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% 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% 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.

Evidence that blood pressure remains under the control of arterial baroreceptors in renal hypertensive rats

The purpose of the present study was to determine the range of the influence of the baroreflex on blood pressure in chronic renal hypertensive rats. Supramaximal electrical stimulation of the aortic depressor nerve and section of the baroreceptor nerves (sinoaortic denervation) were used to obtain a global analysis of the baroreceptor-sympathetic reflex in normotensive control and in chronic (2 months) 1-kidney, 1-clip hypertensive rats. The fall in blood pressure produced by electrical baroreceptor stimulation was greater in renal hypertensive rats than in normotensive controls (right nerve: -47 ± 8 vs -23 ± 4 mmHg; left nerve: -51 ± 7 vs -30 ± 4 mmHg; and both right and left nerves: -50 ± 8 vs -30 ± 4 mmHg; P < 0.05). Furthermore, the increase in blood pressure level produced by baroreceptor denervation in chronic renal hypertensive rats was similar to that observed in control animals 2-5 h (control: 163 ± 5 vs 121 ± 1 mmHg; 1K-1C: 203 ± 7 vs 170 ± 5 mmHg; P < 0.05) and 24 h (control: 149 ± 3 vs 121 ± 1 mmHg; 1K-1C: 198 ± 8 vs 170 ± 5 mmHg; P < 0.05) after sinoaortic denervation. Taken together, these data indicate that the central and peripheral components of the baroreflex are acting efficiently at higher arterial pressure in renal hypertensive rats when the aortic nerve is maximally stimulated or the activity is abolished.

Oral rapamycin attenuates atherosclerosis without affecting the arterial responsiveness of resistance vessels in apolipoprotein E-deficient mice

The objective of the present study was to assess the effects of the immunosuppressant rapamycin (Rapamune®, Sirolimus) on both resistance vessel responsiveness and atherosclerosis in apolipoprotein E-deficient 8-week-old male mice fed a normal rodent diet. Norepinephrine (NE)-induced vasoconstriction, acetylcholine (ACh)- and sodium nitroprusside (SNP)-induced vasorelaxation of isolated mesenteric bed, and atherosclerotic lesions were evaluated. After 12 weeks of orally administered rapamycin (5 mg·kg-1·day-1, N = 9) and compared with untreated (control, N = 9) animals, rapamycin treatment did not modify either NE-induced vasoconstriction (maximal response: 114 ± 4 vs 124 ± 10 mmHg, respectively) or ACh- (maximal response: 51 ± 8 vs 53 ± 5%, respectively) and SNP-induced vasorelaxation (maximal response: 73 ± 6 vs 74 ± 6%, respectively) of the isolated vascular mesenteric bed. Despite increased total cholesterol in treated mice (982 ± 59 vs 722 ± 49 mg/dL, P < 0.01), lipid deposition on the aorta wall vessel was significantly less in rapamycin-treated animals (37 ± 12 vs 68 ± 8 µm² x 10³). These results indicate that orally administered rapamycin is effective in attenuating the progression of atherosclerotic plaque without affecting the responsiveness of resistance vessels, supporting the idea that this immunosuppressant agent might be of potential benefit against atherosclerosis in patients undergoing therapy.

Immediate effects of submaximal effort on pulse wave velocity in patients with Marfan syndrome

Marfan syndrome (MS) is a dominant autosomal disease caused by mutations in chromosome 15, the locus controlling fibrillin 1 synthesis, and may exhibit skeletal, ocular, cardiovascular, and other manifestations. Pulse wave velocity (PWV) is used to measure arterial elasticity and stiffness and is related to the elastic properties of the vascular wall. Since the practice of exercise is limited in MS patients, it was of interest to analyze the acute effect of submaximal exercise on aortic distensibility using PWV and other hemodynamic variables in patients with MS with either mild or no aortic dilatation. PWV and physiological variables were evaluated before and after submaximal exercise in 33 patients with MS and 18 controls. PWV was 8.51 ± 0.58 at rest and 9.10 ± 0.63 m/s at the end of exercise (P = 0.002) in the group with MS and 8.07 ± 0.35 and 8.98 ± 0.56 m/s in the control group, respectively (P = 0.004). Comparative group analysis regarding PWV at rest and at the end of exercise revealed no statistically significant differences. The same was true for the group that used β-blockers and the one that did not. The final heart rate was 10% higher in the control group than in the MS group (P = 0.01). Final systolic arterial pressure was higher in the control group (P = 0.02). PWV in MS patients with mild or no aortic dilatation did not differ from the control group after submaximal effort.

