Vascular calcification by conventional X-ray and mortality in a cohort of predominantly African descent hemodialysis patients.

BACKGROUND/OBJECTIVE: There is a lack of studies describing the prevalence of vascular calcification (VC) and its association with mortality in maintenance hemodialysis (MHD) patients of African descent. We investigated if a VC score based on the number of calcified vascular beds was associated with mortality in MHD patients. METHODS: We analyzed data from 211 MHD patients enrolled from January 2010 to January 2011 in the prospective cohort study, "The Prospective Study of the Prognosis of Chronic Hemodialysis Patients (PROHEMO)," developed in Salvador, BA, Brazil. VC was evaluated using radiographs of the hands, abdomen, hip, and chest; the score was calculated by the number of calcified sites as 0 (absence of calcification), 1 (one calcified site), 2 (two sites), 3 (⩾3 sites). We used Cox's regression to estimate the hazard ratio (HR) and 95% confidence interval (CI) of associations between VC and mortality with adjustments for age and comorbidities. RESULTS: VC was detected in 114 (54.0%) patients; 37 (17.5%) with a VC score = 1; 21 (10%) with VC score = 2 and 56 (26.5%) with VC score = 3. Compared with VC score = 0, the adjusted hazard of death was 2.67 (95% CI: 1.12, 6.33) for patients with VC score = 1; HR = 2.89 (95% CI: 0.95, 7.63) for VC score = 2; and HR = 3.27 (95% CI: 1.47, 7.28) for VC score = 3. CONCLUSION: The present study in an African descent MHD population provides support for the VC score based on conventional radiography as a prediction tool for the clinical practice. As shown, the VC score was monotonically and independently associated with mortality.

Associations of Hemoglobin Levels With Health-Related Quality of Life, Physical Activity, and Clinical Outcomes in Persons With Stage 3-5 Nondialysis CKD.

OBJECTIVE: Conflicting findings and knowledge gaps exist regarding links between anemia, physical activity, health-related quality of life (HRQOL), chronic kidney disease (CKD) progression, and mortality in moderate-to-advanced CKD. Using the CKD Outcomes and Practice Patterns Study, we report associations of hemoglobin (Hgb) with HRQOL and physical activity, and associations of Hgb and physical activity with CKD progression and mortality in stage 3-5 nondialysis (ND)-CKD patients. DESIGN AND METHODS: Prospectively collected data were analyzed from 2,121 ND-CKD stage 3-5 patients, aged ≥18 years, at 43 nephrologist-run US and Brazil CKD Outcomes and Practice Patterns Study-participating clinics. Cross-sectional associations were assessed of Hgb levels with HRQOL and physical activity levels (from validated Kidney Disease Quality of Life Instrument and Rapid Assessment of Physical Activity surveys). CKD progression (first of ≥40% estimated glomerular filtration rate [eGFR] decline, eGFR<10 mL/min/1.73 m2, or end-stage kidney disease) and all-cause mortality with Hgb and physical activity levels were also evaluated. Linear, logistic, and Cox regression analyses were adjusted for country, demographics, smoking, eGFR, serum albumin, very high proteinuria, and 13 comorbidities. RESULTS: HRQOL was worse, with severe anemia (Hgb<10 g/dL), but also evident for mild/moderate anemia (Hgb 10-12 g/dL), relative to Hgb>12 g/dL. Odds of being highly physically active were substantially greater at Hgb>10.5 g/dL. Lower Hgb was strongly associated with greater CKD progression and mortality, even after extensive adjustment. Physical inactivity was strongly associated with greater mortality and weakly associated with CKD progression. Possible residual confounding is a limitation. CONCLUSION: This multicenter international study provides real-world observational evidence for greater HRQOL, physical activity, lower CKD progression, and greater survival in ND-CKD patients with Hgb levels >12 g/dL, exceeding current treatment guideline recommendations. These findings help inform future studies aimed at understanding the impact of new anemia therapies and physical activity regimens on improving particular dimensions of ND-CKD patient well-being and clinical outcomes.

Prescription of renin-angiotensin-aldosterone system inhibitors (RAASi) and its determinants in patients with advanced CKD under nephrologist care.

