Apnéia obstrutiva do sono e resistência à insulina: qual o papel da microcirculação?

Obstructive sleep apnea is an increasingly recognized medical problem. The recent attention to its frequency in the general population and its important role in metabolic, vascular, and behavioral aspects have sharply increased the number and nature of investigations, thereby revealing new aspects that open new approaches in research. Whereas obstructive sleep apnea is a well-known phenomenon accompanying obesity and diabetes, new findings strongly suggest that this close relationship may also operate in the opposite direction. Indeed obstructive sleep apnea may be a primary feature inducing or aggravating a series of vascular and metabolic disturbances closely resembling the metabolic syndrome. This review will discuss established and potential mechanisms responsible for these changes. Obstructive sleep apnea indeed appears to gather all the elements necessary to induce insulin resistance, hypertension, and possibly heart failure. After careful analysis of these modifications and considering how they are intertwined, we propose that microcirculation could represent the common denominator mediating the progression of this pathology, as it is eventually the case in the metabolic syndrome and diabetes domain. This plausible hypothesis is discussed in detail and should be verified by appropriate preclinical and clinical protocols, which are now achievable by using noninvasive techniques in humans.A apnéia obstrutiva do sono é um problema médico cujo reconhecimento tem aumentado. As últimas pesquisas mostrando sua freqüência na população em geral e seu importante papel metabólico, vascular e comportamental aumentou o número e a natureza das investigações revelando, assim, novos aspectos que abrem caminhos para estudos. Embora a apnéia obstrutiva do sono seja um fenômeno bem conhecido acompanhando diabetes e obesidade, novas descobertas sugerem que esta relação causal pode também ser verdadeira no sentido inverso. Na realidade, a apnéia obstrutiva do sono pode ser o marco inicial ou primário que induz ou agrava uma série de distúrbios vasculares e metabólicos que se aproximam da síndrome metabólica. Esta revisão discutirá mecanismos estabelecidos e potenciais responsáveis por estas mudanças. A apnéia obstrutiva do sono parece realmente juntar todos os elementos necessários para induzir resistência à insulina, hipertensão e possivelmente insuficiência cardíaca. Após análise cuidadosa destas modificações, considerando que as mesmas são interligadas, propomos que a microcirculação, como ocorre nos casos de síndrome metabólica e diabetes, poderia representar o denominador comum que mediaria a progressão desta patologia. Esta hipótese é discutida em detalhe e deve ser verificada em estudos pré-clínicos e clínicos apropriados que são atualmente possíveis usando técnicas não-invasivas em humanos

Effects of Buflomedil and Pentoxifylline on Hamster Skin-Flap Microcirculation: Prediction of Flap Viability Using Orthogonal Polarization Spectral Imaging

OBJECTIVE: This study investigated the effects of buflomedil and pentoxifylline, both of which are used in reconstructive surgery of hamster skin flap microcirculation, and evaluated the skin flap survival rate by orthogonal polarization spectral imaging. METHOD: Twenty-four adult male Syrian golden hamsters were divided into three groups: a control (C, 0.1 ml 0.9% saline), buflomedil (B, 3 mg/kg/day), and pentoxifylline group (P, 14.5 mg/kg/day). Treatments administered intraperitoneally were initiated 1 hour before skin flap preparation and continued for 7 days post-operatively at 12-hour intervals. Preparations (skin flaps) were divided into 12 fields, which were organized into six bands. Functional capillary density (FCD, in mm/mm²), distance from the skin flap base to blood flow cessation (Dist with flow, in cm), percentage of viable skin (VA, in%), and qualitative analysis of blood flow by orthogonal polarization spectral imaging were performed at 1 and 24 hours and on the seventh post-operative day. RESULT: Bands IV, V, and VI presented no flow independent of time. The functional capillary density group B was higher than that of groups C and P, primarily after 24 hours. All groups showed an increase in D with time but reached similar final distances (C = 2.73, B = 2.78 and P = 2.70 cm). Moreover, the percentage of viable areas remained at approximately 50%. The orthogonal polarization spectral imaging was useful to assess viability by counting fields with and without blood flow. CONCLUSIONS: Functional capillary density values were higher in the buflomedil group compared to the control and pentoxifylline groups in this model. Functional capillary density did not influence D or the percentage of VA, and the technique showed favorable potential to assess/predict the viability of skin flaps within 1 h after surgery

