Importancia médica del glucocáliz endotelial: Parte 2: su papel en enfermedades vasculares y complicaciones de la diabetes mellitus / Medical significance of endothelial glycocalyx: Part 2: Its role in vascular diseases and in diabetic complications

El glucocáliz endotelial es una capa constituida por glucosaminoglicanos, proteoglicanos y glucoproteínas que cubre al endotelio en su cara luminal. La participación del deterioro del glucocáliz endotelial parece esencial en los pasos iniciales de la fisiopatología de la aterosclerosis, de las complicaciones microangiopáticas de la diabetes mellitus y de la enfermedad venosa crónica. Los factores de riesgo de la aterosclerosis como la hipercolesterolemia, la hiperglucemia, la inflamación, el exceso de sodio y las fuerzas de tensión alteradas causan deterioro del glucocáliz. Esto provoca disfunción endotelial y permite la filtración de lipoproteínas (LDL) y de leucocitos al espacio subendotelial, iniciando la formación de la placa de ateroma. En la diabetes el glucocáliz adelgazado, principalmente por estrés oxidativo, posibilita la filtración de proteínas (albuminuria) y el trastorno endotelial de la microangiopatía. La hipertensión venosa crónica altera las fuerzas de tensión y daña el glucocáliz, lo que permite la filtración de leucocitos a las partes más profundas de la pared venosa, iniciando la inflamación y el deterioro morfológico y funcional de las venas que lleva a la enfermedad venosa crónica. El tratamiento con glucosaminoglicanos (sulodexida) logra prevenir o revertir el daño al glucocáliz endotelial y algunas de sus consecuencias; es eficaz en la enfermedad venosa crónica, especialmente con úlceras venosas. También ha sido útil en aterosclerosis obliterante de miembros inferiores y en la nefropatía diabética con albuminuria.

Endothelial glycocalyx is a layer composed by glycosaminoglycans, proteoglycans and glycoproteins attached to the vascular endothelial luminal surface. Shredding of glycocalyx appears as an essential initial step in the pathophysiology of atherosclerosis and microangiopathic complications of diabetes mellitus, as well as in chronic venous disease. Atherosclerosis risk factors, as hypercholesterolemia (LDL), hyperglycemia, inflammation, salt excess and altered shear stress can damage glycocalyx. This lead to endothelial dysfunction and allows LDL and leukocytes to filtrate to the subendothelial space initiating atheroma plaque formation. Degradation of glycocalyx in diabetes mellitus is mainly due to oxidative stress and enables protein filtration (albuminuria) and endothelial disorder of microangiopathy. Chronic venous hypertension brings to altered shears stress which results in shredded glycocalyx, this allows leukocytes to migrate into venous wall and initiate inflammation leading to morphologic and functional venous changes of the chronic venous disease. Treatment with glycosaminoglycans (sulodexide) prevents or recovers the damaged glycocalyx and several of its consequences. This drug improves chronic venous disease and promotes healing of chronic venous ulcers. It has also been useful in peripheral arterial obstructive disease and in diabetic nephropathy with albuminuria.

Tratamento da hipertensão arterial no diabetes melito / Treatment of hypertension in patients with diabetes

A associação de hipertensão arterial sistêmica (HAS) e diabetes melito (DM) é bastante comum, acometendo mais de 60% dos pacientes com DM tipo 2. Os benefícios do tratamento da HAS nesses pacientes são bem definidos, entretanto há controvérsia em relação ao alvo de pressão a ser atingido nesses pacientes com o tratamento. O esquema terapêutico a ser utilizado deve levar em consideração não só o efeito dos medicamentos sobre a pressão arterial, mas também seus efeitos em mortalidade e complicações do DM. Na maior parte das recomendações nacionais e internacionais, os inibidores da enzima conversora da angiotensina são considerados drogas de primeira linha no tratamento desses pacientes, devido a seu efeito benéfico sobre a albuminúria, mas se discute o uso de diuréticos tiazídicos como terapia inicial, da mesma maneira que na população sem DM. Nessa revisão abordaremos as evidências em relação aos benefícios do tratamento da HAS em pacientes com DM, o alvo de pressão a ser atingido com esse tratamento e as vantagens e riscos do uso das diferentes classes de anti-hipertensivos nessa população.

