Macrovascular Damage Research Articles

Distinct Kinin-Induced Functions Are Altered in Circulating Cells of Young Type 1 Diabetic Patients

Aims/HypothesisWe aimed to understand early alterations in kinin-mediated migration of circulating angio-supportive cells and dysfunction of kinin-sensitive cells in type-1 diabetic (T1D) patients before the onset of cardiovascular disease.MethodsTotal mononuclear cells (MNC) were isolated from peripheral blood of 28 T1D patients free from cardiovascular complications except mild background retinopathy (age: 34.8±1.6 years, HbA1C: 7.9±0.2%) and 28 age- and sex-matched non-diabetic controls (H). We tested expression of kinin receptors by flow cytometry and migratory capacity of circulating monocytes and progenitor cells towards bradykinin (BK) in transwell migration assays. MNC migrating towards BK (BKmig) were assessed for capacity to support endothelial cell function in a matrigel assay, as well as generation of nitric oxide (NO) and superoxide (O2 −*) by using the fluorescent probes diaminofluorescein and dihydroethidium.ResultsCD14hiCD16neg, CD14hiCD16pos and CD14loCD16pos monocytes and circulating CD34pos progenitor cells did not differ between T1D and H subjects in their kinin receptor expression and migration towards BK. T1D BKmig failed to generate NO upon BK stimulation and supported endothelial cell network formation less efficiently than H BKmig. In contrast, O2 −* production was similar between groups. High glucose disturbed BK-induced NO generation by MNC-derived cultured angiogenic cells.Conclusions/InterpretationOur data point out alterations in kinin-mediated functions of circulating MNC from T1D patients, occurring before manifest macrovascular damage or progressed microvascular disease. Functional defects of MNC recruited to the vessel wall might compromise endothelial maintenance, initially without actively promoting endothelial damage, but rather by lacking supportive contribution to endothelial regeneration and healing.

Endothelial Dysfunction: The Common Consequence in Diabetes and Hypertension

Endothelial dysfunction plays a key role in the initiation of cellular events evolving into the development of vascular complications in diabetes and hypertension. Diminished production and function of endothelium-derived nitric oxide and other vasoprotective factors and/or the exaggerated production of proinflammatory and vasoconstrictors such as angiotensin II, endothelin-1, reactive oxygen species, and cyclooxygenase-derived metabolites of arachidonic acid eventually lead to endothelial dysfunction, resulting in elevated vascular tone which contributes to hypertension, vascular, and cardiac remodeling, culminating in microvascular, macrovascular, and renal damages. Specific therapies targeting reactive oxygen species using antioxidants and inhibitors of the rennin-angiotensin system or increasing endothelial nitric oxide synthase activity might assist to reverse endothelial dysfunction and thus reduce the related cardiovascular morbidity and mortality in diabetes and hypertension.

Diagnósticos de enfermagem identificados em pessoas com diabetes tipo 2 mediante abordagem baseada no Modelo de Orem

This research aimed to describe some of the basic conditioning factors to self-care and analyze the nursing diagnosis of the North American Nursing Diagnosis Association among diabetes type 2 carriers by means of an approach based on Orem’s theory. Seven diabetic people took part in this study; they were evaluated during the period of May to June of 2006. The basic conditioning factors to self-care in this group were: ages between 46 and 71, with predominance of the female sex; married people; high-school education; retired people; all with family antecedents for diabetes. The nursing diagnosis identified in all the participants were: ineffective control of the therapeutic regime; health search behavior; risk for ineffective tissue, cardiac, renal, peripheral and/or cerebral perfusion; disturbed sensorial perception (visual); deficient knowledge about food, care with extremities, disease complication and the practice of physical exercise; disposition for increased knowledge about diabetes type 2 and its therapeutic regime; risk of infection; risk of micro and macro vascular damage; risk of falling and risk for skin integrity damage.Key words: Mellitus diabetes type 2; Nursing diagnosis; Nursing theory.

