RESUMEN
Transthyretin amyloidosis (ATTR) is caused by deposition of either wild-type (ATTRwt) or variant (ATTRm) transthyretin. ATTRwt presents with restrictive cardiomyopathy, while ATTRm displays a range of organ involvement. This retrospective analysis includes all patients referred to a single UK center in the last 25 years for clinical and laboratory assessment of known or suspected amyloidosis who underwent TTR gene sequencing. A total of 4459 patients were included in this study; 37% had final diagnosis of ATTR amyloidosis; 27% light chain amyloidosis; 0.7% other types of amyloidosis; 21.3% had no amyloid and 14% had no data. TTR variants were found in 770 (17%) cases; the most prevalent were p.V142I, p.T80A, and p.V50M identified in 42, 25, and 16%, respectively. The median age at referral in each group was: 76 (range 47-93), 66 (40-81), and 45 years (21-86), respectively. Overall 42 rare or novel variants were identified. Forty-two percent patients with ATTRm died at a median age of 73 years (33-89) with a median survival from diagnosis of 50 months. ATTRwt was the final diagnosis in 20% of patients undergoing genetic testing. Our findings of TTR variants in 17% of screened patients highlight the need for routine genetic testing in the evaluation of suspected ATTR amyloidosis.
Asunto(s)
Amiloidosis/genética , Prealbúmina/genética , Adulto , Anciano , Anciano de 80 o más Años , Amiloidosis/diagnóstico , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Mutación/genética , Reino Unido , Adulto JovenRESUMEN
Aims: Cardiac transthyretin (ATTR) amyloidosis is an increasingly recognized, progressive, and fatal cardiomyopathy, the natural history of which remains unclear. We sought to establish and validate a new prognostic staging system applicable to patients with both wild-type ATTR (ATTRwt) and hereditary variant ATTR (ATTRv) amyloid cardiomyopathy. Methods and results: Eight hundred and sixty-nine patients with cardiac ATTR amyloidosis (553 with ATTRwt and 316 with ATTRv) attending the UK National Amyloidosis Centre were stratified into three disease stages at baseline on the basis of cut points in two universally measured biomarkers, N-terminal pro-B-type natriuretic peptide (NT-proBNP) and estimated glomerular filtration rate (eGFR). Stage I was defined as NT-proBNP ≤3000 ng/L and eGFR ≥45 ml/min, Stage III was defined as NT-proBNP >3000 ng/L and eGFR <45 ml/min, and the remainder were Stage II. The staging system was validated in a cohort of 318 patients with cardiac ATTR amyloidosis from France. Median survival among 393 (45%) Stage I patients was 69.2 months, 334 (38%) Stage II patients was 46.7 months, and 142 (16%) Stage III patients was 24.1 months (P < 0.0001). After adjusting for age, compared with Stage I, the hazard ratio (HR) for death for Stage II was 2.05 [confidence interval (CI) 1.54-2.72, P < 0.001] and for Stage III was 3.80 (CI 2.73-5.28, P < 0.001). HRs and statistical significance were little altered by transthyretin genotype and were maintained in the validation cohort. Conclusion: This simple, universally applicable staging system stratifies patients with both ATTRwt and ATTRv amyloid cardiomyopathy into prognostic categories. It will be of value in the design of forthcoming clinical trials of novel amyloid-specific therapies.
