Frequency of and Prognostic Significance of Cardiac Involvement at Presentation in Hereditary Transthyretin-Derived Amyloidosis and the Value of N-Terminal Pro-B-Type Natriuretic Peptide
2017; Elsevier BV; Volume: 121; Issue: 1 Linguagem: Inglês
10.1016/j.amjcard.2017.09.029
ISSN1879-1913
AutoresSebastiaan H.C. Klaassen, Jasper Tromp, Hans L. A. Nienhuis, Peter van der Meer, Maarten P. van den Berg, Hans Blokzijl, Dirk J. van Veldhuisen, Bouke P. C. Hazenberg,
Tópico(s)Cardiomyopathy and Myosin Studies
ResumoThe aim of this study is to assess the prevalence of cardiac involvement in hereditary transthyretin-derived (ATTRm) amyloidosis at the time of diagnosis and to determine the diagnostic and clinical value of N-terminal pro-B-type natriuretic peptide (NT-proBNP). The University Medical Center Groningen is the national center of expertise for amyloidosis. All consecutive patients between 1994 and 2016 with ATTRm amyloidosis were followed prospectively. Baseline was set at the time of the first positive biopsy. All patients underwent a standard cardiac and neurologic work-up. Cardiac involvement was defined by otherwise unexplained left and/or right ventricular wall hypertrophy on cardiac ultrasound and/or advanced conduction disturbances. Seventy-seven patients had ATTRm amyloidosis and were included in the study. The TTR V30M mutation was present in 30 patients (39%). In both the V30M and the non-V30M groups, the neurologic presentation dominated (77% vs 51%), whereas cardiac presentation was infrequent (7% vs 15%). Clinical work-up showed that cardiac involvement was present at baseline in 51% of all patients irrespective of genotype and was associated with increased overall mortality (hazard ratio 5.95, 95% confidence interval 2.12 to 16.7), independent from clinical confounders. At a cutoff level of 125 ng/L, NT-proBNP had a sensitivity of 92% for establishing cardiac involvement. In conclusion, irrespective of the frequent noncardiac presentation of ATTRm amyloidosis, cardiac involvement is already present at diagnosis in half of the patients and is associated with increased mortality. NT-proBNP is a useful marker to determine cardiac involvement in this disease. The aim of this study is to assess the prevalence of cardiac involvement in hereditary transthyretin-derived (ATTRm) amyloidosis at the time of diagnosis and to determine the diagnostic and clinical value of N-terminal pro-B-type natriuretic peptide (NT-proBNP). The University Medical Center Groningen is the national center of expertise for amyloidosis. All consecutive patients between 1994 and 2016 with ATTRm amyloidosis were followed prospectively. Baseline was set at the time of the first positive biopsy. All patients underwent a standard cardiac and neurologic work-up. Cardiac involvement was defined by otherwise unexplained left and/or right ventricular wall hypertrophy on cardiac ultrasound and/or advanced conduction disturbances. Seventy-seven patients had ATTRm amyloidosis and were included in the study. The TTR V30M mutation was present in 30 patients (39%). In both the V30M and the non-V30M groups, the neurologic presentation dominated (77% vs 51%), whereas cardiac presentation was infrequent (7% vs 15%). Clinical work-up showed that cardiac involvement was present at baseline in 51% of all patients irrespective of genotype and was associated with increased overall mortality (hazard ratio 5.95, 95% confidence interval 2.12 to 16.7), independent from clinical confounders. At a cutoff level of 125 ng/L, NT-proBNP had a sensitivity of 92% for establishing cardiac involvement. In conclusion, irrespective of the frequent noncardiac presentation of ATTRm amyloidosis, cardiac involvement is already present at diagnosis in half of the patients and is associated with increased mortality. NT-proBNP is a useful marker to determine cardiac involvement in this disease. Hereditary transthyretin-derived amyloidosis (ATTRm) is a rare protein-folding disease.1Merlini G. Bellotti V. Molecular mechanisms of amyloidosis.N Engl J Med. 2003; 349: 583-596Crossref PubMed Scopus (1444) Google Scholar, 2Hazenberg B.P. Amyloidosis. A clinical overview.Rheum Dis Clin North Am. 2013; 39: 323-345Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar ATTRm amyloidosis usually presents with symptoms of a length-dependent polyneuropathy. At presentation, this disease usually seems to affect 1 single organ or tissue. However, because of the systemic nature of ATTRm amyloidosis, subtle involvement of multiple organ systems may already be present at the time of diagnosis. Limited data are available on the actual presence and the impact on prognosis of cardiac involvement in patients with ATTRm amyloidosis presenting with noncardiac phenotypes. Whereas N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a powerful marker to predict new-onset heart failure in the general population,3Brouwers F.P. van Gilst W.H. Damman K. van den Berg M.P. Gansevoort R.T. Bakker S.J. Hillege H.L. van Veldhuisen D.J. van der Harst P. de Boer R.A. Clinical risk stratification optimizes value of biomarkers to predict new-onset heart failure in a community-based cohort.Circ Hear Fail. 2014; 7: 723-731Crossref PubMed Scopus (64) Google Scholar its role in identifying cardiac involvement in ATTRm amyloidosis is described in only few studies.4Damy T. Deux J.-F. Moutereau S. Guendouz S. Mohty D. Rappeneau S. Guellich A. Hittinger L. Loric S. Lefaucheur J.-P. Plante-Bordeneuve V. Role of natriuretic peptide to predict cardiac abnormalities in patients with hereditary transthyretin amyloidosis.Amyloid. 2013; 20: 212-220Crossref PubMed Scopus (46) Google Scholar, 5Suhr O.B. Anan I. Backman C. Karlsson A. Lindqvist P. Mörner S. Waldenström A. Do troponin and B-natriuretic peptide detect cardiomyopathy in transthyretin amyloidosis?.J Intern Med. 2008; 263: 294-301Crossref PubMed Scopus (42) Google Scholar Therefore, the objective of this study was to investigate the prevalence of cardiac involvement at the time of diagnosis in patients presenting with ATTRm amyloidosis and the utility of NT-proBNP as a tool to detect cardiac involvement. The University Medical Center Groningen is the national center of expertise for all types of systemic and localized amyloidosis in The Netherlands. Patients with proven or suspected amyloidosis are referred by different specialists, depending on the phenotype, for further diagnostic testing and treatment. All patients are followed prospectively in the Groningen Amyloidosis Cohort since 1985. For the purpose of the present study, data of all consecutive patients in this database between 1994 and 2016 with suspected ATTR amyloidosis were reviewed. Family members of patients with ATTRm are routinely referred to our center to be screened, presymptomatic, for the presence of a TTR mutation and of amyloid. Patients were included only when the presence of amyloid was proven in a biopsy, subsequently typed as ATTR, and DNA analysis revealed a mutation in the TTR gene.6Sikkema-Raddatz B. Johansson L.F. de Boer E.N. Almomani R. Boven L.G. van den Berg M.P. van Spaendonck-Zwarts K.Y. van Tintelen J.P. Sijmons R.H. Jongbloed J.D. Sinke R.J. Targeted next-generation sequencing can replace Sanger sequencing in clinical diagnostics.Hum Mutat. 2013; 34: 1035-1042Crossref PubMed Scopus (211) Google Scholar Patient charts were used to collect data on clinical characteristics, laboratory measurements, and electrocardiographic and echocardiographic measurements. Baseline was set at the time of the first biopsy containing amyloid. Measurements were considered to be performed at "baseline" if they took place within a window of 1 year previously or past the date of the positive biopsy. Patients with iatrogenic ATTR amyloidosis caused by a domino liver transplantation of a donor with ATTRm amyloidosis were excluded. The study conformed to the Principles of the Declaration of Helsinki and the local ethics committee. Cardiac involvement was defined by the presence of structural myocardial wall abnormalities and/or conduction disturbances.7Rapezzi C. Quarta C.C. Obici L. Perfetto F. Longhi S. Salvi F. Biagini E. Lorenzini M. Grigioni F. Leone O. Cappelli F. Palladini G. Rimessi P. Ferlini A. Arpesella G. Pinna A.D. Merlini G. Perlini S. Disease profile and differential diagnosis of hereditary transthyretin-related amyloidosis with exclusively cardiac phenotype: an Italian perspective.Eur Heart J. 2013; 34: 520-528Crossref PubMed Scopus (206) Google Scholar Structural abnormalities were defined as otherwise unexplained increased left (>11 mm) or right (>6 mm) ventricular wall thickness.8Lang R.M. Badano L.P. Mor-Avi V. Afilalo J. Armstrong A. Ernande L. Flachskampf F.A. Foster E. Goldstein S.A. Kuznetsova T. Lancellotti P. Muraru D. Picard M.H. Rietzschel E.R. Rudski L. Spencer K.T. Tsang W. Voigt J.U. Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging.Eur Heart J Cardiovasc Imaging. 2015; 16: 233-271Crossref PubMed Scopus (4324) Google Scholar Right ventricular involvement, a common finding in systemic amyloidosis, was included in this definition.9Gertz M.A. Comenzo R. Falk R.H. Fermand J.P. Hazenberg B.P. Hawkins P.N. Merlini G. Moreau P. Ronco P. Sanchorawala V. Sezer O. Solomon A. Grateau G. Definition of organ involvement and treatment response in immunoglobulin light chain amyloidosis (AL): a consensus opinion from the 10th International Symposium on Amyloid and Amyloidosis.Am J Hematol. 2005; 79: 319-328Crossref PubMed Scopus (1056) Google Scholar Conduction disturbances were defined as second- or third-degree atrioventricular block, or hemi- or complete bundle branch block. Low-voltage electrocardiogram was defined by the Sokolow-Lyon index.10Sokolow M. Lyon T.P. The ventricular complex in left ventricular hypertrophy as obtained by unipolar precordial and limb leads.Am Heart J. 1949; 37: 161-186Abstract Full Text PDF PubMed Scopus (1225) Google Scholar The reason for performing the biopsy was retrieved and classified as the presenting phenotype. Furthermore, as part of specialized care, patients underwent cardiac investigations such as echocardiography, electrocardiography, ambulatory 24-hour electrocardiographic monitoring, and measurement of serum NT-proBNP using a standard immunoassay (Elecsys 2010; Roche Diagnostics),11Cauliez B. Guignery J. Marinier S. Mariau I. Lavoinne A. Two-year stability of NT-proBNP in frozen samples using the Roche Elecsys system.Ann Clin Biochem. 2008; 45: 318-319Crossref PubMed Scopus (29) Google Scholar and usually patients were referred to the cardiologist of the team. When the left ventricular ejection fraction had been measured as a range, the median value of that range was used for analysis. Neurophysiologic tests were performed to detect polyneuropathy, autonomic neuropathy (Ewing tests12Ewing D.J. Martyn C.N. Young R.J. Clarke B.F. The value of cardiovascular autonomic function tests: 10 years experience in diabetes.Diabetes Care. 1985; 8: 491-498Crossref PubMed Scopus (1184) Google Scholar), or thin fiber neuropathy. Vitreous opacities were documented by ophthalmologic examination. During follow-up, these tests were repeated when deemed necessary by the attending physician. Data are presented as medians with interquartile ranges, means with standard deviations, or percentages depending on the variable. For testing significance of differences between the 2 groups, the χ2 test, the Kruskal-Wallis equality-of-populations rank test, or the 1-way analysis of variance was used where appropriate. The Pearson test was used for the correlation analyses. Kaplan-Meier curves were used for survival and analyzed using the log-rank test. Univariate and multivariate Cox proportional hazard regression models were used to calculate the hazard ratio of cardiac involvement on mortality. To determine the role of the biomarker NT-proBNP in the discrimination of patients with or without cardiac involvement, a receiver operating characteristic (ROC) curve was constructed. A 2-tailed p value of <0.05 was considered to be statistically significant. Analyses were conducted using STATA version 13 (StataCorp LP, College Station, TX). In total, 155 patients with proven or suspected ATTR were referred to our center between 1994 and 2016. Thirty-five patients were excluded based on a negative biopsy, 12 patients were excluded based on missing biopsy data, 20 patients were excluded because a TTR gene mutation was lacking (wild-type variant), 10 patients were excluded because no sufficient clinical data were available, and 1 patient was excluded because of iatrogenic amyloidosis caused by domino liver transplantation. The remaining 77 patients were included for further