An improved strategy for evaluating the extent of chronic arterial baroreceptor denervation in conscious rats

There is no index or criterion of aortic barodenervation, nor can we differentiate among rats that have suffered chronic sham, aortic or sino-aortic denervation. The objective of this study was to develop a procedure to generate at least one quantitative, reproducible and validated index that precisely evaluates the extent of chronic arterial barodenervation performed in conscious rats. Data from 79 conscious male Wistar rats of about 65-70 days of age with diverse extents of chronic arterial barodenervation and used in previous experiments were reanalyzed. The mean arterial pressure (MAP) and the heart rate (HR) of all rats were measured systematically before (over 1 h) and after three consecutive iv bolus injections of phenylephrine (PHE) and sodium nitroprusside (SNP). Four expressions of the effectiveness of barodenervation (MAP lability, PHE ratio, SNP ratio, and SNP-PHE slope) were assessed with linear fixed models, three-level average variance, average separation among levels, outlier box plot analysis, and overlapping graphic analysis. The analysis indicated that a) neither MAP lability nor SNP-PHE slope was affected by the level of chronic sodium intake; b) even though the Box-Cox transformations of both MAP lability [transformed lability index (TLI)] and SNP-PHE slope [transformed general sensitivity index (TGSI), {((3-(ΔHRSNP-ΔHRPHE/ΔMAPSNP-ΔMAPPHE))-0.4-1)/-0.04597}] could be two promising indexes, TGSI proved to be the best index; c) TLI and TGSI were not freely interchangeable indexes for this purpose. TGSI ranges that permit differentiation between sham (10.09 to 11.46), aortic (8.40 to 9.94) and sino-aortic (7.68 to 8.24) barodenervated conscious rats were defined.

Drag reduction by polyethylene glycol in the tail arterial bed of normotensive and hypertensive rats

This study was designed to evaluate the effect of drag reducer polymers (DRP) on arteries from normotensive (Wistar) and spontaneously hypertensive rats (SHR). Polyethylene glycol (PEG 4000 at 5000 ppm) was perfused in the tail arterial bed with (E+) and without endothelium (E-) from male, adult Wistar (N = 14) and SHR (N = 13) animals under basal conditions (constant flow at 2.5 mL/min). In these preparations, flow-pressure curves (1.5 to 10 mL/min) were constructed before and 1 h after PEG 4000 perfusion. Afterwards, the tail arterial bed was fixed and the internal diameters of the arteries were then measured by microscopy and drag reduction was assessed based on the values of wall shear stress (WSS) by computational simulation. In Wistar and SHR groups, perfusion of PEG 4000 significantly reduced pulsatile pressure (Wistar/E+: 17.5 ± 2.8; SHR/E+: 16.3 ± 2.7%), WSS (Wistar/E+: 36; SHR/E+: 40%) and the flow-pressure response. The E- reduced the effects of PEG 4000 on arteries from both groups, suggesting that endothelial damage decreased the effect of PEG 4000 as a DRP. Moreover, the effects of PEG 4000 were more pronounced in the tail arterial bed from SHR compared to Wistar rats. In conclusion, these data demonstrated for the first time that PEG 4000 was more effective in reducing the pressure-flow response as well as WSS in the tail arterial bed of hypertensive than of normotensive rats and these effects were amplified by, but not dependent on, endothelial integrity. Thus, these results show an additional mechanism of action of this polymer besides its mechanical effect through the release and/or bioavailability of endothelial factors.

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% 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%CI = 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.