The association of hypertension and diabetes mellitus (DM) is quite common, affecting more than 60% of patients with type 2 DM. The benefits of treating hypertension in these patients are well defined, though there is controversy regarding the target pressure to be achieved in these patients. The regimen to be used should take into consideration not only the effect of medication on blood pressure, but also its effects on mortality and DM complications. In most national and international guidelines, angiotensin-converting enzyme inhibitors are considered first-line drugs in the treatment of these patients because of their beneficial effect on albuminuria, but the use of thiazide diuretics as initial therapy as in non-diabetic population is being a matter of discussion. In the present review of the literature we discuss the evidence regarding the benefits of treating hypertension in diabetic patients, the target pressure to be achieved with this treatment, and the benefits and risks of using different classes of antihypertensive drugs in this population.

Potential role of HMG CoA reductase inhibitor on oxidative stress induced by advanced glycation endproducts in vascular smooth muscle cells of diabetic vasculopathy

Advanced glycation endproducts (AGEs)-induced vascular smooth muscle cell (VSMCs) proliferation and formation of reactive oxygen species (ROS) are emerging as one of the important mechanisms of diabetic vasculopathy but little is known about the antioxidative action of HMG CoA reductase inhibitor (statin) on AGEs. We hypothesized that statin might reduce AGEs-induced intracellular ROS of VSMCs and analyzed the possible mechanism of action of statin in AGEs-induced cellular signaling. Aortic smooth muscle cell of Sprague-Dawley rat (RASMC) culture was done using the different levels of AGEs stimulation in the presence or absence of statin. The proliferation of RASMC, ROS formation and cellular signaling was evaluated and neointimal formation after balloon injury in diabetic rats was analyzed. Increasing concentration of AGEs stimulation was associated with increased RASMC proliferation and increased ROS formation and they were decreased with statin in a dose-dependent manner. Increased NF-kappaB p65, phosphorylated ERK, phosphorylated p38 MAPK, cyclooxygenase-2, and c-jun by AGEs stimulation were noted and their expression was inhibited by statin. Neointimal formation after balloon injury was much thicker in diabetic rats than the sham-treated group but less neointimal growth was observed in those treated with statin after balloon injury. Increased ROS formation, subsequent activation of MAPK system and increased VSMC proliferation may be possible mechanisms of diabetic vasculopathy induced by AGEs and statin may play a key role in the treatment of AGEs-induced diabetic atherosclerosis.

Gender-based treatment outcomes in diabetic hypertension.

BACKGROUND: In developing countries, gender-based treatment disparities in cardiovascular preventive therapy have received little attention. AIMS: To evaluate the gender-based differences in cardiovascular disease risk profile, drug prescribing pattern, and blood pressure (BP) and glycemic control rates in diabetic hypertensives treated at primary care setting in Bahrain. SETTINGS AND DESIGN: A retrospective study at primary care setting. MATERIALS AND METHODS: An audit of the medical records of 392 diabetic hypertensives (127 men, 265 women). RESULTS: BP and glycemic targets were achieved in < 10% and < 13% of diabetic hypertensives, respectively. Angiotensin converting enzyme inhibitors monotherapy was more often prescribed in males. Apart from this, no significant differences in prescribing pattern were observed between male and female diabetic hypertensives treated with either antihypertensive mono or multidrug therapies. With the exception of insulin which was more often prescribed to females, a similar prescribing pattern and rank order of antidiabetics, either as monotherapy or combinations, was observed in both genders. The majority of diabetic hypertensives were at high cardiovascular risk. The body mass index and total cholesterol level were greater in females. Prescribing lipid-lowering drugs and aspirin were suboptimal; aspirin was more often prescribed to males. There was no gender-based difference with regard to the use of lipid-lowering drugs. CONCLUSIONS: BP and glycemic controls were suboptimal in both male and female diabetic hypertensives treated by primary care physicians. Cardiovascular disease preventive strategies have received little attention regardless of gender or other risk factors. Gender-based treatment inequities also need to be addressed.

