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Doctor of Philosophy / Department of Anatomy and Physiology / Thomas J. Barstow / The overall aims of this dissertation are to determine the incidence and magnitude of insulin resistance (IR) in a cohort of normoglycemic college-age subjects with a family history of type 2 diabetes, and to ascertain if there is early macro- and microvascular dysfunction relative to IR. Study 1 (Chapter 2) revealed a 7-fold range in IR in healthy college subjects concomitant with measures of insulin, both fasted and during an oral glucose tolerance test, but not related with any measure of plasma glucose. These results emphasize that early in the etiology of carbohydrate dysregulation, abnormalities first occur with regard to insulin sensitivity. Using brachial artery blood flow (BABF, Doppler fluxometry) and near-infrared spectroscopy (NIRS) (Chapter 3) we extended the understanding of the use of these non-invasive tools to assess forearm resting metabolic rate and to compare the parameters of both the NIRS oxy-hemoglobin signal, as a index of perfusion in the microcirculation, and BABF, as an independent measure of microvascular reactivity during post occlusive reactive hyperemia (PORH). Resting metabolic rate ranged ~ 2 fold (2.83-5.15 [Mu]MO[subscript2]/min/100g) similar to direct measures. Amplitude, but not kinetic parameters for NIRS variables correlated with comparable parameters for BABF, providing evidence for the possible utility of NIRS in examining microvascular reactivity. In study 3 (Chapter 4), utilizing our extended understanding of hemodynamics garnered from the results of study 2, we assessed the influence of IR on macro- and microvascular reactivity. We observed that i) the magnitude of IR was significantly correlated with attenuation of endothelium-dependent vasodilation of the brachial artery (P< .01) indicating the possibility of a reduced nitric oxide bioavailability and an enhanced atherogenic milieu. Additionally we found ii) BABF at rest and during reactive hyperemia to be strongly correlated with conductance (reduced downstream resistance—an indicator of microvascular control abnormalities) independent of forearm metabolic rate, and iii) parameters of BABF (microvascular response) were also strongly correlated with brachial artery vasoreactivity (macrovascular response). In conclusion, this body of work furthers our insight into the need for earlier identification of "disease" earlier in the progression to type 2 diabetes, and provides direction for future investigations into prevention / intervention to improve microvessel functionality and to slow the atherosclerotic process in larger vessels.

Cardiovascular disease is the leading cause of death in women. Although overall mortality from coronary heart disease (CHD) has decreased, there are subsets of patients, particularly youngwomen, in whom the mortality rate has increased. Underlying sex differences in CHD may be an explanation. Women have more frequent symptoms, more ischemia, and higher mortality than men, but less obstructive coronary artery disease (CAD). Despite this, traditional risk factor assessment has been ineffective in risk stratifying women, prompting the emergence of novel markers and prediction scores to identify a population at risk. Sex differences inmanifestations and the pathophysiology of CHD also have led to differences in the selection of diagnostic testing and treatment options for women, having profound effects on outcomes. The frequent finding of nonobstructive CAD in women with ischemia suggests microvascular dysfunction as an underlying cause; therefore, coronary reactivity and endothelial function testing may add to diagnostic accuracy in female patients. In spite of evidence that women benefit from the same therapies as men, they continue to receive lessaggressive therapy, which is reflected in higher healthcare resource utilization and adverse outcomes. More sex-specific research is needed in the area of symptomatic nonobstructive CAD to define the optimal therapeutic approach.

Cardiovascular disease is the leading cause of death in women. Although overall mortality from coronary heart disease (CHD) has decreased, there are subsets of patients, particularly youngwomen, in whom the mortality rate has increased. Underlying sex differences in CHD may be an explanation. Women have more frequent symptoms, more ischemia, and higher mortality than men, but less obstructive coronary artery disease (CAD). Despite this, traditional risk factor assessment has been ineffective in risk stratifying women, prompting the emergence of novel markers and prediction scores to identify a population at risk. Sex differences inmanifestations and the pathophysiology of CHD also have led to differences in the selection of diagnostic testing and treatment options for women, having profound effects on outcomes. The frequent finding of nonobstructive CAD in women with ischemia suggests microvascular dysfunction as an underlying cause; therefore, coronary reactivity and endothelial function testing may add to diagnostic accuracy in female patients. In spite of evidence that women benefit from the same therapies as men, they continue to receive lessaggressive therapy, which is reflected in higher healthcare resource utilization and adverse outcomes. More sex-specific research is needed in the area of symptomatic nonobstructive CAD to define the optimal therapeutic approach.