Renin-angiotensin-aldosterone system inhibitors (RAASi) are recommended for chronic kidney disease (CKD) patients. In this study, we describe RAASi prescription patterns in the Chronic Kidney Disease Outcomes and Practice Patterns Study (CKDopps) in Brazil, Germany, France, and the United States (US). 5870 patients (mean age 66-72 years; congestive heart failure [CHF] in 11%-19%; diabetes in 43%-54%; serum potassium ≥5 in 20%-35%) were included. RAASi prescription was more common in Germany (80%) and France (77%) than Brazil (66%) and the United States (52%), where the prevalence of prescription decreases particularly in patients with CKD stage 5. In the multivariable regression model, RAASi prescription was least common in the United States and more common in patients who were younger, had diabetes, hypertension, or less advanced CKD. In conclusion, RAASi prescription patterns vary by country, and by demographic and clinical characteristics. RAASi appear to be underused, even among patients with strong class-specific recommendations. Although the reasons for this variation could not be fully identified in this cross-sectional observation, our data indicate that the risk of hyperkalemia may contribute to the underuse of this class of agents in moderate to advanced CKD.

Phosphodiesterase type 5 inhibitors improve microvascular dysfunction markers in pulmonary arterial hypertension associated with congenital heart disease.

BACKGROUND: Ideally, vasodilator therapies for pulmonary arterial hypertension (PAH) should have a favorable impact on markers of vascular dysfunction, in addition to their known effects on hemodynamics, cardiac function, and patient's physical capacity. METHODS: We analyzed circulating (plasma) markers of endothelial and platelet activation/dysfunction (enzyme-linked immunoassays) in the specific setting of advanced PAH associated with congenital heart disease, during the course of sildenafil and tadalafil therapies. Thirty-one patients were enrolled (age 10-54 years), most of them with chronic hypoxemia and elevated hematocrit. Drugs were administered orally for 6 months (sildenafil [n = 16], 20 mg t.i.d.; tadalafil [n = 15], single daily dose of 40 mg). Measurements were performed at baseline, and 90 and 180 days. RESULTS: Compared to controls, patients had elevated baseline ß-thromboglobulin (ß-TG, P = .002), P-selectin (P = .027), tissue-type plasminogen activator (t-PA, P = .009), and von Willebrand factor antigen (VWF:Ag, P = .010). Thrombomodulin was importantly reduced (TM, P < .001), while soluble CD40 Ligand was not changed (P = .320). Tadalafil administration was associated with improvement of ß-TG (P = .004), t-PA (P = .003) and TM (P = .046) levels, while P-selectin was improved by sildenafil treatment only (P = .034). VWF:Ag improved transiently in the sildenafil group (P = .019). Both therapies were associated with improvement of the physical capacity (functional class and distance walked during the 6-minute test, P < .05), hematocrit and hemoglobin level (P < .05), and health-related quality of life (physical and mental components, P < .05). CONCLUSION: In PAH associated with congenital heart disease, phosphodiesterase 5 inhibitors seem to have beneficial actions at microcirculatory level, beyond the proposed effects as vasodilators.

The sickle cell trait and end stage renal disease in Salvador, Brazil.

BACKGROUND: Carriers of the sickle cell trait (HbAS) usually remain asymptomatic. However, under conditions of low tissue oxygenation, red blood cell sickling and vascular obstruction may develop. Chronic kidney disease (CKD) can arise from conditions promoting low-oxygen in kidney tissue, which may be aggravated by the presence of the sickle cell trait. In addition, CKD can arise from other genetic traits. AIM: To compare the frequency of HbAS among hemodialysis patients and the general newborn population of Salvador (Bahia-Brazil), as well as to investigate the frequencies of apolipoprotein L1 risk variants in patients undergoing hemodialysis. METHODS: A cross-sectional study included 306 patients with ESRD (End Stage Renal Disease) on hemodialysis for no more than three years. Hemoglobin profiles were characterized by high-performance liquid chromatography. To estimate the sickle cell trait frequency in the general population of Salvador, we analyzed data collected by a local neonatal screening program between 2011 and 2016. To exclude the potential contributing effect of the apolipoprotein L1 (APOL1) gene variants, we performed genotyping by PCR and DNA sequencing of 45 patients. RESULTS: The frequency of HbAS was significantly higher in hemodialysis patients (9.8%) than in the general population (4.6%): Odds Ratio = 2.32 (95% CI = 1.59-3.38). No differences in demographic, clinical or laboratory data were found among patients with or without the sickle cell trait. The frequency of patients with none, one or two APOL1 risk haplotypes (G1 and G2) for CKD were 80%, 18% and 2%, respectively. CONCLUSIONS: The frequency of the sickle cell trait is higher in patients with ESRD on hemodialysis compared to the general population. APOL1 haplotypes do not seem to be the determinant of ESRD in these patients.

