natriuretic-peptide--brain and Amyloid-Neuropathies--Familial

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

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amyloid Neuropathies, Familial; Biomarkers; Cardiomyopathies; Double-Blind Method; Female; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Patient Admission; Peptide Fragments; Prealbumin; Recovery of Function; RNA, Small Interfering; RNAi Therapeutics; Time Factors; Treatment Outcome; Ventricular Function, Left; Ventricular Remodeling; Young Adult

Topics: Aged; Aged, 80 and over; Amyloid; Amyloid Neuropathies, Familial; Biomarkers; Cardiomyopathies; Doxycycline; Drug Administration Schedule; Drug Therapy, Combination; Female; Gene Expression; Humans; Male; Middle Aged; Mutation; Natriuretic Peptide, Brain; Patient Dropouts; Peptide Fragments; Prealbumin; Prospective Studies; Survival Analysis; Treatment Failure; Ursodeoxycholic Acid

The uptake of bone-seeking radiotracers in the amyloid heart is well recognised. 99. Patients diagnosed with AL and ATTR (wild-type and inherited) cardiac amyloidosis were prospectively recruited from the Princess Alexandra Hospital Amyloidosis Centre. Patients underwent injection with. 99

Topics: Aged; Amyloid Neuropathies, Familial; Australia; Cardiomyopathies; Echocardiography; Electrocardiography; Female; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Organotechnetium Compounds; Sulfur Compounds; Tomography, Emission-Computed; Troponin I

We included 318 patients in the analysis (n = 86 patients +ATTR-CM; n = 232 patients -ATTR-CM). The median follow-up time was 20.1 months. During the study period, 67% of +ATTR-CM patients received tafamidis (median treatment duration, 17 months). The median H/CL ratio was 1.58 (interquartile range, 1.40-1.75). An H/CL ratio of more than 1.6 or less than 1.6 did not seem to have an impact on survival probability in +ATTR-CM patients (P = .30; hazard ratio, 0.65; 95% confidence interval, 0.31-1.41). Cardiac biomarkers were poorly correlated with H/CL (troponin T, R

Topics: Amyloid Neuropathies, Familial; Cardiomyopathies; Diphosphates; Heart Failure; Humans; Natriuretic Peptide, Brain; Prealbumin; Retrospective Studies; Technetium Tc 99m Pyrophosphate; Troponin T

Timely recognition of cardiac amyloidosis is clinically important, but the diagnosis is frequently delayed.. We sought to identify a multi-modality approach with the highest diagnostic accuracy in patients evaluated by cardiac biopsy, the diagnostic gold standard.. Consecutive patients (N = 242) who underwent cardiac biopsy for suspected amyloidosis within an 18-year period were retrospectively identified. Cardiac biomarker, ECG, and echocardiography results were examined for correlation with biopsy-proven disease. A prediction model for cardiac amyloidosis was derived using multivariable logistic regression.. Among patients with an advanced infiltrative cardiomyopathy phenotype, traditional biomarker, ECG, and echocardiography-based screening tests have limited individual diagnostic utility for cardiac amyloidosis. A prediction algorithm including age, relative wall thickness, E/e', and low limb lead voltage improves the detection of cardiac biopsy-proven disease.

Topics: Age Factors; Aged; Amyloid Neuropathies, Familial; Amyloidosis; Biopsy; Blood Flow Velocity; Cardiomyopathies; Clinical Decision Rules; Echocardiography; Electrocardiography; Female; Heart Ventricles; Humans; Immunoglobulin Light-chain Amyloidosis; Logistic Models; Male; Middle Aged; Multivariate Analysis; Natriuretic Peptide, Brain; Organ Size; Sex Factors; Troponin I

