Susana Ferreira

N-Terminal–Pro-Brain Natriuretic Peptide Predicts Outcome After Hospital Discharge in Heart Failure Patients

Background—Heart failure (HF) is responsible for a huge burden in hospital care. Our goal was to evaluate the value of N-terminal–pro-brain natriuretic peptide (NT-proBNP) in predicting death or hospital readmission after discharge of HF patients. Methods and Results—We included 182 patients consecutively admitted to hospital because of decompensated HF. Patients were followed up for 6 months. The primary end point was death or readmission. Twenty-six patients died in hospital. The median admission NT-proBNP level was 6778.5 pg/mL, and the median level at discharge was 4137.0 pg/mL (P<0.001). Patients were classified into 3 groups: (1) decreasing NT-proBNP levels by at least 30% (n=82), (2) no significant modifications on NT-proBNP levels (n=49), and (3) increasing NT-proBNP levels by at least 30% (n=25). The primary end point was observed in 42.9% patients. Variables associated with an increased hazard of death and/or hospital readmission in univariate analysis were length of hospitalization, heart rate, signs of volume overload, no use of ACE inhibitors, higher NYHA class at discharge, admission and discharge NT-proBNP, and the change in NT-proBNP levels. The variation in NT-proBNP was the strongest predictor of an adverse outcome. Independent variables associated with an increased risk of readmission or death were signs of volume overload and the change in NT-proBNP levels. Conclusions—Variations in NT-proBNP levels are related to hospital readmission and death within 6 months. NT-proBNP levels are potentially useful in the evaluation of treatment efficacy and might help clinicians in planning discharge of HF patients. Whether therapeutic strategies aimed to lower NT-proBNP levels modify prognosis warrants future investigation.

Preliminary data on the potential usefulness of B-type natriuretic peptide levels in predicting outcome after hospital discharge in patients with heart failure

PURPOSEnAmong patients admitted for treatment of heart failure, we aimed to evaluate the value of B-type natriuretic peptide levels in predicting subsequent death or hospital readmission.nnnSUBJECTS AND METHODSnWe observed and followed 50 consecutive patients admitted with decompensated heart failure. B-type natriuretic peptide levels were measured using an immunofluorometric assay at admission and at discharge. We followed patients for 6 months and ascertained readmissions for cardiovascular causes and death.nnnRESULTSnForty-three patients were discharged. There were 20 events during follow-up (15 readmissions and 5 deaths). Mean (+/- SD) B-type natriuretic peptide levels decreased during the initial hospitalization, from 619 +/- 491 pg/mL to 328 +/- 314 pg/mL (P <0.001) among patients who were event free during follow-up, whereas declines were less marked among patients with hospital readmission or death (from 779 +/- 608 pg/mL to 643 +/- 465 pg/mL, P = 0.08). Among the 7 patients with in-hospital increases in B-type natriuretic peptide level, 6 had events, compared with 14 of the 36 patients whose levels declined (P = 0.04). An increase in B-type natriuretic peptide levels during hospital stay was associated with an increased event rate (hazard ratio [HR] = 3.3; 95% confidence interval [CI]: 1.3 to 8.8). Patients whose B-type natriuretic peptide level at discharge was above the median (321 pg/mL) had a somewhat higher rate of dying or being readmitted (HR = 2.3; 95% CI: 0.9 to 5.8).nnnCONCLUSIONnThese preliminary results in a small number of patients suggest that changes in B-type natriuretic peptide levels, as well as predischarge levels, are related to hospital readmission and death within 6 months.

Mutations of the GLA Gene in Young Patients With Stroke The PORTYSTROKE Study—Screening Genetic Conditions in PORTuguese Young STROKE Patients