Management strategy of diabetic macrovascular disease: From intensive glycemic control to harmonious equipoise

Etiology of diabetic macrovascular disease is complex. Although diabetes is closely associated with atherosclerotic cardiovascular diseases (ASCVD), their pathogeneses are different. Recent clinical trails showed that multiplex intervention including anti-hyperglycemia in combination with lipids adjusting and blood pressure lowering procedures significantly reduced the events of ASCVD, but intensive gljcemic control alone did not. To prevent the ongoing diabetic macrovascular lesion, comprehensive evaluation of macrovascular damage and risks is very important. In addition, early treatment of hyperglycemia will blockade the hyperglycemia-induced metabolic memory and ameliorate vascular complications. Management of diabetic macrovascular disease should emphasize the strategy of simultaneously modifying all of the risk factors, harmonious equipoise of intervention and tailoring treatment. Key words: Diabetes mellitus; Macrovascular diseases; Management strategy

Reducing the risk of complications associated with diabetes

Complications associated with type 1 and type 2 diabetes can lead to microvascular and macrovascular damage, which can have financial implications for patients and the NHS, and affect quality of life. This article discusses the identification, management and prevention of complications associated with diabetes to relieve existing symptoms and reduce further damage.

Plasma Homocysteine Levels, The Prevalence of Methylenetetrahydrofolate Reductase Gene C677T Polymorphism and Macrovascular Disorders in Systemic Sclerosis: Risk Factors for Accelerated Macrovascular Damage?

The purpose of this study was to investigate plasma homocysteine (Hcy) levels in patients with systemic sclerosis (SSc) and to study the association between plasma Hcy, C677T polymorphism of 5,10-methylenetetrahydrofolate reductase (MTHFR), and the clinical manifestations in SSc. Associations of Hcy level, C677T MTHFR polymorphism, and macrovascular diseases were investigated in 152 patients with SSc and 58 controls. No significant differences in Hcy levels and MTHFR genotypes were found in SSc patients compared to controls or in SSc patients with limited cutaneous compared to diffuse disease. Significantly higher Hcy concentration was observed in patients with macroangiopathy/thromboembolic events compared to patients without such clinical manifestations (p < 0.05). There was significant correlation between age and macrovascular disorders, between Hcy level and the disease duration (r = 0.164; p < 0.05). Seventy-one percent of patients with macrovascular disorders had MTHFR polymorphism. In addition, 45% of patients with hyperhomocysteinemia had pulmonary hypertension. The presence of MTHFR C677T mutation influences the incidence of macrovascular abnormalities in SSc patients. Elevated Hcy levels may be associated with disease duration and the evolution of macrovascular disorders and pulmonary hypertension in SSc.

Albuminuria: pathophysiology, epidemiology and clinical relevance of an emerging marker for cardiovascular disease

Albuminuria has emerged from being a sign of early kidney disease in diabetes to an independent predictor of cardiovascular risk. Epidemiological studies suggest that microalbuminuria (30-300 mg/d) is present in 5-19% of the general population, in up to 23% of patients with hypertension and in up to 40% of patients with diabetes. Recent data suggest an even higher prevalence in certain patient populations. As it is associated with a variety of important cardiovascular risk factors, including prediabetes, dyslipidemia and the metabolic syndrome, detection of albumin in the urine represents an important diagnostic window for systemic micro- or macrovascular damage. Various studies have demonstrated the predictive value of all levels of albuminuria for future cardiovascular events in patients with diabetes, hypertension or overt cardiovascular disease, as well as in the general population. Annual screening for microalbuminuria is now recommended by international diabetes guidelines for patients with diabetes, and may be appropriate for nondiabetics with risk factors for cardiovascular disease.

Masked Hypertension in Diabetes Mellitus: A Potential Risk

The prevalence and clinical significance of masked hypertension (MHT) in diabetics have infrequently been described. The authors assessed the association of MHT (defined using a clinic blood pressure [BP] <140/90 mm Hg and daytime ambulatory BP > or = 135/85 mm Hg) with microvascular and macrovascular end organ damage in 81 clinically normotensive Japanese diabetic persons. The prevalence of silent cerebral infarcts (SCIs), increased left ventricular mass, and albuminuria were evaluated. Of 81 patients, 38 (46.9%) were classified as having MHT and showed significantly more SCIs (mean +/- SE: 2.5+/-0.5 vs 1.1+/-0.2; P=.017), and more albuminuria (39% vs 16%; P=.025), but no increase in left ventricular mass index, than the normotensive persons in office and on ambulatory BP monitoring group. The prevalence of MHT in this diabetic population was high (47%). Diabetic patients with MHT showed evidence of brain and kidney damage. Hence, out-of-office monitoring of BP may be indicated in diabetics whose BP is normal in the clinic.