Asunto(s)
Neuropatías Amiloides Familiares/clasificación , Neuropatías Amiloides Familiares/diagnóstico , Cardiopatías/clasificación , Cardiopatías/diagnóstico , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Estudios RetrospectivosRESUMEN
BACKGROUND: Cardiac transthyretin (ATTR) amyloidosis is a progressive and fatal cardiomyopathy for which several promising therapies are in development. The diagnosis is frequently delayed or missed because of the limited specificity of echocardiography and the traditional requirement for histological confirmation. It has long been recognized that technetium-labeled bone scintigraphy tracers can localize to myocardial amyloid deposits, and use of this imaging modality for the diagnosis of cardiac ATTR amyloidosis has lately been revisited. We conducted a multicenter study to ascertain the diagnostic value of bone scintigraphy in this disease. METHODS AND RESULTS: Results of bone scintigraphy and biochemical investigations were analyzed from 1217 patients with suspected cardiac amyloidosis referred for evaluation in specialist centers. Of 857 patients with histologically proven amyloid (374 with endomyocardial biopsies) and 360 patients subsequently confirmed to have nonamyloid cardiomyopathies, myocardial radiotracer uptake on bone scintigraphy was >99% sensitive and 86% specific for cardiac ATTR amyloid, with false positives almost exclusively from uptake in patients with cardiac AL amyloidosis. Importantly, the combined findings of grade 2 or 3 myocardial radiotracer uptake on bone scintigraphy and the absence of a monoclonal protein in serum or urine had a specificity and positive predictive value for cardiac ATTR amyloidosis of 100% (positive predictive value confidence interval, 98.0-100). CONCLUSIONS: Bone scintigraphy enables the diagnosis of cardiac ATTR amyloidosis to be made reliably without the need for histology in patients who do not have a monoclonal gammopathy. We propose noninvasive diagnostic criteria for cardiac ATTR amyloidosis that are applicable to the majority of patients with this disease.
Asunto(s)
Neuropatías Amiloides Familiares/diagnóstico , Neuropatías Amiloides Familiares/metabolismo , Prealbúmina/metabolismo , Adulto , Anciano , Femenino , Técnicas de Genotipaje , Humanos , Masculino , Persona de Mediana EdadRESUMEN
AIMS: Transthyretin amyloid cardiomyopathy (ATTR-CM) is an increasingly diagnosed disease. Echocardiography is widely utilized, but studies to confirm the value of echocardiography for tracking changes over time are not available. We sought to describe (i) changes in multiple echocardiographic parameters; (ii) differences in rate of progression of three predominant genotypes; and (iii) the ability of changes in echocardiographic parameters to predict prognosis. METHODS AND RESULTS: We prospectively studied 877 ATTR-CM patients attending our centre between 2000 and 2020. Serial echocardiography findings at baseline, 12 months and 24 months were compared with survival. Overall, 565 patients had wild-type ATTR-CM and 312 hereditary ATTR-CM (201 with V122I; 90 with T60A). There was progressive worsening of structural and functional parameters over time, patients with V122I ATTR-CM showing more rapid worsening of left and right ventricular structural and functional parameters compared to both wild-type and T60A ATTR-CM. Among a wide range of echocardiographic analyses, including deformation-based parameters, only worsening in the degree of mitral (MR) and tricuspid regurgitation (TR) at 12- and 24-month assessments was associated with worse prognosis (change at 12 months: MR, hazard ratio 1.43 [95% confidence interval 1.14-1.80], p = 0.002; TR, hazard ratio 1.38 [95% confidence interval 1.10-1.75], p = 0.006). Worsening in MR remained independently associated with poor prognosis after adjusting for known predictors. CONCLUSION: In ATTR-CM, echocardiographic parameters progressively worsen over time. Patients with V122I ATTR-CM demonstrate the most rapid deterioration. Worsening of MR and TR were the only parameters associated with mortality, MR remaining independent after adjusting for known predictors.