analysis, including the 29 patients who underwent a liver transplantation during follow-up. In 30 of the 77 patients, the TTR V30M genotype was present, and the non-V30M group consisted of 47 patients. Nine different TTR gene mutations were present in the non-V30M group: Y114C (N = 23), V71A (N = 8), G47E (N = 7), G89K (N = 3), V122I (N = 2), V94A (N = 1), A45G (N = 1), A36P (N = 1), and S23N (N = 1). Baseline characteristics are provided in Table 1. Symptoms of a peripheral neuropathy were the most frequent reason for performing the biopsy in both the V30M group (77%) and the non-V30M group (51%). Symptoms of a cardiomyopathy were much less frequently the reason for a biopsy in both the V30M (7%) and the non-V30M group (15%). During diagnostic work-up at baseline, peripheral neuropathy (78%) and autonomic dysfunction (57%) were frequently present. Symptoms of heart failure were absent in most patients.Table 1Clinical characteristics at baselineVariableTotal (n = 77)Non-V30M (n = 47)V30M (n = 30)pAge at diagnosis (years ± SD)54 ± 1450.5 ± 11.456.3 ± 16.10.067Age at death (years ± SD)61 ± 1058.4 ± 9.565.0 ± 9.20.067Men55.8%46.8%70%0.024Reason for a biopsy, signs of: Peripheral neuropathy61.0%51.1%76.7%0.025 Autonomic dysfunction2.6%2.1%3.3%0.750 Cardiomyopathy11.7%14.9%6.7%0.270 Ocular opacities7.8%10.6%3.3%0.240 CTS3.9%6.4%0.00.160 Family history10.0%12.8%6.7%0.390 Miscellaneous3.0%2.1%3.3%0.746Clinical status Peripheral neuropathy77.6%72.3%86.3%0.160 Autonomic dysfunction57.1%59.6%53.6%0.590 Gastro-intestinal complaints32.0%34.0%28.6%0.620 Cardiac involvement51.0%49.0%53.0%0.707 Ocular opacities22.0%31.9%6.7%0.009 CTS19.7%23.4%13.8%0.310NYHA class0.250 I80.5%87.2%72.4%0.063 II13.0%8.5%20.7%0.144 III5.2%4.3%6.9%0.642 IV000-Blood pressure (mmHg) Peak Systolic130.0 (115.0, 145.0)130.0 (110.0, 140.0)140.0 (120.0, 150.0)0.043 End Diastolic80.0 (70.0, 88.0)80.0 (70.0, 88.0)80.0 (70.0, 87.5)0.900Electrocardiographic findings Atrial fibrillation2.8%2.2%3.8%0.680 Low voltage QRS complexes4.2%4.3%3.8%0.920 Bundle branch block13.9%13.0%15.4%0.780 1st degree AV-block11.7%8.5%16.6%0.190 2nd/3rd degree AV-block000-Echocardiogram findings Septum wall thickness (mm)11.0 (9.0, 13.0)11.0 (9.0, 13.0)11.0 (10.0, 14.0)0.310 Left posterior wall thickness (mm)10.0 (8.0, 12.0)10.0 (8.4, 12.0)9.0 (8.0, 12.0)0.430 Right ventricular wall thickness (mm)5.0 (4.0, 6.5)5.0 (4.0, 6.0)5.0 (4.0, 7.0)0.820 LVEF (%)60 (60, 60)60.0 (60.0, 60.0)60.0 (56.0, 60.0)0.320Laboratory findings NT-proBNP (ng/L)202 (78, 646)177 (67, 677)210 (117, 595)0.390 Creatinine (µmol/L)83 (73, 93)80 (66, 93)85 (81, 94)0.340 eGFR (ml/min * 1.73 m2)80.0 (70.0, 104.0)79 (66.0, 97.0)82.0 (74.0, 110.0)0.140Data are presented as medians with interquartile ranges, means with standard deviations, or percentages depending on the nature of the variable. CTS = carpal tunnel syndrome; eGFR = estimated glomerular filtration rate; NYHA = New York Heart Association functional classification of heart failure; LVEF = left ventricular ejection fraction. Open table in a new tab Data are presented as medians with interquartile ranges, means with standard deviations, or percentages depending on the nature of the variable. CTS = carpal tunnel syndrome; eGFR = estimated glomerular filtration rate; NYHA = New York Heart Association functional classification of heart failure; LVEF = left ventricular ejection fraction. At baseline, 39 (51%) patients met the criteria of cardiac involvement, and this did not differ between the 2 genotype groups. In the Supplement Table S1 the basline data is classified by cardiac involvement (Table S1) and also classified bycardiac reason for the biopsy (Table S2). All 9 (12%) patients with a cardiac reason for the biopsy had cardiac involvement. Of the remaining 68 (88%) patients with a noncardiac reason for biopsy, 30 (44%) patients had cardiac involvement, including 2 of 8 patients who were screened because of family history. Supplementary Table S3 shows the results of logistic regression on cardiac involvement. In Figure 1A, the serum levels of NT-proBNP and age at diagnosis are depicted for males and females. A correlation was present in both males and females. Figure 1B depicts the NT-proBNP serum levels and age