DIABETES AND THE ENDOTHELIUM

Abnormal endothelial function plays a pivotal role in the pathogenesis of diabetic complications. Due to lack of autoregulation of glucose transport in the presence of high extracellular glucose concentrations, intracellular hyperglycaemia induces a series of metabolic changes that ultimately lead to the genesis of both microvascular complications (the hallmark of chronic hyperglycaemic states) and macrovascular damage. In type 2 diabetes, the abnormalities associated with insulin resistance and the metabolic syndrome phenotype (such as high blood pressure, dyslipidaemia, abnormal levels of circulating adipokines and free fatty acids e.g.) also contribute to accelerate the endothelial damage sustained as a result of chronic exposure to hyperglycaemia. Only recently was a unifying theory proposed to account for the four major abnormal pathways activated by chronic hyperglycaemia and thought to damage the endothelial cell and to trigger the downstream micro- and macrovascular complications associated with diabetes mellitus. This pathophysiological sequence revolves around the metabolic abnormalities triggered as a result of overproduction of superoxide by the mitochondrial electron transport chain and subsequent inhibition of the key glycolytic enzyme glyceraldehyde-3- phosphate dehydrogenase by increased activity of nuclear poly(ADP-ribose)polymerase.

New-Onset Diabetes and Risk of All-Cause and Cardiovascular Mortality

Cardiovascular risk associated with new-onset diabetes is not well characterized. We hypothesized that risk of all-cause and cardiovascular mortality would be similar among participants with and without new-onset diabetes in the first years of follow-up and rise over time for new-onset diabetes. The Cardiovascular Health Study (CHS) is a longitudinal study of cardiovascular risk factors in adults aged > or =65 years. We used CHS participants to define a cohort (n = 282) with new-onset diabetes during 11 years of follow-up. New-onset diabetes was defined by initiation of antidiabetes medication or by fasting plasma glucose >125 mg/dl among CHS participants without diabetes at study entry. Three CHS participants without diabetes were matched for age, sex, and race to each participant with new-onset diabetes at the time of diabetes identification (n = 837). Survival analysis provided adjusted hazard ratios (HRs) for all-cause and cardiovascular mortality. During a median of 5.9 years of follow-up, there were 352 deaths, of which 41% were cardiovascular. In adjusted analyses, new-onset diabetes was associated with an HR of 1.9 (95% CI 1.4-2.5) for all-cause and 2.2 (1.4-3.4) for cardiovascular mortality compared with no diabetes. Mortality risks were elevated within 2 years of onset, especially cardiovascular risk (4.3 [95% CI 1.7-10.8]), and did not increase over time. Our findings indicate that there may be a mortality differential soon after diabetes onset in older adults and suggest that long-term macrovascular damage from atherosclerosis may not be primarily responsible for increased risk.

Diabetes, aging and physical activity

AbstractDiabetes mellitus (DM) is a metabolic disease affecting the regulation of insulin and glucose causing a disruption in the normal control of counterregulatory hormones and macronutrients, resulting in blood glucose accumulation. Metabolic deregulation leads to the production of noxious substances that have a particular propensity for damaging vascular and nervous structures. Physiological changes observed with aging are correlated with a concomitant increase in DM and its associated complications. Long-term complications, including peripheral and central neuropathies, micro- and macrovascular damage, retinopathy, and nephropathy are the major causes of mortality in diabetics [cardiovascular disease (CVD) being the primary complication causing death in this population]. All-cause mortality is three to four times greater in the DM population; hence, management of DM is of timely importance, particularly with a projected prevalence increase of 134% within the next 25 years among individuals over the age of 65 years. Exercise modalities, including endurance and resistance training, were employed to improve glycemic/metabolic control and to ameliorate the progression of DM-related complications. Several risk factors, including glucose levels, blood pressure, lipid/cholesterol profile, and BMI, are reportedly improved with these modes of exercise. However, not all studies demonstrate an improvement in risk factors, but consistently note improvement in complications and a reduction of DM incidence. There is convincing evidence that exercise, with or without specific improvements to traditional DM-related risk factors, is an effective therapy for the management of DM.

