Progression of myocardial sympathetic denervation assessed by 123I-MIBG imaging in familial amyloid polyneuropathy and the effect of liver transplantation | Revista Portuguesa de Cardiologia (English edition)

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liver transplantation" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "333" "paginaFinal" => "340" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Maria da Conceição Azevedo Coutinho, Nuno Cortez-Dias, Guilhermina Cantinho, Isabel Conceição, Tatiana Guimarães, Gustavo Lima da Silva, Miguel Nobre Menezes, Ana Rita Francisco, Rui Plácido, Fausto J. 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"apellidos" => "Pinto" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] ] "afiliaciones" => array:3 [ 0 => array:3 [ "entidad" => "Serviço de Cardiologia, Hospital Universitário de Santa Maria, Centro Cardiovascular da Universidade de Lisboa, Centro Académico de Medicina de Lisboa, Lisboa, Portugal" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Instituto de Medicina Nuclear, Faculdade de Medicina, Universidade de Lisboa, Portugal" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Departamento de Neurociências, Hospital Universitário de Santa Maria, Lisboa, Portugal" "etiqueta" => "c" "identificador" => "aff0015" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "pt" => array:1 [ "titulo" => "Progressão da desnervação simpática cardíaca avaliada por cintigrafia com MIBG-I123 na polineuropatia amiloidótica familiar e o impacto da transplantação hepática" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 940 "Ancho" => 2924 "Tamanyo" => 119811 ] ] "descripcion" => array:1 [ "en" => "Changes in late H/M ratio over time in two patients with TTR-V30 M familial amyloid polyneuropathy, showing reduction in the ratio with disease progression and apparent stabilization after liver transplantation. H/M: heart-to-mediastinum." ] ] ] "textoCompleto" => "IntroductionFamilial amyloid polyneuropathy (FAP) due to a mutation in the transthyretin (TTR) protein, in which most frequently valine is replaced by methionine in position 30 (TTR-V30 M), is a multisystem hereditary disease characterized by progressive involvement of sensory, motor and autonomic nerve fibers.<a class="elsevierStyleCrossRefs" href="#bib0125">1,2</a> Neurological manifestations are the main clinical feature, but cardiovascular involvement due to autonomic neuropathy and cardiac amyloid deposition is also common.<a class="elsevierStyleCrossRef" href="#bib0135">3</a>Myocardial scintigraphy with iodine-123 labeled metaiodobenzylguanidine (123I-MIBG) is a non-invasive method for quantifying cardiac sympathetic innervation. Previous studies have demonstrated that myocardial sympathetic innervation as detected by 123I-MIBG is decreased in the initial stages of FAP<a class="elsevierStyleCrossRefs" href="#bib0140">4,5</a> and that reduction in the late heart-to-mediastinum (H/M) ratio is an important predictor of prognosis that is strongly associated with long-term risk of mortality.<a class="elsevierStyleCrossRef" href="#bib0150">6</a> However, the progression of cardiac denervation during the clinical course of TTR-V30 M FAP has never been assessed by serial 123I-MIBG scans, and the added value of repeated measurement of late H/M for prognostic stratification is unknown.Liver transplantation is widely used to slow the progression of FAP and until recently was the only treatment option for these patients.<a class="elsevierStyleCrossRef" href="#bib0155">7</a> Transplantation halts neurological involvement and improves survival, especially if performed early in the symptomatic stages of the disease.<a class="elsevierStyleCrossRef" href="#bib0150">6</a> However, amyloid deposition in the heart may continue after transplantation, leading to progressive myocardial thickening, arrhythmias and conduction disturbances.<a class="elsevierStyleCrossRefs" href="#bib0160">8–13</a> Little is known of the course of cardiac denervation following liver transplantation.The aim of this study was to assess the effect of liver transplantation on the progression of cardiac denervation in patients with TTR-V30 M FAP.MethodsThis was a prospective observational study of consecutive patients with the TTR-V30 M mutation. All subjects underwent annual cardiac assessment and periodic measurement of the late H/M ratio. Progression of cardiac denervation was determined by comparing the H/M ratio in successive exams.123I-MIBG scintigraphy was performed following premedication with Lugol's solution (iodine-potassium iodide) to block absorption of free 123I by the thyroid gland. Chronic medication was not suspended before the exam. Planar anterior thoracic images were acquired 15 min (early) and 3 h (late) after intravenous injection of a fixed dose of 185 MBq of 123I-MIBG. A dual-head gamma camera (Millennium, General Electric Healthcare) equipped with a low-energy, high-resolution parallel-hole collimator was used for image acquisition and a 20% energy window was centered over the 159keV photopeak of 123I.123I-MIBG uptake was quantified through the H/M ratio, which was calculated by dividing the mean counts per pixel in the region of interest around the heart by the mean counts per pixel in the mediastinum, without correction for background activity. The myocardial washout rate was calculated as the percentage reduction of myocardial counts between early and late images:<elsevierMultimedia ident="eq0005"></elsevierMultimedia>Statistical analysisContinuous variables with normal distribution were expressed as means±standard deviation and were compared using the Student's t test or analysis of variance, and those with non-normal distribution were expressed as medians and interquartile range (IQR) and compared with the Mann-Whitney or Kruskal-Wallis tests. Scintigraphic parameters were correlated with age, duration of symptoms and time before and after liver transplantation, using Pearson's and Spearman's correlation coefficients.The prognostic impact of scintigraphic parameters on all-cause mortality during follow-up was determined by Cox univariate and multivariate regression analysis adjusted for age. To avoid bias, stepwise methods were used for the multivariate analysis, with non-significant variables being removed from the model at each step (p-value 0.05 for inclusion and 0.10 for removal). The accuracy of predictors of mortality was assessed by the area under the curve (AUC) on receiver operating characteristic analysis for different durations of follow-up. Cumulative event rates by quartiles of H/M ratio were assessed by the Kaplan-Meier method and the log-rank test.The statistical analysis was performed with SPSS version 21.0 (IBM SPSS, Chicago, IL). A p-value <0.05 was considered statistically significant.ResultsPopulation characteristicsBetween September 1998 and July 2015, 305 carriers of the TTR-V30 M mutation underwent annual cardiac assessment. A total of 73 patients were excluded from the analysis: 45 for not having undergone MIBG imaging and 28 because their first MIBG scan was performed after liver transplantation. The final study population thus consisted of 232 patients, median age 40 years (IQR 32-55), 54.7% female (n=127).At the initial cardiac assessment, 144 patients (62.1%) had documented neurological involvement, the other 88 (37.9%) being asymptomatic. Of the symptomatic patients, 99 had developed clinical manifestations by the age of 50, while the other 45 had late onset (after the age of 50). The mean age of symptom onset was 38 years (IQR 31-54) and the mean duration of symptoms at initial assessment was two years (IQR 0-3). Nineteen carriers of the pathogenic mutation aged over 50 were still symptom-free.123I-MIBG scintigraphyAt the initial assessment, the mean early and late H/M ratios were 1.85±0.23 and 1.83±0.03, respectively, and median washout rate was 2.5 (IQR -2.3 to 8.5). Early and late H/M ratios were significantly lower and the washout rate was significantly higher in symptomatic patients (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>During a median follow-up of 4.5 years (IQR 2.1-7.7; maximum 15.6), 121 patients underwent serial MIBG imaging, of whom 36 underwent at least five exams (maximum nine) (<a class="elsevierStyleCrossRef" href="#sec0080">Supplementary Table 1</a>). Including both initial and subsequent assessments, a total of 558 MIBG scans were performed. In these exams, the late H/M ratio decreased with age (by 0.082/year, p<0.001) and with duration of symptoms (by 0.066/year, p<0.001) (<a class="elsevierStyleCrossRef" href="#fig0005">Figure 1</a> and <a class="elsevierStyleCrossRef" href="#sec0080">Supplementary Table 2</a>), to a similar degree in both sexes (<a class="elsevierStyleCrossRef" href="#sec0080">Supplementary Figure 1</a>). <a class="elsevierStyleCrossRef" href="#fig0010">Figure 2</a> presents the progression of late H/M in serial MIBG scans of two typical patients, illustrating the slow reduction in the presymptomatic stage of the disease, the more marked decline after symptom onset, and the apparent stabilization after liver transplantation.<elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia>Prognostic stratificationDuring follow-up, 47 patients (20.3%) died. The most frequent cause of death (40%) was terminal FAP (<a class="elsevierStyleCrossRef" href="#sec0080">Supplementary Table 3</a>). MIBG scintigraphy at inclusion was a strong predictor of prognosis, with the risk of death increasing by 27.8% (95% confidence interval [CI] 17.5-39.1) for each one-tenth reduction in the late H/M ratio (hazard ratio [HR] 0.78; 95% CI 0.72-0.85; p<0.001). Of the MIBG parameters, only late H/M was an independent prognostic predictor (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>). Mortality was nine times higher in patients with lower H/M (first quartile, <1.55) at inclusion than in those with H/M above the median for the study population (≥1.83; HR 9.36; 95% CI 4.27-20.56; p<0.001). Mortality was also four times higher in patients with moderate reductions (1.55-1.83) in late H/M (HR 4.27; 95% CI 1.68-9.05; p=0.002) (<a class="elsevierStyleCrossRef" href="#fig0015">Figure 3</a>A).<elsevierMultimedia ident="tbl0010"></elsevierMultimedia><elsevierMultimedia ident="fig0015"></elsevierMultimedia>To determine the potential added value of serial late H/M assessment for prognostic stratification, we assessed the accuracy of all the MIBG scans (558 scans, 2246 patient-years of follow-up) for predicting post-exam survival, which was found to be significantly reduced with lower late H/M ratio. The risk of death increased by 27.8% for every one-tenth reduction in the late H/M ratio (HR 0.774; 95% CI 0.73-0.82; p<0.001), and was nine times higher in patients in the first H/M quartile (HR 9.15; 95% CI 5.44-15.38; p<0.001) (<a class="elsevierStyleCrossRef" href="#fig0015">Figure 3</a>B).The accuracy of prediction based on serial exams was assessed by the area under the curve (AUC) on receiver operating characteristic analysis for different time intervals and compared with prognostic stratification based only on the initial MIBG scan (<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>). Prognostic stratification based on annual repetition of MIBG imaging was slightly superior, but the differences were trivial for time intervals less than the median follow-up (4.5 years). The statistical power of prognostic stratification based on a single exam and on serial exams was similar, and very high (99%).<elsevierMultimedia ident="tbl0015"></elsevierMultimedia>Effect of liver transplantation on progression of myocardial sympathetic denervation assessed by 123I-MIBG scintigraphySeventy patients (30.2%) underwent liver transplantation. In 39 of these patients surgery was performed less than one year after initial assessment. Perioperative mortality was 7.1% (5/70). The effect of transplantation on progression of sympathetic denervation was determined by comparing reductions in the late H/M ratio in images before (116 exams) and after (100 exams) transplantation. Of the former, 53 were performed less than a year before surgery.In symptomatic patients requiring transplantation, late H/M decreased by 0.19/year (p<0.001) until transplantation; early H/M also decreased progressively and the MIBG washout rate increased. By contrast, all scintigraphic parameters stabilized after transplantation and no statistically significant differences were detected over time (<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a> and <a class="elsevierStyleCrossRef" href="#fig0020">Figure 4</a>).<elsevierMultimedia ident="tbl0020"></elsevierMultimedia><elsevierMultimedia ident="fig0020"></elsevierMultimedia>DiscussionIn this large prospective study of carriers of the TTR-V30 M mutation followed for a median of 4.5 years, we analyzed the progression of cardiac sympathetic denervation as assessed by the H/M MIBG uptake ratio, the prognostic value of this index for long-term survival, and the effect of liver transplantation. The main results are as follows: (1) cardiac denervation progresses slowly in the pre-symptomatic stages of the disease but tends to accelerate after symptom onset; (2) MIBG scintigraphy at inclusion is a strong predictor of prognosis, with the risk of death increasing by 27.8% for each one-tenth reduction in the late H/M ratio; and (3) liver transplantation stabilizes cardiac denervation in long-term follow-up.The cardiovascular manifestations of TTR-V30 M FAP are caused by autonomic dysfunction (disrupted control of blood pressure and heart rate) and by cardiac amyloid deposition (infiltrative cardiomyopathy, arrhythmias and conduction disturbances). However, phenotypic differences are seen in TTR-V30 M carriers according to geographic origin: cohort studies of Swedish patients report a high prevalence of restrictive cardiomyopathy,<a class="elsevierStyleCrossRefs" href="#bib0135">3,14</a> which is rare in Portugal, where cardiac autonomic neuropathy and conduction disturbances tend to dominate the clinical picture.<a class="elsevierStyleCrossRef" href="#bib0150">6</a>Previous studies have shown that MIBG scintigraphy is an indirect way to visualize the impairment of cardiac sympathetic innervation by amyloid deposition. Nakata et al.<a class="elsevierStyleCrossRef" href="#bib0195">15</a> were the first to report a case of a patient with TTR-V30 M FAP with no myocardial activity on MIBG imaging, indicating involvement of the sympathetic nerves. Subsequent small studies demonstrated not only that myocardial denervation was strongly correlated with severity of polyneuropathy<a class="elsevierStyleCrossRef" href="#bib0200">16</a> but also that MIBG uptake may be reduced before the onset of clinically apparent cardiac disease.