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Uric acid as a mediator of endothelial dysfunction, inflammation, and vascular disease.

Recent experimental findings have led to renewed interest in the possible role of uric acid in the pathogenesis of both hypertension and vascular disease. Often considered an antioxidant, biochemical and in vitro data indicate that noncrystalline, soluble uric acid also can react to form radicals, increase lipid oxidation, and induce various pro-oxidant effects in vascular cells. In vitro and in vivo findings suggest that uric acid may contribute to endothelial dysfunction by inducing antiproliferative effects on endothelium and impairing nitric oxide production. Proinflammatory and proliferative effects of soluble uric acid have been described on vascular smooth muscle cells (VSMCs), and in animal models of mild hyperuricemia, hypertension develops in association with intrarenal vascular disease. Possible adverse effects of uric acid on the vasculature have been linked to increased chemokine and cytokine expression, induction of the renin-angiotensin system, and to increased vascular C-reactive protein (CRP) expression. Experimental evidence suggests a complex but potentially direct causal role for uric acid in the pathogenesis of hypertension and atherosclerosis.

Animals↗

Renal vascular disease in neurofibromatosis type 2: association or coincidence?

Neurofibromatosis type 2 (NF2) remains a challenging diagnosis in childhood where there may be no neurological involvement. A 12-month-old male in whom NF2 was suspected because of characteristic ophthalmological and cutaneous lesions is reported. Cranial MRI showed no tumours. A pathogenic mutation was identified on NF2 gene analysis. The child developed hypertension due to renal vascular disease. Although renal vascular disease is a recognized complication of neurofibromatosis type 1 (NF1), it has not been reported in NF2.

Blood Pressure↗

Pulse pressure as a risk factor for peripheral vascular disease in type 2 diabetic patients.

This study examined whether pulse pressure (PP) could be an independent predictor and associated with severity of peripheral vascular disease (PVD) in 396 type 2 diabetic patients (143 men and 253 women, aged 64.1 +/- 11.2 years). Peripheral vascular disease was diagnosed by an ankle-brachial index (ABI) < 0.90 and as severe PVD if ABI < 0.80. Association was evaluated before and after adjustment for age, sex, diabetes duration, hypertension, smoking, fasting plasma glucose (FPG), total cholesterol (TC), usage of insulin, and usage of angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB); and for systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP), respectively. Results showed that PP increased from no (n = 348) to mild (n = 25) and severe (n = 23) PVD (one-way ANOVA, p < 0.001; multiple comparisons, p < 0.05 for any two groups). The PP increase from no to mild PVD was due to SBP increase; while further increase to severe PVD was due to both DBP drop and an even higher SBP. Adjusted odds ratio (AOR) for PVD for every 1-mmHg PP increment was 1.035 (1.012-1.058). When PP was categorized as tertiles (< 50, 50-59 and > or = 60 mmHg), respective AOR for PVD for second and third vs. first tertile was 2.605 (1.008-6.729) and 2.835 (1.123-7.156). Pulse pressure was also predictive for ABI independent of the effects of the confounders and the other parameters of blood pressure. In conclusion, PP was an independent predictor and correlated with severity of PVD in type 2 diabetic patients.

Aged↗

Group rehabilitation for the vascular-disease amputee.

Group therapy for lower-extremity, vascular-disease amputees was successful in the return of these patients to their normal milieu. Thirty men (mean age, 63 years) were studied during a one-year period. The group meetings progressed from a phase of directed therapy to one of nondirected therapy. This group of hospitalized amputees was chosen specifically because of its social, economic and medical identity. After a self-identified adequate period of therapy, all patients returned to their former places in society.

Adjustment Disorders↗

[Prevention of vascular diseases of the nervous system].

On the basis of the literature data and the findings of their own studies the authors consider methodological aspects of the prevention of vascular diseases of the nervous system. Epidemiological, prenosological, systemic, individualized and rehabilitative approaches to the creation of the system for the prevention of vascular diseases of the nervous system have been determined.

Epidemiologic Methods↗

The risk of atherosclerotic vascular disease in subjects with xanthomatosis.

