natriuretic-peptide--brain and Fabry-Disease

Current therapies have not shown benefit in organ damage reversal in Fabry disease (FD), but biomarkers could help risk stratification and prognosis. We investigated if several biomarkers of cardiac fibrosis, cardiac wall stress, myocardial injury, renal function and inflammation, are associated with early cardiac affectation in FD patients. We included FD patients from four cardiology outpatient clinics of southeastern Spain. At inclusion, Galectin-3 (Gal-3), N-terminal proB-type natriuretic peptide, high sensitivity troponin T (hsTnT), β-trace protein (BTP) and interleukin-6 concentrations were measured. The relation of biomarkers concentrations with clinical features, cardiac involvement and organ affectation according to the Mainz Severity Score Index (MSSI) was investigated. 44 FD patients (n = 21 affected and n = 23 unaffected) were compared to age and sex-respectively matched healthy controls. Significant differences in biomarkers' concentration between FD groups were observed. Importantly, Gal-3 and BTP levels were higher in unaffected patients when compared with age and sex-matched healthy controls (both p < 0.05). All the biomarkers correlated with clinical features. When cut-off values for clinical affectation (measured as MSSI ≥ 20) were established, only hsTnT (OR 30.69, 95% CI 2.70-348.42) and male sex (OR 8.17, 95% CI 1.16-57.75) were independently associated with cardiac damage by multivariate regression analysis. Gal-3 and BTP levels are increased in unaffected FD patients compared to healthy controls. This suggests that these biomarkers could be useful for the early detection of cardiac affectation in FD patients. On the other hand, hsTnT and male sex are independent risk factors for established clinical cardiac damage in FD.

Topics: Adult; alpha-Galactosidase; Biomarkers; Blood Proteins; Fabry Disease; Female; Galectin 3; Galectins; Healthy Volunteers; Humans; Interleukin-6; Intramolecular Oxidoreductases; Lipocalins; Male; Middle Aged; Mutation; Natriuretic Peptide, Brain; Peptide Fragments; Prognosis; Risk Factors; Spain; Troponin T; Young Adult

Topics: Aged; alpha-Galactosidase; Biopsy; Echocardiography; Electrocardiography; Enzyme Replacement Therapy; Fabry Disease; Fibrosis; Heart; Heart Ventricles; Humans; Magnetic Resonance Spectroscopy; Male; Multidetector Computed Tomography; Natriuretic Peptide, Brain; Tachycardia, Ventricular

High-sensitivity troponin (hs-TNT), a biomarker of myocardial damage, might be useful for assessing fibrosis in Fabry cardiomyopathy. We performed a prospective analysis of hs-TNT as a biomarker for myocardial changes in Fabry patients and a retrospective longitudinal follow-up study to assess longitudinal hs-TNT changes relative to fibrosis and cardiomyopathy progression.. For the prospective analysis, hs-TNT from 75 consecutive patients with genetically confirmed Fabry disease was analyzed relative to typical Fabry-associated echocardiographic findings and total myocardial fibrosis as measured by late gadolinium enhancement (LE) on magnetic resonance imaging. Longitudinal data (3.9±2.0 years), including hs-TNT, LE, and echocardiographic findings from 58 Fabry patients, were retrospectively collected. Hs-TNT level positively correlated with LE (linear correlation coefficient, 0.72; odds ratio, 32.81 [95% CI, 3.56-302.59]; P=0.002); patients with elevated baseline hs-TNT (>14 ng/L) showed significantly increased LE (median: baseline, 1.9 [1.1-3.3] %; follow-up, 3.2 [2.3-4.9] %; P<0.001) and slightly elevated hs-TNT (baseline, 44.7 [30.1-65.3] ng/L; follow-up, 49.1 [27.6-69.5] ng/L; P=0.116) during follow-up. Left ventricular wall thickness and EF of patients with elevated hs-TNT were decreased during follow-up, indicating potential cardiomyopathy progression.. hs-TNT is an accurate, easily accessible clinical blood biomarker for detecting replacement fibrosis in patients with Fabry disease and a qualified predictor of cardiomyopathy progression. Thus, hs-TNT could be helpful for staging and follow-up of Fabry patients.