Short-Term Treatment with Metformin Improves the Cardiovascular Risk Profile in First-Degree Relatives of Subjects with Type 2 Diabetes Mellitus who have a Metabolic Syndrome and Normal Glucose Tolerance without Changes in C-Reactive Protein or Fibrinogen

OBJECTIVE: To study if metformin, when administered to first-degree relatives of type 2 diabetes mellitus subjects who have metabolic syndrome and normal glucose tolerance, could improve the cardiovascular risk profile and reduce the levels of both C-reactive protein and fibrinogen. INTRODUCTION: Metabolic syndrome is associated with higher cardiovascular morbidity and mortality. Metformin has vasculo-protective effects even in normoglycemic subjects, and C-reactive protein and fibrinogen are considered markers of endothelial injury and inflammation. METHODS: Thirty-one non-diabetic first-degree relatives of type 2 diabetes mellitus subjects with metabolic syndrome were randomized (1:1) and double-blinded for placement in the placebo and metformin groups (850mg bid/±90days); 16 subjects were administered metformin (mean age 40.0 [33.5-50] years; 13 females) and 15 subjects were in the placebo group (mean age 37.0 [32-42] years; 9 females). Blood samples were collected at baseline and at the end of treatment for biochemical analyses, including an assessment of C-reactive protein and fibrinogen levels. RESULTS: Metformin improved the lipid profile and decreased fasting plasma glucose, systolic blood pressure, weight and body mass index without changing body composition. For those in the placebo we identified no changes in fibrinogen (282.2 [220.4-323.7] mg/L vs. 286.7 [249.6-295.1] mg/L; NS) or in C-reactive protein levels (0.68 [0.3-1.2] vs. 0.64 [0.3-1.0] mg/L; NS). The same was also observed for the levels of fibrinogen (303.9 [217.6-347.6] mg/L vs. 290.9 [251.5-301.9] mg/L; NS) and C-reactive proteins (0.78 [0.3-1.1] vs. 0.80 [0.4-0.9] mg/L; NS) in the metformin group. CONCLUSIONS: Metformin treatment in first-degree relatives of type 2 diabetes mellitus sufferers who have metabolic syndrome and normal glucose tolerance improved the cardiovascular risk profile without changing the levels of C-reactive protein and fibrinogen

Preconditioning of the response to ischemia/ reperfusion-induced plasma leakage in hamster cheek pouch microcirculation

OBJECTIVE: Ischemic preconditioning and some drugs can protect tissues from injury by preserving microcirculation. This study evaluated vascular permeability in a hamster cheek pouch preparation using either short ischemic periods or bradykinin as preconditioning stimuli followed by 30 min of ischemia/reperfusion. METHOD: Sixty-six male hamsters were divided into 11 groups: five combinations of different ischemic frequencies and durations (one, three or five shorts periods of ischemia, separated by one or five minutes) with 10 min intervals between the ischemic periods, followed by 30 min ischemia/reperfusion; three or five 1 min ischemic periods with 10 min intervals between them followed by the topical application of histamine (2 µM); bradykinin (400 nM) followed by 30 min of ischemia/reperfusion; and three control groups (30 min of ischemia/reperfusion or histamine or bradykinin by themselves). Macromolecular permeability was assessed by injection of fluorescein-labeled dextran (FITC-dextran, MW= 150 kDa; 250 mg/Kg body weight), and the number of leaks/cm2 was counted using an intravital microscope and fluorescent light in the cheek pouch. RESULTS: Plasma leakage (number of leaks/cm²) was significantly reduced by preconditioning with three and five 1 min ischemic periods, one and three 5 min ischemic periods and by bradykinin. Histamine-induced macromolecular permeability was also reduced after three periods of 5 min of ischemia. CONCLUSION: Short ischemic periods and bradykinin can function as preconditioning stimuli of the ischemia/reperfusion response in the hamster cheek pouch microcirculation. Short ischemic periods also reduced histamineinduced macromolecular permeability

Organic grape juice intake improves functional capillary density and postocclusive reactive hyperemia in triathletes