Cardiovascular disease and Alzheimer's disease: common links

Growing evidence supports a strong and likely causal association between cardiovascular disease (CVD), and its risk factors, with incidence of cognitive decline and Alzheimer's disease. Individuals with subclinical CVD are at higher risk for dementia and Alzheimer's. Several cardiovascular risk factors are also risk factors for dementia, including hypertension, high LDL cholesterol, low HDL cholesterol and especially diabetes. Moderate alcohol appears to be protective for both CVD and dementia. In contrast, inflammatory markers predict cardiovascular risk, but not dementia, despite biological plausibility for such a link. The substantial overlap in risk factors points to new avenues for research and prevention.

High-sensitivity C-reactive protein is only weakly related to cardiovascular damage after adjustment for traditional cardiovascular risk factors

The independent prognostic value of high-sensitivity C-reactive protein (hsCRP) has been questioned, and consequently we decided to investigate whether hsCRP was associated with subclinical cardiovascular (CV) damage independently of traditional CV risk factors. In a population-based sample of 2028 apparently healthy individuals without prior stroke or myocardial infarction not receiving any CV, anti-diabetic or lipid-lowering treatment, aged 41, 51, 61 or 71 years, we measured in 1993 serum hsCRP, traditional CV risk factors (lifestyle, metabolic and hemodynamic) and assessed subclinical CV damage [atherosclerotic plaques in the carotid arteries, pulse wave velocity (PWV), urine albumin/creatinine ratio (UACR), left ventricular (LV) mass and ejection fraction]. Adjusting for age and gender in multiple regression analyses, higher log(hsCRP) was associated with higher logPWV (beta = 0.15) and log(left ventricular mass index) (LVMI) (beta = 0.09, both P < 0.001), LV relative wall thickness (beta = 0.07, P < 0.01), logUACR (beta = 0.04, P = 0.06) and more atherosclerotic plaques (beta = 0.06, P < 0.05). However, higher log(hsCRP) was only weakly associated with higher logPWV(beta = 0.06, P < 0.05) and more atherosclerotic plaques (beta = 0.04, P = 0.06) when adjusting for other significant CV risk factors, such as daily smoking (beta = 0.18), female gender (beta = -0.17), older age (beta = 0.11), lower log(high density lipoprotein cholesterol) (beta = -0.11, all P < 0.001); wider waist (beta = 0.17), higher body mass index (beta = 0.14), higher heart rate (beta = 0.06, all P < 0.01); and higher log(plasma glucose) (beta = 0.05, P < 0.05) (adj. R2 = 0.19, P < 0.001). After adjustment for traditional CV risk factors hsCRP was only associated with PWV and atherosclerotic plaques, indicating a possible effect of low-grade inflammation on macrovascular damage. The close relationship between traditional CV risk factors and hsCRP suggested that hsCRP was an integrated CV risk marker early in the development of atherosclerosis.

Cellular mechanisms and treatment of diabetes vascular complications converge on reactive oxygen species

High glucose activates a myriad of signaling and gene expression pathways in non-insulin-dependent target cells causing diabetes complications. One of the earliest responses to high glucose by vascular cells is the generation of reactive oxygen species (ROS) that act directly on intracellular proteins and DNA, or indirectly as second messengers, transforming these cells into disease phenotypes. ROS are produced by mitochondria and/or NADPH oxidase in all target cells exposed to high glucose studied to date. Reports using cell cultures and diabetic animal models indicate that inhibition of ROS generation prevents the amplification of signaling and gene expression that are implicated in vascular complications. These models convincingly demonstrate that maneuvers preventing ROS production attenuate or completely abrogate early micro- and macrovascular end-organ damage of diabetes, including nephropathy, retinopathy, and large-vessel atherosclerosis. Attention now turns to the development of more effective antioxidants that could be used in clinical trials in the prevention and treatment of diabetes complications.