The severity of heart disease varies widely among patients with transthyretin-related cardiac amyloidosis (ATTR-CA) at presentation, and availability of tools able to predict prognosis is essential for clinical and research purposes. Currently, two biomarker-based staging systems are available. The aim of this study was to compare their predictive performance.. A total of 175 patients diagnosed with ATTR-CA (133 wild-type and 42 hereditary) were stratified into different stages based on 2 systems: the first system included N-terminal pro-B-type natriuretic peptide (NT-proBNP) and estimated glomerular filtration rate (eGFR), and the second one included NT-proBNP and troponin I (TnI). Survival estimates and age-adjusted survival for all-cause mortality were analysed over a median follow-up of 27 months (interquartile range 16-43 months).. Predictive performance was more accurate when NT-proBNP and eGFR were used, resulting in effective survival stratification: 64.4 months for stage 1, 44.6 months for stage 2, and 20.5 months for stage 3 (P < 0.01 for stages 1 vs 2; P < 0.0001 for stages 1 vs 3; P < 0.0001 stages 2 vs 3). The combination of NT-proBNP and TnI was unable to effectively differentiate survival: 64.5 months for stage 1, 50.9 months for stage 2, and 27.3 months for stage 3 (P = 0.223 for stages 1 vs 2; P < 0.0001 for stages 1 vs 3; P < 0.0001 for stages 2 vs 3). The same results were seen after age adjustment.. A staging system using NT-proBNP and eGFR had better prognostic accuracy for ATTR-CA patients compared with one using NTproBNP and TnI.

Topics: Aged; Aged, 80 and over; Amyloid Neuropathies, Familial; Biomarkers; Cardiomyopathies; Female; Glomerular Filtration Rate; Humans; Male; Natriuretic Peptide, Brain; Peptide Fragments; Prognosis; Retrospective Studies; Severity of Illness Index; Troponin I

Light Chain (AL) and transthyretin (ATTR) amyloidosis are the most common forms of amyloid cardiomyopathy. Population based studies describing the epidemiology and clinical features of amyloid cardiomyopathy are often based in tertiary medical centers and thus may be limited by referral bias.. We performed a cohort study of 198 patients diagnosed and treated in the Kaiser Permanente Northern California health care system who had a confirmed diagnosis of cardiac amyloidosis between 2001 and 2016. Associations between demographic, clinical, laboratory and imaging data and patient outcomes were quantified using multivariable Cox proportional hazard models for both the AL and ATTR groups. The average length of follow up was 2.8 years (SD 2.9 years) and overall survival was 69.1 percent at one year and 35.4 percent at five years. In the AL group, lower left ventricular ejection fraction (HR 1.33 per 5-point decrease, P < .001), coronary artery disease (HR 3.56, P < .001), and diabetes mellitus (HR 3.19, P < .001) were associated with all-cause mortality. Increasing age at the time of diagnosis with associated with higher all-cause mortality in both the AL and ATTR groups. Higher levels of B-type natriuretic peptide were associated with all-cause mortality in both groups: Top quartile BNP HR 6.17, P < .001 for AL and HR 8.16, P = .002 for ATTR.. This study describes a large cohort of patients with amyloid cardiomyopathy derived from a community based, integrated healthcare system and describes demographic, clinical, and laboratory characteristics associated with mortality and heart failure hospitalization. In this population, coronary artery disease, diabetes mellitus, and high BNP levels were strongly associated with mortality.

Topics: Age Factors; Aged; Aged, 80 and over; Amyloid Neuropathies, Familial; California; Cardiomyopathies; Cause of Death; Cohort Studies; Coronary Artery Disease; Delivery of Health Care, Integrated; Diabetes Mellitus; Echocardiography; Female; Heart Failure; Hospitalization; Humans; Immunoglobulin Light-chain Amyloidosis; Kaplan-Meier Estimate; Male; Middle Aged; Natriuretic Peptide, Brain; Proportional Hazards Models; Stroke Volume; Treatment Outcome

