Vascular endothelial growth factor and pulmonary hypertension in children with beta thalassemia major / Fator de crescimento endotelial vascular e hipertensão pulmonar em crianças com talassemia beta maior

Abstract Objective: The purpose of this study was to illustrate the association between vascular endothelial growth factor level and pulmonary artery hypertension in children with β-thalassemia major. Method: This case-control study was conducted on 116 children with β-thalassemia major; 58 of them had pulmonary artery hypertension. They were compared to 58 healthy children who were age and sex-matched (control group). Serum levels of vascular endothelial growth factor and echocardiographic assessment were done for all children. Results: Vascular endothelial growth factor serum level was significantly higher in children with β-thalassemia major with pulmonary artery hypertension than in those without pulmonary artery hypertension, as well as in control groups (p < 0.001). Vascular endothelial growth factor serum level had a significant positive correlation with pulmonary artery pressure and serum ferritin, as well as a significant negative correlation with the duration of chelation therapy. Logistic regression analysis revealed that elevated vascular endothelial growth factor (Odd Ratio = 1.5; 95% Confidence Interval, 1.137-2.065; p = 0.005) was an independent risk factor of pulmonary artery hypertension in such children. Vascular endothelial growth factor serum level at a cutoff point of >169 pg/mL had 93.1% sensitivity and 93.1% specificity for the presence of pulmonary artery hypertension in children with β-thalassemia major. Conclusion: Elevated vascular endothelial growth factor serum level is associated with pulmonary artery hypertension in children with β-thalassemia.

Resumo: Objetivo: A finalidade deste estudo foi exemplificar a associação entre o nível de fator de crescimento endotelial vascular e a hipertensão arterial pulmonar em crianças com talassemia beta maior. Método: Este estudo caso-controle foi realizado em 116 crianças com talassemia beta maior; 58 das quais apresentaram hipertensão arterial pulmonar em comparação com 58 crianças saudáveis pareadas por idade e sexo (grupo de controle). Os níveis séricos do fator de crescimento endotelial vascular e a avaliação ecocardiográfica foram realizados em todas as crianças. Resultados: O nível sérico do fator de crescimento endotelial vascular foi significativamente maior em crianças com talassemia beta maior com hipertensão arterial pulmonar que as crianças sem hipertensão arterial pulmonar e os grupos de controle (p < 0,001). O nível sérico do fator de crescimento endotelial vascular apresentou uma correlação positiva significativa com a pressão arterial pulmonar e a ferritina sérica e correlação negativa significativa com a duração da terapia de quelação. A análise de regressão logística revelou que o fator de crescimento endotelial vascular elevado (RC = 1,5; IC de 95%: 1,137-2,065; p = 0,005) foi um fator de risco independente de hipertensão arterial pulmonar nessas crianças. O nível sérico do fator de crescimento endotelial vascular no ponto de corte > 169 (pg/mL) apresentou 93,1% de sensibilidade e 93,1% de especificidade na presença de hipertensão arterial pulmonar em crianças com talassemia beta maior. Conclusão: O nível sérico do fator de crescimento endotelial vascular elevado está associado à hipertensão arterial pulmonar em crianças com talassemia beta.

Galectin-3: A Link between Myocardial and Arterial Stiffening in Patients with Acute Decompensated Heart Failure? / Galectina-3: Ligação entre Rigidez Miocárdica e Arterial em Pacientes com Insuficiência Cardíaca Descompensada?

Abstract Background: Heart failure is accompanied by abnormalities in ventricular-vascular interaction due to increased myocardial and arterial stiffness. Galectin-3 is a recently discovered biomarker that plays an important role in myocardial and vascular fibrosis and heart failure progression. Objectives: The aim of this study was to determine whether galectin-3 is correlated with arterial stiffening markers and impaired ventricular-arterial coupling in decompensated heart failure patients. Methods: A total of 79 inpatients with acute decompensated heart failure were evaluated. Serum galectin-3 was determined at baseline, and during admission, transthoracic echocardiography and measurements of vascular indices by Doppler ultrasonography were performed. Results: Elevated pulse wave velocity and low arterial carotid distensibility are associated with heart failure in patients with preserved ejection fraction (p = 0.04, p = 0.009). Pulse wave velocity, carotid distensibility and Young’s modulus did not correlate with serum galectin-3 levels. Conversely, raised galectin-3 levels correlated with an increased ventricular-arterial coupling ratio (Ea/Elv) p = 0.047, OR = 1.9, 95% CI (1.0‑3.6). Increased galectin-3 levels were associated with lower rates of left ventricular pressure rise in early systole (dp/dt) (p=0.018) and raised pulmonary artery pressure (p = 0.046). High galectin-3 levels (p = 0.038, HR = 3.07) and arterial pulmonary pressure (p = 0.007, HR = 1.06) were found to be independent risk factors for all-cause mortality and readmissions. Conclusions: This study showed no significant correlation between serum galectin-3 levels and arterial stiffening markers. Instead, high galectin-3 levels predicted impaired ventricular-arterial coupling. Galectin-3 may be predictive of raised pulmonary artery pressures. Elevated galectin-3 levels correlate with severe systolic dysfunction and together with pulmonary hypertension are independent markers of outcome.