Background and Purpose— Fabry disease is an X-linked monogenic disorder caused by mutations in the GLA gene. Recent data suggest that stroke in young adults may be associated with Fabry disease. We aimed to ascertain the prevalence of this disorder among young adult patients with stroke in Portugal by GLA genotyping. Methods— During 1 year, all patients aged 18 to 55 years with first-ever stroke, who were admitted into any of 12 neurology hospital departments in Portugal, were prospectively enrolled (n=625). Ischemic stroke was classified according to Trial of Org 10172 in Acute Stroke Treatment criteria. Alpha-galactosidase activity was further assayed in all patients with GLA mutations. Results— Four hundred ninety-three patients (mean age, 45.4 years; 61% male) underwent genetic analyses: 364 with ischemic stroke, 89 with intracerebral hemorrhage, 26 with subarachnoid hemorrhage, and 14 with cerebral venous thrombosis. Twelve patients had missense GLA mutations: 9 with ischemic stroke (p.R118C: n=4; p.D313Y: n=5), including 5 patients with an identified cause of stroke (cardiac embolism: n=2; small vessel disease: n=2; other cause: n=1), 2 with intracerebral hemorrhage (p.R118C: n=1; p.D313Y: n=1), and one with cerebral venous thrombosis (p.R118C: n=1). Leukocyte &agr;-galactosidase activity was subnormal in the hemizygous males and subnormal or low-normal in the heterozygous females. Estimated prevalence of missense GLA mutations was 2.4% (95% CI, 1.3% to 4.1%). Conclusions— Despite a low diagnostic yield, screening for GLA mutations should probably be considered in different types of stroke. Restricting investigation to patients with cryptogenic stroke may underestimate the true prevalence of Fabry disease in young patients with stroke.

The alpha-galactosidase A p.Arg118Cys variant does not cause a Fabry disease phenotype: Data from individual patients and family studies

Lysosomal α-galactosidase A (α-Gal) is the enzyme deficient in Fabry disease (FD), an X-linked glycosphingolipidosis caused by pathogenic mutations affecting the GLA gene. The early-onset, multi-systemic FD classical phenotype is associated with absent or severe enzyme deficiency, as measured by in vitro assays, but patients with higher levels of residual α-Gal activity may have later-onset, more organ-restricted clinical presentations. A change in the codon 118 of the wild-type α-Gal sequence, replacing basic arginine by a potentially sulfhydryl-binding cysteine residue - GLA p.(Arg118Cys) -, has been recurrently described in large FD screening studies of high-risk patients. Although the Cys118 allele is associated with high residual α-Gal activity in vitro, it has been classified as a pathogenic mutation, mainly on the basis of theoretical arguments about the chemistry of the cysteine residue. However its pathogenicity has never been convincingly demonstrated by pathology criteria. We reviewed the clinical, biochemical and histopathology data obtained from 22 individuals of Portuguese and Spanish ancestry carrying the Cys118 allele, including 3 homozygous females. Cases were identified either on the differential diagnosis of possible FD manifestations and on case-finding studies (n=11; 4 males), or on unbiased cascade screening of probands close relatives (n=11; 3 males). Overall, those data strongly suggest that the GLA p.(Arg118Cys) variant does not segregate with FD clinical phenotypes in a Mendelian fashion, but might be a modulator of the multifactorial risk of cerebrovascular disease. The Cys118 allelic frequency in healthy Portuguese adults (n=696) has been estimated as 0.001, therefore not qualifying for rare condition.

Prevalence and characteristics of sleep apnoea in patients with stable heart failure: Results from a heart failure clinic

BackgroundHeart failure (HF) and sleep apnoea (SA) association has been recognized but whether it results from confounding factors (hypertension, ischaemia, obesity) remains unclear.We aimed to determine the prevalence of SA in HF and to identify potential risk factors for SA in HF population.MethodsWe prospectively evaluated 103 patients with stable HF on optimized therapy. In-laboratory polysomnography was performed. Type and severity of SA were defined according international criteria. Demographic, anthropometric and clinical characteristics were collected. Continuous data are expressed as median and interquartile range.ResultsSA was found in 72.8%, moderate to severe in a significant proportion (apnoea-hypopnoea index ≥ 15- 44.7% of all patients) and predominantly obstructive (60.0% of patients with SA). Most patients were non-sleepy (Epworth < 10- 66%). SA patients were predominantly men (85.3 vs 60.7%, p-0.015), had larger neck (38.0 (35.0-42.0) vs 35.0 (33.2-38.0) cm, p-0.003), severe systolic dysfunction, (63.9 vs 33.3%, p-0.018), left ventricle (LV) hypertrophy (16.2 vs 0.0%, p-0.03), LV and left atria (LA) dilatation (49.0 (44.0-52.0) vs 42.0 (38.0-48.0) mm, p < 0.001; 60.0 (54.0-65.0) vs 56.0 (52.0-59.0) mm, p-0.01). However, only LA diameter was an independent predictor of SA. Higher body-mass index (BMI) was associated with moderate to severe SA. Patients with obstructive SA had larger neck and a trend for higher BMI, snoring and sleepiness. Hypocapnia was not associated with central SA.ConclusionsIn our HF population, SA was prevalent, frequently asymptomatic and without characteristic risk factors. Unlike previously reported, obstructive SA was the predominant type. These results suggest that SA is underdiagnosed in HF and there is a possible correlation between them, independent of confounding factors. Recent advances in HF therapy might influence prevalence and type of SA in this population.