Dupla artéria torácica esqueletizada versus convencional na revascularização do miocárdio sem CEC em diabéticos / Double skeletonized internal thoracic artery vs. double conventional internal thoracic artery in diabetic patients submitted to OPCAB

OBJETIVO: Avaliar a influência da técnica utilizada na dissecção das artérias torácicas na evolução de pacientes diabéticos submetidos a revascularização sem CEC. MÉTODOS: Setenta pacientes diabéticos submetidos a revascularização sem CEC com duas artérias torácicas foram avaliados. No grupo A, as artérias torácicas foram dissecadas de modo convencional, enquanto no grupo B foram esqueletizadas. RESULTADOS: A idade média do grupo A foi de 52,14±7,35 anos contra 55,71±8,1 anos no grupo B (p=0,057). No grupo A, seis (17,1%) pacientes eram diabéticos insulinodependentes contra nove (25,7%) no grupo B (p=0,561). O EUROSCORE foi de 3,97±2,49 para o grupo A contra 4,14±3,06 no grupo B (p=0,879). O número médio de anastomoses distais no grupo A foi de 3±0,77 contra 3,03±0,89 para o grupo B (p=0,981). Três (8,57%) dos pacientes do grupo A apresentaram mediastinite contra nenhum do grupo B (p=0,239). A diabetes insulino-dependente foi o único fator estatisticamente significativo (p=0,008) para mediastinite. Neste grupo, a utilização de artéria torácica interna esqueletizada diminuiu significativamente a incidência de mediastinite (p=0,044). CONCLUSÃO: A incidência de mediastinite foi menor no grupo onde ambas as artérias torácicas foram dissecadas de forma esqueletizada, apesar de, devido ao baixo número de casos, não apresentar diferença estatística. Nos portadores de diabetes insulino-dependente, 50 por cento dos pacientes do grupo em que a artéria torácica foi obtida de forma convencional apresentaram mediastinite, sendo que a utilização de artéria torácica esqueletizada diminuiu significativamente a incidência de mediastinite.

OBJECTIVE: To evaluate the influence of the technique used in the dissection of thoracic arteries in the evolution of diabetic patients submitted to OPCAB. METHODS: Seventy diabetic patients submitted to OPCAB using bilateral thoracic arteries were evaluated. In Group A, thoracic arteries were dissected as a pedicle, while in Group B they were skeletonized. RESULTS: The mean age of patients in Group A was 52.14 ± 7.35 years old versus 55.71 ± 8.1 years for Group B (p=0.057). In Group A, six patients (17.1%) were insulin dependent against nine (25.7%) in Group B (p = 0.561). The EUROSCORE was 3.97 ± 2.49 for Group A opposed to 4.14 ± 3.06 for Group B (p = 0.879). The number of distal anastomoses in Group A was 3 ± 0.77 versus 3.03 ± 0.89 in Group B (p = 0.981). Three patients (8.57%) from Group A presented with mediastinitis. Insulin dependence was the only significant risk factor (p=0.008) for mediastinitis. In this group the use of skeletonized internal thoracic arteries significantly decreased the incidence of mediastinitis (p = 0.044). Conclusion: The incidence of mediastinitis was lower in the group for which mammary arteries were dissected using skeletonization. Among insulin-dependent diabetics, 50 percent of the patients from the group in which the pedicled internal thoracic artery was utilized presented with mediastinitis; the utilization of skeletonized internal thoracic arteries significantly decreases the incidence of mediastinitis.