Resumo Fundamento: A insuficiência cardíaca é acompanhada por anormalidades na interação ventrículo-vascular devido à rigidez miocárdica e arterial aumentada. A galectina-3 é um biomarcador recentemente descoberto que exerce um importante papel na fibrose miocárdica e vascular, e na progressão da insuficiência cardíaca. Objetivos: O objetivo deste estudo foi determinar se a galectina-3 está correlacionada com marcadores de rigidez arterial e acoplamento ventriculoarterial deficiente em pacientes com insuficiência cardíaca descompensada. Métodos: Um total de 79 pacientes internados com insuficiência cardíaca descompensada foi avaliado. Galectina-3 sérica basal foi determinada e, durante a admissão hospitalar, foram realizadas ecocardiografia transtorácica e medidas de índices vasculares por ultrassonografia Doppler. Resultados: Velocidade de onda de pulso elevada e baixa distensibilidade da artéria carótida estão associadas com insuficiência cardíaca em pacientes com fração de ejeção preservada (p = 0,04, p = 0,009). Velocidade de pulso, distensibilidade da artéria carótida e módulo de Young não se correlacionaram com níveis séricos de galectina-3. Por outro lado, níveis elevados de galectina-3 correlacionaram com razão de acoplamento ventriculoarterial aumentada (Ea/Elv) p = 0,047, OR = 1,9, IC 95% (1,0-3,6). Níveis aumentados de galectina-3 estavam associados com taxas mais baixas de pressão ventricular esquerda na fase inicial da sístole (dp/dt) (p = 0,018), e pressão arterial pulmonar aumentada (p = 0,046). Os resultados mostraram que níveis elevados de galectina-3 (p = 0,038, HR = 3,07) e pressão pulmonar arterial (p = 0,007, HR = 1,06) são fatores de risco independentes para mortalidade de todas as causas e reinternações hospitalares. Conclusões: O estudo mostrou que não houve correlação significativa entre níveis séricos de galectina-3 e marcadores de rigidez arterial. Altos níveis de galectina-3, por outro lado, foi um preditor de acoplamento ventriculoarterial deficiente. A galectina-3 pode ser um preditor de pressões arteriais pulmonares aumentadas. Níveis elevados de galectina-3 correlacionam-se com disfunção sistólica grave e, juntamente com hipertensão pulmonar, é um marcador independente de desfecho.

Remodelado auricular derecho y niveles plasmáticos de galectina-3 se relacionan con la capacidad funcional de pacientes con hipertensión arterial pulmonar / Right atrial remodeling and plasma leves of galectin-3 are related to functional capacity in patiensts with pulmonary artery hypertension

Introducción: En pacientes con hipertensión arterial pulmonar (HAP) Galectina- 3, biomarcador de fibrosis miocárdica, se ha asociado a marcadores ecocardiográficos de remodelado ventricular derecho. La relación entre Galectina- 3, remodelado auricular derecho (AD) y capacidad funcional (CF) en pacientes con HAP no ha sido explorado. El objetivo fue medir niveles de Galectina-3 y su relación con CF y remodelado AD en pacientes con HAP Metodos: Estudio prospectivo observacional en que se incluyeron 14 pacientes con HAP En todos los pacientes se midieron los niveles de Galectina-3, proBNP, se evaluó la CF mediante test de caminata 6 minutos (TC6M) y se evaluó remodelado AD. Se consideraron para el análisis dos grupos según la distancia caminada en TC6M (> 200 m vs. ≤ 200 m). Resultados: La edad promedio fue 43 ± 10 años, el 84% mujeres. Los niveles de Galectina-3 fueron 16,1 ± 7,4 ng/mL y el TC6M fue 371 ± 142 mts. Los pacientes con TC6M< 200 m presentaron mayores niveles de Galectina-3 (27,3 ± 4,6 vs 13,7 ± 3,8; p=0,006) y mayor volumen AD (151 ± 21 vs 94 ± 43; p=0,04). Además, se observó una correlación inversa entre el área AD y TC6M (-0,71; p=0,03). Conclusión: Niveles elevados de Galectina-3 y parámetros de remodelado adverso en AD se relacionan con una menor CF en pacientes con HAP. Estos hallazgos apuntan a una mejor caracterización de pacientes con HAP y eventualmente la búsqueda de nuevos objetivos terapéuticos.