Asunto(s)
Neuropatías Amiloides Familiares , Cardiomiopatías , Insuficiencia Cardíaca , Neuropatías Amiloides Familiares/diagnóstico por imagen , Neuropatías Amiloides Familiares/genética , Cardiomiopatías/diagnóstico por imagen , Cardiomiopatías/genética , Ecocardiografía , Humanos , Prealbúmina , PronósticoRESUMEN
AIMS: African-American carriers of the transthyretin (TTR) valine-to-isoleucine substitution (V122I) are at increased risk of heart failure, yet many have relatively subtle abnormalities of left ventricular (LV) function. We sought to explore the influence of this mutation on left atrial (LA) structure and function in this population. METHODS AND RESULTS: We assessed 1225 genotyped African-Americans (age range, 67-89 years) participating in the Atherosclerosis Risk in Communities study who underwent echocardiography and were in sinus rhythm at study Visit 5 (2011 to 2013). Six LA parameters [LA maximum/minimum volume index, ejection fraction, and LA reservoir, conduit, and contractile longitudinal strains (LS)] were compared between V122I TTR variant carriers (n = 46) and non-carriers (n = 1179). LA minimum volume index was significantly greater and LA contractile LS was worse in carriers than non-carriers (19.5 ± 10.6 mL/m2 vs. 16.3 ± 8.4 mL/m2 ; 15.0 ± 5.8% vs. 16.8 ± 5.7%, respectively, both P < 0.05). Carriers had a significantly higher number of LA abnormalities than non-carriers (1.8 ± 2.2 vs. 1.1 ± 1.6, P = 0.009). The number of subjects with at least four LA abnormalities was significantly increased among carriers compared with non-carriers (27% vs. 12%; odds ratio 2.43; 95% confidence interval 1.06-5.58 after adjusting for age, sex, body mass index, and LV wall thickness and global LS). CONCLUSIONS: Left atrial enlargement and dysfunction were common in V122I TTR carriers with sinus rhythm than non-carriers, suggesting that abnormalities of LA function may represent early markers of subclinical disease in these individuals.
Asunto(s)
Cardiomiopatías , Insuficiencia Cardíaca , Negro o Afroamericano/genética , Anciano , Anciano de 80 o más Años , Atrios Cardíacos/diagnóstico por imagen , Humanos , Prealbúmina/genética , Volumen Sistólico , Función Ventricular IzquierdaRESUMEN
BACKGROUND: Most studies of amyloidotic cardiomyopathy consider as a single entity the 3 main systemic cardiac amyloidoses: acquired monoclonal immunoglobulin light-chain (AL); hereditary, mutated transthyretin-related (ATTRm); and wild-type transthyretin-related (ATTRwt). In this study, we compared the diagnostic/clinical profiles of these 3 types of systemic cardiac amyloidosis. METHODS AND RESULTS: We conducted a longitudinal study of 233 patients with clear-cut diagnosis by type of cardiac amyloidosis (AL, n=157; ATTRm, n=61; ATTRwt, n=15) at 2 large Italian centers providing coordinated amyloidosis diagnosis/management facilities since 1990. Average age at diagnosis was higher in AL than in ATTRm patients; all ATTRwt patients except 1 were elderly men. At diagnosis, mean left ventricular wall thickness was higher in ATTRwt than in ATTRm and AL. Left ventricular ejection fraction was moderately depressed in ATTRwt but not in AL or ATTRm. ATTRm patients less often displayed low QRS voltage (25% versus 60% in AL; P<0.0001) or low voltage-to-mass ratio (1.1+/-0.5 versus 0.9+/-0.5; P<0.0001). AL patients appeared to have greater hemodynamic impairment. On multivariate analysis, ATTRm was a strongly favorable predictor of survival, and ATTRwt predicted freedom from major cardiac events. CONCLUSIONS: AL, ATTRm, and ATTRwt should be considered 3 different cardiac diseases, probably characterized by different pathophysiological substrates and courses. Awareness of the diversity underlying the cardiac amyloidosis label is important on several levels, ranging from disease classification to diagnosis and clinical management.