Topics: Adult; Analysis of Variance; Biomarkers; Cardiomyopathies; Disease Progression; Echocardiography; Fabry Disease; Female; Fibrosis; Humans; Hypertrophy, Left Ventricular; Magnetic Resonance Angiography; Male; Myocardium; Natriuretic Peptide, Brain; Peptide Fragments; Prospective Studies; Retrospective Studies; Troponin

In spite of several research studies help to describe the heart in Fabry disease (FD), the cardiomyopathy is not entirely understood. In addition, the impact of blood pressure and alterations in geometry have not been systematically evaluated.. In 74 FD patients (mean age 36±12 years; 45 females) the extent of myocardial fibrosis and its progression were quantified using cardiac magnetic-resonance-imaging with late enhancement technique (LE). Results were compared to standard echocardiography complemented by 2D-speckle-tracking, 3D-sphericity-index (SI) and standardized blood pressure measurement. At baseline, no patient received enzyme replacement therapy (ERT). After 51±24 months, a follow-up examination was performed.. Systolic blood pressure (SBP) was higher in patients with vs. without LE: 123±17 mmHg vs. 115±13 mmHg; P = 0.04. A positive correlation was found between SI and the amount of LE-positive myocardium (r = 0.51; P<0.001) indicating an association of higher SI in more advanced stages of the cardiomyopathy. SI at baseline was positively associated with the increase of LE-positive myocardium during follow-up. The highest SBP (125±19 mmHg) and also the highest SI (0.32±0.05) was found in the subgroup with a rapidly increasing LE (ie, ≥0.2% per year; n = 16; P = 0.04). Multivariate logistic regression analysis including SI, SBP, EF, left ventricular volumes, wall thickness and NT-proBNP adjusted for age and sex showed SI as the most powerful parameter to detect rapid progression of LE (AUC = 0.785; P<0.05).. LV geometry as assessed by the sphericity index is altered in relation to the stage of the Fabry cardiomyopathy. Although patients with FD are not hypertensive, the SBP has a clear impact on the progression of the cardiomyopathy.

Topics: Adult; Blood Pressure; Cardiomyopathies; Cohort Studies; Disease Progression; Electrocardiography; Fabry Disease; Female; Fibrosis; Follow-Up Studies; Heart Ventricles; Humans; Logistic Models; Magnetic Resonance Imaging; Male; Multivariate Analysis; Natriuretic Peptide, Brain; Peptide Fragments; ROC Curve; Ultrasonography

Enzyme replacement therapy has the potential to delay or reverse adverse cardiac remodeling in Anderson-Fabry disease (AFD); however, the current indications for enzyme replacement therapy rely on detecting relatively advanced features of the disease. We aimed to determine the relation between the serum N-terminal pro-brain natriuretic peptide (NT-proBNP) concentration and cardiac abnormalities in patients with AFD. We hypothesized that it might help to detect early disease. NT-proBNP was measured under at rest conditions in 117 patients with AFD (age 48 ± 15 years, 46.2% men). All patients underwent clinical evaluation with electrocardiography and echocardiography. The median NT-proBNP concentration was 24 pmol/L (range <5 to 6,059). Of the 117 patients, 67 (57%) had elevated, age-corrected, NT-proBNP levels. In the 56 patients (48%) with normal echocardiographic findings, the NT-proBNP levels were greater than the age-predicted cutoffs in 10 of 25 patients with abnormal electrocardiographic findings and 3 of 31 patients with normal electrocardiographic findings (p <0.05). On multiple regression analysis, age, creatinine, left atrial volume index, E/Ea, and the presence of abnormal electrocardiographic findings were independently associated with log NT-proBNP (R(2) = 0.67, p <0.05). In conclusion, NT-proBNP concentrations were elevated in patients with AFD and early cardiac involvement, suggesting its measurement could assist in decisions regarding the timing of enzyme replacement therapy.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Biomarkers; Biopsy; Cross-Sectional Studies; Diagnosis, Differential; Echocardiography, Doppler; Electrocardiography; Fabry Disease; Female; Follow-Up Studies; Heart Ventricles; Humans; Hypertrophy, Left Ventricular; Incidence; Male; Microscopy, Electron; Middle Aged; Myocytes, Cardiac; Natriuretic Peptide, Brain; Peptide Fragments; Prognosis; Prospective Studies; Protein Precursors; Risk Factors; United Kingdom; Ventricular Function, Left; Young Adult

Fabry disease (FD) is a lysosomal storage disorder caused by mutations in the α-galactosidase A gene. It is characterized by the deposition of the incompletely metabolized substrate globotriaosylceramide in several cell types and multisystem involvement. Major morbidity results from renal, cardiac and cerebrovascular pathology, mediated by endothelial dysfunction. We examined the potential utility of Cystatin C and natriuretic peptides as biomarkers in FD, and evaluated serum levels in 89 FD patients with varying degrees of disease severity. The results revealed that as a prognostic marker, Cystatin C is a good and cost effective indicator of early renal dysfunction and/or heart failure in FD. It is also more useful than serum creatinine in detecting mild renal damage and small decreases in glomerular filtration. In addition, the natriuretic peptide NT-proBNP, was elevated in patients with FD and cardiac involvement, and found to be an adequate detection marker, not only of cardiac involvement, but also of diastolic dysfunction.