Background: Galectin-3 is a biomarker of myo-cardial fibrosis and has been associated with echocar-diographic markers of right ventricular remodeling in patients with pulmonary artery hypertension (PAH). The association among Galectin-3 level, right atrial (RA) remodeling and functional capacity (FC) has not been explored. The objective was to measure plasma Galectin-3 concentrations and its relation with RA remodeling and FC in PAH patients. Methods: This is a prospective observational study and 14 PAH patients were included. Galectin-3 and proBNP levels were measured in all patients. FC was estimated by the 6-minute walk test (6MWT) and used to define 2 groups of subjects (≤200m or >200m). RA area and volume were measured by echocardiography from a 4 chamber view. Results: The average age was 43±10 years, 84% of patients were female. Galectin-3 levels were 16.1±7.4 ng / mL and 6MWT was 371±142 m. We observed an inverse correlation between RA area and 6MWT (-0.71;p=0.03). Conclusions: Higher Galectin-3 concentrations and RA adverse remodeling are related to a decreased FC in PAH patients. These findings may lead to a better characterization of PAH patients and eventually new therapeutic targets.

Plasma von Willebrand factor as a predictor of survival in pulmonary arterial hypertension associated with congenital heart disease

Biomarkers have been identified for pulmonary arterial hypertension, but are less well defined for specific etiologies such as congenital heart disease-associated pulmonary arterial hypertension (CHDPAH). We measured plasma levels of eight microvascular dysfunction markers in CHDPAH, and tested for associations with survival. A cohort of 46 inoperable CHDPAH patients (age 15.0 to 60.2 years, median 33.5 years, female:male 29:17) was prospectively followed for 0.7 to 4.0 years (median 3.6 years). Plasma levels of von Willebrand factor antigen (VWF:Ag), tissue plasminogen activator (t-PA) and its inhibitor (PAI-1), P-selectin, reactive C-protein, tumor necrosis factor alpha, and interleukin-6 and -10 were measured at baseline, and at 30, 90, and 180 days in all subjects. Levels of six of the eight proteins were significantly increased in patients versus controls (13 to 106 percent increase, P < 0.003). Interleukin-10 level was 2.06 times normal (P = 0.0003; Th2 cytokine response). Increased levels of four proteins (t-PA, PAI-1, P-selectin, and interleukin-6) correlated with disease severity indices (P < 0.05). Seven patients died during follow-up. An average VWF:Ag (mean of four determinations) above the level corresponding to the 95th percentile of controls (139 U/dL) was independently associated with a high risk of death (hazard ratio = 6.56, 95 percentCI = 1.46 to 29.4, P = 0.014). Thus, in CHDPAH, microvascular dysfunction appears to involve Th2 inflammatory response. Of the biomarkers studied, plasma vWF:Ag was independently associated with survival.

Plasma C-Reactive Protein and Endothelin-1 Level in Patients with Chronic Obstructive Pulmonary Disease and Pulmonary Hypertension

Pulmonary hypertension is a frequent complication of chronic obstructive pulmonary disease (COPD) and associated with a worse survival and increased risk of hospitalization for exacerbation of COPD. However, little information exists regarding the potential role of systemic inflammation in pulmonary hypertension of COPD. The purpose of the present study was to investigate the degree of C-reactive protein (CRP) and endothelin-1 (ET-1) levels in COPD patient with and without pulmonary hypertension. The levels of CRP and ET-1 were investigated in 58 COPD patient with pulmonary hypertension and 50 patients without pulmonary hypertension. Pulmonary hypertension was defined as a systolic pulmonary artery pressure (Ppa) > or =35 mmHg assessed by Doppler echocardiography. Plasma CRP and ET-1 levels were significantly higher in patients with pulmonary hypertension than in patients without hypertension. There were significant positive correlations between the plasma ET-1 level and CRP level in the whole study groups. For COPD patients, systolic Ppa correlated significantly with plasma CRP levels and plasma ET-1 levels. These findings support a possibility that CRP and ET-1 correlate to pulmonary hypertension in COPD patients.