The morbidity and mortality in 172 males and 164 females with xanthomatosis have been investigated. Symptoms of coronary heart disease (CHD) were the most frequent initial manifestation of atherosclerotic vascular disease. Angina pectoris was the first symptom in about 3/4 of males as well as females; myocardial infarction was the first event in 26% of the males and 9% of the females. Other manifestations of atherosclerosis were comparatively rare and occurred late in life. Half of the subjects were affected with symptoms of atherosclerotic vascular disease by the age of 52 in men and 62 in women, the mean age for first symptoms being 49 and 56 years, respectively. No significant influence of other CHD risk factors than xanthomatosis and hyperlipidaemia was found in these patients. An increase in the number of cardiovascular deaths was seen in xanthomatosis patients, compared with the general population, in particular in the number of "sudden deaths". Half of the males died before the age of 66 and half of the females before the age of 74.5, which is about 10 and 7 years earlier than predicted at 30 years of age for the normal population. The cumulative relative mortality in both men and women was about twice that expected for the general Norwegian population until 70 years of age.

Adolescent↗

Erectile dysfunction as a marker for vascular disease.

A body of evidence from basic science and clinical research is emerging to provide a compelling argument for endothelial dysfunction as a central etiologic factor in the development of atherosclerosis and systemic vascular diseases (hypertension, dyslipidemia, diabetes, ischemic heart disease, stroke, or claudication). Erectile dysfunction (ED) is another prevalent vascular disorder that, like cardiovascular disease, is now thought to be caused by endothelial dysfunction. In fact, a burgeoning literature is now available that suggests that ED may be an early marker for atherosclerosis, cardiovascular risk, and subclinical systemic vascular disease. The emerging awareness of ED as a barometer for vascular health and occult cardiovascular disease represents a unique opportunity for primary prevention of vascular disease in all men. Although the implications of this relationship for primary and secondary prevention of cardiovascular disease are not fully appreciated, the available literature makes a strong argument for the role of ED as an early marker for the development of significant cardiovascular risk factors and cardiovascular disease.

Cardiovascular Diseases↗

Cost-effective strategies for the management of vascular disease.

Cardiovascular disease accounts for over 950,000 deaths and an estimated $151 billion in direct and indirect costs. Because of this escalating clinical and financial burden, economic analysis has become essential for the evaluation of preventative therapies for vascular disease. Economic analysis compares competing interventions or management strategies for costs and benefits; more specifically, cost-effectiveness analysis compares cost in financial terms like dollars to measures of effectiveness like years of life saved. Important concepts in the creation of a valid cost-effectiveness analysis include perspective, time horizon, measurement of costs and effectiveness and sensitivity analysis. In patients with peripheral arterial occlusive disease, most morbidity and mortality arises from complications of coronary artery disease. Because coronary artery disease and peripheral arterial occlusive disease commonly occur together and share risk factors, pathophysiology and response to preventative therapy, economic evaluations of preventative therapies for coronary artery disease have relevance for patients with vascular disease. Cost-effectiveness analysis reveals that modification of vascular risk factors like tobacco use, hypertension and hypercholesterolemia improve clinical outcomes at acceptable cost-effectiveness ratios, usually less than $20,000 per year of life saved. More importantly, interventions like smoking cessation or lipid modification in high-risk groups may be cost saving, with treatment costs outweighed by financial benefits. From the patient, clinician and societal perspective, cost-effectiveness analysis supports the aggressive modification of cardiovascular risk factors in patients with peripheral arterial occlusive disease.

Cost-Benefit Analysis↗

Our experience with spinal cord stimulation (SCS) in peripheral vascular disease.

Spinal cord stimulation (SCS) by epidural electrodes is being used more often in the treatment of patients with severe intractable ischemic pain. The promising clinical results and the objective increase in lower extremity blood flow (plethysmography, thelethermography, etc.), suggests that spinal cord stimulation may have an important role in the management of advanced arterial disease when other forms of treatment have failed. The selection criteria for implantation of SCS are very important. Our indications in patients with peripheral vascular disease are: 1. Peripheral vascular disease with severe, intractable symptoms that are untreatable by medical or surgical therapy. 2. Inflammatory or diabetic arterial disease resistant to medical treatment and/or sympathectomy. 3. Persistent and severe ischemic pain and/or ulcers in patients with patent grafts. 4. Patients for lumbar sympathectomy who have a high myocardial risk. Contraindications to implantation of SCS are claudication intermittent, large necrotic lesions (gangrene) and patients who have undergone prolonged narcotic therapy.

Adult↗

[Late results of coronary bypass grafting in patients with concomitant multifocal arteriosclerotic vascular diseases].