Cardiac transthyretin 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 clinical manifestations, routine electrocardiogram, echocardiography and the traditional requirement for endomyocardial biopsy confirmation.. A 68-year-old female had suffered from lumbago for 5 years with progressive weakness, numbness in both lower limb.. The patient's clinical signs were not specific, but cardiac amyloidosis was suspected based on relative left ventricular apical sparing of longitudinal strain on echocardiography and continuous elevated serum levels of cardiac biomarkers (ultrasensitive cardiac troponin I and NT-proBNP). She was finally diagnosed hereditary transthyretin-related cardiac amylodosis by specific findings of cardiovascular magnetic resonance imaging (CMR), -technetium pyrophosphate (Tc-PYP) scintigraphy and genetic testing.. The patient received medications including diuretics, beta-blockers and angiotensin-converting enzyme inhibitors at the time of hospitalization. Ultimately, however, she refused further treatments and requested discharge from our hospital.. A series of noninvasive technique enables the diagnosis of hereditary transthyretin-related cardiac amyloidosis.. While endomyocardial biopsy is not able to performed, this case demonstrates that a combination of noninvasive techniques, especially CMR, nuclear imaging, and genetic testing, may help us to make a correct diagnosis of hereditary transthyretin-related cardiac amyloidosis.

Topics: Aged; Amyloid Neuropathies, Familial; Cardiac Imaging Techniques; Echocardiography; Female; Genetic Testing; Humans; Magnetic Resonance Imaging; Natriuretic Peptide, Brain; Peptide Fragments; Radionuclide Imaging; Radiopharmaceuticals; Technetium Tc 99m Pyrophosphate; Troponin I

To analyze clinical predictors of mortality in wild-type transthyretin amyloidosis (wt-ATTR).. In total, 191 patients (73.8 ± 0.5 years; 176 males, 15 females) with histologically proven wt-ATTR amyloidosis and genetic exclusion of a transthyretin gene variant were included. Comprehensive clinical characteristics, ECG, biomarkers, and echocardiography were analyzed retrospectively. Strain analyses were performed offline using TomTec Imaging Systems, Germany. Univariable and multivariable analyses predicting all-cause mortality were carried out.. Patients presented with significant heart failure (NYHA 2.5 ± 0.8; NT-proBNP 3644 (4981) pg/ml; LV ejection fraction 45.8 ± 15.0%). LogNT-proBNP correlated with indicators of disease severity. Similar results were obtained for basal and midventricular, but not apical longitudinal strain. During median follow-up of 26.2 ± 1.7 months 46 (25.5%) patients died (40 males, 23%; six females, 40%). In female patients 1-/2-year survival was lower [92.9/67.7%; median survival 30.6 (21.1-40.1) months] when compared to male patients [96.5%/86.6%; median survival 63.9 (45.8-82.0) months]. Parameters associated with survival were NT-proBNP, NYHA class, heart rate, midventricular longitudinal strain, mitral annular plane systolic excursion (MAPSE), Karnofsky Index, systolic blood pressure, estimated glomerular filtration rate. Multivariable analysis revealed MAPSE and NT-proBNP as independent predictors of mortality in the whole cohort and midventricular strain in the subgroup of patients in sinus rhythm.. No sex-specific bias was observed between male and female patients with wt-ATTR regarding age at onset and morphological characteristics. Multivariable analysis revealed MAPSE and NT-proBNP as independent predictors of survival in the whole cohort, whereas midventricular longitudinal strain was the only independent predictor in patients in sinus rhythm.

Topics: Aged; Aged, 80 and over; Amyloid Neuropathies, Familial; Biomarkers; Blood Pressure; Cardiomyopathies; Echocardiography; Electrocardiography; Female; Germany; Heart Rate; Humans; Kaplan-Meier Estimate; Karnofsky Performance Status; Male; Mitral Valve; Multivariate Analysis; Natriuretic Peptide, Brain; Peptide Fragments; Prognosis; Proportional Hazards Models; Retrospective Studies; Risk Assessment; Risk Factors; Stroke Volume; Time Factors; Ventricular Function, Left

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.