Dislipidemias no diabetes melito tipo 1: abordagem atual / Dyslipidemias in type 1 diabetes: a current approach

Com a intensificação do controle glicêmico no tratamento do diabetes melito tipo 1 (DM1), houve uma mudança progressiva das causas de mortalidade com destaque para a DCV. A identificação de fatores de risco, como a dislipidemia, tornou-se de grande importância para minimizar o risco de complicações crônicas micro e macrovasculares. As diretrizes para prevenção de doença coronariana em diabetes, geralmente, fazem referência ao diabetes melito tipo 2 (DM2), com pouca recomendação específica para o DM1. Definir alvos terapêuticos ou indicação de intervenção farmacológica é mais controverso nesse tipo de diabetes, em virtude da faixa etária desses pacientes. O presente estudo busca destacar a importância de estabelecer o diagnósti-co da dislipidemia nesse grupo de pacientes e instituir terapêutica adequa- da e precoce, objetivando alcançar as metas estabelecidas para reduzir o perfil lipídico aterogênico desses pacientes.

With the intensive glycemic control in the therapy of type 1 diabetes mellitus (T1DM) patients, cardiovascular disease has been the main cause of mortality. Identification of risk factors, such as dyslipidemia is considered of great importance in terms of avoiding chronic micro and macro vascular complications. The statements for prevention of coronary artery disease in diabetes are generally are related do type 2 diabetes mellitus and little attention is paid to T1DM. Defining therapeutical targets and indications for treatment are more controversial in these patients due to their young ages. The present study aims to emphasize the importance of establishing the diagnosis of dyslipidemia in this group of patients as well as indicate the appropriate and early treatment, in order to reach the targets of treatment and reduce the atherogenic lipid profile.

Effects of ACE-I on diabetic cardiovascular complications: anti-hypertensive and non-antihypertensive doses.

To evaluate the effects of angiotensin converting enzyme inhibitor (ACE-I) on diabetic cardiovascular complications, a streptozotozin (STZ, i.p., 70 mg/kg BW) induced diabetes rat model was used. The animals were separated into four major groups including: control (NSS), STZ-treated rats, STZ-treated rats received daily oral feeding of cilazapril starting one day after STZ injection (STZ-C1), and STZ-treated rats received daily oral feeding of cilazapril eight weeks after the STZ injection (STZ-C8). Within the groups of STZ-C1 and STZ-C8, the animals were also divided into three subgroups of six rats that received different doses of cilazapril treatment, 0.01 mg/Kg BW, 1 mg/Kg BW, and 10 mg/Kg BW. By using the modified isolated heart model, the parameters of mean arterial pressure (MAP), heart rate (HR), left ventricular isotonic contraction (LVIC), aortic flow rate (AFR), coronary flow rate (CFR), and ratio of heart weight per body weight (R) were assessed for each groups 8 and 20 weeks after the STZ injections. Moreover, the changes of wall thickness of the left ventricular wall (LV), right ventricular wall (RV), and interventricular septal wall (IVS) were monitored from the scanning electron micrographs of each heart. The results indicated that in both STZ-C1 and STZ-C8, the diabetic hypertension could be prevented or treated by anti-hypertensive doses of cilazaprils. Besides, the values of AFR, CFR, and LVIC were significantly increased when comparing between the STZ and STZ-C1 or STZ-C8. The results of morphological examinations indicated that: (1) left ventricular walls of the three hearts of STZ-rats had increased significantly more than controls. (2) Right ventricular walls and interventricular septal walls were not significantly different among STZ-rats, cilazapril treated STZ-rats and age matched controls. Therefore, it is concluded that ACE-I could act either as a cardioprotective or therapeutic agent for diabetic hearts. Both major anti-hypertension and anti-trophic effects of ACE-I have already been elucidated.