Asunto(s)
Amiloidosis/diagnóstico por imagen , Amiloidosis/mortalidad , Cardiomiopatías/diagnóstico por imagen , Cardiomiopatías/mortalidad , Ecocardiografía , Adulto , Anciano , Amiloidosis/genética , Presión Sanguínea , Cardiomiopatías/genética , Progresión de la Enfermedad , Electrocardiografía , Femenino , Estudios de Seguimiento , Humanos , Cadenas Ligeras de Inmunoglobulina/sangre , Modelos Logísticos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Análisis Multivariante , Miocardio/patología , Miocitos Cardíacos/patología , Mutación Puntual , Prealbúmina/genética , Presión Esfenoidal Pulmonar , Factores de Riesgo , Análisis de SupervivenciaRESUMEN
OBJECTIVES: This cross-sectional study aimed to describe the functional and structural cardiac abnormalities that occur across a spectrum of cardiac amyloidosis burden and to identify the strongest cardiac functional and structural prognostic predictors in amyloidosis using cardiac magnetic resonance (CMR) and echocardiography. BACKGROUND: Cardiac involvement in light chain and transthyretin amyloidosis is the main driver of prognosis and influences treatment strategies. Numerous measures of cardiac structure and function are assessed by multiple imaging modalities in amyloidosis. METHODS: A total f 322 subjects (311 systemic amyloidosis and 11 transthyretin gene mutation carriers) underwent comprehensive CMR and transthoracic echocardiography. The probabilities of 11 commonly measured structural and functional cardiac parameters being abnormal with increasing cardiac amyloidosis burden were evaluated. Cardiac amyloidosis burden was quantified using CMR-derived extracellular volume. The prognostic capacities of these parameters to predict death in amyloidosis were assessed using Cox proportional hazards models. RESULTS: Left ventricular mass and mitral annular plane systolic excursion by CMR along with strain and E/e' by echocardiography have high probabilities of being abnormal at low cardiac amyloid burden. Reductions in biventricular ejection fractions and elevations in biatrial areas occur at high burdens of infiltration. The probabilities of indexed stroke volume, myocardial contraction fraction, and tricuspid annular plane systolic excursion (TAPSE) being abnormal occur more gradually with increasing extracellular volume. Ninety patients (28%) died during a median follow-up of 22 months (interquartile range: 10 to 38 months). Univariable analysis showed that all imaging markers studied significantly predicted outcome. Multivariable analysis showed that TAPSE (hazard ratio: 1.46; 95% confidence interval: 1.16 to 1.85; p < 0.01) and indexed stroke volume (hazard ratio: 1.24; 95% confidence interval: 1.04 to 1.48; p < 0.05) by CMR were the only independent predictors of mortality. CONCLUSIONS: Specific functional and structural abnormalities characterize different burdens of cardiac amyloid deposition. In a multimodality imaging assessment of a large cohort of amyloidosis patients, CMR-derived TAPSE and indexed stroke volume are the strongest prognostic cardiac functional markers.
Asunto(s)
Neuropatías Amiloides Familiares/diagnóstico por imagen , Amiloide/análisis , Cardiomiopatías/diagnóstico por imagen , Ecocardiografía Doppler de Pulso , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/diagnóstico por imagen , Imagen por Resonancia Cinemagnética , Miocardio/patología , Adulto , Anciano , Anciano de 80 o más Años , Neuropatías Amiloides Familiares/mortalidad , Neuropatías Amiloides Familiares/patología , Neuropatías Amiloides Familiares/fisiopatología , Cardiomiopatías/mortalidad , Cardiomiopatías/patología , Cardiomiopatías/fisiopatología , Estudios Transversales , Progresión de la Enfermedad , Femenino , Humanos , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/mortalidad , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/patología , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/fisiopatología , Masculino , Persona de Mediana Edad , Miocardio/química , Valor Predictivo de las Pruebas , Pronóstico , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Índice de Severidad de la EnfermedadRESUMEN
OBJECTIVE: Systemic AA amyloidosis is a serious complication of chronic inflammation; however, there are relatively few published data on its incidence. We investigated the changing epidemiology of AA amyloidosis over a 25-year period at a single national referral centre. METHODS: We conducted a retrospective study of all patients diagnosed with AA amyloidosis who had attended the centre between 1990 and 2014 inclusive. Six hundred and twenty-five patients were studied in three cohorts: C1: 1990-1997; C2: 1998-2006; C3: 2007-2014. RESULTS: Mean age at presentation increased from 46 in C1 to 56 in C3 (p < .0001). The proportion of South Asian patients increased from 4% in C1 to 17% in C3 (p = .0006). Comparison of underlying diseases between C1 and C3 revealed a reduction in patients with juvenile idiopathic arthritis from 25% to 2% (p < .0001), but an increase in patients with chronic infection due to intravenous recreational drug use from 1% to 13% (p < .0001), and uncharacterized inflammatory disorders from 10% to 27% (p <.0001). More patients were in end-stage renal failure at presentation in C3 (29%) than C1 (15%) (p = .0028). Median age at death was later in C3 (62 years) than C1 (54 years) (p = .0012). CONCLUSION: These data suggest both falling incidence and better outcome in AA amyloidosis over a quarter of a century, reflecting advances in therapeutics and overall management of complex chronic disease in an ageing population. AA amyloidosis of uncertain aetiology presents an emerging major problem. Newer techniques such as next-generation sequencing may aid diagnosis and effective treatment, thereby improving overall survival.