Adrenomedullin and adrenotensin regulate collagen synthesis and proliferation in pulmonary arterial smooth muscle cells

To understand the pathophysiological mechanisms of pulmonary arterial smooth muscle cell (PASMC) proliferation and extracellular-matrix accumulation in the development of pulmonary hypertension and remodeling, this study determined the effects of different doses of adrenomedullin (ADM) and adrenotensin (ADT) on PASMC proliferation and collagen synthesis. The objective was to investigate whether extracellular signal-regulated kinase (ERK1/2) signaling was involved in ADM- and ADT-stimulated proliferation of PASMCs in 4-week-old male Wistar rats (body weight: 100-150 g, n=10). The proliferation of PASMCs was examined by 5-bromo-2-deoxyuridine incorporation. A cell growth curve was generated by the Cell Counting Kit-8 method. Expression of collagen I, collagen III, and phosphorylated ERK1/2 (p-ERK1/2) was evaluated by immunofluorescence. The effects of different concentrations of ADM and ADT on collagen I, collagen III, and p-ERK1/2 protein expression were determined by immunoblotting. We also investigated the effect of PD98059 inhibition on the expression of p-ERK1/2 protein by immunoblotting. ADM dose-dependently decreased cell proliferation, whereas ADT dose-dependently increased it; and ADM and ADT inhibited each other with respect to their effects on the proliferation of PASMCs. Consistent with these results, the expression of collagen I, collagen III, and p-ERK1/2 in rat PASMCs decreased after exposure to ADM but was upregulated after exposure to ADT. PD98059 significantly inhibited the downregulation by ADM and the upregulation by ADT of p-ERK1/2 expression. We conclude that ADM inhibited, and ADT stimulated, ERK1/2 signaling in rat PASMCs to regulate cell proliferation and collagen expression.

Histidine-tryptophan-ketoglutarate solution decreases mortality and morbidity in high-risk patients with severe pulmonary arterial hypertension associated with complex congenital heart disease: an 11-year experience from a single institution

Cardioplegic reperfusion during a long term ischemic period interrupts cardiac surgery and also increases cellular edema due to repeated solution administration. We reviewed the clinical experiences on myocardial protection of a single perfusion with histidine-tryptophan-ketoglutarate (HTK) for high-risk patients with severe pulmonary arterial hypertension associated with complex congenital heart disease. This retrospective study included 101 high-risk patients undergoing arterial switch operation between March 2001 and July 2012. We divided the cohort into two groups: HTK group, myocardial protection was carried out with one single perfusion with HTK solution; and St group, myocardial protection with conventional St. Thomas' crystalloid cardioplegic solution. The duration of cardiopulmonary bypass did not differ between the two groups. The mortality, morbidity, ICU stay, post-operative hospitalization time, and number of transfusions in HTK group were lower than those in St group (P<0.05). Univariate and multivariate analysis showed that HTK is a statistically significant independent predictor of decreased early mortality and morbidity (P<0.05). In conclusion, HTK solution seems to be an effective and safe alternative to St. Thomas' solution for cardioplegic reperfusion in high-risk patients with complex congenital heart disease.

Efeito da dieta, estatina e ácidos graxos ômega-3 sobre a pressão arterial e a lipidemia em humanos

As doenças cardiovasculares são responsáveis pela alta taxa de mortalidade nos países desenvolvidos e em desenvolvimento, assim, têm sido alvo de vários estudos. O objetivo deste trabalho foi avaliar as concentrações de colesterol e suas frações, triglicérides e pressão arterial em humanos. O estudo foi dividido em três tratamentos - dieta (placebo), estatina e ácidos graxos ômega-3 com dieta de 1200 kcal por dia para todos os grupos com oito pacientes cada, e vários parâmetros foram avaliados no tempo zero e 30 dias. Conclui-se que para o tratamento dieta houve diminuição de peso, colesterol total, HDL-c, triglicérides, Pressão arterial sistólica (PAS), Pressão arterial diastólica (PAD) e aumento no LDL-c. No tratamento estatina, houve redução de peso, colesterol total, LDL-c, triglicérides, PAS, PAD e aumento do HDL-c. Já no tratamento com ômega-3, constatou-se a diminuição de peso, colesterol total, LDL-c, triglicérides; aumento de PAS e PAD e níveis de HDL-c iguais.

