardiovascular dysautonomia is commonly encountered in ATTR and may affect patient outcome, although it is not known yet which technique should be used in the field to evaluate it. METHODS: In a series of 215 consecutive mATTR patients who underwent LT, cardiac dysautonomia was assessed by a dedicated clinical score, time-domain heart rate variability, 123-meta-iodobenzylguanidine heart/mediastinum (123-MIBG H/M) ratio on scintigraphy, and heart rate response to atropine (HRRA). RESULTS: Patient median age was 43 years, 62% were male and 69% carried the Val30Met mutation. Cardiac dysautonomia was documented by at least 1 technique for all patients but 6 (97%). In univariate analysis, clinical score, 123-MIBG H/M ratio and HRRA were associated with mortality but not heart rate variability. The 123-MIBG H/M ratio and HRRA had greater area under the curve (AUC) of receiver-operating characteristic curves than clinical score and heart rate variability (AUC: 0.787, 0.748, 0.656, and 0.523, respectively). Multivariate score models were then built using the following variables: New York Heart Association functional class, interventricular septum thickness, and either 123-MIBG H/M ratio (SMIBG) or HRRA (Satropine). AUC of SMIBG and Satropine were greater than AUC of univariate models, although nonsignificantly (AUC: 0.798 and 0.799, respectively). Predictive powers of SMIBG, Satropine, and a reference clinical model (AUC: 0.785) were similar. CONCLUSIONS: Evaluation of cardiac dysautonomia is a valuable addition for predicting survival of mATTR patients following LT. Among the different techniques that evaluate cardiac dysautonomia, 123-MIBG scintigraphy and heart rate response to atropine had better prognostic accuracy. Multivariate models did not improve significantly prediction of outcome.

The Multi-center Evaluation of the Accuracy of the Contrast MEdium INduced Pd/Pa RaTiO in Predicting FFR (MEMENTO-FFR) Study.

AIMS: Adenosine administration is needed for the achievement of maximal hyperaemia fractional flow reserve (FFR) assessment. The objective was to test the accuracy of Pd/Pa ratio registered during submaximal hyperaemia induced by non-ionic contrast medium (contrast FFR [cFFR]) in predicting FFR and comparing it to the performance of resting Pd/Pa in a collaborative registry of 926 patients enrolled in 10 hospitals from four European countries (Italy, Spain, France and Portugal). METHODS AND RESULTS: Resting Pd/Pa, cFFR and FFR were measured in 1,026 coronary stenoses functionally evaluated using commercially available pressure wires. cFFR was obtained after intracoronary injection of contrast medium, while FFR was measured after administration of adenosine. Resting Pd/Pa and cFFR were significantly higher than FFR (0.93±0.05 vs. 0.87±0.08 vs. 0.84±0.08, p<0.001). A strong correlation and a close agreement at Bland-Altman analysis between cFFR and FFR were observed (r=0.90, p<0.001 and 95% CI of disagreement: from -0.042 to 0.11). ROC curve analysis showed an excellent accuracy (89%) of the cFFR cut-off of ≤0.85 in predicting an FFR value ≤0.80 (AUC 0.95 [95% CI: 0.94-0.96]), significantly better than that observed using resting Pd/Pa (AUC: 0.90, 95% CI: 0.88-0.91; p<0.001). A cFFR/FFR hybrid approach showed a significantly lower number of lesions requiring adenosine than a resting Pd/Pa/FFR hybrid approach (22% vs. 44%, p<0.0001). CONCLUSIONS: cFFR is accurate in predicting the functional significance of coronary stenosis. This could allow limiting the use of adenosine to obtain FFR to a minority of stenoses with considerable savings of time and costs.

Incomplete resolution of ST-segment elevation is a marker of transient microcirculatory dysfunction after stenting for acute myocardial infarction.

BACKGROUND: Incomplete ST-segment resolution (STR) after successful primary angioplasty for acute myocardial infarction (AMI) is associated with a poor prognosis. We used intracoronary Doppler velocimetry to investigate whether incomplete STR after primary angioplasty is a marker of severe microcirculatory dysfunction. METHODS AND RESULTS: Fifty patients with < or =12-hour AMI underwent successful primary angioplasty and systematic stenting with a Doppler guidewire. Patients with incomplete (<50%) STR 60 minutes after TIMI 3 flow was restored had flow velocity features suggestive of severe microcirculatory dysfunction, including a higher incidence of early systolic retrograde flow (41% versus 9%, P=0.007) and lower coronary flow velocity reserve (CVR, 1.3 versus 1.6, P<0.001). CVR improved immediately after stenting in patients with > or =50% STR but not in patients with <50% STR. There was a significant correlation between STR and poststent CVR. At 3 months, CVR was similar in patients with <50% and > or =50% STR. However, left ventriculography indicated lower global (42% versus 55%, P=0.001) and regional (16% versus 20%, P=0.03) left ventricular ejection fractions and 201Tl rest-redistribution scintigraphy indicated a larger infarct size (34% versus 16% 201Tl defect, P=0.007) in patients with <50% STR. CONCLUSIONS: After successful primary angioplasty with systematic stenting, <50% STR is a marker of severe albeit transient microcirculatory dysfunction in patients with AMI and is associated with more extensive myocardial damage.