BACKGROUND: Microvascular dysfunction (MD: impaired performance of blood flow, tissue perfusion, blood pressure, etc.) is one of the earliest stages in the progression of various chronic diseases. OBJECTIVE: The aim of this study was to determine if a difference in microvascular function existed between two metabolically healthy groups that differed in BMI and waist circumference. DESIGN: This study employed a causal comparative design, with two groups: I) normal weight (n =14, BMI 28 kg/m2). METHODS: Microvascular function was assessed by measuring skin blood flow (SkBF) using laser Doppler flowmetry during postocclusive reactive hyperemia (PORH). The area under the SkBF time curve during the 60-second PORH response was used to quantify the magnitude of the microvascular response. RESULTS: Group I (control) had a significantly higher average area under the SkBF time curve (3240 ± 879) than Group II (1948 ± 808) (Z= -3.0094, p = 0.0026). CONCLUSIONS: The overweight/obese subjects exhibited a diminished skin blood flow response to occlusion compared to their normal-weight counterparts. This supports the hypothesis that overweight/obese subjects who are otherwise metabolically healthy exhibit a biological change that is linked to chronic disease.

Yes / Coronary microvascular dysfunction (CMD) is an under-diagnosed condition characterized by functional alteration of the small coronary arterioles and the cardiac capillary bed. The vessels do not dilate appropriately in response to changes in cardiac oxygen demand, leading to chest pain and symptoms of angina. These blood vessels contain two major cell types: the endothelial cells, which line the blood vessels and detect changes in oxygen demand, and smooth muscle cells (SMC) which respond to these changes by contracting or relaxing to provide an optimal blood supply to the cardiac tissue. Many CMD studies have focused on the endothelial cells as these cells secrete vasorelaxants and vasoconstrictors. However, comparably fewer studies have examined SMC despite their functional role in contracting and relaxing. A variety of health conditions and lifestyle choices, such as diabetes, hypertension and cigarette smoking, can promote the development of both CMD and macrovascular coronary artery disease; a condition where SMC have been studied extensively. This review article will consider the influence of CMD on SMC phenotype. It will discuss the structural, cellular and molecular changes in CMD, and will summarise how co-morbidities can have differing effects on micro- and macro-vascular SMC phenotype and function, which complicates the development of new therapeutic avenues for CMD.

Embasamento racional: O uso rotineiro da cineangiocoronariografia tem demonstrado que nem todos os pacientes com suspeita clínica de doença arterial coronária (DAC) apresentam-se com lesões obstrutivas nas artérias coronárias epicárdicas. Esse achado de dor precordial associado a coronárias angiograficamente normais é relativamente comum, estando presente em aproximadamente 30 % dos pacientes que realizam cateterismo cardíaco para investigação de DAC. Em uma parcela destes pacientes a isquemia miocárdica está presente e pode ser demonstrada através de um teste ergométrico convencional ou até mesmo pela aplicação da cintilografia miocárdica de perfusão (CMP) que é um método de maior acurácia para detecção da extensão/gravidade da isquemia. Pacientes que apresentam o quadro de dor precordial associada a coronárias angiograficamente normais e defeitos perfusionais reversíveis (DPR) na CMP são diagnosticados como portadores de disfunção microvascular coronária (DMC). Ainda que muito se conheça em relação à sua fisiopatologia, essa síndrome ainda não dispõe de opções terapêuticas adequadas. Objetivo: O objetivo do presente estudo é avaliar o efeito do treinamento físico aeróbico (TFA) sobre as alterações da perfusão miocárdica, da potência aeróbica máxima (VO2 pico), da qualidade de vida e dos sintomas anginosos em pacientes com diagnóstico de DMC. Métodos: Foram estudados prospectivamente 12 indivíduos de ambos os gêneros (7 mulheres), idade média de 53,8 ± 9,7 anos, com diagnóstico de DMC dor precordial, artérias coronárias livres de lesões obstrutivas de qualquer magnitude e presença de dois ou mais segmentos miocárdicos com DPR documentados pela CMP. Os defeitos perfusionais nas imagens de repouso e esforço foram