Rosuvastatin and vascular dysfunction markers in pulmonary arterial hypertension: a placebo-controlled study

We investigated whether chronic rosuvastatin administration could improve the abnormalities of the circulating levels of vascular dysfunction markers in pulmonary arterial hypertension (PAH). Sixty patients, aged 13 to 60 years, with idiopathic (N = 14) or congenital heart disease-associated PAH (N = 46) were equally but randomly assigned to rosuvastatin treatment (10 mg a day, orally) or placebo for 6 months in a blind fashion. Plasma levels of P-selectin, tissue-plasminogen activator and its inhibitor as well as von Willebrand factor antigen were measured by enzyme-linked immunoassay before and after 1, 3, and 6 months of treatment. Baseline levels of biomarkers were elevated (68, 16, 45 and 46 percent increase relative to controls, for P-selectin, von Willebrand factor antigen, tissue-plasminogen activator and its inhibitor, respectively; P < 0.001). P-selectin values at baseline, 1, 3, and 6 months were 39.9 ± 18.5, 37.6 ± 14.6, 34.8 ± 14.6, and 35.4 ± 13.9 ng/mL, respectively, for the rosuvastatin group and 45.7 ± 26.8, 48.0 ± 26.9, 48.1 ± 25.7, and 45.7 ± 25.6 ng/mL for the placebo group. The P-selectin level was lower in the rosuvastatin group compared with placebo throughout treatment (P = 0.037, general linear model). A trend was observed towards a decrease in tissue-plasminogen activator in the statin group (16 percent reduction, P = 0.094), with no significant changes in the other markers. Since P-selectin is crucial in inflammation and thrombosis, its reduction by rosuvastatin is potentially relevant in the pathophysiological scenario of PAH.

Plasma levels of nitric oxide in children with congenital heart disease and increased pulmonary blood flow.

BACKGROUND: Development of pulmonary hypertension commonly accompanies congenital heart disease; nitric oxide (NO) is evidently an important mediator of pulmonary vascular reactivity. OBJECTIVE: Investigate the effect of pulmonary hypertension (PH) associated with congenital heart disease on NO production. MATERIAL AND METHOD: The authors measured plasma levels of nitric oxide-related compounds in 28 patients, aged 3 months to 12 years with congenital heart disease (CHD) and increased pulmonary blood flow. Blood samples were obtained during their cardiac catheterization. The subjects were subsequently divided into two groups, namely: group 1 CHD were those with left-to-right shunt; and group 2, CHD with right-to-left shunt. RESULTS: Four patients had severe pulmonary hypertension (mean pulmonary arterial pressure > 60 mmHg). The total levels of NO-related compounds between the two groups were not statistically different as well as the levels in pre- and post-pulmonary artery. In patients with left-to-right shunt with mild to moderate pulmonary hypertension, the levels of total NO-related compounds were directly correlated with the level of pulmonary arterial pressure and pulmonary vascular resistance (r = 0.67; p-value < 0.05, and r = 0.75; p-value < 0.05). Additionally, in patients with severe pulmonary hypertension, the levels of total NO-related compounds decreased when compared to the levels in patients with mild to moderate pulmonary hypertension. CONCLUSION: The present results suggested that the hemodynamic status of the pulmonary circulation in congenital heart defect is at least partly correlated with the blood levels of nitric oxide.

Niveles de péptido natriurético cerebral y su relación con capacidad funcional y hemodinamia pulmonar en pacientes con hipertensión pulmonar primaria: Correlation with functional capacity and hemodynamic parameters / Brain natriuretic peptide in primary pulmonary ypertension

Background: Primary pulmonary hipertension (PPH) is a progressive disease leading to right heart failure and death. Right heart catherization and maximal or submaximal tests are employed to assess the course of the disease. A neurohormonal parameter such as pro-brain natriuretic peptide (BNP) would be helpful in the assessment of these patients. Aim: To study the correlation of BNP with functional status and non-invasive hemodynamic determinations in patients with PPH. Material and methods: Twelve patients (mean age: 48 years; 58% female) were evaluated with 6 minutes walk distance test (6-min WT), plasma BNP, systolic pulmonary artery pressure (PAP), pulmonary vascular resistance (PVR) and cardiac output (CO) determined by echocardiogram. Plasma BNP levels were compared with normal subjects. Results: BNP levels were increased in PPH patients (1270±547 vs 48±8 pg/ml, p-value <0.01). Mean PAPs was 82±27 mmHg and the mean distance walked in 6 minutes was 407±113 meters. BNP levels were positively correlated with PVR (r=0.58, p-value=0.006) and negatively correlated with 6-min WT (r=-0.83, p-value <0.001). No correlation was found between BNP levels, PAPs and CO. Conclusions: In PPH patients, BNP levels are increased and correlate with functional class and PVR. Follow-up studies are needed to evaluate the role of BNP as a marker of progression and therapeutic response in PPH patients.