Topics: Adult; Aged; Amyloid Neuropathies, Familial; Biomarkers; Cohort Studies; Female; Heart Diseases; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Prognosis; Sensitivity and Specificity

Cardiac troponins and natriuretic peptides are established for risk stratification in light-chain amyloidosis. Data on cardiac biomarkers in transthyretin amyloidosis (ATTR) are lacking.. Patients (n = 1617) with any of the following cardiac biomarkers, BNP (n = 1079), NT-proBNP (n = 550), troponin T (n = 274), and troponin I (n = 108), available at baseline in the Transthyretin Amyloidosis Outcomes Survey (THAOS) were analyzed for differences between genotypes and phenotypes and their association with survival. Median level of BNP was 68.0 pg/mL (IQR 30.5-194.9), NT-proBNP 337.9 pg/mL (IQR 73.0-2584.0), troponin T 0.03 μg/L (IQR 0.01-0.05), and troponin I 0.08 μg/L (IQR 0.04-0.13). NT-proBNP and BNP were higher in wild-type than mutant-type ATTR, troponin T and I did not differ, respectively. Non-Val30Met patients had higher BNP, NT-proBNP and troponin T levels than Val30Met patients, but not troponin I. Late-onset Val30Met was associated with higher levels of troponin I and troponin T compared with early-onset. 115 patients died during a median follow-up of 1.2 years. Mortality increased with increasing quartiles (BNP/NT-proBNP Q1 = 1.7%, Q2 = 5.2%, Q3 = 21.7%, Q4 = 71.3%; troponin T/I Q1 = 6.5%, Q2 = 14.5%, Q3 = 33.9%, Q4 = 45.2%). Three-year overall-survival estimates for BNP/NT-proBNP and troponin T/I quartiles differed significantly (p<0.001). Stepwise risk stratification was achieved by combining NT-proBNP/BNP and troponin T/I. From Cox proportional hazards model, age, modified body mass index, mutation (Val30Met vs. Non-Val30Met) and BNP/NT-proBNP (Q1-Q3 pooled vs. Q4) were identified as independent predictors of survival in patients with mutant-type ATTR.. In this ATTR patient cohort, cardiac biomarkers were abnormal in a substantial percentage of patients irrespective of genotype. Along with age, mBMI, and mutation (Val30Met vs. Non-Val30Met), cardiac biomarkers were associated with surrogates of disease severity with BNP/NT-proBNP identified as an independent predictor of survival in ATTR.. ClinicalTrials.gov NCT00628745.

Topics: Amyloid Neuropathies, Familial; Biomarkers; Genotype; Humans; Natriuretic Peptide, Brain; Phenotype; Surveys and Questionnaires; Troponin I; Troponin T

Topics: Amyloid; Amyloid Neuropathies, Familial; Animals; Biomarkers; Cardiomyopathies; Collagen Type IV; Disease Models, Animal; Doxycycline; Drug Administration Schedule; Drug Therapy, Combination; Gene Expression; Heart; Heat Shock Transcription Factors; Humans; Male; Mice; Mice, Transgenic; Mutation; Natriuretic Peptide, Brain; Peptide Fragments; Prealbumin; Ursodeoxycholic Acid

