High Risk Of Vascular Disease Research Articles

Achieving normal blood pressure 1,2,3

Hypertension is a continuous challenge for many people on dialysis. This problem is complicated by a variety of factors, including high salt and fluid intake, lack of physical activity, and derangements in lipid metabolism. Because many dialysis patients are at high risk for vascular disease, education is needed to help patients maintain a healthy heart and vascular system. The dietitians and social workers of Saint Alphonsus Nephrology Center developed a handout for patients called, “A Gift for Your Heart.” This brochure reviews simple steps patients can take to manage their blood pressure and reduce their risk for heart disease and stroke. Patients were given plastic 8-ounce cups to illustrate portion sizes and fluid restrictions. In addition, to promote a lower salt diet, samples and coupons for spice blends were distributed. Moreover, as a person’s response to stress can be associated with higher blood pressure with subsequent vascular problems, the facility social workers provided tips on helping patients manage and reduce stress. We used a card insert in the pamphlet to outline normal, above normal, and high-risk blood pressures. Patients were encouraged to take an active role in monitoring their own blood pressures. The other side of the inserted card suggests patients try mouth sprays to help reduce fluid intake. Of interest, mouth sprays can be prepared by patients themselves and are very cost effective. Certainly, the steps to reaching a normal blood pressure and reducing vascular risk are an ongoing educational challenge. This brochure has helped our facilities begin emphasizing the importance of prevention of vascular disease, and we hope you will find it useful as well.

Study of Heart and Renal Protection (SHARP)

Among patients with preexisting coronary heart disease, large-scale randomized trials have demonstrated that lowering low-density lipoprotein (LDL)-cholesterol concentration by about 1 mmol/L for 4-5 years reduces the risk of coronary events and strokes by about 25%. Patients with established chronic kidney disease (CKD) are at high risk of vascular disease, so the benefits of cholesterol-lowering therapy might be expected to be substantial in this population. Patients with CKD have generally been excluded from previous trials, however, and there is currently no reliable randomized evidence that lowering LDL-cholesterol would be beneficial among them. There are several reasons why the demonstrated benefits of lowering blood cholesterol in other populations might not translate to patients with CKD. First, observational studies among dialysis patients have reported a negative association between blood total cholesterol and mortality. Second, only about one quarter of cardiac mortality in such patients appears to be attributable to acute myocardial infarction, and potentially avoidable with cholesterol lowering, while the other common causes (e.g., cardiac arrest, arrhythmia, and heart failure) may not be as dependent on cholesterol levels. Finally, the long-term safety of cholesterol reduction among patients with CKD remains unclear. Hence, there is an important need for reliable direct evidence on whether lowering cholesterol prevents a worthwhile proportion of vascular events, without unacceptable toxicity, among patients with CKD. The Study of Heart and Renal Protection (SHARP) aims to assess the effects of cholesterol-lowering therapy with a combination of simvastatin and the cholesterol-absorption inhibitor ezetimide among around 9000 patients with CKD.

Intranasal civamide for the treatment of episodic cluster headaches.