Late results of coronary bypass graftings (CABG) in the patients with multifocal arteriosclerotic vascular diseases were reviewed. Between September 1978 and July 1989, 819 consecutive patients underwent CABG. There were 693 males and 126 females, mean ages 58 +/- 8.5 years. Of 819 consecutive patients underwent CABG, 95 patients had the coexistence of multifocal atherosclerosis (Group A). Seventy two patients had aortoiliac or femoropopliteal disease, and 29 patients had aortic aneurysm. The remaining 724 patients had no coexistence of multifocal atherosclerosis (Group B). The mean follow-up periods was 4.0 +/- 2.1 years, and the follow-up ratio was 99.4%. The 5- and 10-year survival rates were 80% and 52% in group A, and 92% and 82% in Group B, respectively. The 5- and 10-year free ratio from cardiac events were 79% and 42% in Group A, and 85% and 61% in Group B, respectively. The 5- and 10-year free ratio from noncardiac events were 53% and 38% in Group A, and 85% and 76% in Group B, respectively. The results showed that the coexistence of multifocal atherosclerotic vascular disease in patients underwent CABG significantly increase the ratio of noncardiac and cardiac events, and decreased life expectancy.

Aged↗

Cutaneous delayed hypersensitivity, T cell subsets, and IL-2 secretion in patients with peripheral vascular disease.

To determine whether anergy in patients with peripheral vascular disease is related to an abnormality of their T cells, the distribution of T-cell subsets and monocytes in peripheral blood was studied in relation to the delayed hypersensitivity response following the intradermal injection of 7 recall antigens. Positive correlation coefficients were observed between either the sum of the induration at 48 hr or the number of antigens giving a positive response and the percentage of total T cells (OKT 3) and helper T cells (OKT 4). The percentages of suppressor/cytotoxic T cells (OKT 8) and monocytes (OKM 1) showed no correlation with skin reactivity to the recall antigens. In vitro secretion of IL-2 by purified T cells was similar in anergic patients and in patients with normal delayed hypersensitivity responses. Addition of IL-2 to unstimulated T cells or T cells stimulated in vitro with either tetanus toxoid or PPD sometimes potentiated incorporation of 3H-thymidine into the cells after 6 days of culture.

Adult↗

A patient centered approach to the treatment of renal vascular disease to prevent end stage renal failure.

Atherosclerotic renal vascular disease (RVD) is a cause of renal failure especially in the elderly. There has never been a clinical trial to determine how effective invasive therapy is over medical therapy to prevent end stage renal disease. The objective of this study was to determine how effective invasive therapy for RVD to prevent renal failure should be from the perspective of the patient to warrant implementation. Subjects included 28 elderly dialysis patients and 26 renal health care workers (HCW). Subjects were asked directly how effective invasive therapy should be if they were to undertake the procedure. Invasive therapy would have to eliminate the need for dialysis permanently by 41 +/- 6% for the dialysis patients and 21 +/- 4% for the HCW to be acceptable. This difference in efficacy between the two groups was statistically significant (P = 0.014). Efficacy was also determined using a medical decision analysis model that incorporated patient health related quality of life status for dialysis and non-dialysis. To be cost-effective (< $50,000 incremental cost/quality adjusted life year) invasive therapy had to reduce the development of end stage renal failure by 35 +/- 1% (M +/- SE) for dialysis patients and 15 +/- 1% for HCW. These results show that patients demand better efficacy rates than their providers and that this difference appears to be appropriate based on their perceptions of health and projected outcomes. Both patient and health care workers are more conservative than predicted by the medical decision analysis model. Since the range of patient responses was large, methods of documenting patient perspectives for risky procedures may help clinicians determine how aggressively to investigate and treat patients with RVD.

Aged↗

Is erectile dysfunction predictive of peripheral vascular disease?

The association between erectile dysfunction (ED) and peripheral vascular disease (PVD) among men was examined in the Integrated Healthcare Information Services National Managed Care Benchmark Database (IHCIS). The IHCIS is a fully de-identified, Health Insurance Portability and Accountability Act compliant database and includes complete medical histories for more than 17 million managed-care lives; data from more than 30 US health plans, covering seven census regions; and patient demographics, including morbidity, age and gender. A total of 12 825 ED patients and an equal number of male patients without ED were included in the retrospective cohort study. Logistic regression analyses were performed to assess the adjusted risk of PVD that accounted for age at ED diagnosis, smoking, obesity and medications including angiotensin converting enzyme (ACE) inhibitors, beta blockers and statins. The cohort of men with ED were observed to have a 75% increase in risk for PVD (odds ratio (OR) = 1.75, 95% confidence interval (CI) = 1.06, 2.90) after adjusting for age at ED diagnosis, smoking, obesity and use of ACE inhibitors, beta blockers and statins. Some evidence of a possible trend towards increased risk was detected by age group. After controlling for the aforementioned covariates and compared to men aged 30-39 years, it was noted that patients aged 40-44 years were 2.1 times more likely to develop PVD (OR = 2.07, 95% CI = 0.89, 4.81), 45-49-year-old men were also more than twice as likely to have PVD (OR = 2.32, 95% CI = 1.03, 5.22), and 50-55-year-old patients had a three-fold increased risk of developing PVD (OR = 3.00, 95% CI = 1.40, 6.43). The results of this study indicate that ED may serve as a marker for PVD. The risk becomes more pronounced with increasing age, indicating the need for cardiologists and internists to monitor ED patients who may not necessarily present with cardiovascular symptoms.