Sex-age-specific handgrip strength and mortality in an incident hemodialysis cohort: The risk explained by nutrition and comorbidities.

OBJECTIVE:: To investigate associations of sex-age-specific handgrip strength by a dynamometer with all-cause mortality and the percent excess risk explained (%ERE) by comorbidities and nutritional indicators in incident maintenance hemodialysis patients. METHODS:: Prospective cohort of 413 adult patients (165 women, 248 men, 299 <60 years and 114 ⩾60 years) with <6 months (82% <3 months) on dialysis enrolled in PROHEMO in Salvador, Brazil. Low and high handgrip strength groups were based on sex-age-specific cutoffs (17.8 kg for women <60 years, 13.8 kg for women ⩾60 years, 29.5 kg for men <60 years, and 21.9 kg for men ⩾60 years). We used Cox regression to estimate the mortality hazard ratio. The %ERE was determined by the equation (HR1 - HR2)/(HR1 - 1) × 100, in which HR1 represented the hazard ratio in a model with a smaller number of covariates and HR2 represented the hazard ratio in a subsequent model with the inclusion of new covariates plus the variables included in the previous model. RESULTS:: The mortality hazard ratio comparing low and high handgrip strength was 2.58 (95% confidence interval: 1.73, 3.85) in the model with sociodemographic factors and vintage and 2.25 (95% confidence interval: 1.49, 3.43) with addition of comorbidities, corresponding to a %ERE of 21%. The hazard ratio was 1.98 (95% confidence interval: 1.29, 3.06) after addition of nutritional indicators corresponding to %ERE of 38%. Results stratified by age and gender followed similar patterns. CONCLUSION:: These results provide support for the assessment of handgrip strength in all maintenance hemodialysis patients for early identification of those who may require special care to improve nutritional status and survival.

A Web-Based Platform to Collect Data from ESRD Patients Undergoing Dialysis: Methods and Preliminary Results from the Brazilian Dialysis Registry.

INTRODUCTION: The methods and initial results of a web-based platform to collect data from patients receiving maintenance dialysis in Brazil are reported. METHODS: Companies providing management software for dialysis centers adapted their system to comply with a formulary of the Brazilian Society of Nephrology. Baseline and follow-up individual patients' data were transmitted via Internet on monthly bases to the coordinating center from 2011 to 2017. RESULTS: 73 dialysis centers provided information of 24,930 patients: 57% were male, 28% were 64 years old or older, and 13% were overweight/obese. Median dialysis vintage was 28 months. Hemodialysis was the most frequent initial therapy (93%) with venous catheters used in 64% of cases. Conventional hemodialysis remained the main current therapy (90%). Seropositivity for hepatitis C, hepatitis B, and HIV was 2.7%, 1.1%, and 0.5%, respectively. Erythropoietin (53.9%), iron (35.1%), and sevelamer (23.4%) were the most used medications. Hemoglobin < 100 g/L and serum P > 1.74 mmol/L were present in 33.1% and 36.6% of the cases, respectively. The 5-year survival of incident cases (n = 7,538) was 57%. CONCLUSION: The initiative represents an innovative strategy to collect clinical and epidemiologic data of dialysis patients which may be applied to other settings and provides information that can contribute to guiding clinical practice and health care policy.

Associations of physical activity energy expenditure with nutritional-inflammatory markers in hemodialysis patients.