at diagnosis for the V30M and non-V30M groups. The regression lines of both V30M and non-V30M are shown and seem to run parallel and nearby the 97.5% upper limit of controls.13Hess G. Runkel S. Zdunek D. Hitzler W.E. Reference interval determination for N-terminal-B-type natriuretic peptide (NT-proBNP): a study in blood donors.Clin Chim Acta. 2005; 360: 187-193Crossref PubMed Scopus (55) Google Scholar Figure 1C depicts the NT-proBNP serum levels and age at diagnosis for patients with and without cardiac involvement. Levels were higher in the patients with cardiac involvement (p < 0.001). In Figure 2, the ROC curve for NT-proBNP for cardiac involvement is shown; the area under the curve was 0.905. Based on this ROC curve, 2 cutoff levels were set: one with high sensitivity and another with high specificity. The sensitive cutoff level of 164 ng/L had negative predictive value 87.5%. The specific cutoff level of 365 ng/L had a positive predictive value of 93%. The 2 chosen cutoff levels are shown in Figure 1C. The literature-based cutoff level of 125 ng/L14Ponikowski P. Voors A.A. Anker S.D. Bueno H. Cleland J.G. Coats A.J. Falk V. González-Juanatey J.R. Harjola V.P. Jankowska E.A. Jessup M. Linde C. Nihoyannopoulos P. Parissis J.T. Pieske B. Riley J.P. Rosano G.M. Ruilope L.M. Ruschitzka F. Rutten F.H. van der Meer P. 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: the task force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) developed with the special contribution of the Heart Failure Association (HFA) of the ESC.Eur Heart J. 2016; 37: 2129-2200Crossref PubMed Scopus (8818) Google Scholar yielded a sensitivity of 92% and a specificity of 65%. Median follow-up was 6 years, and in this period, 33 (43%) patients died. Mean age at death was 61 years. The Kaplan-Meier survival curve (Figure 3A) shows that no significant difference in mortality was observed between the V30M group and the non-V30M group. Figure 3B shows that patients with cardiac involvement at baseline had reduced survival during follow-up compared with patients without cardiac involvement. Patients with cardiac involvement had a 50% all-cause mortality of 4 years, whereas the 50% all-cause mortality was not reached in the patients without cardiac involvement. Supplementary Figure S1 shows the survival curves for patients with high and low NT-proBNP. A Cox survival analysis was performed to determine the hazard ratio of cardiac involvement on mortality (Table 2). Even when adjusted for age, sex, systolic pressure, renal function, and V30M genotype, cardiac involvement remained associated with increased mortality (model 2 in Table 2).Table 2Cox regression analysisHR (95% CI)p-valueCardiac InvolvementUnivariate6.23 (2.49 - 15.6)0.000Model 16.34 (2.20 - 18.3)0.001Model 25.95 (2.12 - 16.7)0.001Model 1: Adjusted for age and sex. Model 2: Adjusted for age, sex, systolic pressure, eGFR, and V30M genotype. Open table in a new tab Model 1: Adjusted for age and sex. Model 2: Adjusted for age, sex, systolic pressure, eGFR, and V30M genotype. This study shows that cardiac involvement is present in half of the patients presenting with ATTRm amyloidosis, regardless of initial clinical presentation and genotype (V30M vs non-V30M). Furthermore, the results indicate that cardiac involvement is associated with adverse outcomes, independent of other clinical characteristics. Lastly, NT-proBNP appears to be a useful marker in determining cardiac involvement in patients presenting with ATTRm amyloidosis. Although ATTRm amyloidosis is a heterogeneous disease, most TTR mutations induce neurologic symptoms. It was therefore initially described as familial amyloid polyneuropathy.15Parman Y. Adams D. Obici L. Galán L. Guergueltcheva V. Suhr O.B. Coelho T. Sixty years of transthyretin familial amyloid polyneuropathy (TTR-FAP) in Europe: where are we now? A European network approach to defining the epidemiology and management patterns for TTR-FAP.Curr Opin Neurol. 