Aortic stenosis (AS) and transthyretin cardiac amyloidosis (TTR-CA) are both frequent in elderly. The combination of these two diseases has never been investigated.. To describe patients with concomitant AS and TTR-CA.. Six cardiologic French centres identified retrospectively cases of patients with severe or moderate AS associated with TTR-CA hospitalized during the last 6 years.. Sixteen patients were included. Mean ± SD age was 79 ± 6 years, 81% were men. Sixty per cent were NYHA III-IV, 31% had carpal tunnel syndrome, and 56% had atrial fibrillation. Median (Q1;Q4) NT-proBNP was 4382 (2425;4730) pg/mL and 91% had elevated cardiac troponin level. Eighty-eight per cent had severe AS (n = 14/16), of whom 86% (n = 12) had low-gradient AS. Mean ± SD interventricular septum thickness was 18 ± 4 mm. Mean left ventricular ejection fraction and global LS were 50 ± 13% and -7 ± 4%, respectively. Diagnosis of TTR-CA was histologically proven in 38%, and was based on strong cardiac uptake of the tracer at biphosphonate scintigraphy in the rest. Eighty-one per cent had wild-type TTR-CA (n = 13), one had mutated Val122I and 19% did not had genetic test (n = 3). Valve replacement was surgical in 63% and via transcatheter in 13%. Median follow-up in survivors was 33 (16;65) months. Mortality was of 44% (n = 7) during the whole follow-up period.. Combination of AS and TTR-CA may occur in elderly patients particularly those with a low-flow low-gradient AS pattern and carries bad prognosis. Diagnosis of TTR-CA in AS is relevant to discuss specific treatment and management.

Topics: Aged; Amyloid Neuropathies, Familial; Aortic Valve Stenosis; Female; Humans; Male; Natriuretic Peptide, Brain; Peptide Fragments; Prealbumin; Stroke Volume; Treatment Outcome

Wild-type transthyretin cardiac amyloidosis (ATTRwt) is increasingly recognized as an important cause of heart failure.. The purpose of this study was to determine the natural history of ATTRwt and the predictors of survival.. We retrospectively reviewed patients diagnosed with ATTRwt at the Mayo Clinic through 2013 and recorded clinical data and survival data. Factors affecting overall survival (OS) were identified, and a prognostic staging system was developed.. The median age of the 360 patients diagnosed before death was 75 years (range: 47 to 94 years), and 91% were male. Presenting signs and symptoms included dyspnea or heart failure in 67% and atrial arrhythmias in 62%. Median OS from diagnosis was 3.6 years and did not change over time. Multivariate predictors of mortality included age, ejection fraction, pericardial effusion, N-terminal pro-B-type natriuretic peptide, and troponin T. A staging system was developed that used thresholds of troponin T (0.05 ng/ml) and N-terminal pro-B-type natriuretic peptide (3,000 pg/ml). The respective 4-year OS estimates were 57%, 42%, and 18% for stage I (both values below cutoff), stage II (one above), and stage III (both above), respectively. Stage III patients were at an increased risk of mortality after adjustment for age and sex compared with stage I patients (hazard ratio: 3.6; p < 0.001).. The natural history of ATTRwt is poor. We report a novel cardiac biomarker staging system that enables risk stratification in an era of emerging treatment strategies.

Topics: Aged; Aged, 80 and over; Amyloid Neuropathies, Familial; Female; Heart Diseases; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Prognosis; Retrospective Studies; Risk Assessment; Survival Rate; Troponin T

Few studies have analyzed the clinical and echocardiographic differences between light-chain (AL) and transthyretin (TTR) amyloidosis.. The aim of the present research was to compare, in a real-world setting, the clinical and echocardiographic profiles of these kinds of amyloidosis, at the time of diagnosis, using new-generation echocardiography.. Seventy-nine patients with AL and 48 patients with TTR amyloidosis were studied.. According to the criterion of mean left ventricular (LV) thickness >12 mm, 45 AL (C-AL) and all TTR patients had cardiac amyloidotic involvement, whereas 34 AL patients did not. TTR patients had increased right ventricular (RV) and LV chambers with increased RV and LV wall thickness and reduced LV ejection fraction and fractional shortening. Furthermore, TTR patients showed lower N-terminal pro Brain Natriuretic Peptide concentrations and New York Heart Association functional class when compared with C-AL.. Our data show that at time of first diagnosis, TTR patients have a more advanced amyloidotic involvement of the heart, despite less severe symptoms and biohumoral signs of heart failure. We can hypothesize that we observed different diseases at different stages. In fact, AL amyloidosis is a multiorgan disease with quick progression rate, that becomes rapidly symptomatic, whereas TTR amyloidosis might have a slow progression rate and might remain poorly symptomatic for a greater amount of time.