Efeito da associação entre obesidade neuroendócrina e exócrina experimental sobre a pressão arterial de cauda e o metabolismo de glicose de ratos Wistar

OBJETIVO: Estudar dois modelos de obesidade, exócrina e endócrina, e sua associação sobre a pressão arterial de cauda (PAC), o peso corporal (PC), o metabolismo glicídico (ISI) e gordura epididimal relativa (GER). MÉTODOS: Foram estudados ratos machos da cepa Wistar. O grupo MSG recebeu glutamato monossódico no período neonatal. Aos 3 meses de idade parte desses animais passou a receber dieta cafeteria (CAF). Os animais receberam controle salina no período neonatal. Durante 12 semanas foram pesados (PC) e tiveram a pressão arterial de cauda (PAC) aferida. O Teste de Tolerância Oral à Glicose foi realizado e o Índice de Sensibilidade à Insulina (ISI), calculado. O peso ventricular relativo (PVR) e a gordura epididimal relativa (GER) também foram calculados. RESULTADOS: Não se verificou alterações no PC e na PAC. A obesidade induzida pela administração de MSG e CAF, isoladamente, promoveu aumento da resistência à insulina (WST = 23,25 ± 9,31; CAF = 15,92 ± 9,10*; MSG = 13,41 ± 3,84* mg-1mU-1, p < 0,05 vs WST) e da gordura visceral (WST = 6,20 ± 0,57; CAF = 8,27 ± 1,53*; MSG = 8,23 ± 1,98* g/100 g, *p < 0,05), quando esses animais foram comparados com os controles. A associação de ambos os modelos de obesidade produziu um efeito sinérgico sobre a resistência à insulina (MSG+CAF = 9,34 ± 5,77 mg-1mU-1, p<0,05 vs MSG e CAF) e sobre o conteúdo de gordura visceral (MSG+CAF = 11,12 ± 3,85 g/100g, p < 0,05 vs MSG e CAF). CONCLUSÃO : A associação de dois modelos de obesidade agrava a resistência à insulina e esse fato pode ser atribuído pelo menos em parte ao aumento da GER.

Avaliação de influências sociais e econômicas sobre a pressão arterial de adolescentes de escolas públicas e privadas: um estudo epidemiológico

INTRODUÇÃO: Anteriormente, a alta prevalência de hipertensão arterial em alunos do Ensino Médio de Sorocaba, em São Paulo, foi descrita. Neste estudo, em nova amostra de alunos da mesma faixa etária, oriundos de escolas públicas e privadas, foi avaliado se as diferenças socioeconômicas e o modo de vida podem influenciar os valores da pressão arterial. MÉTODOS: Trata-se de um estudo epidemiológico, inserido entre as atividades de um trabalho comunitário, em que estudantes de Medicina fazem palestras para alunos do Ensino Médio, objetivando estimular hábitos de vida saudáveis e a prevenção primária da hipertensão arterial. Em amostra aleatória de 410 alunos do segundo ano do Ensino Médio (209 de escolas públicas e 201 de escolas privadas), foram determinados o peso, a altura e a pressão arterial, e foi aplicado um questionário epidemiológico e socioeconômico. RESULTADOS: Não há diferenças estatísticas entre os alunos das escolas públicas e privadas quanto à distribuição de sexo, ao índice de massa corporal (IMC), à pressão arterial sistólica e diastólica, à prevalência de hipertensão arterial (16,3%), à porcentagem de fumantes (5,9%), à atividade física regular e aos antecedentes familiares de hipertensão arterial. Nas escolas públicas há maior porcentagem de afro-descendentes, os alunos trabalham fora de casa com maior frequência e têm menor renda familiar. Nas escolas públicas e privadas, os homens têm maior prevalência de hipertensão arterial e a média da pressão arterial é maior que nas mulheres. O IMC tem correlação positiva com a pressão arterial sistólica e diastólica. CONCLUSÕES: A hipertensão arterial e outros fatores de risco cardiovasculares têm início precoce e necessitam de intervenções educativas para a prevenção primária. Fatores socioeconômicos não influenciam a pressão arterial na adolescência.