2016; 29: S3-S13Crossref PubMed Scopus (157) Google Scholar However, Rapezzi et al described a mixed presentation of both neurologic and cardiac symptoms in their Italian cohort of patients with ATTR amyloidosis comprising a sizeable number of mutations.7Rapezzi C. Quarta C.C. Obici L. Perfetto F. Longhi S. Salvi F. Biagini E. Lorenzini M. Grigioni F. Leone O. Cappelli F. Palladini G. Rimessi P. Ferlini A. Arpesella G. Pinna A.D. Merlini G. Perlini S. Disease profile and differential diagnosis of hereditary transthyretin-related amyloidosis with exclusively cardiac phenotype: an Italian perspective.Eur Heart J. 2013; 34: 520-528Crossref PubMed Scopus (206) Google Scholar Because of these findings, we aimed to investigate the presence of cardiac involvement in our population of Dutch patients with ATTRm amyloidosis subdivided in V30M and non-V30M TTR genotypes. Length-dependent peripheral neuropathy is typically seen in patients with ATTR amyloidosis and is characterized by numbness, spontaneous pain, muscle weakness, and atrophy. Similar to autonomic dysfunction, these peripheral neuropathic characteristics all contribute to a decreased performance and impaired exercise tolerance.16Ando Y. Coelho T. Berk J.L. Cruz M.W. Ericzon B.-G. Ikeda S. Lewis W.D. Obici L. Planté-Bordeneuve V. Rapezzi C. Said G. Salvi F. Guideline of transthyretin-related hereditary amyloidosis for clinicians.Orphanet J Rare Dis. 2013; 8: 31Crossref PubMed Scopus (455) Google Scholar Exercise intolerance can already be explained by these neurologic limitations; however, one of the hallmarks of cardiac disease is also a decreased exercise tolerance.17Arruda-Olson A.M. Zeldenrust S.R. Dispenzieri A. Gertz M.A. Miller F.A. Bielinski S.J. Klarich K.W. Scott C.G. Grogan M. Genotype, echocardiography, and survival in familial transthyretin amyloidosis.Amyloid. 2013; 20: 263-268Crossref PubMed Scopus (27) Google Scholar Irrespective of phenotype, patients with ATTR amyloidosis do not challenge their exercise capacity and therefore cardiac symptoms may be camouflaged by concurrent neurologic symptoms, making cardiac involvement of amyloidosis a challenging feature to diagnose. More speculative is that autonomic dysfunction may cause lower filling pressures in the heart because of venous blood pooling, thereby masking underlying cardiac abnormalities.18Pang C.C. Autonomic control of the venous system in health and disease: effects of drugs.Pharmacol Ther. 2001; 90: 179-230Crossref PubMed Scopus (178) Google Scholar In only a small proportion of our population the reason for a biopsy was symptoms suggestive of a cardiomyopathy, their presenting symptoms were shortness of breath, edema, and/or signs of congestion. Typical amyloidosis-related electrocardiogram findings, that is, low voltages and advanced atrioventricular blocks, were not prominent, and evident echocardiographic abnormalities were also absent in most of these patients at presentation.19Di Bella G. Minutoli F. Piaggi P. Casale M. Mazzeo A. Zito C. Oreto G. Baldari S. Vita G. Pingitore A. Khandheria B.K. Carerj S. Usefulness of combining electrocardiographic and echocardiographic findings and brain natriuretic peptide in early detection of cardiac amyloidosis in subjects with transthyretin gene mutation.Am J Cardiol. 2015; 116: 1122-1127Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar Of note, the criteria of cardiac involvement used in this study were a little less stringent than those used by Rapezzi et al.7Rapezzi C. Quarta C.C. Obici L. Perfetto F. Longhi S. Salvi F. Biagini E. Lorenzini M. Grigioni F. Leone O. Cappelli F. Palladini G. Rimessi P. Ferlini A. Arpesella G. Pinna A.D. Merlini G. Perlini S. Disease profile and differential diagnosis of hereditary transthyretin-related amyloidosis with exclusively cardiac phenotype: an Italian perspective.Eur Heart J. 2013; 34: 520-528Crossref PubMed Scopus (206) Google Scholar In our study, cardiac hypertrophy was defined as an interventricular septum or posterior wall thickness of >11 mm or when right ventricular hypertrophy (>6 mm) was present, whereas in the study of Rapezzi et al right ventricular dimensions were not included in the definition, and a thickness of 13 mm or greater was used for the left ventricle. In our opinion, especially the wall thickness cutoff criteria of our study are more in line with regard to the current echocardiography guidelines.8Lang R.M. Badano L.P. Mor-Avi V. Afilalo J. Armstrong A. Ernande L. Flachskampf F.A. Foster E. Goldstein S.A. Kuznetsova T. Lancellotti P. Muraru D. Picard M.H. Rietzschel E.R. Rudski L. Spencer K.T. Tsang W. Voigt J.U. Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging.Eur Heart J Cardiovasc Imaging. 2015; 16: 233-271Crossref PubMed Scopus (4324) Google Scholar Irrespective of the noncardiac clinical presentation or the genotype, the heart was already affected at diagnosis in about half of our patients. If myocardial radiotracer uptake on bone scintigraphy had been used to detect cardiac involvement in this study, even more patients might have been identified.20Gillmore J.D. Maurer M.S. Falk R.H. Merlini G. Damy T. Dispenzieri A. Wechalekar A.D. Berk J.L. Quarta C.C. Grogan M. Lachmann H.J. Bokhari S. Castano A. Dorbala S. Johnson G.B. Glaudemans A.W. Rezk T. Fontana M. Palladini G. Milani P. Guidalottie P.L. Flatman K. Lane T. Vonberg F.W. Whelan C.J. Moon J.C. Ruberg F.L. Miller E.J. Hutt D.F. Hazenberg B.P. Rapezzi C. Hawkins P.N. Non-biopsy diagnosis of cardiac transthyretin amyloidosis.Circulation. 2016; 133: 2404-2412Crossref PubMed Scopus (970) Google Scholar In recent years, the natriuretic peptide BNP and NT-proBNP biomarkers became available in heart failure. These natriuretic peptides predict outcome not only in the general population,21Linssen G.C. Bakker S.J. Voors A.A. Gansevoort R.T. Hillege H.L. de Jong P.E. van Veldhuisen D.J. Gans R.O. de Zeeuw D. N-terminal pro-B-type natriuretic peptide is an independent predictor of cardiovascular morbidity and mortality in the general population.Eur Heart J. 2010; 31: 120-127Crossref PubMed Scopus (99) Google Scholar but also in patients with heart failure.22van Veldhuisen D.J. Linssen G.C. Jaarsma T. van Gilst W.H. Hoes A.W. Tijssen J.G. Paulus W.J. Voors A.A. Hillege H.L. B-type natriuretic peptide and prognosis in heart failure patients with preserved and reduced ejection fraction.J Am Coll Cardiol. 2013; 61: 1498-1506Crossref PubMed Scopus (311) Google Scholar Several studies described the prognostic value of NT-proBNP on outcome in patients with ATTR amyloidosis, including a recent study using the THAOS Registry, but few studies described the diagnostic value of NT-proBNP of cardiac involvement in these patients.4Damy T. Deux J.-F. Moutereau S. Guendouz S. Mohty D. Rappeneau S. Guellich A. Hittinger L. Loric S. Lefaucheur J.-P. Plante-Bordeneuve V. Role of natriuretic peptide to predict cardiac abnormalities in patients with hereditary transthyretin amyloidosis.Amyloid. 2013; 20: 212-220Crossref PubMed Scopus (46) Google Scholar, 5Suhr O.B. Anan I. Backman C. Karlsson A. Lindqvist P. Mörner S. Waldenström A. Do troponin and B-natriuretic peptide detect cardiomyopathy in transthyretin amyloidosis?.J Intern Med. 2008; 263: 294-301Crossref PubMed Scopus (42) Google Scholar, 23Kristen A.V. Maurer M.S. Rapezzi C. Mundayat R. Suhr O.B. Damy T. Impact of genotype and phenotype on cardiac biomarkers in patients with transthyretin amyloidosis—report from the Transthyretin Amyloidosis Outcome Survey (THAOS).PLoS ONE. 2017; 12: e0173086Crossref PubMed Scopus (46) Google Scholar, 24Daniels L.B. Maisel A.S. Natriuretic peptides.J Am Coll Cardiol. 2007; 50: 2357-2368Crossref PubMed Scopus (827) Google Scholar The NT-proBNP levels did not differ in the 2 genotype groups (V30M vs non-V30M), and the NT-proBNP levels correlated with age for both males and females in both genotype groups. This age-related increase of NT-proBNP in our study group was at a higher level than the well-known physiological age-dependent increase of NT-proBNP.13Hess G. Runkel S. Zdunek D. Hitzler W.E. Reference interval determination for N-terminal-B-type natriuretic peptide (NT-proBNP): a study in blood donors.Clin Chim Acta. 2005; 360: 187-193Crossref PubMed Scopus (55) Google Scholar It therefore appears that cardiac involvement in ATTRm amyloidosis is not so much determined by genotype but by the age at disease onset. The current findings emphasize the importance of NT-proBNP measurements in patients with ATTR amyloidosis, because increased serum levels of NT-proBNP reveal cardiac involvement.14Ponikowski P. Voors A.A. Anker S.D. Bueno H. Cleland J.G. Coats A.J. Falk V. González-Juanatey J.R. Harjola V.P. Jankowska E.A. Jessup M. Linde C. Nihoyannopoulos P. Parissis J.T. Pieske B. Riley J.P. Rosano G.M. Ruilope L.M. Ruschitzka F. Rutten F.H. van der Meer P. 