BACKGROUND: Sedentariness, high inflammation status and malnutrition are highly prevalent in end-stage kidney disease patients on maintenance hemodialysis (MHD). This study investigated associations of weekly physical activity energy expenditure (PAEE) with clinical and anthropometric markers of nutrition and inflammation. METHODS: The analysis was performed using baseline cross-sectional data of 640 patients enrolled in the prospective cohort "The Prospective Study of the Prognosis of Patients Treated Chronically by Hemodialysis" (PROHEMO) developed in Salvador, BA, Brazil. The long version of the International Physical Activity Questionnaire was used to determine a summary measure of PAEE, the metabolic equivalent of task (MET), taking into account physical activities related to occupation, recreation, travel, sports, and housework. PAEE was the predictor variable. To assess associations of PAEE with outcomes, the sex-age-specific median MET was used. The malnutrition-inflammation score (MIS) with range of 0 to 30 (higher is worse), conicity index as indicator of abdominal adiposity and C-reactive protein (CRP) were the nutritional-inflammatory outcomes. RESULTS: The mean age of the patients was 48.9 ± 13.8 y, 60.3% were males, 16.7% diabetic, 88.1% nonwhite. In multivariable logistic regression models with adjustments for sociodemographic variables and comorbidities, PAEE ≤median was associated with MIS ≥6 (odds ratio [OR] = 1.57; 95% confidence interval [CI] = 1.08, 2.29), conicity index ≥1.3 (OR = 1.52, 95% CI = 1.03, 2.23) and CRP >1.30 mg/dL (OR = 1.69, 95% CI = 1.08, 2.84). CONCLUSIONS: Greater physical activity assessed by PAEE was associated with indicators of better nutritional and inflammation status. These results indicate opportunities for improving outcomes in MHD patients by counseling and treatment intervention.

Factors influencing outcomes in patients with Eisenmenger syndrome: a nine-year follow-up study.

In patients with Eisenmenger syndrome, life expectancy is usually longer than in patients with other forms of pulmonary arterial hypertension (PAH). We conducted a cohort study in which patients were followed over a long period of time in an attempt to identify potential predictors of clinical outcomes. Sixty-seven treatment-naïve patients were enrolled (age range = 12-60 years; median age = 33 years). Baseline demographic, diagnostic, and functional parameters, plasma levels of endothelial dysfunction markers, and treatment-related data were tested for possible correlations with event-free survival. Patients were started on oral PAH drugs at the beginning of follow-up (n = 23), during follow-up (n = 33), or remained untreated (n = 11). The duration of follow-up was 0.54-9.89 years (median = 7.13 years), with an overall survival rate of 82% and an event-free survival rate of 70%. The estimated mean for event-free survival time was 7.71 years (95% confidence interval [CI] = 6.86-8.55 years). Of the 16 variables that were analyzed, the duration of exposure to PAH drugs was identified as an independent protective factor (hazard ratio [HR] = 0.25 for quartiles, 95% CI = 0.14-0.47, P < 0.001). The initial functional class (HR = 3.07; 95% CI = 1.01-9.34; P = 0.048), the severity of right ventricular dysfunction (HR = 2.51 [mild, moderate or severe dysfunction]; 95% CI = 1.22-5.19; P = 0.013) and plasma von Willebrand factor concentration (HR = 1.74 for quartiles; 95% CI = 1.07-2.83; P = 0.026) were identified as risk factors. The length of exposure to oral PAH therapies influences survival favorably in Eisenmenger patients. This may be of interest for communities where access to medications is restricted.

Chronic kidney disease among adult participants of the ELSA-Brasil cohort: association with race and socioeconomic position.

BACKGROUND: There is increased interest in understanding why chronic kidney disease (CKD) rates vary across races and socioeconomic groups. We investigated the distribution of estimated glomerular filtration rate (eGFR), urinary albumin-creatinine ratio (ACR) and CKD according to these factors in Brazilian adults. METHODS: Using baseline data (2008-2010) of 14,636 public sector employees (35-74 years) enrolled in the Brazilian Longitudinal Study of Adult Health (ELSA)-Brasil multicentre cohort, we estimated the prevalence of CKD by sex, age, race and socioeconomic factors. CKD was defined as ACR ≥ 30 mg/g and/or eGFR < 60 mL/min/1.73 m(2). GFR was estimated by CKD epidemiology collaboration without correction for race. We used logistic regression to estimate the association of race and socioeconomic position (education, income, social class and occupational nature) with CKD after adjusting for sex, age and several health-related factors. RESULTS: The prevalence of high ACR or low eGFR, in isolation and combined, increased with age, and was higher in individuals with lower socioeconomic position and among black individuals and indigenous individuals. The overall prevalence of CKD was 8.9%. After full adjustments, it was similar in men and women (OR=0.90; 95% CI 0.79 to 1.02) and increased with age (OR=1.07; 95% CI 1.06 to 1.08). Compared to white individuals, black individuals (OR=1.23; 95% CI 1.03 to 1.47), 'pardos' (OR=1.16; 95% CI 1.00 to 1.35) and Indigenous (OR=1.72; 95% CI 1.07 to 2.76) people had higher odds for CKD. Having high school (OR=1.15; 95% CI 1.00 to 1.34) or elementary education (OR=1.23; 95% CI 1.03 to 1.47) increased the odds for CKD compared to those having a university degree. CONCLUSIONS: There were marked discrepancies in the increases in reduced eGFR and high ACR with age and race. The higher prevalences of CKD in individuals with lower educational status and in non-whites were not explained by differences in health-related factors.