Valor da equação Cockcroft-Gault na triagem de função renal reduzida em pacientes com hipertensão arterial sistêmica

INTRODUÇÃO: A hipertensão arterial é um problema de saúde pública mundial e um dos principais fatores de risco para o desenvolvimento da doença renal crônica. MÉTODOS: Com a finalidade de comparar a equação Cockcroft-Gault com a creatinina sérica e o clearance de creatinina (ClCr) na triagem de função renal reduzida, realizouse um estudo transversal com 198 hipertensos de uma unidade básica de saúde. Foram analisados dados demográficos, nutricionais e clínico-laboratoriais. A função renal foi analisada pela creatinina sérica e pelo ClCr em urina de 24 horas. A taxa de filtração glomerular foi também estimada segundo a equação Cockcroft-Gault. RESULTADOS: Os pacientes apresentaram idade média de 60,6 ± 11,6 anos, e 73,7% eram do sexo feminino. A prevalência de creatinina sérica > 1,2 mg/dL foi de 7,6% e da taxa de filtração glomerular < 60 mL/ minutos foi de 24,2%, quando avaliadas pelo ClCr e pela equação Cockcroft-Gault. A filtração glomerular reduzida foi observada em homens mais velhos, com menor índice de massa corporal, valores normais de glicemia de jejum e maiores níveis de ácido úrico e pressão arterial sistólica. DISCUSSÃO: A prevalência de função renal reduzida entre hipertensos varia consideravelmente dependendo da abordagem laboratorial utilizada. O clearance de creatinina, principalmente quando estimado pela equação de Cockcroft-Gault, mostrou ser um marcador mais acurado que a creatinina sérica na avaliação da taxa de filtração glomerular. CONCLUSÕES: A equação Cockcroft-Gault apresentou maior concordância com o clearance de creatinina, provando ser um confiável teste de triagem para o diagnóstico precoce e manejo de hipertensos com função renal reduzida na atenção básica.

Efeito da sobreposição de um modelo de obesidade neuroendócrina experimental e hipertensão arterial sobre a pressão arterial, peso corporal e parâmetros metabólicos e renais de ratos

INTRODUÇÃO: A elevação do índice de massa corporaleapresençadesíndromemetabólica se associam com diminuição da função renal e o aparecimento de doença renal terminal. OBJETIVO: Avaliar o efeito da sobreposição de um modelo de obesidade experimental e hipertensão arterial sobre a pressão arterial, peso corporal e parâmetros metabólicos e renais de ratos. MÉTODOS: Foram estudados ratos machos das cepas Wistar e espontaneamente hipertensos (SHR). Os grupos MSG receberam glutamato monossódico no período neonatal (WST + MSG e SHR + MSG). Os animais controles receberam salina no período neonatal (WST e SHR). Após completarem três meses de vida, por 12 semanas foram pesados e tiveram a pressão arterial de cauda aferida semanalmente. A determinação de microalbuminúria foi realizada nas semanas 0, 4, 8 e 12. Ao final do período de acompanhamento, coletou-se sangue para glicemia de jejum, creatinina e perfil lipídico. Os rins foram retirados, corados e o índice de esclerose glomerular foi calculado. RESULTADOS: A administração de MSG produziu maior ganho percentual de peso corporal, elevação da glicemia de jejum e maior grau de lesão glomerular nos ratos WST -MSG e SHR -MSG quando comparados aos seus controles. Houve maior excreção urinária de albumina nos ratos do Grupo SHR + MSG quando comparados aos SHR. Não houve diferença estatística na pressão arterial de cauda, creatinina e parâmetros do metabolismo lipídico. CONCLUSÕES: A associação de obesidade neuroendócrina e a hipertensão arterial promoveram alterações morfológicas e funcionais no glomérulo mais severas do que aquelas observadas nos ratos somente hipertensos.