Arch Neurol. 2002 Jun;59(6):990‐994Objective: To evaluate the safety and efficacy of intranasal civamide solution for preventive treatment during an episodic cluster headache period. Subjects And Methods: This was a multicenter, double‐blind, randomized, vehicle‐controlled study with a 7‐day treatment period and a 20‐day posttreatment period performed at 14 headache/neurology centers in the United States. Twenty‐eight subjects were randomized to receive civamide or its vehicle in a 2:1 ratio; 18 received civamide and 10 received the vehicle. Subjects received 100 microL of 0.025% civamide (25 microg) or 100 microL of the vehicle to each nostril via dropper once daily for 7 days. The total daily dose of civamide was 50 microg. Main Outcome Measures: The number of cluster headaches per week during the treatment and posttreatment periods, pain intensity, presence of associated symptoms, and the incidence of adverse events were assessed.Results: Subjects in the civamide group had a significantly greater percent decrease in the number of headaches from baseline to posttreatment during days 1 through 7 (−55.5% vs −25.9%; P = .03) and a trend toward significance during days 8 through 14 (−66.9% vs −32.3%; P = .07) and days 15 through 20 (−70.6% vs −34.9%; P = .07), as well as a near‐significant decrease during the entire posttreatment period (days 1 through 20 [P = .054]) compared with the vehicle group. There were larger decreases in the number of headaches per week during the posttreatment period in the civamide‐treated group, with trends toward significance during posttreatment days 8 through 14 (−8.6 vs −3.6; P = .09) and days 15 through 20 (−8.9 vs −3.6; P = .07). There were no significant differences between groups in cluster headache pain intensity, number of severe headaches, or associated symptoms. The most common adverse events included nasal burning (14 of 18 civamide‐treated subjects, 1 of 10 vehicle‐treated subjects; P = .001) and lacrimation (9 of 18 civamide‐treated subjects, 0 of 10 vehicle‐treated subjects; P = .01).Conclusion: Intranasal civamide solution at a dose of 50 microg may be modestly effective in the preventive treatment of episodic cluster headache.Comment: Civamide is a capsaicin‐like medication being studied for the prevention of cluster headache, a follow‐up compound to an idea first described in a study published in 1993 suggesting that intranasal capsaicin appeared useful in preventing episodic cluster (Marks DR, Rapoport A, Padla D, Weeks R, Rosum R, Sheftell F, Arrowsmith F. A double‐blind placebo‐controlled trial of intranasal capsaicin for cluster headache. Cephalalgia. 1993;13:114‐116). The current study did not meet several primary endpoints; the question is whether a larger study would. The issue is not insignificant. Dr. Peter Goadsby has pointed out that there is a specific need for nonvascular treatments for cluster, given the epidemiology of patients with cluster as smoking, middle‐aged men at high risk for vascular disease. Civamide, if it can be shown effective in prophylaxis, depletes substance P and other nociceptive peptides, without causing vascular changes or cardiac effects, as can be seen with calcium‐channel blockers. It has far less systemic toxicity than lithium or antiepileptic drugs. Further study seems warranted, even if overall clinical effect is moderate. SJT

Statin Therapy Benefits Patients Aged 70 to 82

The primary- and secondary-prevention benefits of cholesterol-lowering therapy are clear in middle-aged people but somewhat less clear in the elderly. In this industry-sponsored trial, researchers randomized 5804 patients (age range, 70-82) at high risk for vascular disease to pravastatin (40 mg/day) or placebo for a mean of 3.2 years. Mean baseline cholesterol level was …

Prevalence of hyperhomocysteinemia in an elderly population

Background Currently, total hyperhomocysteinemia (tHHcy) is a well-known condition linked to a higher risk of vascular disease. Prevalence of HHcy increases in elderly persons as the risk associated with it persists. Because factors can be potentially reduced in the elderly, it is important to carry out epidemiologic studies of HHcy. Procedure Previously we described the prevalence of hypertension control in an elder population; now, in an observational cross-sectional simple blind study, total homocysteine (tHcy) concentration was determined in 196 of 400 patients from the original cohort. Results Mean Hcy concentration was 13.2 μmol/L (95% confidence interval 12.4–14.0; range, 5.0 to 48.9); 15.0 μmol/L for men and 12.3 μmol/L for women. Mean serum folic acid levels were 4.9 ± 3.1 ng/mL (range, 2.0 to 20.0 ng/mL), and vitamin B12 levels were 384.8 ± 314.1 pg/mL (range, 48.0 to 1500.0 pg/mL). Taking into account the reference values established by the Third National Health and Nutrition Examination Survey III study, HHcy was detected in 69.8% of all the subjects evaluated. The study showed that 76.2% of the men and 66.4% of the women had high Hcy levels. Conclusions The very high prevalence of tHHcy in the elderly population, and the consequent risks associated with it suggest that although there are no trials that effectively prove the benefit of tHcy decrease, nutritional intervention is still justified.

Autoantibodies and endothelial dysfunction in well-controlled, uncomplicated insulin-dependent diabetes mellitus patients

Patients with insulin-dependent diabetes mellitus (IDDM) are well known to be at high risk of vascular disease, and dysfunction of vascular endothelium is considered as an early step in the development of diabetic complications. Because of the involvement of autoimmunity in the pathogenesis of IDDM, our aim was to assess, in 45 IDDM patients without clinically evident vascular complications, whether early signs of endothelial cell dysfunction were correlated to alterations of the immune system. IDDM patients were characterized by significantly increased serum levels of C-reactive protein, of polymorphonuclear cells-derived elastase, of endothelin-1 (ET-1) and of thrombomodulin, while plasma concentrations of fibronectin (FNT) were significantly decreased, with a statistically significant inverse correlation between ET-1 and FNT values. The presence of circulating immune complexes (CIC) was investigated in 36 out of our 45 IDDM patients, and values above the cut-off were found in 17 (47.2%) of them. One-third of all patients showed values above the cut-off for IgG-aCL. In IDDM patients, at variance from the control group, the levels of ET-1 were directly correlated to those of von Willebrand factor, of anticardiolipin β 2-GPI and of CIC, with an inverse correlation with plasma FNT. An association between antiphospholipid antibodies and endothelial dysfunction and/or activation is therefore suggested, pointing to a synergism, in the early phases of IDDM vascular disease, between generation of autoantibodies and endothelial activation.