semi-quantificados, mediante atribuição de escores visuais (0 = normal; 4 = ausente) em modelo de 17 segmentos das paredes do ventrículo esquerdo. Foram calculados para cada paciente escores somados nas imagens de repouso e estresse e a extensão global da reversibilidade (isquemia) foi medida pelo escore da diferença estresse-repouso. Teste cardiopulmonar (TCP) em esteira ergométrica foi usado para obtenção do VO2 pico e prescrição da intensidade do TFA. Por fim, os pacientes responderam a um questionário de qualidade de vida SF36. Após as avaliações basais os indivíduos foram submetidos a TFA durante quatro meses em esteira ergométrica, três vezes por semana, uma hora por dia e com intensidade prescrita entre 60 % e 85 % do VO2 pico atingido no TCP. Ao final dos quatro meses os pacientes foram novamente avaliados pela CMP, TCP e SF36. Resultados: Dos 12 pacientes, 10 (83,4%) apresentaram redução dos DPR, tendo-se resolvido completamente em 8 (66,7%). Foi observada entre as avaliações basais e póstreinamento melhora estatisticamente significante na redução do DPR (10,1 ± 8,8 para 2,8 ± 4,9 p = 0,008), do número de segmentos do ventrículo esquerdo (VE) isquêmicos (7,67 ± 4,52 para 2,3 ± 4,1 p = 0,002), da porcentagem do VE com isquemia (45,1 ± 26,58 para 13,7 ± 24,1 p = 0,002), do escore somado no pico do estresse na CMP (10,8 ± 8,7 para 3,1 ± 5 p = 0,004), aumento do VO2 pico (19,4 ± 4,8 para 22,1 ± 6,2 p = 0,01), do pulso de oxigênio pico (2550 ± 1040 para 3043 ± 1332 p = 0,01), melhora nos domínios analisados pelo SF36 relacionados à capacidade funcional (44,6 ± 25,8 para 88,3 ± 9,1 p = 0,0002), ao aspecto físico (25 ± 31,9 para 89,6 ± 19,8 p = 0,002), à dor (38,4 ± 22,2 para 68,4 ± 22,3 p = 0,007), à vitalidade (49,2 ± 28,2 para 83,8 ± 12,6 p = 0,0005), aos aspectos sociais (47,9 ± 27,1 para 93,8 ± 15,5 p = 0,002), aos aspectos emocionais (30,6 ± 38,8 para 80,6 ± 33,2 p = 0,005) e à saúde mental (53 ± 22,1 para 80 ± 15,9 p = 0,001). Conclusão: Os resultados mostram que o TFA aplicado aos pacientes com DMC foi associado à significativa melhora da capacidade funcional, da qualidade de vida, incluindo melhora dos escores de dor e redução dos defeitos perfusionais reversíveis (extensão/gravidade da isquemia). Nossos achados sugerem que o TFA seja opção terapêutica válida para tratar pacientes com DMC. Esses resultados iniciais necessitam de validação mais ampla em estudo clínico randomizado e com maior número de pacientes. / Rationale: The routine use of cineangiocoronariography has demonstrated that not all patients with clinical suspicion of coronary artery disease (CAD) present with obstructive lesions in epicardial coronary arteries. This finding of chest pain associated with angiographically normal coronary arteries is relatively common, occurring in approximately 30 % of patients undergoing cardiac catheterization for investigation of CAD. In these patients the myocardial ischemia can be demonstrated by a conventional exercise stress test or by utilization of myocardial perfusion scintigraphy (MPS) which is a more accurate method to detect the extent/severity of ischemia. The diagnosis of coronary microvascular dysfunction (CMD) can be made in patients with chest pain associated to angiographically normal coronary arteries and reversible perfusion defects (RPD) in the MPS. Despite the growing knowledge about the pathophysiology of this syndrome, effective therapeutic options are still missing. Objective: The aim of this study is to evaluate the effect of aerobic exercise training (AET) on myocardial perfusion, oxygen uptake (VO2 peak), quality of life and anginal symptoms in patients with CMD. Methods: We prospectively studied 12 individuals of both gender (7 females), mean age was 53.8 ± 9.7 years, diagnosed with CMD, characterized by chest pain, coronary artery free of obstructive lesions and presence of two or more myocardial segments with RPD documented by using MPS. The perfusion defects on stress and rest images were semi-quantified by attributing visual scores (0 = normal, 4 = absent) in a 17 segment model of left ventricular wall. For each patient, we calculated score summed stress and rest scores and the global extent of reversibility (ischemia) was measured by the difference between stress-rest scores. We applied a treadmill cardiopulmonary test (CPT) obtaining VO2 peak and allowing the prescription of the AET intensity. Finally the