Asunto(s)
Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas , Adulto , Edad de Inicio , Anciano , Supervivencia sin Enfermedad , Femenino , Humanos , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/diagnóstico , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/mortalidad , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/terapia , Incidencia , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Riesgo , Tasa de SupervivenciaRESUMEN
BACKGROUND: Cardiac transthyretin amyloidosis (ATTR) is an increasingly recognized cause of heart failure. Cardiac magnetic resonance (CMR), with late gadolinium enhancement (LGE) and T1 mapping, is emerging as a reference standard for diagnosis and characterization of cardiac amyloidosis. OBJECTIVES: The authors used CMR with extracellular volume fraction (ECV) measurement to characterize cardiac involvement in relation to outcome in ATTR. METHODS: Subjects comprised 263 patients with cardiac ATTR corroborated by grade 2 to 3 99mTc-DPD (99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid) cardiac uptake, 17 with suspected cardiac ATTR (grade 1 99mTc-DPD), and 12 asymptomatic individuals with amyloidogenic transthyretin (TTR) mutations. Fifty patients with cardiac light-chain (AL) amyloidosis acted as disease comparators. RESULTS: Unlike cardiac AL amyloidosis, asymmetrical septal left ventricular hypertrophy (LVH) was present in 79% of patients with ATTR (70% sigmoid septum and 30% reverse septal contour), whereas symmetrical LVH was present in 18%, and 3% had no LVH. In patients with cardiac amyloidosis, the pattern of LGE was always typical for amyloidosis (29% subendocardial, 71% transmural), including right ventricular LGE (96%). During follow-up (19 ± 14 months), 65 patients died. ECV independently correlated with mortality and remained independent after adjustment for age, N-terminal pro-B-type natriuretic peptide, ejection fraction, E/E', and left ventricular mass (hazard ratio: 1.164; 95% confidence interval: 1.066 to 1.271; p < 0.01). CONCLUSIONS: Asymmetrical hypertrophy, traditionally associated with hypertrophic cardiomyopathy, was the commonest pattern of ventricular remodeling in ATTR. LGE imaging was typical in all patients with cardiac ATTR. ECV correlated with amyloid burden and was an independent prognostic factor for survival in this cohort of patients.