<a class="elsevierStyleCrossRef" href="#bib0145">5</a> In a previous study of 143 individuals, we showed that cardiovascular abnormalities as assessed by electrocardiography, Holter monitoring, ambulatory blood pressure monitoring, echocardiography and MIBG scintigraphy are common in TTR-V30 M FAP, particularly in patients with neurological involvement.<a class="elsevierStyleCrossRef" href="#bib0150">6</a> Unlike other forms of systemic amyloidosis, the cardiovascular involvement in our study was mostly subclinical and obvious cardiac manifestations were rare. However, we did find that subclinical cardiovascular manifestations often preceded neurological involvement, which offers the possibility of earlier recognition of the onset of disease in asymptomatic carriers. We also demonstrated the prognostic value of MIBG imaging, which was in fact the strongest prognostic predictor of all the cardiac and neurological parameters assessed: patients with late H/M of less than 1.60 had a seven-fold higher risk of death during follow-up.The present study confirms previous findings in a larger population and broadens the results to include serial H/M assessments. As expected, late H/M decreased significantly over time, but progression of cardiac denervation was so slow that annual repetition of MIBG imaging did not increase its accuracy in predicting all-cause death. Our results therefore suggest that repeated assessment of the H/M ratio is not justified for the purposes of prognostic stratification, at least not more often than at intervals of less than five years (the median duration of follow-up in the present study).Liver transplantation has been widely used for the last twenty years to remove the main source of mutant transthyretin, in order to slow the progression of clinical manifestations, including peripheral neuropathy, gastrointestinal symptoms and other visceral complications.<a class="elsevierStyleCrossRefs" href="#bib0155">7,17–20</a> Transplantation also improves long-term survival, especially when performed in the early stages of symptomatic disease.<a class="elsevierStyleCrossRefs" href="#bib0150">6,21</a> However, the effect of liver transplantation on the progression of cardiomyopathy in TTR-V30 M FAP is the subject of debate, with some studies suggesting that transplanted patients do not develop overt cardiomyopathy,<a class="elsevierStyleCrossRefs" href="#bib0230">22,23</a> while others – in Swedish,<a class="elsevierStyleCrossRefs" href="#bib0170">10,13</a> French<a class="elsevierStyleCrossRef" href="#bib0180">12</a> and Japanese<a class="elsevierStyleCrossRef" href="#bib0165">9</a> patients – report progression of arrhythmias and myocardial thickening due to amyloid deposition. This adverse outcome appears to be more frequent in Swedish patients with late-onset TTR-V30 M FAP.<a class="elsevierStyleCrossRefs" href="#bib0135">3,10,13</a>It has been suggested that the main component of cardiac amyloid deposits following liver transplantation is normal (wild-type) transthyretin.<a class="elsevierStyleCrossRef" href="#bib0240">24</a> Nevertheless, none of the studies that monitored the progression of amyloid infiltration by echocardiography following liver transplantation assessed its effect on cardiac autonomic denervation. In a small group of 31 French patients, Delahaye et al.<a class="elsevierStyleCrossRef" href="#bib0180">12</a> compared the H/M ratio before and after liver transplantation, complemented with echocardiography; as in our study, no change was seen in sympathetic innervation following transplantation in a short follow-up (24±15 months), even though cardiac amyloid infiltration, as measured by myocardial thickness, had progressed. In the present study, of a larger group (70) of transplanted patients, the rate of decrease in H/M was assessed by comparing MIBG scintigraphy before (116 exams) and after (100 exams) transplantation. Of note, all scintigraphic parameters stabilized after surgery. There thus appears to be a distinction between amyloid deposition as assessed by myocardial thickness on echocardiography, which may progress after transplantation, and autonomic nerve involvement, which tends to stabilize.ConclusionsCardiac denervation is common during the progression of TTR-V30 M FAP and quantification of the late H/M ratio on MIBG scintigraphy is valuable for prognostic stratification of these patients. Liver transplantation stabilizes cardiac denervation. Following transplantation, cardiac 123I-MIBG uptake remains stable over time, with no further recovery or deterioration. It is thus essential to perform transplantation sufficiently early in the natural history of the disease.Ethical disclosuresProtection of human and animal subjectsThe authors declare that the procedures followed were in accordance with the regulations of the relevant clinical research ethics committee and with those of the Code of Ethics of the World Medical Association (Declaration of Helsinki).Confidentiality of dataThe authors declare that they have followed the protocols of their work center on the publication of patient data.Right to privacy and informed consentThe authors declare that no patient data appear in this article.Conflicts of interestThe authors have no conflicts of interest to declare." "textoCompletoSecciones" => array:1 [ "secciones" => array:12 [ 0 => array:3 [ "identificador" => "xres851848" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec846457" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres851849" "titulo" => "Resumo" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Fundamentação" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusão" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec846458" "titulo" => "Palavras-chave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Methods" "secciones" => array:1 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Statistical analysis" ] ] ] 6 => array:3 [ "identificador" => "sec0020" "titulo" => "Results" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0025" "titulo" => "Population characteristics" ] 1 => array:2 [ "identificador" => "sec0030" "titulo" => "I-MIBG scintigraphy" ] 2 => array:2 [ "identificador" => "sec0035" "titulo" => "Prognostic stratification" ] 3 => array:2 [ "identificador" => "sec0040" "titulo" => "Effect of liver transplantation on progression of myocardial sympathetic denervation assessed by I-MIBG scintigraphy" ] ] ] 7 => array:2 [ "identificador" => "sec0045" "titulo" => "Discussion" ] 8 => array:2 [ "identificador" => "sec0050" "titulo" => "Conclusions" ] 9 => array:3 [ "identificador" => "sec0055" "titulo" => "Ethical disclosures" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0060" "titulo" => "Protection of human and animal subjects" ] 1 => array:2 [ "identificador" => "sec0065" "titulo" => "Confidentiality of data" ] 2 => array:2 [ "identificador" => "sec0070" "titulo" => "Right to privacy and informed consent" ] ] ] 10 => array:2 [ "identificador" => "sec0075" "titulo" => "Conflicts of interest" ] 11 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2016-06-18" "fechaAceptado" => "2016-08-11" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec846457" "palabras" => array:3 [ 0 => "Amyloid" 1 => "Scintigraphy" 2 => "Liver transplantation" ] ] ] "pt" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palavras-chave" "identificador" => "xpalclavsec846458" "palabras" => array:3 [ 0 => "Amiloide" 1 => "Cintigrafia" 2 => "Transplante hepático" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "IntroductionFamilial amyloid polyneuropathy (FAP) is a rare disease caused by systemic deposition of amyloidogenic variants of the transthyretin (TTR) protein. The TTR-V30M mutation is caused by the substitution of valine by methionine at position 30 and mainly affects the peripheral and autonomic nervous systems. Cardiovascular manifestations are common and are due to autonomic denervation and to amyloid deposition in the heart. Cardiac sympathetic denervation detected by iodine-123 labeled metaiodobenzylguanidine (MIBG) is an important prognostic marker in TTR-V30 M FAP. Liver transplantation, widely used to halt neurological involvement, appears to have a varying effect on the progression of amyloid cardiomyopathy. Its effect on the progression of cardiac denervation remains unknown. MethodsIn this observational study, patients with the TTR-V30 M mutation underwent annual cardiac assessment and serial MIBG imaging with quantification of the late heart-to-mediastinum (H/M) ratio. ResultsWe studied 232 patients (median age 40 years, 54.7% female, 37.9% asymptomatic at the time of inclusion) who were followed for a median of 4.5 years and underwent a total of 558 MIBG scans. During follow-up, 47 patients (20.3%) died. MIBG scintigraphy at inclusion was a strong predictor of prognosis, with the risk of death increasing by 27.8% for each one-tenth reduction in the late H/M ratio. The late H/M ratio decreased with age (0.082/year, p<0.001), but progression of cardiac denervation was so slow that annual repetition of MIBG imaging did not increase its prognostic accuracy. During follow-up, 70 symptomatic patients underwent liver transplantation. The late H/M ratio decreased by 0.19/year until transplantation but no statistically significant differences were detected after the procedure. ConclusionsCardiac denervation is common during the progression of TTR-V30 M FAP and quantification of the late H/M ratio on MIBG scintigraphy is valuable for prognostic stratification of these patients. Liver transplantation stabilizes cardiac denervation, without recovery or further deterioration in cardiac MIBG uptake after the procedure." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] "pt" => array:3 [ "titulo" => "Resumo" "resumen" => "FundamentaçãoA polineuropatia amiloidótica familiar (PAF) é uma doença rara devida à deposição sistémica de variantes amiloidogénicas da proteína transtirretina (TTR-V30M), atingindo especialmente o sistema nervoso periférico. As manifestações cardiovasculares são muito comuns e devem-se à desnervação autonómica e à deposição de amiloide no coração. A desnervação simpática cardíaca, detetada por cintigrafia com metaiodobenzilguanidina (MIBG) marcada com I123, é um importante estratificador prognóstico na PAF TTR-V30M. O transplante hepático, amplamente utilizado para interromper a progressão do envolvimento neurológico, parece ter impacto heterogéneo na evolução da miocardiopatia amiloidótica. O seu impacto na progressão da desnervação cardíaca permanece desconhecido. MétodosEstudo observacional de portadores da mutação TTR-V30M submetidos a avaliação cardiológica anual e a cintigrafias com MIBG seriadas, com quantificação do índice de captação coração/mediastino (C/M) tardio. ResultadosForam estudados 232 doentes (idade mediana de 40 anos, 54,7% do sexo feminino, 37,9% assintomáticos aquando da inclusão), seguidos durante uma mediana de 4,5 anos e submetidos a um total de 558 cintigrafias MIBG. Durante o seguimento, 47 doentes (20,3%) morreram. A cintigrafia com MIBG inicial foi um forte preditor prognóstico, detetando-se aumento do risco de morte em 27,8% por cada redução decimal do índice C/M tardio. O índice C/M tardio diminuiu com a idade (0,082 por ano; p<0,001), mas a progressão da desnervação cardíaca foi tão lenta que a repetição anual do exame não aumentou a sua precisão prognóstica. Durante o seguimento, 70 doentes sintomáticos foram submetidos a transplante hepático. O índice C/M tardio diminuiu 0,19/ano até ao transplante, deixando de ser detetadas variações estatisticamente significativas a partir do procedimento. ConclusãoA desnervação cardíaca é frequente durante a progressão da PAF TTR-V30M e a quantificação do índice C/M tardio por cintigrafia MIBG é valiosa para a estratificação prognóstica destes doentes. O transplante hepático permite a estabilização da desnervação cardíaca, não havendo recuperação ou deterioração adicional da captação cardíaca de MIBG após o procedimento." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Fundamentação" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusão" ] ] ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Azevedo Coutinho MdC, Cortez-Dias N, Cantinho G, Conceição I, Guimarães T, Lima da Silva G, et al. Progressão da desnervação simpática cardíaca avaliada por cintigrafia com MIBG-I123 na polineuropatia amiloidótica familiar e o impacto da transplantação hepática. Rev Port Cardiol. 2017;36:333–340." ] ] "apendice" => array:1 [ 0 => array:1 [ "seccion" => array:1 [ 0 => array:4 [ "apendice" => "<elsevierMultimedia ident="upi0005"></elsevierMultimedia>" "etiqueta" => "Appendix A" "titulo" => "Supplementary Material" "identificador" => "sec0085" ] ] ] ] "multimedia" => array:10 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1435 "Ancho" => 3084 "Tamanyo" => 267863 ] ] "descripcion" => array:1 [ "en" => "Changes in late H/M ratio by age (A) and duration of symptoms (B). H/M: heart-to-mediastinum." ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 940 "Ancho" => 2924 "Tamanyo" => 119811 ] ] "descripcion" => array:1 [ "en" => "Changes in late H/M ratio over time in two patients with TTR-V30 M familial amyloid polyneuropathy, showing reduction in the ratio with disease progression and apparent stabilization after liver transplantation. H/M: heart-to-mediastinum." ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1718 "Ancho" => 3111 "Tamanyo" => 288400 ] ] "descripcion" => array:1 [ "en" => "Survival by quartiles of H/M ratio assessed by first scintigraphic scan (A) and all scans performed during follow-up (B). CI: confidence interval; H/M: heart-to-mediastinum; HR: hazard ratio." ] ] 3 => array:7 [ "identificador" => "fig0020" "etiqueta" => "Figure 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 1422 "Ancho" => 1595 "Tamanyo" => 171452 ] ] "descripcion" => array:1 [ "en" => "Changes in late H/M over time before and after liver transplantation. H/M: heart-to-mediastinum." ] ] 4 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "H/M: heart-to-mediastinum ratio; IQR: interquartile range." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Symptomatic (n=144) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Asymptomatic (n=88) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">p \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Early H/M \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1.75±0.33 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2.03±0.28 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><0.001 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Late H/M \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1.70±0.37 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2.09±0.31 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><0.001 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Washout rate \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3.98 (IQR 0.0 to 10.0) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0 (IQR -6.26 to 4.66) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><0.001 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1438162.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Comparison of scintigraphic parameters according to neurological involvement." ] ] 5 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "CI: confidence interval; H/M: heart-to-mediastinum ratio; HR: hazard ratio; IQR: interquartile range; NS: non-significant." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td-with-role" title="table-head ; entry_with_role_rowhead " align="left" valign="top" scope="col">Variable \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col">Survival (n=185, 79.7%) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col">All-cause death (n=47, 20.3%) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col">p \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " colspan="3" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Univariate Cox regression</th><th class="td" title="table-head " colspan="3" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Multivariate Cox regression</th></tr><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">HR \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">95% CI \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">p \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">HR \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">95% CI \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">p \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Median age, years (IQR) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">37 (31-49) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">59 (42-69) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><0.001 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1.067 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1.046-1.089 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><0.001 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1.052 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1.046-1.089 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><0.001 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Early H/M \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1.91±0.33 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1.62±0.33 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><0.001 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.085 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.035-0.206 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><0.001 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">- \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">- \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NS \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Late H/M \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1.90±0.37 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1.58±0.40 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><0.001 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.086 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.037-0.199 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><0.001 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.183 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.075-0.450 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><0.001 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Washout rate \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2.50 (-2.30-7.14) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3.85 (0.0-12.50) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NS (0.134) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1.037 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1.008-1.066 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.012 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">- \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">- \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NS \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1438163.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Mortality during follow-up by age and MIBG parameters at inclusion." ] ] 6 => array:8 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at3" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "AUC: area under the curve on receiver operating characteristic analysis. All other abbreviations as in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td-with-role" title="table-head ; entry_with_role_rowhead " align="left" valign="top" scope="col">Variable \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " colspan="5" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Late H/M assessment at inclusion (232 scans in 232 patients)</th><th class="td" title="table-head " colspan="5" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Serial late H/M assessments (558 scans in 232 patients)</th></tr><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Patient-years \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">No. of events \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">AUC \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">95% CI \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">p \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Patient-years \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">No. of events \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">AUC \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">95% CI \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">p \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">At any time \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1171.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">38 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.74 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.65-0.82 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><0.001 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2583.2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">68 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.73 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.67-0.80 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top"><0.001 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">12 months \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">109.1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.72 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.58-0.86 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NS (0.131) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">457.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.84 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.77-0.91 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.001 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">24 months \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">352.7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.83 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.75-0.92 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><0.001 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">806.8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">17 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.84 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.77-0.91 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top"><0.001 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">36 months \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">467.3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">15 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.77 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.69-0.87 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><0.001 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1097.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">27 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.79 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.71-0.86 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top"><0.001 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">48 months \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">534.4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">17 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.77 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.66-0.87 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><0.001 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1261.4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">33 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.79 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.72-0.87 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top"><0.001 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">60 months \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">553.8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">22 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.78 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.68-0.88 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><0.001 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1268.2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">38 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.79 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.72-0.86 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top"><0.001 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1438161.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Accuracy of initial and serial late H/M ratios in MIBG scans for predicting mortality assessed by receiver operating characteristic analysis." ] ] 7 => array:8 [ "identificador" => "tbl0020" "etiqueta" => "Table 4" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at4" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "Abbreviations as in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td-with-role" title="table-head ; entry_with_role_rowhead " align="left" valign="top" scope="col">Variable \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " colspan="4" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Before liver transplantation</th><th class="td" title="table-head " colspan="4" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">After liver transplantation</th></tr><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " colspan="2" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Pearson's correlation</th><th class="td" title="table-head " colspan="2" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Spearman's correlation</th><th class="td" title="table-head " colspan="2" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Pearson's correlation</th><th class="td" title="table-head " colspan="2" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Spearman's correlation</th></tr><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">R \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">p \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Rho \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">p \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">R \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">p \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Rho \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">p \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Early H/M \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">-0.322 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top"><0.001 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">-0.216 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.021 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.144 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NS (0.154) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.180 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NS (0.073) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Late H/M \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">-0.446 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top"><0.001 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">-0.339 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top"><0.001 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.160 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NS (0.113) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.179 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NS (0.074) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Washout rate \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.266 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.004 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.288 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.002 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">-0.037 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NS (0.713) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">-0.093 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NS (0.358) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1438164.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Correlations between scintigraphic parameters and time before and after liver transplantation." ] ] 8 => array:5 [ "identificador" => "upi0005" "tipo" => "MULTIMEDIAECOMPONENTE" "mostrarFloat" => false "mostrarDisplay" => true "Ecomponente" => array:2 [ "fichero" => "mmc1.docx" "ficheroTamanyo" => 2113260 ] ] 9 => array:5 [ "identificador" => "eq0005" "tipo" => "MULTIMEDIAFORMULA" "mostrarFloat" => false "mostrarDisplay" => true "Formula" => array:5 [ "Matematica" => "Washout rate=([early H/M−late H/M]/early H/M)×100" "Fichero" => "STRIPIN_si1.jpeg" "Tamanyo" => 3398 "Alto" => 14 "Ancho" => 381 ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:24 [ 0 => array:3 [ "identificador" => "bib0125" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A peculiar form of peripheral neuropathy" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "C. 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Original Article