patients answered a quality of life questionnaire SF36. After baseline assessments subjects undergone 4 months AET on a treadmill three times a week for an hour a day and prescribed intensity between 60 % and 85% of VO2 peak. At the end of four months the patients were re-evaluated by using MPS, CPT and SF36. Results: Of 12 patients, 10 (83.4 %) showed any reduction of RPD, and RPD was resolved completely in 8 (66.7 %). The comparison between baseline and post-training assessments showed statistically significant improvements in reducing the RPD (10.1 ± 8.8 to 2.8 ± 4.9 p = 0.008), number of segments of the left ventricle (LV) ischemic (7.67 ± 4.52 to 2.3 ± 4.1 p = 0.002), percentage of LV ischemia (45.1 ± 26.58 to 13.7 ± 24.1 p = 0.002), summed score at peak stress MPS (10.8 ± 8.7 to 3.1 ± 5 p = 0.004), increase VO2 peak (19.4 ± 4.8 to 22.1 ± 6.2 p = 0.01), peak oxygen pulse (2550 ± 1040 to 3043 ± 1332 p = 0.01), SF36 domains related to: functional capacity (44.6 ± 25.8 to 88.3 ± 9.1 p = 0.0002), the physical appearance (25 ± 31.9 to 89.6 ± 19.8 p = 0.002), pain (38.4 ± 22.2 to 68.4 ± 22.3 p = 0.007), vitality (49.2 ± 28.2 to 83.8 ± 12.6 p = 0.0005), social aspects (47.9 ± 27.1 to 93.8 ± 15.5 p = 0.002), emotional aspects (30.6 ± 38.8 to 80.6 ± 33.2 p = 0.005) and mental health (53 ± 22.1 to 80 ± 15.9 p = 0.001). Conclusion: The results show that AET applied to patients with CMD was associated with significant improvement in functional capacity, quality of life, including improvement in pain scores and reduction of extent/severity of reversible perfusion defects (ischemia). Our findings suggest that AET is a valid therapeutic option for treating patients with CMD. These initial results require further confirmation in a large randomized placebo controlled clinical trial.

Embasamento racional: O uso rotineiro da cineangiocoronariografia tem demonstrado que nem todos os pacientes com suspeita clínica de doença arterial coronária (DAC) apresentam-se com lesões obstrutivas nas artérias coronárias epicárdicas. Esse achado de dor precordial associado a coronárias angiograficamente normais é relativamente comum, estando presente em aproximadamente 30 % dos pacientes que realizam cateterismo cardíaco para investigação de DAC. Em uma parcela destes pacientes a isquemia miocárdica está presente e pode ser demonstrada através de um teste ergométrico convencional ou até mesmo pela aplicação da cintilografia miocárdica de perfusão (CMP) que é um método de maior acurácia para detecção da extensão/gravidade da isquemia. Pacientes que apresentam o quadro de dor precordial associada a coronárias angiograficamente normais e defeitos perfusionais reversíveis (DPR) na CMP são diagnosticados como portadores de disfunção microvascular coronária (DMC). Ainda que muito se conheça em relação à sua fisiopatologia, essa síndrome ainda não dispõe de opções terapêuticas adequadas. Objetivo: O objetivo do presente estudo é avaliar o efeito do treinamento físico aeróbico (TFA) sobre as alterações da perfusão miocárdica, da potência aeróbica máxima (VO2 pico), da qualidade de vida e dos sintomas anginosos em pacientes com diagnóstico de DMC. Métodos: Foram estudados prospectivamente 12 indivíduos de ambos os gêneros (7 mulheres), idade média de 53,8 ± 9,7 anos, com diagnóstico de DMC dor precordial, artérias coronárias livres de lesões obstrutivas de qualquer magnitude e presença de dois ou mais segmentos miocárdicos com DPR documentados pela CMP. Os defeitos perfusionais nas imagens de repouso e esforço foram semi-quantificados, mediante atribuição de escores visuais (0 = normal; 4 = ausente) em modelo de 17 segmentos das paredes do ventrículo esquerdo. Foram calculados para cada paciente escores somados nas imagens de repouso e estresse e a extensão global da reversibilidade (isquemia) foi medida pelo escore da diferença estresse-repouso. Teste cardiopulmonar (TCP) em esteira ergométrica foi usado para obtenção do VO2 pico e prescrição da intensidade do TFA. Por fim, os pacientes responderam a um questionário de qualidade de vida SF36. Após as avaliações basais os indivíduos foram submetidos a TFA durante quatro meses em esteira ergométrica, três vezes por semana, uma hora por dia e com intensidade prescrita entre 60 % e 85 % do VO2 pico atingido no TCP. Ao final dos quatro meses os pacientes foram novamente avaliados pela CMP, TCP e SF36. Resultados: Dos 12 pacientes, 10 (83,4%) apresentaram redução dos DPR, tendo-se resolvido completamente em 8 (66,7%). Foi observada entre as avaliações basais e póstreinamento melhora estatisticamente significante na redução do DPR (10,1 ± 8,8 para 2,8 ± 4,9 p = 0,008), do número de segmentos do ventrículo esquerdo (VE) isquêmicos (7,67 ± 4,52 para 2,3 ± 4,1 p = 0,002), da porcentagem do VE com isquemia (45,1 ± 26,58 para 13,7 ± 24,1 p = 0,002), do escore somado no pico do estresse na CMP (10,8 ± 8,7 para 3,1 ± 5 p = 0,004), aumento do VO2 pico (19,4 ± 4,8 para 22,1 ± 6,2 p = 0,01), do pulso de oxigênio pico (2550 ± 1040 para 3043 ± 1332 p = 0,01), melhora nos domínios analisados pelo SF36 relacionados à capacidade funcional (44,6 ± 25,8 para 88,3 ± 9,1 p = 0,0002), ao aspecto físico (25 ± 31,9 para 89,6 ± 19,8 p = 0,002), à dor (38,4 ± 22,2 para 68,4 ± 22,3 p = 0,007), à vitalidade (49,2 ± 28,2 para 83,8 ± 12,6 p = 0,0005), aos aspectos sociais (47,9 ± 27,1 para 93,8 ± 15,5 p = 0,002), aos aspectos emocionais (30,6 ± 38,8 para 80,6 ± 33,2 p = 0,005) e à saúde mental (53 ± 22,1 para 80 ± 15,9 p = 0,001). Conclusão: Os resultados mostram que o TFA aplicado aos pacientes com DMC foi associado à significativa melhora da capacidade funcional, da qualidade de vida, incluindo melhora dos escores de dor e redução dos defeitos perfusionais reversíveis (extensão/gravidade da isquemia). Nossos achados sugerem que o TFA seja opção terapêutica válida para tratar pacientes com DMC. Esses resultados iniciais necessitam de validação mais ampla em estudo clínico randomizado e com maior número de pacientes. / Rationale: The routine use of cineangiocoronariography has demonstrated that not all patients with clinical suspicion of coronary artery disease (CAD) present with obstructive lesions in epicardial coronary arteries. This finding of chest pain associated with angiographically normal coronary arteries is relatively common, occurring in approximately 30 % of patients undergoing cardiac catheterization for investigation of CAD. In these patients the myocardial ischemia can be demonstrated by a conventional exercise stress test or by utilization of myocardial perfusion scintigraphy (MPS) which is a more accurate method to detect the extent/severity of ischemia. The diagnosis of coronary microvascular dysfunction (CMD) can be made in patients with chest pain associated to angiographically normal coronary arteries and reversible perfusion defects (RPD) in the MPS. Despite the growing knowledge about the pathophysiology of this syndrome, effective therapeutic options are still missing. Objective: The aim of this study is to evaluate the effect of aerobic exercise training (AET) on myocardial perfusion, oxygen uptake (VO2 peak), quality of life and anginal symptoms in patients with CMD. Methods: We prospectively studied 12 individuals of both gender (7 females), mean age was 53.8 ± 9.7 years, diagnosed with CMD, characterized by chest pain, coronary artery free of obstructive lesions and presence of two or more myocardial segments with RPD documented by using MPS. The perfusion defects on stress and rest images were semi-quantified by attributing visual scores (0 = normal, 4 = absent) in a 17 segment model of left ventricular wall. For each patient, we calculated score summed stress and rest scores and the global extent of reversibility (ischemia) was measured by the difference between stress-rest scores. We applied a treadmill cardiopulmonary test (CPT) obtaining VO2 peak and allowing the prescription of the AET intensity. Finally the patients answered a quality of life questionnaire SF36. After baseline assessments subjects undergone 4 months AET on a treadmill three times a week for an hour a day and prescribed intensity between 60 % and 85% of VO2 peak. At the end of four months the patients were re-evaluated by using MPS, CPT and SF36. Results: Of 12 patients, 10 (83.4 %) showed any reduction of RPD, and RPD was resolved completely in 8 (66.7 %). The comparison between baseline and post-training assessments showed statistically significant improvements in reducing the RPD (10.1 ± 8.8 to 2.8 ± 4.9 p = 0.008), number of segments of the left ventricle (LV) ischemic (7.67 ± 4.52 to 2.3 ± 4.1 p = 0.002), percentage of LV ischemia (45.1 ± 26.58 to 13.7 ± 24.1 p = 0.002), summed score at peak stress MPS (10.8 ± 8.7 to 3.1 ± 5 p = 0.004), increase VO2 peak (19.4 ± 4.8 to 22.1 ± 6.2 p = 0.01), peak