The g.1170C>T polymorphism of the 5′ untranslated region of the human alpha-galactosidase gene is associated with decreased enzyme expression—Evidence from a family study

SummarySubnormal leukocyte α-galactosidase (α-Gal) activity was found during evaluation of an adolescent male with cryptogenic cerebrovascular small-vessel disease. The only molecular abnormality found was the g.1170C>T single-nucleotide polymorphism (SNP) in the 5′ untranslated region of exon 1 in the α-Gal gene (GLA). Historically, this polymorphism has been considered to be biologically neutral. To test the hypothesis that the g.1170T allele might be associated with lower α-Gal expression, we genotyped GLA exon 1 and measured leukocyte and plasma α-Gal in the parents, brother and sister of the index case. The g.1170T allele co-segregated with a subnormal leukocyte α-Gal activity in the three siblings. Although plasma enzyme activities were within the normal range in all five relatives, the ranking of their values suggested a dosage effect of the g.1170T allele. Western blotting assays of leukocyte protein extracts showed that the relative expression of α-Gal in both the patient and his sister was significantly lower than in sex-matched hemizygous or homozygous controls for the g.1170C allele, either normalized to the β-actin immunoblot expression or standardized to a known amount of recombinant human α-Gal. These family data, in combination with results from a recent GLA SNP screening study among healthy Portuguese individuals, suggest that the g.1170C>T SNP may be co-dominantly associated with a relatively decreased GLA expression at the transcription and/or translation level. Larger population studies are needed to confirm these findings and to test the hypothesis that the GLA g.1170C>T may contribute to the multifactorial risk of ischaemic small-vessel cerebrovascular disease.

Cost analysis of renal replacement therapy by transplant in a system of bundled payment of dialysis

Rocha MJ, Ferreira S, Martins LS, Almeida M, Dias L, Pedroso S, Henriques AC, Almeida R, Cabrita A. Cost analysis of renal replacement therapy by transplant in a system of bundled payment of dialysis.

Detection of prognostic significant translocations in childhood acute lymphoblastic leukaemia by one-step multiplex reverse transcription polymerase chain reaction.

The search for chromosomal translocations in de novo cases of childhood acute lymphoblastic leukaemia (ALL) is crucial for the selection of the appropriate therapeutic protocol. In this work, we describe a new method – one‐step multiplex reverse transcription polymerase chain reaction (RT‐PCR) – to screen for prognostic significant translocations in childhood ALL. Our approach involves a single PCR reaction for the simultaneous detection of the molecular rearrangements resulting from the t(9;22), t(12;21), t(4;11) and t(1;19), with a turnaround time of less than 24u2003h. This assay proved to be highly sensitive, specific, reproducible and easy to implement in a routine genetics laboratory.

Heart failure and sleep apnoea: To sleep perchance to dream

Heart failure and sleep apnoea are major health problems with an increasingly recognized association; evidence suggests that sleep apnoea may play a role in the progression of heart failure. However, confounding factors such as obesity, hypertension and coronary heart disease make this relationship uncertain and an independent correlation remains unproven.

Variations in the GLA gene correlate with globotriaosylceramide and globotriaosylsphingosine analog levels in urine and plasma

Recent data have shown that lyso-Gb3, the deacylated derivative of globotriaosylceramide (Gb3), is possibly involved in the pathogenesis of Fabry disease (FD) and might be a clinically useful biomarker of its metabolic load. To test this hypothesis, we assayed Gb3 and lyso-Gb3 and related analogs in plasma and/or urine samples of 12 clinically well-characterized subjects carrying several different GLA variant alleles associated with a wide range of residual α-galactosidase A activities. Urinary Gb3 was measured by HPLC-MS/MS; plasma and urinary lyso-Gb3 and related analogs were measured by UPLC-MS/MS. Individual profiles of Gb3 and lyso-Gb3 and related analogs closely correlated with the phenotypic data for each subject, discerning the classical FD patient from the two patients carrying cardiac variants as well as those from all the others without FD. The lyso-Gb3 analog at m/z 836 was found at increased levels only in patients manifesting clinically severe heart disease, irrespective of the pathogenicity of the GLA variant they carried. This finding suggests that this lyso-Gb3 analog might be an earlier biomarker of progressive heart disease, non-specific of the FD cardiomyopathy. The possibility that urinary Gb3 is a specific marker of kidney involvement in FD deserves further study.