Progression of myocardial sympathetic denervation assessed by 123I-MIBG imaging in familial amyloid polyneuropathy and the effect of liver transplantation

Progressão da desnervação simpática cardíaca avaliada por cintigrafia com MIBG-I123 na polineuropatia amiloidótica familiar e o impacto da transplantação hepática

Maria da Conceição Azevedo Coutinhoa,

Corresponding author

cacoutinho@sapo.pt

Corresponding author.

, Nuno Cortez-Diasa, Guilhermina Cantinhob, Isabel Conceiçãoc, Tatiana Guimarãesa, Gustavo Lima da Silvaa, Miguel Nobre Menezesa, Ana Rita Franciscoa, Rui Plácidoa, Fausto J. Pintoa

a Serviço de Cardiologia, Hospital Universitário de Santa Maria, Centro Cardiovascular da Universidade de Lisboa, Centro Académico de Medicina de Lisboa, Lisboa, Portugal

b Instituto de Medicina Nuclear, Faculdade de Medicina, Universidade de Lisboa, Portugal

c Departamento de Neurociências, Hospital Universitário de Santa Maria, Lisboa, Portugal

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          "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Changes in late H&#47;M ratio over time in two patients with TTR-V30 M familial amyloid polyneuropathy&#44; showing reduction in the ratio with disease progression and apparent stabilization after liver transplantation&#46; H&#47;M&#58; heart-to-mediastinum&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Familial amyloid polyneuropathy &#40;FAP&#41; due to a mutation in the transthyretin &#40;TTR&#41; protein&#44; in which most frequently valine is replaced by methionine in position 30 &#40;TTR-V30 M&#41;&#44; is a multisystem hereditary disease characterized by progressive involvement of sensory&#44; motor and autonomic nerve fibers&#46;<a class="elsevierStyleCrossRefs" href="#bib0125"><span class="elsevierStyleSup">1&#44;2</span></a> Neurological manifestations are the main clinical feature&#44; but cardiovascular involvement due to autonomic neuropathy and cardiac amyloid deposition is also common&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">3</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Myocardial scintigraphy with iodine-123 labeled metaiodobenzylguanidine &#40;<span class="elsevierStyleSup">123</span>I-MIBG&#41; is a non-invasive method for quantifying cardiac sympathetic innervation&#46; Previous studies have demonstrated that myocardial sympathetic innervation as detected by <span class="elsevierStyleSup">123</span>I-MIBG is decreased in the initial stages of FAP<a class="elsevierStyleCrossRefs" href="#bib0140"><span class="elsevierStyleSup">4&#44;5</span></a> and that reduction in the late heart-to-mediastinum &#40;H&#47;M&#41; ratio is an important predictor of prognosis that is strongly associated with long-term risk of mortality&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">6</span></a> However&#44; the progression of cardiac denervation during the clinical course of TTR-V30 M FAP has never been assessed by serial <span class="elsevierStyleSup">123</span>I-MIBG scans&#44; and the added value of repeated measurement of late H&#47;M for prognostic stratification is unknown&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">Liver transplantation is widely used to slow the progression of FAP and until recently was the only treatment option for these patients&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">7</span></a> Transplantation halts neurological involvement and improves survival&#44; especially if performed early in the symptomatic stages of the disease&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">6</span></a> However&#44; amyloid deposition in the heart may continue after transplantation&#44; leading to progressive myocardial thickening&#44; arrhythmias and conduction disturbances&#46;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">8&#8211;13</span></a> Little is known of the course of cardiac denervation following liver transplantation&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">The aim of this study was to assess the effect of liver transplantation on the progression of cardiac denervation in patients with TTR-V30 M FAP&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Methods</span><p id="par0025" class="elsevierStylePara elsevierViewall">This was a prospective observational study of consecutive patients with the TTR-V30 M mutation&#46; All subjects underwent annual cardiac assessment and periodic measurement of the late H&#47;M ratio&#46; Progression of cardiac denervation was determined by comparing the H&#47;M ratio in successive exams&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleSup">123</span>I-MIBG scintigraphy was performed following premedication with Lugol&#39;s solution &#40;iodine-potassium iodide&#41; to block absorption of free <span class="elsevierStyleSup">123</span>I by the thyroid gland&#46; Chronic medication was not suspended before the exam&#46; Planar anterior thoracic images were acquired 15 min &#40;early&#41; and 3 h &#40;late&#41; after intravenous injection of a fixed dose of 185 MBq of <span class="elsevierStyleSup">123</span>I-MIBG&#46; A dual-head gamma camera &#40;Millennium&#44; General Electric Healthcare&#41; equipped with a low-energy&#44; high-resolution parallel-hole collimator was used for image acquisition and a 20&#37; energy window was centered over the 159<span class="elsevierStyleHsp" style=""></span>keV photopeak of <span class="elsevierStyleSup">123</span>I&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleSup">123</span>I-MIBG uptake was quantified through the H&#47;M ratio&#44; which was calculated by dividing the mean counts per pixel in the region of interest around the heart by the mean counts per pixel in the mediastinum&#44; without correction for background activity&#46; The myocardial washout rate was calculated as the percentage reduction of myocardial counts between early and late images&#58;<elsevierMultimedia ident="eq0005"></elsevierMultimedia></p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Statistical analysis</span><p id="par0040" class="elsevierStylePara elsevierViewall">Continuous variables with normal distribution were expressed as means<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>standard deviation and were compared using the Student&#39;s t test or analysis of variance&#44; and those with non-normal distribution were expressed as medians and interquartile range &#40;IQR&#41; and compared with the Mann-Whitney or Kruskal-Wallis tests&#46; Scintigraphic parameters were correlated with age&#44; duration of symptoms and time before and after liver transplantation&#44; using Pearson&#39;s and Spearman&#39;s correlation coefficients&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">The prognostic impact of scintigraphic parameters on all-cause mortality during follow-up was determined by Cox univariate and multivariate regression analysis adjusted for age&#46; To avoid bias&#44; stepwise methods were used for the multivariate analysis&#44; with non-significant variables being removed from the model at each step &#40;p-value 0&#46;05 for inclusion and 0&#46;10 for removal&#41;&#46; The accuracy of predictors of mortality was assessed by the area under the curve &#40;AUC&#41; on receiver operating characteristic analysis for different durations of follow-up&#46; Cumulative event rates by quartiles of H&#47;M ratio were assessed by the Kaplan-Meier method and the log-rank test&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">The statistical analysis was performed with SPSS version 21&#46;0 &#40;IBM SPSS&#44; Chicago&#44; IL&#41;&#46; A p-value &#60;0&#46;05 was considered statistically significant&#46;</p></span></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Results</span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Population characteristics</span><p id="par0055" class="elsevierStylePara elsevierViewall">Between September 1998 and July 2015&#44; 305 carriers of the TTR-V30 M mutation underwent annual cardiac assessment&#46; A total of 73 patients were excluded from the analysis&#58; 45 for not having undergone MIBG imaging and 28 because their first MIBG scan was performed after liver transplantation&#46; The final study population thus consisted of 232 patients&#44; median age 40 years &#40;IQR 32-55&#41;&#44; 54&#46;7&#37; female &#40;n&#61;127&#41;&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">At the initial cardiac assessment&#44; 144 patients &#40;62&#46;1&#37;&#41; had documented neurological involvement&#44; the other 88 &#40;37&#46;9&#37;&#41; being asymptomatic&#46; Of the symptomatic patients&#44; 99 had developed clinical manifestations by the age of 50&#44; while the other 45 had late onset &#40;after the age of 50&#41;&#46; The mean age of symptom onset was 38 years &#40;IQR 31-54&#41; and the mean duration of symptoms at initial assessment was two years &#40;IQR 0-3&#41;&#46; Nineteen carriers of the pathogenic mutation aged over 50 were still symptom-free&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090"><span class="elsevierStyleSup">123</span>I-MIBG scintigraphy</span><p id="par0065" class="elsevierStylePara elsevierViewall">At the initial assessment&#44; the mean early and late H&#47;M ratios were 1&#46;85&#177;0&#46;23 and 1&#46;83&#177;0&#46;03&#44; respectively&#44; and median washout rate was 2&#46;5 &#40;IQR -2&#46;3 to 8&#46;5&#41;&#46; Early and late H&#47;M ratios were significantly lower and the washout rate was significantly higher in symptomatic patients &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0070" class="elsevierStylePara elsevierViewall">During a median follow-up of 4&#46;5 years &#40;IQR 2&#46;1-7&#46;7&#59; maximum 15&#46;6&#41;&#44; 121 patients underwent serial MIBG imaging&#44; of whom 36 underwent at least five exams &#40;maximum nine&#41; &#40;<a class="elsevierStyleCrossRef" href="#sec0080">Supplementary Table 1</a>&#41;&#46; Including both initial and subsequent assessments&#44; a total of 558 MIBG scans were performed&#46; In these exams&#44; the late H&#47;M ratio decreased with age &#40;by 0&#46;082&#47;year&#44; p&#60;0&#46;001&#41; and with duration of symptoms &#40;by 0&#46;066&#47;year&#44; p&#60;0&#46;001&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Figure 1</a> and <a class="elsevierStyleCrossRef" href="#sec0080">Supplementary Table 2</a>&#41;&#44; to a similar degree in both sexes &#40;<a class="elsevierStyleCrossRef" href="#sec0080">Supplementary Figure 1</a>&#41;&#46; <a class="elsevierStyleCrossRef" href="#fig0010">Figure 2</a> presents the progression of late H&#47;M in serial MIBG scans of two typical patients&#44; illustrating the slow reduction in the presymptomatic stage of the disease&#44; the more marked decline after symptom onset&#44; and the apparent stabilization after liver transplantation&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Prognostic stratification</span><p id="par0075" class="elsevierStylePara elsevierViewall">During follow-up&#44; 47 patients &#40;20&#46;3&#37;&#41; died&#46; The