oxygen pulse (2550 ± 1040 to 3043 ± 1332 p = 0.01), SF36 domains related to: functional capacity (44.6 ± 25.8 to 88.3 ± 9.1 p = 0.0002), the physical appearance (25 ± 31.9 to 89.6 ± 19.8 p = 0.002), pain (38.4 ± 22.2 to 68.4 ± 22.3 p = 0.007), vitality (49.2 ± 28.2 to 83.8 ± 12.6 p = 0.0005), social aspects (47.9 ± 27.1 to 93.8 ± 15.5 p = 0.002), emotional aspects (30.6 ± 38.8 to 80.6 ± 33.2 p = 0.005) and mental health (53 ± 22.1 to 80 ± 15.9 p = 0.001). Conclusion: The results show that AET applied to patients with CMD was associated with significant improvement in functional capacity, quality of life, including improvement in pain scores and reduction of extent/severity of reversible perfusion defects (ischemia). Our findings suggest that AET is a valid therapeutic option for treating patients with CMD. These initial results require further confirmation in a large randomized placebo controlled clinical trial.

A disfunção microvascular, envolvendo células endoteliais, plaquetas e leucócitos, está presente na hipertensão arterial pulmonar (HAP), associando-se a risco aumentado de trombose e menor sobrevida. Estudos sobre disfunção microvascular são escassos em outras formas da doença que não a idiopática. Os objetivos do estudo foram: caracterizar a disfunção microvascular em diferentes formas de HAP através da dosagem de marcadores bioquímicos, avaliando possíveis correlações com índices de gravidade; investigar os efeitos da administração de rosuvastatina em níveis circulantes de marcadores de disfunção microvascular nesses pacientes; e investigar possível associação entre o nível plasmático dos marcadores e prognóstico. Foram incluídos sessenta pacientes: 14 com HAP idiopática ou hereditária, e 46 com HAP associada a cardiopatia congênita (HAPCCg) sem hipoxemia (N=18) ou com hipoxemia (N=28), com idades entre 13 e 60 anos. Foram dosados os níveis plasmáticos circulantes do antígeno do fator de von Willebrand (vWF:Ag), ativador tecidual do plasminogênio (t-PA); inibidor do ativador do plasminogênio (PAI-1), fator de necrose tumoral (TNF-), proteína C reativa (PCR), selectina-P; interleucina-6 (IL-6); e interleucina-10 (IL -10), na condição basal e após 30, 60 e 180 dias de tratamento, por método imunoenzimático. Após randomização, administrouse placebo (N=30) ou dose única oral diária (10mg) de rosuvastatina (N=30), por seis meses. Dados demográficos e funcionais como idade, distância caminhada em seis minutos, saturação periférica de oxigênio em repouso e após esforço, bem como hematócrito, também foram registrados. Pacientes com HAPCCg foram acompanhados por um período de 0,7 a 4,0 anos (mediana de 3,6 anos). Na condição basal, excetuando-se TNF- e PCR, todas as proteínas apresentaram-se significantemente elevadas em relação aos controles (p<0,001), havendo correlação com índices de gravidade clínica. No estudo com rosuvastatina, houve redução significante nos níveis de selectina-P em relação ao placebo (p=0,037), ao longo do tratamento. Houve melhora na saturação periférica de oxigênio após seis minutos de caminhada, no grupo estatina, em pacientes com HAPCCg com hipoxemia, em relação ao placebo. Considerando-se o período de acompanhamento, em portadores de HAPCCg, níveis plasmáticos persistentemente elevados do vWF:Ag (média de quatro determinações), acima do nível correspondente ao percentil 95 dos controles (139 U/d/L) associaram-se maior risco de morte (razão de risco 6,56, IC 95% 1,46 a 29,4, p=0.014), sem alteração após ajustamento para variáveis demográficas, funcionais e de tratamento, à análise multivariada. Assim, a disfunção microvascular está presente em indivíduos com HAP idiopática, hereditária ou associada a cardiopatias congênitas. Na HAP, o uso crônico de rosuvastatina em dose baixa associase à redução do nível circulante de selectina-P, e propicia aumento na saturação periférica de oxigênio ao final do exercício, em indivíduos com HAPCCg e hipoxemia. Em indivíduos portadores de HAPCCg, níveis plasmáticos persistentemente elevados do vWF:Ag são indicativo de pior prognóstico / Microvascular dysfunction, involving endothelial cells, platelets and leukocytes, is present in pulmonary arterial hypertension (PAH), and is associated to higher risk to thrombotic complications and mortality. Most data about microvascular dysfunction in PAH do not include other forms of the disease beyond idiopathic PAH. The present study was