Topics: Aged; Aged, 80 and over; Amyloid Neuropathies, Familial; Amyloidosis; Biomarkers; Cardiomyopathies; Cross-Sectional Studies; Disease Progression; Echocardiography, Doppler; Female; Humans; Immunoglobulin Light Chains; Male; Middle Aged; Mutation; Natriuretic Peptide, Brain; Peptide Fragments; Prealbumin; Predictive Value of Tests; Severity of Illness Index; Troponin I; Ventricular Function, Left; Ventricular Function, Right

Cardiac amyloidosis due to amyloid fibril deposition in the heart results in cardiomyopathy (CMP) with heart failure (HF) and/or conduction disturbances. Immunoglobulin light chain-related CMP (AL-CMP) features rapidly progressive HF with an extremely poor prognosis compared with a CMP due to the deposition of mutant (ATTR) amyloidosis or wild-type (senile systemic amyloidosis, SSA) transthyretin (TTR) proteins. Amyloid fibril deposition disrupts the myocardial extracellular matrix (ECM) homeostasis, which is partly regulated by matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs). We therefore tested the hypothesis that circulating levels of MMPs and TIMPs in patients with AL-CMP and TTR-related CMP (TTR-CMP) are dissimilar and indicative of cardiac amyloid disease type.. Fifty AL-CMP patients were compared with 50 TTR-CMP patients (composed of 38 SSA and 12 ATTR patients). Clinical and laboratory evaluations including echocardiography were performed at the initial visit to our center and analyzed. Serum MMP-2, MMP-9, TIMP-1, and TIMP-2 levels were determined by ELISA. Compared with TTR-CMP patients, AL-CMP patients had higher levels of brain natriuretic peptide (BNP), troponin I (TnI), MMP-2, TIMP-1, and MMP-2/TIMP-2 ratio, despite less left ventricular (LV) hypertrophy and better preserved LV ejection fraction. Mortality was worse in AL-CMP patients than in TTR-CMP patients (log-rank P<0.01). MMP-2/TIMP-2 plus BNP and TnI showed the highest discriminative ability for distinguishing AL-CMP from TTR-CMP. Female sex (HR, 2.343; P=0.049) and BNP (HR, 1.041; P<0.01) were predictors for mortality for all patients with cardiac amyloidoses. Only BNP was a predictor of death in AL-CMP patients (HR, 1.090; P<0.01). There were no prognostic factors for all-cause death in TTR-CMP patients.. Circulating concentrations of MMPs and TIMPs may be useful in differentiating patients with AL-CMP from those with TTR-CMP, resulting in earlier diagnostic vigilance, and may add prognostic information. In addition to an elevated BNP level, female sex increased the risk of death in patients with cardiac amyloidoses.

Topics: Aged; Amyloid Neuropathies, Familial; Amyloidosis; Cardiomyopathies; Extracellular Matrix; Female; Humans; Hypertrophy, Left Ventricular; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Matrix Metalloproteinases; Myocardium; Natriuretic Peptide, Brain; Stroke Volume; Tissue Inhibitor of Metalloproteinase-1; Tissue Inhibitor of Metalloproteinase-2; Tissue Inhibitor of Metalloproteinases; Troponin I; Ultrasonography

Topics: Amyloid Neuropathies, Familial; Cardiomegaly; Female; Heart Failure; Humans; Male; Natriuretic Peptide, Brain; Peptide Fragments; Ultrasonography