most frequent cause of death &#40;40&#37;&#41; was terminal FAP &#40;<a class="elsevierStyleCrossRef" href="#sec0080">Supplementary Table 3</a>&#41;&#46; MIBG scintigraphy at inclusion was a strong predictor of prognosis&#44; with the risk of death increasing by 27&#46;8&#37; &#40;95&#37; confidence interval &#91;CI&#93; 17&#46;5-39&#46;1&#41; for each one-tenth reduction in the late H&#47;M ratio &#40;hazard ratio &#91;HR&#93; 0&#46;78&#59; 95&#37; CI 0&#46;72-0&#46;85&#59; p&#60;0&#46;001&#41;&#46; Of the MIBG parameters&#44; only late H&#47;M was an independent prognostic predictor &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46; Mortality was nine times higher in patients with lower H&#47;M &#40;first quartile&#44; &#60;1&#46;55&#41; at inclusion than in those with H&#47;M above the median for the study population &#40;&#8805;1&#46;83&#59; HR 9&#46;36&#59; 95&#37; CI 4&#46;27-20&#46;56&#59; p&#60;0&#46;001&#41;&#46; Mortality was also four times higher in patients with moderate reductions &#40;1&#46;55-1&#46;83&#41; in late H&#47;M &#40;HR 4&#46;27&#59; 95&#37; CI 1&#46;68-9&#46;05&#59; p&#61;0&#46;002&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Figure 3</a>A&#41;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0080" class="elsevierStylePara elsevierViewall">To determine the potential added value of serial late H&#47;M assessment for prognostic stratification&#44; we assessed the accuracy of all the MIBG scans &#40;558 scans&#44; 2246 patient-years of follow-up&#41; for predicting post-exam survival&#44; which was found to be significantly reduced with lower late H&#47;M ratio&#46; The risk of death increased by 27&#46;8&#37; for every one-tenth reduction in the late H&#47;M ratio &#40;HR 0&#46;774&#59; 95&#37; CI 0&#46;73-0&#46;82&#59; p&#60;0&#46;001&#41;&#44; and was nine times higher in patients in the first H&#47;M quartile &#40;HR 9&#46;15&#59; 95&#37; CI 5&#46;44-15&#46;38&#59; p&#60;0&#46;001&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Figure 3</a>B&#41;&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">The accuracy of prediction based on serial exams was assessed by the area under the curve &#40;AUC&#41; on receiver operating characteristic analysis for different time intervals and compared with prognostic stratification based only on the initial MIBG scan &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46; Prognostic stratification based on annual repetition of MIBG imaging was slightly superior&#44; but the differences were trivial for time intervals less than the median follow-up &#40;4&#46;5 years&#41;&#46; The statistical power of prognostic stratification based on a single exam and on serial exams was similar&#44; and very high &#40;99&#37;&#41;&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Effect of liver transplantation on progression of myocardial sympathetic denervation assessed by <span class="elsevierStyleSup">123</span>I-MIBG scintigraphy</span><p id="par0090" class="elsevierStylePara elsevierViewall">Seventy patients &#40;30&#46;2&#37;&#41; underwent liver transplantation&#46; In 39 of these patients surgery was performed less than one year after initial assessment&#46; Perioperative mortality was 7&#46;1&#37; &#40;5&#47;70&#41;&#46; The effect of transplantation on progression of sympathetic denervation was determined by comparing reductions in the late H&#47;M ratio in images before &#40;116 exams&#41; and after &#40;100 exams&#41; transplantation&#46; Of the former&#44; 53 were performed less than a year before surgery&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">In symptomatic patients requiring transplantation&#44; late H&#47;M decreased by 0&#46;19&#47;year &#40;p&#60;0&#46;001&#41; until transplantation&#59; early H&#47;M also decreased progressively and the MIBG washout rate increased&#46; By contrast&#44; all scintigraphic parameters stabilized after transplantation and no statistically significant differences were detected over time &#40;<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a> and <a class="elsevierStyleCrossRef" href="#fig0020">Figure 4</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0020"></elsevierMultimedia><elsevierMultimedia ident="fig0020"></elsevierMultimedia></span></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Discussion</span><p id="par0100" class="elsevierStylePara elsevierViewall">In this large prospective study of carriers of the TTR-V30 M mutation followed for a median of 4&#46;5 years&#44; we analyzed the progression of cardiac sympathetic denervation as assessed by the H&#47;M MIBG uptake ratio&#44; the prognostic value of this index for long-term survival&#44; and the effect of liver transplantation&#46; The main results are as follows&#58; &#40;1&#41; cardiac denervation progresses slowly in the pre-symptomatic stages of the disease but tends to accelerate after symptom onset&#59; &#40;2&#41; MIBG scintigraphy at inclusion is a strong predictor of prognosis&#44; with the risk of death increasing by 27&#46;8&#37; for each one-tenth reduction in the late H&#47;M ratio&#59; and &#40;3&#41; liver transplantation stabilizes cardiac denervation in long-term follow-up&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">The cardiovascular manifestations of TTR-V30 M FAP are caused by autonomic dysfunction &#40;disrupted control of blood pressure and heart rate&#41; and by cardiac amyloid deposition &#40;infiltrative cardiomyopathy&#44; arrhythmias and conduction disturbances&#41;&#46; However&#44; phenotypic differences are seen in TTR-V30 M carriers according to geographic origin&#58; cohort studies of Swedish patients report a high prevalence of restrictive cardiomyopathy&#44;<a class="elsevierStyleCrossRefs" href="#bib0135"><span class="elsevierStyleSup">3&#44;14</span></a> which is rare in Portugal&#44; where cardiac autonomic neuropathy and conduction disturbances tend to dominate the clinical picture&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">6</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">Previous studies have shown that MIBG scintigraphy is an indirect way to visualize the impairment of cardiac sympathetic innervation by amyloid deposition&#46; Nakata et al&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">15</span></a> were the first to report a case of a patient with TTR-V30 M FAP with no myocardial activity on MIBG imaging&#44; indicating involvement of the sympathetic nerves&#46; Subsequent small studies demonstrated not only that myocardial denervation was strongly correlated with severity of polyneuropathy<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">16</span></a> but also that MIBG uptake may be reduced before the onset of clinically apparent cardiac disease&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">5</span></a> In a previous study of 143 individuals&#44; we showed that cardiovascular abnormalities as assessed by electrocardiography&#44; Holter monitoring&#44; ambulatory blood pressure monitoring&#44; echocardiography and MIBG scintigraphy are common in TTR-V30 M FAP&#44; particularly in patients with neurological involvement&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">6</span></a> Unlike other forms of systemic amyloidosis&#44; the cardiovascular involvement in our study was mostly subclinical and obvious cardiac manifestations were rare&#46; However&#44; we did find that subclinical cardiovascular manifestations often preceded neurological involvement&#44; which offers the possibility of earlier recognition of the onset of disease in asymptomatic carriers&#46; We also demonstrated the prognostic value of MIBG imaging&#44; which was in fact the strongest prognostic predictor of all the cardiac and neurological parameters assessed&#58; patients with late H&#47;M of less than 1&#46;60 had a seven-fold higher risk of death during follow-up&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">The present study confirms previous findings in a larger population and broadens the results to include serial H&#47;M assessments&#46; As expected&#44; late H&#47;M decreased significantly over time&#44; but progression of cardiac denervation was so slow that annual repetition of MIBG imaging did not increase its accuracy in predicting all-cause death&#46; Our results therefore suggest that repeated assessment of the H&#47;M ratio is not justified for the purposes of prognostic stratification&#44; at least not more often than at intervals of less than five years &#40;the median duration of follow-up in the present study&#41;&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">Liver transplantation has been widely used for the last twenty years to remove the main source of mutant transthyretin&#44; in order to slow the progression of clinical manifestations&#44; including peripheral neuropathy&#44; gastrointestinal symptoms and other visceral complications&#46;<a class="elsevierStyleCrossRefs" href="#bib0155"><span class="elsevierStyleSup">7&#44;17&#8211;20</span></a> Transplantation also improves long-term survival&#44; especially when performed in the early stages of symptomatic disease&#46;<a class="elsevierStyleCrossRefs" href="#bib0150"><span class="elsevierStyleSup">6&#44;21</span></a> However&#44; the effect of liver transplantation on the progression of cardiomyopathy in TTR-V30 M FAP is the subject of debate&#44; with some studies suggesting that transplanted patients do not develop overt cardiomyopathy&#44;<a class="elsevierStyleCrossRefs" href="#bib0230"><span class="elsevierStyleSup">22&#44;23</span></a> while others &#8211; in Swedish&#44;<a class="elsevierStyleCrossRefs" href="#bib0170"><span class="elsevierStyleSup">10&#44;13</span></a> French<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">12</span></a> and Japanese<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">9</span></a> patients &#8211; report progression of arrhythmias and myocardial thickening due to amyloid deposition&#46; This adverse outcome appears to be more frequent in Swedish patients with late-onset TTR-V30 M FAP&#46;<a class="elsevierStyleCrossRefs" href="#bib0135"><span class="elsevierStyleSup">3&#44;10&#44;13</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">It has been suggested that the main component of cardiac amyloid deposits following liver transplantation is normal &#40;wild-type&#41; transthyretin&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">24</span></a> Nevertheless&#44; none of the studies that monitored the progression of amyloid infiltration by echocardiography following liver transplantation assessed its effect on cardiac autonomic denervation&#46; In a small group of 31 French patients&#44; Delahaye et al&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">12</span></a> compared the H&#47;M ratio before and after liver transplantation&#44; complemented with echocardiography&#59; as in our study&#44; no change was seen in sympathetic innervation following transplantation in a short follow-up &#40;24&#177;15 months&#41;&#44; even