Uso de pentoxifilina (Trental 400) en microangiopatia diabética / The use of pentoxifylline (Trental 400) in diabetic microangiopathies

Se presenta el resultado de un estudio clínico practicado con el uso de Pentoxifilina (Trental 400) en 20 pacientes con microangiopatía diabética, con lesiones isquémicas únicamente localizada en extremidades inferiores, de estos 20 pacientes: 10 (50%) son del sexo femenino y 10 (50%) del sexo masulino, y con una media de edad de 56.5 años (45 años mínimos y 75 años máximo). El período de tratamiento varía entre cuatro semanas, y 12 semanas, con dosis de 400 mgs de Pentoxifilina tres veces al día; en 6 de los casos, se indicó reposo en cama por período comprendido de 7 a 14 días. en 4 pacientes se utilizó Pentoxifilina por infusión intravenosa a goteo para 24 horas a igual dosis

Tratamento da microangiopatia diabética com buflomedil oral / Treatment of diabetic microangiopathies with oral buflomedil

Foram estudados 28 pacientes com diabetes do tipo II, com lesöes obstrutivas de artérias distais de membros inferiores (microangiopatias), sem úlcera ou lesäo obstrutiva de grandes troncos. Avaliou-se nesses diabéticos a açäo do buflomedil oral (300 mg, duas vezes ao dia, por 90 dias), através da evoluçäo clínica e de dopplerometria, capilaroscopia periungueal, pletismografia, termometria cutânea e exames complementares, com acompanhamento aos 30, 60 e 90 dias. A melhora clínica foi notável e estatisticamente significativa na palidez, claudicaçäo intermitente, parestesias e alteraçäo de volume dos membros inferiores. O aumento da amplitude dos pulsos das tibiais, anterior e posterior, foi estatisticamente significativo. A dopplerometria mostrou significância estatística na elevaçäo dos valores pressóricos da pediosa e na reduçäo da diferencial entre PSCB e PSSM. A pletismografia evidenciou aumento notável na área da curva de pulso e a capilaroscopia mostrou mudanças favoráveis e estatisticamente significantes em todos os parâmetros. Conclui-se que o tratamento com buflomedil oral tem capacidade de melhorar o quadro clínico de pacientes com microangiopatias diabéticas e que existe a possibilidade de que previna as alteraçöes vasculares irreversiveis do diabetes de longa duraçäo, desde que usado precocemente, devendo esta hipótese merecer maiores estudos

Evaluación de distintos procederes terapéuticos para elevar el colesterol de las HDL / Validation of different therapeutical procedures to raise HDL cholesterol

Se distribuyen en forma aleatoria, en 3 grupos, un total de 80 pacientes diabéticos que presentan una macroangiopatía en miembros inferiores; 27 de ellos recibieron ácido ascórbico en dosis de 1 gramo diario, 28 levadura de cerveza (por su contenido en cromo) a dosis de 7 tabletas diarias y 25 pacientes fueron asignados a un grupo placebo. Una vez practicada uniformidad a los grupos mediante tratamiento dietético, se les impone el tratamiento indicado previo examen de colesterol total, triglicéridos y medición de las lipoproteínas de alta densidad (HDL) 6 semanas antes y después del tratamiento. El grupo tratado con ácido ascórbido elevó el índice de protección contra el desarrollo de enfermedad aterogénica para una P<0,05, no así el grupo que ingirió levadura de cerveza, en el cual no fue significativo. Este último, sin embargo, elevó el índice de valores de colesterol total para una p<0,01. Se hace una hipótesis fisiopatológica del mecanismo, y se anuncia que el ácido ascórbico produce hidroxilacia del colesterol en ácidos biliares del hígado. Para el análisis estadístico se utilizaron: la prueba de los signos para encontrar el aumento significativo en el riesgo aterosclerótico (RAC) con vitamina C. Para el análisis de la comparación de los cambios entre los distintos tratamientos, se tomaron las diferencias entre antes y después del tratamiento para cada individuo; se comparan las diferencias de las medias de cada grupo mediante una prueba U de Mann-Whitney