Familial amyloid polyneuropathy (FAP) mainly targets the peripheral nervous system and heart. Early noninvasive detection of cardiac impairment is critical for therapeutic management.. To assess if amino-terminal pro-brain natriuretic peptide (NT-proBNP) or troponin T (cTnT) can predict echocardiographic left-ventricle (LV) impairment in FAP.. Thirty-six asymptomatic carriers and patients with FAP had echocardiographic measurement of left-ventricular (LV) systolic function, hypertrophy (LVH) and estimation of filling pressure (FP).. Overall, median age, NT-proBNP, and LV ejection fraction were, respectively, 59 years (41-74), 323 pg/ml (58-1960), and 60% (51-66). Twelve patients had increased cTnT. Prevalence of ATTR gene mutations was 53% for Val30Met. Four individuals were asymptomatic, 6 patients had isolated neurological clinical signs, and 26 had echo-LV abnormalities. The ROC curve identified NT-proBNP patients with echo-LV abnormalities (area: 0.92; (0.83-0.99), p = 0.001) at a threshold >82 pg/ml with a sensitivity of 92%, and a specificity of 90%. Increased in NT-proBNP occurred in patients with SD and/or LVH with or without increase in FP. Elevated cTnT (>0.01 ng/ml) was only observed in patients with LVH and systolic dysfunction, with or without FP.. In FAP, NT-proBNP was associated with cardiac impairment suggesting that NT-proBNP could be used in carriers or in FAP patients with only neurologic symptoms for identifying the appropriate time to start cardiac echocardiographic assessment and follow-up. cTnT identified patients with severe cardiac disease.

Topics: Adult; Aged; Amyloid Neuropathies, Familial; Cardiomyopathies; Echocardiography; Female; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Troponin T

To characterize patients with cardiac amyloidosis using echocardiography, electrocardiogram (ECG) and right heart catheterization (RHC).. Fourteen patients with biopsy verified light chain or transthyretin cardiac amyloidosis were included. All patients had heart failure with markedly elevated NT-proBNP. Echocardiography demonstrated biventricular hypertrophy, left atrial enlargement and normal to slightly reduced left ventricular ejection fraction. Tissue Doppler septal é was low and median E/é was high. Within 6 months RHC was performed in eight of the patients. The restrictive filling pattern demonstrated by echocardiography corresponded well to median pulmonary wedge pressure (21 mmHg). Systolic pulmonary artery pressure (SPAP) was increased, whereas cardiac output and stroke volume were seen to be decreased with both methods. ECG demonstrated: low voltage (36%), abnormal R-progression (65%), ST-T abnormalities (71%) and high incidence of fibrillation (36%). In addition, a case report following the treatment of melphalan and dexamethasone is presented with improvement of hypertrophy, SPAP, left ventricular mass and é.. These findings should lead to a suspicion of cardiac amyloidosis and suggest further investigation.

Topics: Aged; Aged, 80 and over; Amyloid Neuropathies, Familial; Cardiac Catheterization; Cardiomegaly; Dexamethasone; Echocardiography, Doppler; Electrocardiography; Female; Heart Failure; Humans; Male; Melphalan; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Pulmonary Wedge Pressure; Stroke Volume; Ventricular Function, Left

Familial amyloid polyneuropathy (FAP) is a dominantly inherited multi-system disease associated with transthyretin (TTR) mutations. Previous series have predominantly described patients with the TTR variant Val30Met (V30M), which is the most prevalent cause of FAP worldwide. Here, we report the dominant cardiac phenotype and outcome of FAP associated with TTR Thr60Ala (T60A), the most common UK variant.. Sixty consecutive patients with FAP associated with TTR T60A (FAP T60A) were prospectively evaluated in two centres between 1992 and 2009. Median (range) age of symptom development was 63 (45-78) years. A family history of amyloidosis was present in only 37%. Autonomic and peripheral neuropathy were present in 44 and 32 patients, respectively, at diagnosis. Cardiac involvement was evident on echocardiography at diagnosis in 56 patients, but was associated with reduced QRS voltages on electrocardiography in only 16% evaluable cases. Seventeen patients received implantable anti-arrhythmic devices. Median survival was 6.6 years following onset of symptoms and 3.4 years from diagnosis, and correlated with serum N-terminal prohormone brain natriuretic peptide (NT-proBNP) concentration and certain echocardiographic parameters at the latter. Orthotopic liver transplantation (OLT), performed to eliminate the predominant hepatic source of variant TTR T60A protein, was performed in eight patients including one who received a concomitant cardiac transplant. Cardiac amyloidosis progressed in all lone OLT recipients, of whom four died within 5 years.. Cardiac amyloidosis is almost always present at diagnosis in FAP T60A, and is a major determinant of its poor prognosis. Outcome of liver transplantation in FAP T60A has been discouraging.