though cardiac amyloid infiltration&#44; as measured by myocardial thickness&#44; had progressed&#46; In the present study&#44; of a larger group &#40;70&#41; of transplanted patients&#44; the rate of decrease in H&#47;M was assessed by comparing MIBG scintigraphy before &#40;116 exams&#41; and after &#40;100 exams&#41; transplantation&#46; Of note&#44; all scintigraphic parameters stabilized after surgery&#46; There thus appears to be a distinction between amyloid deposition as assessed by myocardial thickness on echocardiography&#44; which may progress after transplantation&#44; and autonomic nerve involvement&#44; which tends to stabilize&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Conclusions</span><p id="par0130" class="elsevierStylePara elsevierViewall">Cardiac denervation is common during the progression of TTR-V30 M FAP and quantification of the late H&#47;M ratio on MIBG scintigraphy is valuable for prognostic stratification of these patients&#46; Liver transplantation stabilizes cardiac denervation&#46; Following transplantation&#44; cardiac <span class="elsevierStyleSup">123</span>I-MIBG uptake remains stable over time&#44; with no further recovery or deterioration&#46; It is thus essential to perform transplantation sufficiently early in the natural history of the disease&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Ethical disclosures</span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Protection of human and animal subjects</span><p id="par0135" class="elsevierStylePara elsevierViewall">The authors declare that the procedures followed were in accordance with the regulations of the relevant clinical research ethics committee and with those of the Code of Ethics of the World Medical Association &#40;Declaration of Helsinki&#41;&#46;</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Confidentiality of data</span><p id="par0140" class="elsevierStylePara elsevierViewall">The authors declare that they have followed the protocols of their work center on the publication of patient data&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Right to privacy and informed consent</span><p id="par0145" class="elsevierStylePara elsevierViewall">The authors declare that no patient data appear in this article&#46;</p></span></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Conflicts of interest</span><p id="par0150" class="elsevierStylePara elsevierViewall">The authors have no conflicts of interest to declare&#46;</p></span></span>"
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            0 => "Amiloide"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Introduction</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Familial amyloid polyneuropathy &#40;FAP&#41; is a rare disease caused by systemic deposition of amyloidogenic variants of the transthyretin &#40;TTR&#41; protein&#46; The TTR-V30M mutation is caused by the substitution of valine by methionine at position 30 and mainly affects the peripheral and autonomic nervous systems&#46; Cardiovascular manifestations are common and are due to autonomic denervation and to amyloid deposition in the heart&#46; Cardiac sympathetic denervation detected by iodine-123 labeled metaiodobenzylguanidine &#40;MIBG&#41; is an important prognostic marker in TTR-V30 M FAP&#46; Liver transplantation&#44; widely used to halt neurological involvement&#44; appears to have a varying effect on the progression of amyloid cardiomyopathy&#46; Its effect on the progression of cardiac denervation remains unknown&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">In this observational study&#44; patients with the TTR-V30 M mutation underwent annual cardiac assessment and serial MIBG imaging with quantification of the late heart-to-mediastinum &#40;H&#47;M&#41; ratio&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">We studied 232 patients &#40;median age 40 years&#44; 54&#46;7&#37; female&#44; 37&#46;9&#37; asymptomatic at the time of inclusion&#41; who were followed for a median of 4&#46;5 years and underwent a total of 558 MIBG scans&#46; During follow-up&#44; 47 patients &#40;20&#46;3&#37;&#41; died&#46; MIBG scintigraphy at inclusion was a strong predictor of prognosis&#44; with the risk of death increasing by 27&#46;8&#37; for each one-tenth reduction in the late H&#47;M ratio&#46; The late H&#47;M ratio decreased with age &#40;0&#46;082&#47;year&#44; p&#60;0&#46;001&#41;&#44; but progression of cardiac denervation was so slow that annual repetition of MIBG imaging did not increase its prognostic accuracy&#46; During follow-up&#44; 70 symptomatic patients underwent liver transplantation&#46; The late H&#47;M ratio decreased by 0&#46;19&#47;year until transplantation but no statistically significant differences were detected after the procedure&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Cardiac denervation is common during the progression of TTR-V30 M FAP and quantification of the late H&#47;M ratio on MIBG scintigraphy is valuable for prognostic stratification of these patients&#46; Liver transplantation stabilizes cardiac denervation&#44; without recovery or further deterioration in cardiac MIBG uptake after the procedure&#46;</p></span>"
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        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Fundamenta&#231;&#227;o</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">A polineuropatia amiloid&#243;tica familiar &#40;PAF&#41; &#233; uma doen&#231;a rara devida &#224; deposi&#231;&#227;o sist&#233;mica de variantes amiloidog&#233;nicas da prote&#237;na transtirretina &#40;TTR-V30<span class="elsevierStyleHsp" style=""></span>M&#41;&#44; atingindo especialmente o sistema nervoso perif&#233;rico&#46; As manifesta&#231;&#245;es cardiovasculares s&#227;o muito comuns e devem-se &#224; desnerva&#231;&#227;o auton&#243;mica e &#224; deposi&#231;&#227;o de amiloide no cora&#231;&#227;o&#46; A desnerva&#231;&#227;o simp&#225;tica card&#237;aca&#44; detetada por cintigrafia com metaiodobenzilguanidina &#40;MIBG&#41; marcada com I<span class="elsevierStyleSup">123</span>&#44; &#233; um importante estratificador progn&#243;stico na PAF TTR-V30<span class="elsevierStyleHsp" style=""></span>M&#46; O transplante hep&#225;tico&#44; amplamente utilizado para interromper a progress&#227;o do envolvimento neurol&#243;gico&#44; parece ter impacto heterog&#233;neo na evolu&#231;&#227;o da miocardiopatia amiloid&#243;tica&#46; O seu impacto na progress&#227;o da desnerva&#231;&#227;o card&#237;aca permanece desconhecido&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">M&#233;todos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Estudo observacional de portadores da muta&#231;&#227;o TTR-V30<span class="elsevierStyleHsp" style=""></span>M submetidos a avalia&#231;&#227;o cardiol&#243;gica anual e a cintigrafias com MIBG seriadas&#44; com quantifica&#231;&#227;o do &#237;ndice de capta&#231;&#227;o cora&#231;&#227;o&#47;mediastino &#40;C&#47;M&#41; tardio&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Foram estudados 232 doentes &#40;idade mediana de 40 anos&#44; 54&#44;7&#37; do sexo feminino&#44; 37&#44;9&#37; assintom&#225;ticos aquando da inclus&#227;o&#41;&#44; seguidos durante uma mediana de 4&#44;5 anos e submetidos a um total de 558 cintigrafias MIBG&#46; Durante o seguimento&#44; 47 doentes &#40;20&#44;3&#37;&#41; morreram&#46; A cintigrafia com MIBG inicial foi um forte preditor progn&#243;stico&#44; detetando-se aumento do risco de morte em 27&#44;8&#37; por cada redu&#231;&#227;o decimal do &#237;ndice C&#47;M tardio&#46; O &#237;ndice C&#47;M tardio diminuiu com a idade &#40;0&#44;082 por ano&#59; p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&#41;&#44; mas a progress&#227;o da desnerva&#231;&#227;o card&#237;aca foi t&#227;o lenta que a repeti&#231;&#227;o anual do exame n&#227;o aumentou a sua precis&#227;o progn&#243;stica&#46; Durante o seguimento&#44; 70 doentes sintom&#225;ticos foram submetidos a transplante hep&#225;tico&#46; O &#237;ndice C&#47;M tardio diminuiu 0&#44;19&#47;ano at&#233; ao transplante&#44; deixando de ser detetadas varia&#231;&#245;es estatisticamente significativas a partir do procedimento&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclus&#227;o</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">A desnerva&#231;&#227;o card&#237;aca &#233; frequente durante a progress&#227;o da PAF TTR-V30<span class="elsevierStyleHsp" style=""></span>M e a quantifica&#231;&#227;o do &#237;ndice C&#47;M tardio por cintigrafia MIBG &#233; valiosa para a estratifica&#231;&#227;o progn&#243;stica destes doentes&#46; O transplante hep&#225;tico permite a estabiliza&#231;&#227;o da desnerva&#231;&#227;o card&#237;aca&#44; n&#227;o havendo recupera&#231;&#227;o ou deteriora&#231;&#227;o adicional da capta&#231;&#227;o card&#237;aca de MIBG ap&#243;s o procedimento&#46;</p></span>"
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        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Azevedo Coutinho MdC&#44; Cortez-Dias N&#44; Cantinho G&#44; Concei&#231;&#227;o I&#44; Guimar&#227;es T&#44; Lima da Silva G&#44; et al&#46; Progress&#227;o da desnerva&#231;&#227;o simp&#225;tica card&#237;aca avaliada por cintigrafia com MIBG-I<span class="elsevierStyleSup">123</span> na polineuropatia amiloid&#243;tica familiar e o impacto da transplanta&#231;&#227;o hep&#225;tica&#46; Rev Port Cardiol&#46; 2017&#59;36&#58;333&#8211;340&#46;</p>"
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          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Changes in late H&#47;M ratio by age &#40;A&#41; and duration of symptoms &#40;B&#41;&#46; H&#47;M&#58; heart-to-mediastinum&#46;</p>"
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          "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Changes in late H&#47;M ratio over time in two patients with TTR-V30 M familial amyloid polyneuropathy&#44; showing reduction in the ratio with disease progression and apparent stabilization after liver transplantation&#46; H&#47;M&#58; heart-to-mediastinum&#46;</p>"
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          "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Survival by quartiles of H&#47;M ratio assessed by first scintigraphic scan &#40;A&#41; and all scans performed during follow-up &#40;B&#41;&#46; CI&#58; confidence interval&#59; H&#47;M&#58; heart-to-mediastinum&#59; HR&#58; hazard ratio&#46;</p>"