Coping with fluid restriction and the quality of life in hemodialysis patients with very low or no daily urine output.

PURPOSE: Fluid restriction is crucial to prevent circulatory overload in maintenance hemodialysis (MHD) patients with very low urine volume, but fluid restriction may result in psychological distress. We studied MHD patients with urine volume ≤ 200 ml/day to investigate if their acceptance of fluid restriction was associated with their health-related quality of life (HRQOL). METHODS: Cross-sectional study of 271 Brazilian adult MHD patients enrolled in the Prospective Study of the Prognosis of Chronic Hemodialysis Patients (PROHEMO). To assess the acceptance of fluid restriction, patients were asked about the extent of feeling bothered by living on this restriction. The KDQOL was used to determine HRQOL scores. Higher scores indicate better HRQOL with differences of >3.0 points considered clinically significant. RESULTS: 52.4% reported being "moderately to extremely" bothered by fluid restriction and had lower scores for all HRQOL scales than patients less bothered by fluid restriction. The largest covariate-adjusted differences in HRQOL were 19.5 for emotional role (p<0.001), 15.1 for emotional well-being (p<0.001), and 14.1 for vitality (p<0.001). Adjusted differences were larger for mental component (7.53 points, p<0.001) than for physical component (2.07, p = 0.075) summaries. CONCLUSIONS: These results indicate that MHD patients with a lower level of acceptance of fluid restriction have poorer HRQOL, particularly in mental domains of HRQOL. The high prevalence of poor acceptance of fluid restriction in the present study underscores the need for interventions to improve acceptance of fluid restriction and determine if such interventions improve HRQOL of MHD patients with very low urine volume.

Clasificación funcional de la hipertensión pulmonar en niños: informe del task force pediátrico del Pulmonary Vascular Research Institute (PVRI), Panamá 2011 / Functional classification of pulmonary hypertension in children: Report from the PVRI pediatric taskforce, Panama 2011

Los miembros del Task Force pediátrico del Pulmonary Vascular Research Institute (PVRI, su sigla en Inglés) fueron conscientes de la necesidad de desarrollar una clasificación funcional de la hipertensión pulmonar en niños. La clasificación que se propone sigue el mismo patrón y utiliza los mismos criterios de la clasificación de la hipertensión pulmonar específica para adultos de Dana Point. Fue necesario incluir modificaciones para los niños, teniendo en cuenta que la edad, el crecimiento físico y la madurez influyen en la expresión funcional de la enfermedad. Es necesario definir el estado clínico del niño, pues ello facilita revisar la evolución del mismo en una forma consistente y objetiva a medida que él/ella crecen. Particularmente en los niños más jóvenes, se trató de incluir indicadores objetivos como el crecimiento, la necesidad de alimentos suplementarios y los registros de asistencia al colegio y a la guardería. Esto ayuda a monitorear la evolución clínica y la respuesta al tratamiento a través de los años y facilita el desarrollo de algoritmos de tratamiento en estos pacientes. Se presenta un artículo de consenso sobre una clasificación aplicable a los niños con hipertensión pulmonar que se discutió en la reunión anual del PVRI que se llevó a cabo en Panamá en febrero de 2011.