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: the task force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) developed with the special contribution of the Heart Failure Association (HFA) of the ESC.Eur Heart J. 2016; 37: 2129-2200Crossref PubMed Scopus (8818) Google Scholar In as many as half of our patients, cardiac involvement could be demonstrated at presentation, and our results indicate that NT-proBNP is a good diagnostic tool for medical specialists other than cardiologists to detect cardiac involvement. Recognition of cardiac involvement is of great importance in the proper treatment of ATTR amyloidosis. This study shows that cardiac involvement predicts overall survival and confirms previous studies.23Kristen A.V. Maurer M.S. Rapezzi C. Mundayat R. Suhr O.B. Damy T. Impact of genotype and phenotype on cardiac biomarkers in patients with transthyretin amyloidosis—report from the Transthyretin Amyloidosis Outcome Survey (THAOS).PLoS ONE. 2017; 12: e0173086Crossref PubMed Scopus (46) Google Scholar, 25Zeldenrust S.R. Cooper L.T. Getting to the heart of the matter: cardiac involvement in transthyretin-related amyloidosis.Eur Heart J. 2013; 34: 483-485Crossref PubMed Scopus (5) Google Scholar In the last few years, TTR tetramer-stabilizing treatment for ATTR amyloidosis became available for polyneuropathy.26Merlini G. Planté-Bordeneuve V. Judge D.P. Schmidt H. Obici L. Perlini S. Packman J. Tripp T. Grogan D.R. Effects of tafamidis on transthyretin stabilization and clinical outcomes in patients with non-Val30Met transthyretin amyloidosis.J Cardiovasc Transl Res. 2013; 6: 1011-1020Crossref PubMed Scopus (116) Google Scholar A similar randomized clinical trial in patients with cardiomyopathy as disease manifestation will be completed in 2018.27Anonymous Safety and Efficacy of Tafamidis in Patients With Transthyretin Cardiomyopathy (ATTR-ACT).https://clinicaltrials.gov/ct2/show/NCT01994889?term=tafamidis&rank=4Date accessed: March 15, 2017Google Scholar Early identification of cardiac involvement is therefore mandatory to treat amyloidosis adequately, because late-stage cardiomyopathy probably will benefit less from treatment.16Ando Y. Coelho T. Berk J.L. Cruz M.W. Ericzon B.-G. Ikeda S. Lewis W.D. Obici L. Planté-Bordeneuve V. Rapezzi C. Said G. Salvi F. Guideline of transthyretin-related hereditary amyloidosis for clinicians.Orphanet J Rare Dis. 2013; 8: 31Crossref PubMed Scopus (455) Google Scholar Limitations of our study are the relatively small population size and small number of mutations. Loss of renal function and cardiac rhythm abnormalities may cause elevated NT-proBNP levels, but severe renal function loss was not present, whereas only 2 patients had atrial fibrillation. Because of the long study period of more than 20 years, it was not possible to use more recent and advanced techniques to detect cardiac involvement, such as bisphosphonate scintigraphy, magnetic resonance imaging T1-myomapping, and strain measurement and speckle tracking by echocardiography. In conclusion, cardiac involvement in ATTRm amyloidosis is not limited to certain genotypes or a specific clinical presentation and is of great influence on the overall survival. Measuring the cardiac biomarker NT-proBNP is useful in the early evaluation of cardiac involvement in ATTR amyloidosis. The authors have no conflicts of interest to disclose. The following are the supplementary data to this article: Download .zip (.02 MB) Help with zip files Fig. S1Kaplan-Meier survival curves between patients with low values of NT-proBNP (solid line and ≤125 ng/L) and high values of NT-proBNP (dashed line and >125 ng/L). Censored values are shown as ticks. Download .docx (.02 MB) Help with docx files Table S1Clinical characteristics at baseline stratified for cardiac involvement. Download .docx (.02 MB) Help with docx files Table S2Clinical characteristics at baseline stratified for cardiac reason of biopsy. Download .docx (.02 MB) Help with docx files Table S3Logistic regression and odds ratio on cardiac involvement.
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