Topics: Adolescent; Adult; Aged; Biomarkers; Cystatin C; Enzyme Replacement Therapy; Fabry Disease; Female; Glomerular Filtration Rate; Humans; Kidney; Logistic Models; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Phenotype; ROC Curve; Statistics, Nonparametric

Fabry disease is an X-linked lysosomal storage disorder caused by mutations of the α-galactosidase A gene (GLA), and the disease is a relatively prevalent cause of left ventricular hypertrophy mimicking idiopathic hypertrophic cardiomyopathy. We assessed clinically 5 patients of a three-generation family and also searched for GLA mutations in 10 family members. The proband had left ventricular hypertrophy with localized thinning in the basal posterior wall and late gadolinium enhancement (LGE) in the near-circumferential wall in cardiovascular magnetic resonance images and her sister had vasospastic angina pectoris without organic stenosis of the coronary arteries. LGE notably appeared in parallel with decreased α-galactosidase A activity and increased NT-pro BNP in our patients. We detected a new GLA missense mutation (G195V) in exon 4, resulting in a glycine-to-valine substitution. Of the 10 family members, 5 family members each were positive and negative for this mutation. These new data extend our clinical and molecular knowledge of GLA gene mutations and confirm that a novel missense mutation in the GLA gene is important not only for a precise diagnosis of heterozygous status, but also for confirming relatives who are negative for this mutation.

Topics: Adult; alpha-Galactosidase; Amino Acid Substitution; Bundle-Branch Block; Coronary Angiography; Coronary Vasospasm; DNA Mutational Analysis; Echocardiography; Electrocardiography; Exons; Fabry Disease; Female; Genotype; Glycine; Humans; Hypertrophy, Left Ventricular; Japan; Magnetic Resonance Imaging; Male; Microscopy, Electron; Middle Aged; Mutation, Missense; Myocardium; Natriuretic Peptide, Brain; Pedigree; Peptide Fragments; Signal Processing, Computer-Assisted; Valine; Young Adult

A case of cardiomyopathy and ventricular tachycardia previously assumed to be idiopathic in origin is described. Investigation with cardiac magnetic resonance imaging prompted the diagnosis and successful treatment of an underlying disorder based on typical scarring patterns seen with late gadolinium enhancement. The present report suggests that clinicians should have a low threshold for actively excluding this condition in patients presenting with cardiomyopathy, even in the absence of other disease features, particularly if typical scarring patterns are found on cardiac magnetic resonance imaging because disease-specific therapy appears to significantly improve both symptoms and prognosis.

Topics: alpha-Galactosidase; Cardiomyopathies; Enzyme Replacement Therapy; Fabry Disease; Heart Ventricles; Humans; Magnetic Resonance Imaging, Cine; Male; Middle Aged; Natriuretic Peptide, Brain; Tachycardia, Ventricular

There are no data regarding changes in plasma brain natriuretic peptide (BNP) levels in patients with Fabry's diseases during enzyme replacement therapy (ERT). We describe a patient with Fabry's disease who demonstrated the improvement in plasma brain BNP levels in response to ERT. Fabry's disease is an X-linked lysosomal storage disorder caused by a deficiency of the enzyme alpha-galactosidase A, which results in progressive intracellular accumulation of globotriaosylceramide (Gb3) in various organs including the heart. Cardiac involvement is frequent in Fabry's disease, resulting in cardiac dysfunction due to hypertrophic changes of the myocardium and thickening of the valves. Although ERT has been reported to improve cardiac function, no consensus has been reached regarding the effectiveness of ERT in female patients with heterozygous Fabry's disease. We report a 44-year-old woman having heterozygous Fabry's disease, who showed mitral valve thickening and regurgitation on echocardiogram. ERT was performed by intravenous infusion of recombinant alpha-galactosidase A every 2 weeks. We assessed the influences of ERT on cardiac function by measuring echocardiograhic parameters and monitoring BNP levels, which show treatment-induced drop in patients with heart failure. Although her cardiac function and mitral regurgitation assessed by echocardiography had not improved 18 months after the beginning of ERT, the plasma BNP level, which was 91.5 pg/ml before ERT, fell to 18.9 pg/ml. In conclusion, plasma BNP levels may be useful for evaluating the effectiveness of ERT for heterozygous Fabry's disease, even in patients who demonstrate no improvement in echocardiographic parameters of cardiac structure and function.

Topics: Adult; alpha-Galactosidase; Echocardiography; Electrocardiography; Fabry Disease; Female; Humans; Infusions, Intravenous; Natriuretic Peptide, Brain; Pedigree