planned to measure plasma levels microvascular dysfunction markers in two different forms of PAH, and investigate possible correlations with indices of severity of the disease; to investigate the effects of chronic rosuvastatin administration versus placebo on the circulating levels of these markers; and to investigate possible associations between levels of these parameters and prognosis. Sixty patients (aged 13 to 60 years) were included, 14 with idiopathic or hereditary PAH, and 46 with congenital heart disease-associated PAH (CHDPAH), in the absence (N=18) or presence (N=28) of hypoxemia. Plasma levels of von Willebrand factor antigen (vWF:Ag), tissue-plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1), tumor necrosis factor alpha (TNF-), reactive C protein (RCP), P-selectin, interleukin-6 (IL- 6), and interleukin-10 (IL-10) were measured before treatment and 30, 90, and 180 days on treatment using high-sensitivity enzyme-linked immunosorbent assay kits. Patients were randomly assigned to placebo (N=30) or a single oral dose of rosuvastatin (N=30), 10mg/day, for six months. Demographic and functional data such as age, six-minute walk distance, peripheral oxygen saturation at rest and at the end of the six-minute walk, as well as the hematocrit, were recorded. Patients with CHDPAH were followed-up for 0.7 to 4.0 years (median 3.6 years). At baseline, levels of all proteins (except TNF- and RCP) were significantly increased in patients versus controls (p<0,001), and correlated significantly with indices of severity of the disease. P-selectin level was lower in the rosuvastatin group compared with placebo throughout the treatment (p = 0.037). In hypoxemic CHDPAH patients, the peripheral oxygen saturation, at the end of the six-minute walk, was higher in the rosuvastatin group, compared with placebo. During the follow-up of patients with CHDPAH, an average vWF:Ag (mean of four determinations) above the level corresponding to the 95th percentile of controls (139 U/dL) was associated with a high risk of death (hazard ratio 6.56, 95% CI 1.46 to 29.4, p=0.014). This was not modified after adjustment for demographic, functional and treatment-related variables in multivariate analysis. In conclusion, microvascular dysfunction is present in individuals with idiopathic, hereditary and the congenital heart disease-associated PAH. The chronic use of low-dose rosuvastatin is associated to reduction of circulating levels of P-selectin. In patients with CHDPAH with hypoxemia, rosuvastatin also increases peripheral oxygen saturation during exercise. In CHDPAH patients, a sustained increase in plasma vWF:Ag is indicative of poor prognosis

A disfunção microvascular, envolvendo células endoteliais, plaquetas e leucócitos, está presente na hipertensão arterial pulmonar (HAP), associando-se a risco aumentado de trombose e menor sobrevida. Estudos sobre disfunção microvascular são escassos em outras formas da doença que não a idiopática. Os objetivos do estudo foram: caracterizar a disfunção microvascular em diferentes formas de HAP através da dosagem de marcadores bioquímicos, avaliando possíveis correlações com índices de gravidade; investigar os efeitos da administração de rosuvastatina em níveis circulantes de marcadores de disfunção microvascular nesses pacientes; e investigar possível associação entre o nível plasmático dos marcadores e prognóstico. Foram incluídos sessenta pacientes: 14 com HAP idiopática ou hereditária, e 46 com HAP associada a cardiopatia congênita (HAPCCg) sem hipoxemia (N=18) ou com hipoxemia (N=28), com idades entre 13 e 60 anos. Foram dosados os níveis plasmáticos circulantes do antígeno do fator de von Willebrand (vWF:Ag), ativador tecidual do plasminogênio (t-PA); inibidor do ativador do plasminogênio (PAI-1), fator de necrose tumoral (TNF-), proteína C reativa (PCR), selectina-P; interleucina-6 (IL-6); e interleucina-10 (IL -10), na condição basal e após 30, 60 e 180 dias de tratamento, por método imunoenzimático. Após randomização, administrouse placebo (N=30) ou dose única oral diária (10mg) de rosuvastatina (N=30), por seis meses. Dados demográficos e funcionais como idade, distância caminhada em seis minutos, saturação periférica de oxigênio em repouso e após esforço, bem como hematócrito, também foram registrados. Pacientes com HAPCCg foram acompanhados por um período de 0,7 a 4,0 anos (mediana de 3,6 anos). Na condição