Asunto(s)
Neuropatías Amiloides Familiares/diagnóstico , Cardiomiopatías/diagnóstico , Imagen por Resonancia Cinemagnética/métodos , Miocardio/patología , Anciano , Diagnóstico Diferencial , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Estudios RetrospectivosRESUMEN
AIMS: High-grade (Perugini grade 2 or 3) cardiac uptake on bone scintigraphy with 99mTechnetium labelled 3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD) has lately been confirmed to have high diagnostic sensitivity and specificity for cardiac transthyretin (ATTR) amyloidosis. We sought to determine whether patient stratification by Perugini grade on 99mTc-DPD scintigraphy has prognostic significance in ATTR amyloidosis. METHODS AND RESULTS: Patient survival from time of 99mTc-DPD scintigraphy was determined in 602 patients with ATTR amyloidosis, including 377 with wild-type ATTR (ATTRwt) and 225 with mutant ATTR (ATTRm) amyloidosis. Patients were stratified according to Perugini grade (0-3) on 99mTc-DPD scan. The prognostic significance of additional patient and disease-related factors at baseline were determined. In the whole cohort, the finding of a Perugini grade 0 99mTc-DPD scan (n = 28) was invariably associated with absence of cardiac amyloid according to consensus criteria as well as significantly better patient survival compared to a Perugini grade 1 (n = 28), 2 (n = 436) or 3 (n = 110) 99mTc-DPD scan (P < 0.005). There were no differences in survival between patients with a grade 1, grade 2 or grade 3 99mTc-DPD scan in ATTRwt (n = 369), V122I-associated ATTRm (n = 92) or T60A-associated ATTRm (n = 59) amyloidosis. Cardiac amyloid burden, determined by equilibrium contrast cardiac magnetic resonance imaging, was similar between patients with Perugini grade 2 and Perugini grade 3 99mTc-DPD scans but skeletal muscle/soft tissue to femur ratio was substantially higher in the latter group (P < 0.001). CONCLUSION: 99mTc-DPD scintigraphy is exquisitely sensitive for identification of cardiac ATTR amyloid, but stratification by Perugini grade of positivity at diagnosis has no prognostic significance.
Asunto(s)
Neuropatías Amiloides Familiares/diagnóstico por imagen , Neuropatías Amiloides Familiares/mortalidad , Cardiopatías/diagnóstico por imagen , Cardiopatías/mortalidad , Tomografía Computarizada por Tomografía Computarizada de Emisión de Fotón Único/métodos , Adulto , Anciano , Anciano de 80 o más Años , Neuropatías Amiloides Familiares/fisiopatología , Amiloidosis , Estudios de Cohortes , Ecocardiografía/métodos , Femenino , Cardiopatías/fisiopatología , Humanos , Estimación de Kaplan-Meier , Imagen por Resonancia Cinemagnética/métodos , Masculino , Persona de Mediana Edad , Músculo Esquelético/diagnóstico por imagen , Músculo Esquelético/fisiopatología , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Sensibilidad y Especificidad , Índice de Severidad de la Enfermedad , Estadísticas no Paramétricas , Análisis de Supervivencia , Tecnecio Tc 99m Sestamibi , Adulto JovenRESUMEN
Abstract The clinical phenotype of familial ATTR amyloidosis depends to some extent on the particular mutation, but differences exist also within mutations. We have previously described that two types of amyloid fibril compositions exist among Swedish ATTRV30M amyloidosis patients, one consisting of a mixture of intact and fragmented ATTR (type A) and one consisting of mainly intact ATTR (type B). The fibril types are correlated to phenotypic differences. Patients with ATTR fragments have a late onset and develop cardiomyopathy, while patients without fragments have an early onset and less myocardial involvement. The present study aimed to determine whether this correlation between fibril type and phenotype is valid for familial ATTR amyloidosis in general. Cardiac or adipose tissues from 63 patients carrying 29 different TTR non-V30M mutations as well as 13 Japanese ATTRV30M patients were examined. Fibril type was determined by western blotting and compared to the patients' age of onset and degree of cardiomyopathy. All ATTR non-V30M patients had a fibril composition with ATTR fragments, except two ATTRY114C patients. No clear conclusions could be drawn about a phenotype to fibril type correlation among ATTR non-V30M patients. In contrast, Japanese ATTRV30M patients showed a similar correlation as previously described for Swedish ATTRV30M patients. This study shows that a fibril composition with fragmented ATTR is very common in ATTR amyloidosis, and suggests that fibrils composed of only full-length ATTR is an exception found only in a subset of patients.