Topics: Aged; Amyloid Neuropathies, Familial; Arrhythmias, Cardiac; Cardiomyopathies; Electrocardiography; Humans; Kaplan-Meier Estimate; Liver Transplantation; Middle Aged; Mutation; Natriuretic Peptide, Brain; Peptide Fragments; Phenotype; Prealbumin; Prospective Studies

The progression of cardiac amyloidosis is a prognostic factor after liver transplantation (LT) in familial amyloid polyneuropathy (FAP). The aim of this study was to assess myocardial changes in FAP amyloidgenic transthyretin (ATTR) Val30Met after LT.. Twelve Japanese FAP ATTR Val30Met patients who underwent LT and were followed for more than 2 years, were examined with serial echocardiography after LT. Serum BNP levels were measured in 9 patients.. A significant increase in mean left atrial diameter and interventricular septal thickness was observed after LT. The increase in left atrial diameter was correlated with the presence of granular sparkling echo (GSE) at preoperative examination. Serum brain natriuretic peptide (BNP) levels in patients with left atrial diameter dilation (152.0+/-157.6 pg/mL) were higher than in those without left atrial diameter dilation (32.0+/-30.0 pg/mL).. LAD and IVS were significantly increased after LT compared with preoperative examinations in Japanese FAP ATTR Val30Met patients. BNP is an important biochemical indicator of myocardiac dysfunction in FAP patients. GSE is a useful echocardiographic marker to predict cardiac amyloidosis after LT.

Topics: Adult; Aged; Amyloid Neuropathies, Familial; Amyloidosis; Biomarkers; Cardiomyopathies; Female; Humans; Liver Transplantation; Male; Middle Aged; Natriuretic Peptide, Brain; Ultrasonography

Cardiomyopathy is a well known complication in familial amyloidotic polyneuropathy (FAP). Troponin T and B-natriuretic peptide (BNP) have been shown to be excellent markers for heart complications in AL-amyloidosis. The aim of the study was to investigate troponin T, troponin I and BNP as markers for myocardial damage and failure in FAP.. Retrospective investigation of patients with FAP.. Tertiary referral centre.. Twenty-nine patients who had been submitted for evaluation of FAP.. Two-dimensional M-mode and Doppler echocardiography and strain echocardiographic examination. Measurement of Troponin T, troponin I and BNP.. Troponin T was detectable in only three patients who all had abnormal interventricular septal (IVS) thickness. Troponin I was abnormal in six patients (21%), of which only two had an increased IVS thickness. The heart function was generally well preserved in the patients in spite of hypertrophy of the IVS in 14 patients. BNP was elevated in 22 patients (76%), and it correlated significantly with IVS thickness and basal septal strain.. Transthyretin amyloid seems to be less harmful to myocytes than that of AL amyloid as evaluated by serum troponin T and I as well as by echocardiography. BNP appears to be a sensitive marker for cardiomyopathy in FAP, and could prove valuable for follow-up purposes as has been shown for AL-amyloidosis patients.

Topics: Adult; Aged; Amyloid; Amyloid Neuropathies, Familial; Biomarkers; Cardiomyopathies; Female; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Prealbumin; Retrospective Studies; Troponin I; Troponin T; Ultrasonography