basal, excetuando-se TNF- e PCR, todas as proteínas apresentaram-se significantemente elevadas em relação aos controles (p<0,001), havendo correlação com índices de gravidade clínica. No estudo com rosuvastatina, houve redução significante nos níveis de selectina-P em relação ao placebo (p=0,037), ao longo do tratamento. Houve melhora na saturação periférica de oxigênio após seis minutos de caminhada, no grupo estatina, em pacientes com HAPCCg com hipoxemia, em relação ao placebo. Considerando-se o período de acompanhamento, em portadores de HAPCCg, níveis plasmáticos persistentemente elevados do vWF:Ag (média de quatro determinações), acima do nível correspondente ao percentil 95 dos controles (139 U/d/L) associaram-se maior risco de morte (razão de risco 6,56, IC 95% 1,46 a 29,4, p=0.014), sem alteração após ajustamento para variáveis demográficas, funcionais e de tratamento, à análise multivariada. Assim, a disfunção microvascular está presente em indivíduos com HAP idiopática, hereditária ou associada a cardiopatias congênitas. Na HAP, o uso crônico de rosuvastatina em dose baixa associase à redução do nível circulante de selectina-P, e propicia aumento na saturação periférica de oxigênio ao final do exercício, em indivíduos com HAPCCg e hipoxemia. Em indivíduos portadores de HAPCCg, níveis plasmáticos persistentemente elevados do vWF:Ag são indicativo de pior prognóstico / Microvascular dysfunction, involving endothelial cells, platelets and leukocytes, is present in pulmonary arterial hypertension (PAH), and is associated to higher risk to thrombotic complications and mortality. Most data about microvascular dysfunction in PAH do not include other forms of the disease beyond idiopathic PAH. The present study was planned to measure plasma levels microvascular dysfunction markers in two different forms of PAH, and investigate possible correlations with indices of severity of the disease; to investigate the effects of chronic rosuvastatin administration versus placebo on the circulating levels of these markers; and to investigate possible associations between levels of these parameters and prognosis. Sixty patients (aged 13 to 60 years) were included, 14 with idiopathic or hereditary PAH, and 46 with congenital heart disease-associated PAH (CHDPAH), in the absence (N=18) or presence (N=28) of hypoxemia. Plasma levels of von Willebrand factor antigen (vWF:Ag), tissue-plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1), tumor necrosis factor alpha (TNF-), reactive C protein (RCP), P-selectin, interleukin-6 (IL- 6), and interleukin-10 (IL-10) were measured before treatment and 30, 90, and 180 days on treatment using high-sensitivity enzyme-linked immunosorbent assay kits. Patients were randomly assigned to placebo (N=30) or a single oral dose of rosuvastatin (N=30), 10mg/day, for six months. Demographic and functional data such as age, six-minute walk distance, peripheral oxygen saturation at rest and at the end of the six-minute walk, as well as the hematocrit, were recorded. Patients with CHDPAH were followed-up for 0.7 to 4.0 years (median 3.6 years). At baseline, levels of all proteins (except TNF- and RCP) were significantly increased in patients versus controls (p<0,001), and correlated significantly with indices of severity of the disease. P-selectin level was lower in the rosuvastatin group compared with placebo throughout the treatment (p = 0.037). In hypoxemic CHDPAH patients, the peripheral oxygen saturation, at the end of the six-minute walk, was higher in the rosuvastatin group, compared with placebo. During the follow-up of patients with CHDPAH, an average vWF:Ag (mean of four determinations) above the level corresponding to the 95th percentile of controls (139 U/dL) was associated with a high risk of death (hazard ratio 6.56, 95% CI 1.46 to 29.4, p=0.014). This was not modified after adjustment for demographic, functional and treatment-related variables in multivariate analysis. In conclusion, microvascular dysfunction is present in individuals with idiopathic, hereditary and the congenital heart disease-associated PAH. The chronic use of low-dose rosuvastatin is associated to reduction of circulating levels of P-selectin. In patients with CHDPAH with hypoxemia, rosuvastatin also increases peripheral oxygen saturation during exercise. In CHDPAH patients, a sustained increase in plasma vWF:Ag is indicative of poor prognosis