Asunto(s)
Amiloide/química , Amiloidosis Familiar/metabolismo , Cardiomiopatías/metabolismo , Fragmentos de Péptidos/química , Prealbúmina/química , Tejido Adiposo/metabolismo , Tejido Adiposo/patología , Adulto , Amiloide/genética , Amiloide/metabolismo , Amiloidosis Familiar/complicaciones , Amiloidosis Familiar/etnología , Amiloidosis Familiar/patología , Pueblo Asiatico , Cardiomiopatías/complicaciones , Cardiomiopatías/etnología , Cardiomiopatías/patología , Femenino , Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Mutación , Miocardio/metabolismo , Miocardio/patología , Fragmentos de Péptidos/genética , Fragmentos de Péptidos/metabolismo , Fenotipo , Prealbúmina/genética , Prealbúmina/metabolismo , Población BlancaRESUMEN
BACKGROUND: Knowledge of the patterns of myocardial amyloid accumulation could improve the interpretation of electrocardiographic, echocardiographic and magnetic resonance imaging findings of amyloidosis. We assessed the extent and pattern of myocardial amyloid infiltration in explanted or autopsied hearts of patients with cardiomyopathy related to acquired monoclonal immunoglobulin light-chain (AL) or hereditary transthyretin (TTR) related amyloidosis (ATTR). METHODS: We analyzed nine explanted/autopsied hearts from patients with AL (n = 4) and ATTR (n = 5) cardiac amyloidosis. For each heart, a biventricular histological macrosection was obtained at mid-ventricular level and analyzed with both inspective and computer-assisted histologic and histomorphometric analysis aimed in particular at quantifying muscle cells, fibrosis and amyloid infiltration. RESULTS: The extent of amyloid infiltration of the left ventricle (LV) ranged from 45 to 76% (median [interquartile range (IQR)] = 57% [51-64]) of the overall surface. Although LV trabecular and subendocardial were the most infiltrated layers (45-94%, median [IQR] = 73% [67-84] and from 44 to 71%, median [IQR] = 57% [49-59], respectively), intra- and inter-patient heterogeneity was high. Three main patterns of amyloid infiltration of the LV were identified: diffuse (five cases), mainly subendocardial (two cases), and mainly segmental (two cases). The extent of amyloid infiltration of the right ventricle ranged from 48 to 93% (median [IQR] = 61% [59-83]); contributions of parietal and trabecular layers ranged from 32 to 99% (median [IQR] = 63% [47-88]) and from 49 to 93% (median [IQR] = 74% [64-79]), respectively. CONCLUSIONS: In amyloidotic cardiomyopathy, amyloid deposition is highly heterogeneous. Different patterns of infiltration are identifiable, including diffuse, mainly segmental and mainly subendocardial. Awareness of this variability can help the interpretation of ECGs, echocardiograms and magnetic resonance imaging.
Asunto(s)
Amiloidosis Familiar/diagnóstico , Cardiomiopatías/diagnóstico , Amiloidosis Familiar/patología , Amiloidosis Familiar/cirugía , Cardiomiopatías/patología , Cardiomiopatías/cirugía , Femenino , Trasplante de Corazón , Humanos , Masculino , Persona de Mediana Edad , Miocardio/metabolismo , Miocardio/patología , Tamaño de los Órganos , Placa Amiloide/metabolismoRESUMEN
OBJECTIVES: In a cohort of patients with hereditary transthyretin-related amyloidosis (ATTR), we aimed to assess the role of (99m)Tc-3,3-diphosphono-1,2-propanodicarboxylic acid ((99m)Tc-DPD) in detecting myocardial amyloid infiltration across a wide spectrum of cardiac involvement and in predicting major adverse cardiac events (MACE). BACKGROUND: Hereditary transthyretin-related amyloidosis is a challenging and underdiagnosed condition where both early diagnosis and prognosis remain problematic. METHODS: We evaluated 63 patients with ATTR: 40 with and 23 without echocardiographically diagnosed amyloidotic cardiomyopathy (AC). Myocardial uptake of (99m)Tc-DPD scintigraphy was semiquantitatively and visually assessed at 5 min and 3 h. RESULTS: All patients with AC showed moderate-to-severe myocardial tracer uptake (i.e., visual score ≥2). Within the subgroup without AC, only 4 patients (with Ala36Pro, Gly47Ala, Thr49Ala, and Glu89Gln transthyretin mutations) showed myocardial tracer uptake and abnormal heart/whole body retention (H/WB) values: in all these cases endomyocardial biopsies showed amyloidotic infiltration. The H/WB was positively correlated with left ventricular (LV) mean wall thickness (Pearson's r=0.695, p<0.001) and negatively with LV ejection fraction (r=-0.368, p=0.004). The H/WB was an unfavorable predictor of MACE-free survival at Cox univariate analysis and contributed to the multivariate model. Notably, LV wall thickness >12 mm in combination with H/WB >7.5 was associated with the highest event rate. CONCLUSIONS: In ATTR, (99m)Tc-DPD scintigraphy can identify myocardial infiltration across a wide spectrum of morphologic/functional cardiac involvement, allowing an early diagnosis of the disease (even before the appearance of echocardiographic abnormalities). The (99m)Tc-DPD myocardial uptake is a prognostic determinant of "cardiac" outcome in ATTR, either alone or in combination with LV wall thickness.