The members of the Pediatric Task Force of the Pulmonary Vascular Research Institute (PVRI) were aware of the need to develop a functional classification of pulmonary hypertension in children. The proposed classification follows the same pattern and uses the same criteria as the Dana Point pulmonary hypertension specific classification for adults. Modifications were necessary for children, since age, physical growth and maturation influences the way in which the functional effects of a disease are expressed. It is essential to encapsulate a child's clinical status, to make it possible to review progress with time as he/she grows up, as consistently and as objectively as possible. Particularly in younger children we sought to include objective indicators such as thriving, need for supplemental feeds and the record of school or nursery attendance. This helps monitor the clinical course of events and response to treatment over the years. It also facilitates the development of treatment algorithms for children. We present a consensus paper on a functional classification system for children with pulmonary hypertension, discussed at the Annual Meeting of the PVRI in Panama City, February 2011.

Consenso sobre la clasificación de la enfermedad vascular pulmonar hipertensiva en niños: reporte del task force pediátrico del Pulmonary Vascular Research Institute (PVRI) Panamá 2011 / A consensus approach to the classification of pediatric pulmonary hypertensive vascular disease: Report from the PVRI Pediatric Taskforce, Panama 2011

Las clasificaciones actuales de la hipertensión pulmonar han contribuido significativamente al conocimiento de la enfermedad vascular pulmonar, han facilitado ensayos farmacológicos y han mejorado nuestro conocimiento de las cardiopatías congénitas del adulto; sin embargo estas clasificaciones no son aplicables completamente a la enfermedad en el niño. La clasificación que aquí se propone se basa principalmente en la práctica clínica. Los objetivos específicos de esta nueva clasificación son mejorar las estrategias diagnósticas, promover la investigación clínica, mejorar nuestro conocimiento de la patogénesis, de la fisiología y de la epidemiología de la enfermedad y orientar el desarrollo de modelos de la enfermedad humana en el laboratorio y estudios en animales; también puede servir como un recurso docente. Se hace énfasis en los conceptos de maladaptación perinatal, alteraciones del desarrollo e hipoplasia pulmonar como factores causantes de la hipertensión pulmonar pediátrica; así mismo, en la importancia de los múltiples síndromes malformativos congénitos, genéticos y cromosómicos en la presentación de la hipertensión pulmonar pediátrica. La enfermedad vascular pulmonar hipertensiva en niños se divide en diez grandes categorías.

Current classifications of pulmonary hypertension have contributed a great deal to our understanding of pulmonary vascular disease, facilitated drug trials, and improved our understanding of congenital heart disease in adult survivors. However, these classifications are not applicable readily to pediatric disease. The classification system that we propose is based firmly in clinical practice. The specific aims of this new system are to improve diagnostic strategies, to promote appropriate clinical investigation, to improve our understanding of disease pathogenesis, physiology and epidemiology, and to guide the development of human disease models in laboratory and animal studies. It should be also an educational resource. We emphasize the concepts of perinatal maladaptation, maldevelopment and pulmonary hypoplasia as causative factors in pediatric pulmonary hypertension. We highlight the importance of genetic, chromosomal and multiple congenital malformation syndromes in the presentation of pediatric pulmonary hypertension. We divide pediatric pulmonary hypertensive vascular disease into 10 broad categories.

Functional classification of pulmonary hypertension in children: Report from the PVRI pediatric taskforce, Panama 2011.

The members of the Pediatric Task Force of the Pulmonary Vascular Research Institute (PVRI) were aware of the need to develop a functional classification of pulmonary hypertension in children. The proposed classification follows the same pattern and uses the same criteria as the Dana Point pulmonary hypertension specific classification for adults. Modifications were necessary for children, since age, physical growth and maturation influences the way in which the functional effects of a disease are expressed. It is essential to encapsulate a child's clinical status, to make it possible to review progress with time as he/she grows up, as consistently and as objectively as possible. Particularly in younger children we sought to include objective indicators such as thriving, need for supplemental feeds and the record of school or nursery attendance. This helps monitor the clinical course of events and response to treatment over the years. It also facilitates the development of treatment algorithms for children. We present a consensus paper on a functional classification system for children with pulmonary hypertension, discussed at the Annual Meeting of the PVRI in Panama City, February 2011.

A consensus approach to the classification of pediatric pulmonary hypertensive vascular disease: Report from the PVRI Pediatric Taskforce, Panama 2011.