Plasma endothelin-1, homocysteine and serum nitric oxide values in patients with left-to-right shunt.

BACKGROUND: This study aimed to evaluate the effect of pulmonary blood flow and pulmonary hypertension on plasma endothelin-1, homocysteine and serum nitric oxide levels in patients with left-to-right shunt lesions with pulmonary hypertension and also with normal pulmonary arterial pressure. METHODS AND RESULTS: Plasma endothelin-1, homocysteine and nitric oxide levels were measured in 44 patients (Group 1) with left-to-right shunt and normal pulmonary arterial pressure (Qp/Qs: 2.1), 65 patients (Group 2) with left-to-right shunt and pulmonary hypertension (Qp/Qs: 2.4), 20 healthy control subjects (Group 3), and 17 post-operative patients (Group 4). Plasma endothelin-1 and serum nitric oxide levels were significantly higher in Group 2 than in groups 1, 3, and 4 (p<0.001). Plasma homocysteine levels were significantly higher in Group 2 than in Groups 1 and 4 (p<0.001 and p<0.01, respectively). CONCLUSIONS: The increase in serum nitric oxide levels in patients with left-to-right shunt and pulmonary hypertension may be attributed to the compensatory mechanism. However, this increase does not improve pulmonary hypertension because of increased endothelin-1 and homocysteine levels. In the light of present study, we conclude that vascular changes caused by increased homocysteine and endothelin-1 may provoke pulmonary hypertension in patients with left-to-right shunt.

Plasma lipoprotein(a) levels in patients with pulmonary arterial hypertension.

BACKGROUND: Pulmonary artery hypertension is a common sequelae of a variety of cardiac and lung diseases. Pathogenesis of primary and secondary pulmonary artery hypertension is still debatable. METHODS AND RESULTS: We studied the serum lipoprotein(a) levels in patients with primary (n=27) and secondary (n=19) pulmonary artery hypertension (Eisenmenger syndrome). The results were compared with age and sex matched controls (n=46). We also studied the frequency of high levels of lipoprotein(a) (> 30 mg/dl) in pulmonary artery hypertension. Mean lipoprotein(a) levels were significantly higher in the pulmonary artery hypertension group compared to age- and sex-matched controls (31.60+/-15.49 mg/dl v. 14.66+/-14.7; p=0.0001). All patients were classified into two groups on the basis of their lipoprotein(a) levels (<30 mg/dl and >30 mg/dl). There was a higher frequency of lipoprotein(a) >30 mg/dl in patients of pulmonary artery hypertension v. controls (52% v. 24%; p= <0.001). Younger age, higher functional class, more severe congestive heart failure, shorter duration of symptoms. and more cases of hemoptysis were observed in the group with lipoprotein(a) >30 mg/dl. CONCLUSIONS: High lipoprotein(a) may be a marker and be associated with a more adverse prognosis in severe pulmonary artery hypertension. Larger prospective studies are needed to establish lipoprotein(a) as a risk factor for the development of pulmonary artery hypertension.

Nitric oxide level in children with pulmonary hypertension.

Nitric oxide is a gas and free radical, which modulates pulmonary and vascular tone. Pulmonary vascular endothelial cell produce the nitric oxide. To define the relation between nitric oxide and hemodynamic parameters in children with pulmonary hypertension, we measured the nitric oxide concentrations of the right atrium, right ventricle, pulmonary artery, left ventricle and aorta in 40 patients during cardiac catheterizations. Patients were divided into two groups according to their pulmonary arterial pressure. In group I, the mean pulmonary arterial pressure was higher than 25 mmHg and in group II, lower than 25 mmHg. Pulmonary nitric oxide level in group I was significantly lower than group II (P < 0.05). The right ventricle and mean pulmonary arterial pressures, pulmonary vascular resistance and pulmonary flow/systemic flow of the patients in group I were significantly higher than those of group II (P < 0.05). In conclusion, we found low nitric oxide levels in patients with pulmonary hypertension and congenital heart defects.