OBJECTIVE: The aim of this study was to evaluate the effect of organic grape juice intake on biochemical variables and microcirculatory parameters in triathlon athletes. INTRODUCTION: The physiological stress that is imposed by a strenuous sport, such as a triathlon, together with an insufficient amount of antioxidants in the diet may cause oxidative imbalance and endothelial dysfunction. METHODS: Ten adult male triathletes participated in this study. A venous blood sample was drawn before (baseline) and after 20 days of organic grape juice intake (300 ml/day). Serum insulin, plasma glucose and uric acid levels, the total content of polyphenols, and the erythrocyte superoxide dismutase activity were determined. The functional microcirculatory parameters (the functional capillary density, red blood cell velocity at baseline and peak levels, and time required to reach the peak red blood cell velocity during postocclusive reactive hyperemia after a one-min arterial occlusion) were evaluated using nailfold videocapillaroscopy. RESULTS: Compared with baseline levels, the peak levels of serum insulin ( p = 0.02), plasma uric acid ( p = 0.04), the functional capillary density ( p = 0.003), and the red blood cell velocity (p < 0.001) increased, whereas the plasma glucose level (p,0.001), erythrocyte superoxide dismutase activity ( p = 0.04), and time required to reach red blood cell velocity during postocclusive reactive hyperemia ( p = 0.04) decreased after organic grape juice intake. CONCLUSION: Our data showed that organic grape juice intake improved glucose homeostasis, antioxidant capacity, and microvascular function, which may be due to its high concentration of polyphenols. These results indicate that organic grape juice has a positive effect in endurance athletes

Relação entre as adipocinas, inflamação e reatividade vascular em controles magros e pacientes obesos com síndrome metabólica

PURPOSE: Metabolic syndrome is an important risk factor for cardiovascular disease. Adipokines interfere with insulin action and endothelial cell function. We investigated the relationship among adipokines, metabolic factors, inflammatory markers, and vascular reactivity in obese subjects with metabolic syndrome and lean controls. METHODS: Cross-sectional study of 19 obese subjects with metabolic syndrome and 8 lean volunteers evaluated as controls. Vascular reactivity was assessed by venous occlusion pletysmography measuring braquial forearm blood flow (FBF) and vascular resistance (VR) responses to intra-arterial infusions of endothelium-dependent (acetylcholine-Ach) and independent (sodium nitroprusside-SNP) vasodilators. Blood samples were obtained to evaluate C reactive protein (CRP), plasminogen activator inhibitor 1 (PAI-1), fibrinogen, adiponectin, resistin, and lipid profile. Patients were classified with regard to insulin resistance through the HOMA-IR index. RESULTS: PAI-1, CRP and fibrinogen were higher and adiponectin was lower in metabolic syndrome subjects compared to controls. Metabolic syndrome subjects had impaired vascular reactivity. Adiponectin and PAI-1 were associated with insulin, HOMA-IR, triglycerides, and HDLc; and resistin with CRP. Adiponectin was associated with VR after Ach in the pooled group and resistin with D FBF after Ach in the metabolic syndrome group. CONCLUSION: Metabolic syndrome subjects exhibited low levels of adiponectin and high levels of CRP, fibrinogen, and PAI-1. Adiponectin and PAI-1 correlated with insulin resistance markers. Adiponectin and resistin correlated with vascular reactivity parameters. An adipocyte-endothelium interaction might be an important mechanism of inflammation and vascular dysfunction.A Síndrome Metabólica é um importante fator de risco para doenças cardiovasculares. As adipocinas interferem com a ação da insulina e com a função endotelial. OBJETIVO: Investigar a relação entre adipocinas, fatores metabólicos, marcadores inflamatórios e reatividade vascular para inferência da função endotelial em pacientes obesos e controles magros. MATERIAL E MÉTODO: Estudo transversal de 19 pacientes obesos com Síndrome Metabólica e 8 controles magros. A reatividade vascular foi avaliada pela pletismografia de oclusão venosa medindo o fluxo sangüíneo da artéria braquial e sua resistência vascular a partir de infusões intra-arteriais de vasodilatadores endotélio-dependente (acetilcolina) e endotélio-independente (nitroprussiato de sódio). Foram também avaliados no sangue a proteína C reativa (PCR), o inibidor do ativador do plasminogênio 1 (PAI-1), fibrinogênio, adiponectina, resistina e o perfil lipídico. Os pacientes foram classificados quanto à resistência insulínica pelo índice HOMA-IR. RESULTADO: PAI-1, PCR e fibrinogênio apresentaram valores mais altos e a adiponectina mais baixos para os pacientes com Síndrome Metabólica do que com os controles. Pacientes com Síndrome Metabólica apresentaram prejuízo da reatividade vascular. A adiponectina e PAI-1 estiveram associadas à insulina, HOMA-IR, triglicerídeos e HDLc; e resistina com o PCR. Adiponectina esteve associada com a resistência vascular e a resistina com o fluxo sangüíneo depois da acetilcolina em pacientes com Síndrome Metabólica. CONCLUSÃO: Pacientes com Síndrome Metabólica exibiram baixas concentrações sangüíneas de adiponectina e altos níveis de PCR, fibrinogênio e PAI-1. Adiponectina e PAI-1 correlacionaram com os marcadores da resistência insulínica. Adiponectina e resistina correlacionaram com a reatividade vascular. A interação adipócito-endotélio vascular pode ser um importante mecanismo de inflamação e disfunção vascular