Current classifications of pulmonary hypertension have contributed a great deal to our understanding of pulmonary vascular disease, facilitated drug trials, and improved our understanding of congenital heart disease in adult survivors. However, these classifications are not applicable readily to pediatric disease. The classification system that we propose is based firmly in clinical practice. The specific aims of this new system are to improve diagnostic strategies, to promote appropriate clinical investigation, to improve our understanding of disease pathogenesis, physiology and epidemiology, and to guide the development of human disease models in laboratory and animal studies. It should be also an educational resource. We emphasize the concepts of perinatal maladaptation, maldevelopment and pulmonary hypoplasia as causative factors in pediatric pulmonary hypertension. We highlight the importance of genetic, chromosomal and multiple congenital malformation syndromes in the presentation of pediatric pulmonary hypertension. We divide pediatric pulmonary hypertensive vascular disease into 10 broad categories.

Sleep in infants with congenital heart disease.

OBJECTIVES: To investigate hypoxia and sleep disordered breathing in infants with congenital heart disease. METHODS: Prospective study. In-hospital full polysomnography was performed on 14 infants with congenital heart disease, age 7 +/-1 months, and in 7 normal infants, age 10 +/-2 months. Congenital heart disease infants were classified as acyanotic (n=7) or cyanotic (n=7). RESULTS: Nutritional status, assessed by the Gomez classification and expressed as % weight for age, was 70 +/-7, 59 +/-11 and 94 +/-16 in the acyanotic, cyanotic congenital heart disease and control infants, respectively (p<0.001). The respiratory disturbance index (AHI, events per hour) was [median (25-75%)]: 2.5 (1.0-3.4), 2.4 (1.5-3.1) and 0.7 (0.7-0.9) in acyanotic, cyanotic CHD infants and controls, respectively (p=0.013). Almost all congenital heart disease infants (11 out of 14) and only one control infant had an AHI >1 event/hour. The minimum oxygen saturation was 79% (74-82), 73% (57-74) and 90% (90-91) in the acyanotic, cyanotic congenital heart disease infants and controls, respectively (p <0.001). The arousal index (events/hour) was similar among the three groups at 8.4 +/-2.4, 10.3 +/-8.7 and 6.5 +/-3, respectively (p=0.451). CONCLUSIONS: Infants with congenital heart disease frequently present with sleep-disordered breathing associated with oxygen desaturations but not arousals. Therefore, sleep may represent a significant burden to infants with congenital heart disease.

ALDH1A2 (RALDH2) genetic variation in human congenital heart disease.

BACKGROUND: Signaling by the vitamin A-derived morphogen retinoic acid (RA) is required at multiple steps of cardiac development. Since conversion of retinaldehyde to RA by retinaldehyde dehydrogenase type II (ALDH1A2, a.k.a RALDH2) is critical for cardiac development, we screened patients with congenital heart disease (CHDs) for genetic variation at the ALDH1A2 locus. METHODS: One-hundred and thirty-three CHD patients were screened for genetic variation at the ALDH1A2 locus through bi-directional sequencing. In addition, six SNPs (rs2704188, rs1441815, rs3784259, rs1530293, rs1899430) at the same locus were studied using a TDT-based association approach in 101 CHD trios. Observed mutations were modeled through molecular mechanics (MM) simulations using the AMBER 9 package, Sander and Pmemd programs. Sequence conservation of observed mutations was evaluated through phylogenetic tree construction from ungapped alignments containing ALDH8 s, ALDH1Ls, ALDH1 s and ALDH2 s. Trees were generated by the Neighbor Joining method. Variations potentially affecting splicing mechanisms were cloned and functional assays were designed to test splicing alterations using the pSPL3 splicing assay. RESULTS: We describe in Tetralogy of Fallot (TOF) the mutations Ala151Ser and Ile157Thr that change non-polar to polar residues at exon 4. Exon 4 encodes part of the highly-conserved tetramerization domain, a structural motif required for ALDH oligomerization. Molecular mechanics simulation studies of the two mutations indicate that they hinder tetramerization. We determined that the SNP rs16939660, previously associated with spina bifida and observed in patients with TOF, does not affect splicing. Moreover, association studies performed with classical models and with the transmission disequilibrium test (TDT) design using single marker genotype, or haplotype information do not show differences between cases and controls. CONCLUSION: In summary, our screen indicates that ALDH1A2 genetic variation is present in TOF patients, suggesting a possible causal role for this gene in rare cases of human CHD, but does not support the hypothesis that variation at the ALDH1A2 locus is a significant modifier of the risk for CHD in humans.