Adult↗

The role of hypertension in the vascular disease and myocardial infarcts associated with murine systemic lupus erythematosus.

The several kinds of mice that spontaneously develop acute systemic lupus erythematosus (SLE)--BXSB males, MRL/l males and females, and (NZB X W)F1 females--have a 15-20% incidence of degenerative vascular disease (DVD) and myocardial infarcts (MI) in which the affected coronaries contain deposits of immunoreactants, presumably in the form of immune complexes. Among the F1 hybrid crosses of SLE mice, only the (NZW X BXSB)F1, (W X B)F1 male has a significantly higher incidence of DVD/MI (80%). Search for possible causes of this high incidence of myocardial infarcts revealed several unique features of this mouse: hypertension, thrombocytosis, and early onset of circulating immune complexes and glomerulonephritis. Our attempts to prevent this DVD/MI focused on: reduction of hypertension, prevention of thrombosis, and immunosuppression. Immunosuppression by Cytoxan resulted in almost complete prevention of both the SLE disease and DVD/MI. Administration of bretylium, an antihypertensive and anti-arrhythmic agent, resulted in reduction of blood pressure and the severities of glomerulonephritis, DVD, and MI; it also slightly reduced the levels of circulating immune complexes and leukocytosis. Of the 4 antithrombotic agents used, only aspirin showed some reduction in the incidence of DVD/MI and delay of glomerulonephritis-associated mortality.

Animals↗

Interdependent serotonin transporter and receptor pathways regulate S100A4/Mts1, a gene associated with pulmonary vascular disease.

Heightened expression of the S100 calcium-binding protein, S100A4/Mts1, is observed in pulmonary vascular disease. Loss of serotonin (5-hydroxytryptamine [5-HT]) receptors or of the serotonin transporter (SERT) attenuates pulmonary hypertension in animals, and polymorphisms causing gain of SERT function are linked to clinical pulmonary vascular disease. Because 5-HT induces release of S100beta, we investigated the codependence of 5-HT receptors and SERT in regulating S100A4/Mts1 in human pulmonary artery smooth muscle cells (hPA-SMC). 5-HT elevated S100A4/Mts1 mRNA levels and increased S100A4/Mts1 protein in hPA-SMC lysates and culture media. S100A4/Mts1 in the culture media stimulated proliferation and migration of hPA-SMC in a manner dependent on the receptor for advanced glycation end products. Treatment with SB224289 (selective antagonist of 5-HT1B), fluoxetine (SERT inhibitor), SERT RNA-interference, and iproniazid (monoamine oxidase-A inhibitor), blocked 5-HT-induced S100A4/Mts1. 5-HT signaling mediated phosphorylation (p) of extracellular signal-regulated kinase 1/2 (pERK1/2), but pERK1/2 nuclear translocation depended on SERT, monoamine oxidase activity, and reactive oxygen species. Nuclear translocation of pERK1/2 was required for pGATA-4-mediated transcription of S100A4/Mts1. These data provide evidence for a mechanistic link between the 5-HT pathway and S100A4/Mts1 in pulmonary hypertension and explain how the 5-HT1B receptor and SERT are codependent in regulating S100A4/Mts1.

Active Transport, Cell Nucleus↗

Immune mechanisms in patients with proven vascular disease.

Lymphocyte transformation and serum levels of immunoglobulins and complement were measured in groups of patients with old myocardial infarction, with peripheral vascular disease and in age- and sex-matched controls. There were no significant differences between the groups in phytohaemagglutinin (PHA) induced lymphocyte transformation, in IgA or in serum complement levels. The levels of IgG and IgM were significantly raised in patients with old proven infarcts while the level of IgM was raised in patients with peripheral vascular disease.

Complement System Proteins↗