Treatment of Essential Hypertension does not Normalize Capillary Rarefaction

OBJECTIVES: To determine if capillary rarefaction persists when hypertension is treated with angiotensin converting enzyme inhibitor, thiazidic diuretic and/or beta-blocker, and to identify which microcirculatory alterations (structural and functional) persist after anti-hypertensive treatment. METHODS: We evaluated 28 well-controlled essential hypertensive patients and 19 normotensive subjects. Nailfold videocapillaroscopy examination of the fourth finger of the left hand was used to determine the functional capillary densities at baseline, during post-occlusive hyperemia, and after venous congestion. Capillary loop diameters (afferent, apical and efferent) and red blood cell velocity were also quantified. RESULTS: Compared with normotensive subjects, hypertensive patients showed lower mean functional capillary density at baseline (25.1±1.4 vs. 33.9±1.9 cap/mm², p<0.01), during post-occlusive reactive hyperemia (29.3±1.9 vs. 38.2±2.2 cap/mm², p<0.01) and during venous congestion responses (31.4±1.9 vs. 41.1±2.3 cap/mm², p<0.01). Based on the density during venous congestion, the estimated structural capillary deficit was 25.1%. Mean capillary diameters were not different at the three local points, but red blood cell velocity at baseline was significantly lower in the hypertensive group (0.98±0.05 vs. 1.17±0.04 mm/s, p<0.05). CONCLUSIONS: Patients treated for essential hypertension showed microvascular rarefaction, regardless of the type of therapy used. In addition, the reduced red blood cell velocity associated with capillary rarefaction might reflect the increased systemic vascular resistance, which is a hallmark of hypertension

Evaluation of sublingual microcirculation in children with dengue shock

OBJECTIVE: To report the sublingual microcirculation observed using Sidestream Dark Field imaging in two children with dengue shock. METHOD: Two children, aged 9 and 10 years, were admitted to the pediatric intensive care unit with dengue shock and multiple organ dysfunction. Sublingual microcirculation was assessed in each patient on the first and second days of shock and was assessed a final time when the patients were no longer in shock (on the day prior to extubation) using Sidestream Dark Field technology. The De Backer score and microvascular flow index were used for the analyses. RESULTS: Both patients had reduced perfused small vessel density in the first two days and showed predominantly intermittent or no microcirculation flow, as demonstrated by a low microvascular flow index. The blood flow in the large vessels was not affected. Prior to the extubation, the microvascular flow index had increased, although the perfused small vessel density remained diminished, suggesting persistent endothelial dysfunction. CONCLUSIONS: Severe microcirculation changes may be involved in the pathophysiological mechanisms that lead to the final stages of dengue shock, which is frequently irreversible and associated with high mortality rates. Microcirculatory monitoring may help elucidate the physiopathology of dengue shock and prove useful as a prognostic tool or therapeutic target

Effects of moderate and high intensity isocaloric aerobic training upon microvascular reactivity and myocardial oxidative stress in rats

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