Cognitive dysfunction in chronic Chagas disease cardiomyopathy.

Chagas disease (CD) remains a major cause of stroke in developing countries, but cognitive repercussion of CD has not been well studied. OBJECTIVE: To compare the frequency and pattern of cognitive dysfunction in patients with CD cardiomyopathy (CDC) and other cardiomyopathies (OC). METHODS: We studied 37 patients with CDC and 42 patients with OC with similar age, educational level and cardiac systolic function. Cognitive tests were applied to both groups by a single examiner blinded to CD status. Logistic regression multivariable models were constructed to ascertain predictors of cognitive dysfunction for each test. RESULTS: Cognitive dysfunction was detected in 9 (24%) CDC patients and 6 (14%) OC patients by Mini Mental State Exam (MMSE) corrected for educational level. Independent predictors of abnormal MMSE (p<0.05) included stroke history (OR=5.51; 95% CI=1.27-24.01) and digoxin use (OR=0.23, 95% CI=0.06-0.89), while CD showed a trend toward statistical significance (OR=4.63; 95% CI=0.87-24.73, p=0.07). Delayed recall of Rey's Complex Figure Test was significantly worse in CD patients, where this remained a significant predictor in the multivariable analysis (OR=4.67; 95% CI=1.23-17.68). CONCLUSIONS: Cognitive dysfunction is frequent in Chagas disease and should be considered as an outcome measure in Chagas disease studies.

A doença de Chagas (DC) permanence uma causa importante de acidente vascular cerebral em países em desenvolvimento, mas a repercussão cognitiva dessa doença não tem sido bem estudada. OBJETIVO: Comparar a frequência e padrão de disfunção cognitiva em pacientes com cardiomiopatia associada à DC (CDC) em comparação com outras cardiomiopatias (OC). MÉTODOS: Foram estudados 37 pacientes com CDC e 42 portadores de OC com idade, nível de instrução e função sistólica cardíaca semelhantes. Testes cognitivos foram realizados em ambos os grupos por um único investigador cegado quanto ao diagnóstico de DC. Modelos de regressão logística multi-variável foram construídos para detectar preditores de disfunção cognitiva para cada teste. RESULTADOS: Disfunção cognitiva foi detectada em 9 (24%) pacientes com CDC e 6 (14%) com OC pelo Mini Exame do Estado Mental (MEEM) corrigido pelo nível de instrução. Preditores independentes de MEEM anormal (p<0,05) foram: história de AVC (OR=5,51; IC 95%=1,27­24,01) e uso de digoxina (OR=0,23, IC 95%=0,06­0,89); DC mostrou tendência a significância estatística (OR=4,63; IC 95%=0,87­24,73, p=0,07). Pacientes com CDC apresentaram pior desempenho na evocação tardia da figura complexa de Rey. Neste teste, a DC se manteve um preditor significante de disfunção cognitiva na análise multivariável (OR=4,67; IC 95%=1,23­17,68). CONCLUSÕES: Disfunção cognitiva é frequente na doença de Chagas e deve ser considerada como desfecho quantificado nos estudos da doença de Chagas.

Validation of the National Institutes of Health Stroke Scale, modified Rankin Scale and Barthel Index in Brazil: the role of cultural adaptation and structured interviewing.

BACKGROUND: We aimed to validate three widely used scales in stroke research in a multiethnic Brazilian population. METHODS: The National Institutes of Health Stroke Scale (NIHSS), modified Rankin Scale (mRS) and Barthel Index (BI) were translated, culturally adapted and applied by two independent investigators. The mRS was applied with or without a previously validated structured interview. Interobserver agreement (kappa statistics) and intraclass correlation coefficients were calculated. RESULTS: 84 patients underwent mRS (56 with and 28 without a structured interview), 57 BI and 62 NIHSS scoring. Intraclass correlation coefficient was 0.902 for NIHSS and 0.967 for BI. For BI, interobserver agreement was good (kappa = 0.70). For mRS, the structured interview improved interobserver agreement (kappa = 0.34 without a structured interview; 0.75 with a structured interview). CONCLUSION: The NIHSS, BI and mRS show good validity when translated and culturally adapted. Using a structured interview for the mRS improves interobserver concordance rates.