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          "leyenda" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">H&#47;M&#58; heart-to-mediastinum ratio&#59; IQR&#58; interquartile range&#46;</p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Symptomatic &#40;n&#61;144&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Asymptomatic &#40;n&#61;88&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">p&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Early H&#47;M&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#46;75&#177;0&#46;33&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#46;03&#177;0&#46;28&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#60;0&#46;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Late H&#47;M&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#46;70&#177;0&#46;37&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#46;09&#177;0&#46;31&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#60;0&#46;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Washout rate&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&#46;98 &#40;IQR 0&#46;0 to 10&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0 &#40;IQR -6&#46;26 to 4&#46;66&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#60;0&#46;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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          "en" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Comparison of scintigraphic parameters according to neurological involvement&#46;</p>"
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        "identificador" => "tbl0010"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
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          "leyenda" => "<p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">CI&#58; confidence interval&#59; H&#47;M&#58; heart-to-mediastinum ratio&#59; HR&#58; hazard ratio&#59; IQR&#58; interquartile range&#59; NS&#58; non-significant&#46;</p>"
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            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td-with-role" title="table-head ; entry_with_role_rowhead " align="left" valign="top" scope="col">Variable&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col">Survival &#40;n&#61;185&#44; 79&#46;7&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col">All-cause death &#40;n&#61;47&#44; 20&#46;3&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col">p&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " colspan="3" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Univariate Cox regression</th><th class="td" title="table-head  " colspan="3" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Multivariate Cox regression</th></tr><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">HR&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">95&#37; CI&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">p&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">HR&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">95&#37; CI&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">p&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Median age&#44; years &#40;IQR&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">37 &#40;31-49&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">59 &#40;42-69&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#60;0&#46;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#46;067&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#46;046-1&#46;089&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#60;0&#46;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#46;052&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#46;046-1&#46;089&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#60;0&#46;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Early H&#47;M&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#46;91&#177;0&#46;33&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#46;62&#177;0&#46;33&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#60;0&#46;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;085&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;035-0&#46;206&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#60;0&#46;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">-&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">-&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Late H&#47;M&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#46;90&#177;0&#46;37&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#46;58&#177;0&#46;40&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#60;0&#46;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;086&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;037-0&#46;199&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#60;0&#46;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;183&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;075-0&#46;450&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#60;0&#46;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Washout rate&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#46;50 &#40;-2&#46;30-7&#46;14&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&#46;85 &#40;0&#46;0-12&#46;50&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NS &#40;0&#46;134&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#46;037&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#46;008-1&#46;066&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;012&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">-&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">-&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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        "descripcion" => array:1 [
          "en" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">Mortality during follow-up by age and MIBG parameters at inclusion&#46;</p>"
        ]
      ]
      6 => array:8 [
        "identificador" => "tbl0015"
        "etiqueta" => "Table 3"
        "tipo" => "MULTIMEDIATABLA"
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          "leyenda" => "<p id="spar0090" class="elsevierStyleSimplePara elsevierViewall">AUC&#58; area under the curve on receiver operating characteristic analysis&#46; All other abbreviations as in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#46;</p>"
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            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td-with-role" title="table-head ; entry_with_role_rowhead " align="left" valign="top" scope="col">Variable&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " colspan="5" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Late H&#47;M assessment at inclusion<br>&#40;232 scans in 232 patients&#41;</th><th class="td" title="table-head  " colspan="5" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Serial late H&#47;M assessments<br>&#40;558 scans in 232 patients&#41;</th></tr><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Patient-years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">No&#46; of events&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">AUC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">95&#37; CI&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">p&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Patient-years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">No&#46; of events&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">AUC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">95&#37; CI&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">p&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">At any time&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1171&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">38&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;74&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;65-0&#46;82&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#60;0&#46;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2583&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">68&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;73&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;67-0&#46;80&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#60;0&#46;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">12 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">109&#46;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;72&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;58-0&#46;86&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NS &#40;0&#46;131&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">457&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;84&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;77-0&#46;91&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">24 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">352&#46;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;83&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;75-0&#46;92&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#60;0&#46;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">806&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">17&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;84&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;77-0&#46;91&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#60;0&#46;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">36 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">467&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">15&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;77&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;69-0&#46;87&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#60;0&#46;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1097&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">27&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;79&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;71-0&#46;86&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#60;0&#46;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">48 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">534&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">17&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;77&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1261&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">33&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;79&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#60;0&#46;001&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">553&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">22&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;78&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;68-0&#46;88&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#60;0&#46;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1268&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">38&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;79&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;72-0&#46;86&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#60;0&#46;001&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;144&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;180&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-0&#46;339&nbsp;\t\t\t\t\t\t\n
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                      "titulo" => "Development of cardiomyopathy after liver transplantation in Swedish hereditary transthyretin amyloidosis &#40;ATTR&#41; patients"
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Article information