The interplay of cardiovascular risk factors in the metabolic syndrome and type 2 diabetes

Cardiovascular disease (CVD) is the major cause of morbidity and mortality in the western world, and patients with diabetes have a 2- to 3-fold greater risk of CVD death than those without. This suggests an interaction between diabetes and other CVD risk factors such as hypertension and dyslipidaemia. The treatment of CVD risk factors in patients with diabetes reduces the incidence of CVD death but macrovascular damage is present in patients prior to the onset of overt diabetes, so the early identification and treatment of patients at risk of diabetes is essential for the primary prevention of CVD. Risk factors for diabetes and CVD are more likely to occur simultaneously than would be expected by chance, and this cluster of disorders is collectively called the metabolic syndrome. Individuals with the metabolic syndrome have an increased risk of CVD prior to the development of impaired glucose tolerance and diabetes, and patients with both the metabolic syndrome and diabetes are at greater risk of coronary heart disease death than patients with either diabetes or the metabolic syndrome alone. Although reducing glucose levels significantly reduces the risk of microvascular disease in patients with diabetes and/or the metabolic syndrome, it is not sufficient to significantly reduce the incidence of macrovascular disease. Additional risk factors, including hypertension and dyslipidaemia, must also be targeted in patients with these disorders.

Review of diabetes: identification of markers for early detection, glycemic control, and monitoring clinical complications.

The hallmark of diabetes mellitus, whether type I or type II, is hyperglycemia. Clinical complications associated with diabetes are most likely the consequence of hyperglycemia via both altered metabolic pathways and nonenzymatic glycation of proteins. The nonenzymatic glycation of proteins is accelerated in diabetes due to elevated blood glucose concentration. The Amadori product of nonenzymatic glycation will further cross-link with other proteins to form advanced glycosylation end products (AGEs). The reaction of AGEs with long-lived proteins, such as collagen, and the uptake of AGEs by the receptors on macrophages, endothelial cells, and platelets are major reasons for the development of various clinical complications in diabetes. Several markers have been identified for the screening, diagnosis, and monitoring of the disease. Autoantibodies against beta cells are the best markers for mass screening and for early detection of type I diabetes. In addition to glycated hemoglobin, AGEs and blood glycated proteins of various half-lives could be used for monitoring glycemic control. Several abnormal metabolites have been identified as potential markers for monitoring the severity of various clinical complications. The most interesting findings in diabetic markers could be AGEs. The amount of AGEs found in the tissues could be related to the extent of micro- and macrovascular damage and might prove useful for monitoring the treatment of patients at early stages of either nephropathy, atherosclerosis, retinopathy, or neuropathy.

Diabetic nephropathy. Future avenue.

Diabetes mellitus has become the leading cause of ESRF in the United States. Patients with diabetic nephropathy suffer high cardiovascular morbidity and mortality. Because only 40% of diabetic patients eventually develop diabetic kidney disease, it may be possible to devise primary prevention measures targeted at the subset of patients at risk. Recently, a predisposition to hypertension, a family history of diabetic nephropathy, and a family history of CVD disease each have been associated independently with the development of diabetic renal complication in IDDM. Risk factors for macrovascular damage, including raised arterial BP, dyslipidemia, and insulin resistance, can be detected early in the course of progression to diabetic nephropathy. These risk indicators recently have been shown to be already present at the stage of normoalbuminuria in those patients who eventually will progress to microalbuminuria. Treatment of established renal disease can only delay the onset of ESRF, and lowering of microalbuminuria has been shown to retard the onset of persistent proteinuria. However, no study to date has demonstrated prevention of renal disease in these patients. The ultimate aim should, therefore, be the prevention of the transition from normoalbuminuria to microalbuminuria in individuals who are at higher risk of diabetic renal disease and CVD.