Asunto(s)
Amiloidosis Familiar/genética , Cardiomiopatías/diagnóstico por imagen , Difosfonatos , Miocardio/patología , Compuestos de Organotecnecio , Prealbúmina/genética , Radiofármacos , Tomografía Computarizada de Emisión de Fotón Único , Adulto , Anciano , Amiloidosis Familiar/complicaciones , Amiloidosis Familiar/mortalidad , Biopsia , Cardiomiopatías/genética , Cardiomiopatías/mortalidad , Cardiomiopatías/fisiopatología , Estudios de Casos y Controles , Distribución de Chi-Cuadrado , Supervivencia sin Enfermedad , Ecocardiografía Doppler de Pulso , Electrocardiografía , Femenino , Humanos , Italia , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Pronóstico , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Índice de Severidad de la Enfermedad , Volumen Sistólico , Factores de Tiempo , Función Ventricular IzquierdaAsunto(s)
Amiloidosis/diagnóstico , Cardiomiopatías/diagnóstico , Anciano , Amiloidosis/complicaciones , Cardiomiopatías/complicaciones , Diagnóstico Diferencial , Electroencefalografía/métodos , Insuficiencia Cardíaca/complicaciones , Insuficiencia Cardíaca/diagnóstico , Humanos , Masculino , Paraproteinemias/complicaciones , Paraproteinemias/diagnósticoAsunto(s)
Neuropatías Amiloides Familiares/complicaciones , Cardiomiopatías/diagnóstico por imagen , Difosfonatos , Corazón/diagnóstico por imagen , Compuestos de Organotecnecio , Anciano , Anciano de 80 o más Años , Neuropatías Amiloides Familiares/diagnóstico por imagen , Cardiomiopatías/epidemiología , Cardiomiopatías/etiología , Femenino , Estudios de Seguimiento , Humanos , Italia/epidemiología , Masculino , Prevalencia , Cintigrafía , Radiofármacos , Reproducibilidad de los Resultados , Estudios RetrospectivosRESUMEN
Although statins have proven efficacy in lowering lipids and improving survival in heart transplantation (HT) recipients, potential drug interactions may limit efficacy and reduce tolerability. This observational study explored the efficacy and tolerability of ezetimibe (10 mg/day) combined with simvastatin (10 or 20 mg/day) prescribed to HT recipients with intolerance to statins (n = 11) or inadequate lipid control despite high-dose statins (n = 14). Substantial reductions in lipid levels were apparent after 2 months (total cholesterol, -22%; low-density lipoproteins, -28%; triglycerides, -31%) and were maintained at 6 months. Reductions were significant in both subgroups of recipients; the vast majority (12 of 14, 85%) of recipients with a history of statins intolerance were able to tolerate ezetimibe plus low-dose simvastatin. This study provides suggestive evidence that treatment with ezetimibe plus low-dose simvastatin is well tolerated by HT recipients and may be effective for treatment of dyslipidemia in HT recipients with statins intolerance or resistance.