ISSN: 21742049
Original language: English

DOI:10.1016/j.repce.2016.08.009

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2024 November	2	4	6
2024 October	35	32	67
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2024 August	30	27	57
2024 July	26	22	48
2024 June	24	16	40
2024 May	25	27	52
2024 April	23	16	39
2024 March	24	26	50
2024 February	27	37	64
2024 January	24	40	64
2023 December	16	28	44
2023 November	24	21	45
2023 October	15	15	30
2023 September	17	21	38
2023 August	17	16	33
2023 July	18	9	27
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2023 May	33	23	56
2023 April	24	7	31
2023 March	42	20	62
2023 February	29	19	48
2023 January	27	14	41
2022 December	28	17	45
2022 November	52	21	73
2022 October	34	26	60
2022 September	32	25	57
2022 August	28	22	50
2022 July	35	29	64
2022 June	36	18	54
2022 May	33	34	67
2022 April	37	23	60
2022 March	31	29	60
2022 February	33	21	54
2022 January	42	21	63
2021 December	17	22	39
2021 November	34	42	76
2021 October	86	27	113
2021 September	56	35	91
2021 August	56	26	82
2021 July	27	23	50
2021 June	25	22	47
2021 May	27	43	70
2021 April	48	28	76
2021 March	88	18	106
2021 February	63	24	87
2021 January	37	23	60
2020 December	44	11	55
2020 November	39	10	49
2020 October	35	13	48
2020 September	74	15	89
2020 August	13	9	22
2020 July	46	12	58
2020 June	85	18	103
2020 May	39	11	50
2020 April	41	11	52
2020 March	45	15	60
2020 February	82	30	112
2020 January	33	11	44
2019 December	27	8	35
2019 November	27	10	37
2019 October	32	6	38
2019 September	13	8	21
2019 August	33	7	40
2019 July	30	10	40
2019 June	17	15	32
2019 May	33	9	42
2019 April	14	17	31
2019 March	21	10	31
2019 February	44	9	53
2019 January	26	8	34
2018 December	41	12	53
2018 November	79	19	98
2018 October	190	19	209
2018 September	43	11	54
2018 August	83	11	94
2018 July	21	6	27
2018 June	34	13	47
2018 May	29	6	35
2018 April	44	12	56
2018 March	40	14	54
2018 February	32	10	42
2018 January	19	9	28
2017 December	53	24	77
2017 November	65	8	73
2017 October	47	12	59
2017 September	51	26	77
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