Editor's note:

The above letter was sent to the authors of the original article and their reply follows. In reply: We appreciate the interest of G. Gambassi et al. in our paper. The limitations of our data are acknowledged in our paper. The data analysis was cross-sectional in nature; therefore, attribution to causation has to be made with caution. No information was included on dosage, length of treatment, or compliance. Importantly, by not having data on blood pressure, our study does not indicate whether or not the drug effects were determined by control of hypertension. Their scenario, that our findings could be explained by a different prescribing (treatment?) pattern by the physician for the cognitively impaired subject, is implausible, however. Our research faculty, not the physician, made the diagnoses of cognitive impairment. It is very unlikely that the physician recognized this degree of impairment. Even in the case of dementia, it was only in a relatively small proportion of subjects that this diagnosis had been made previously by the treating physician. The strengths of our study were that it was conducted on a large, community-based population of older African Americans at high risk for vascular disease. The associations between the medications and cognitive function were consistent across four sets of diagnostic criteria for cognitive impairment. We regret that our study, with its modest conclusions, aroused in Gambassi et al. sentiments of “confusion” and that our diagnostic data were “not interpretable” to them. Part of their lack of comprehension may arise from their attempt to compare secondary data derived from their Systematic Assessment of Geriatric Drug Use via Epidemiology (SAGE) study to our data and to other primary data derived from population-based and clinical-based studies. The SAGE study consists of “a longitudinal data base that comprises data collected with the minimum data set on residents of nursing homes in five states.”1 Thus, their conclusions, based upon their data, appear to be at variance with those of other studies, which should not be surprising. Nursing home subjects are different from community-dwelling subjects and the medical care provided to them is not necessarily similar. Take a simple example. The age-adjusted prevalence rate for dementia in our community-dwelling sample of African Americans was 4.8%. In our nursing home sample of African Americans, age-specific prevalence rates rose from 45% in the group age 65 to 74 to 76% in the group age 85 and older.2 Diagnosis of dementia and its subtypes taken from existing nursing records, as in the SAGE study, are neither reliable nor comparable with diagnoses derived from standard comprehensive clinical and neurological assessments by neurologists, neuropsychologists, and psychiatrists (as in the SAGE study). In three major population-based studies of older community-dwelling African Americans in North Carolina,3 New York,4 and in our own study in Indianapolis,2 Alz-heimer's disease (AD) was the most common subtype of dementia. AD is associated with increased mortality, but the incidence and the prevalence of AD increases with age.5 Thus in all published studies; the rates of AD are highest in the oldest age categories. Women may or may not be at increased risk for AD, but they certainly live longer than men. Our finding that AD was most common in the oldest age category of women is consistent with all other studies.6 Comorbid conditions are common in dementia for both women and men. Studies of the association between diabetes mellitus and AD have produced mixed results, but at least one report has suggested that diabetic subjects are at increased risk for developing AD.7 A gender difference with regard to comorbidity and treatment for either AD patients or non-AD patients is certainly not a uniform finding and was not our experience in our study. To the best of our knowledge, none of the current expert panel treatment guidelines have gender issue recommendations. Our study is prospective in design. We hope that by following this population and conducting longitudinal analysis, some of the current uncertainties will be resolved.

Global risk assessment for lipid therapy to prevent coronary heart disease.

Randomized clinical trials have established that lipid- lowering pharmacologic therapy can substantially reduce morbidity and mortality in patients with known coronary artery disease (CAD). Researchers are now working to define the role of lipid-lowering agents in the primary prevention of CAD to extend their benefit to patients at increased risk for future coronary events. The risk assessment models presently used for secondary prevention are not sufficient to identify high-risk, asymptomatic patients. Building on the accumulated data about the physiologic mechanisms and metabolic factors that contribute to CAD, novel serum markers and diagnostic tests are being critically studied to gauge their utility for the assessment of high-risk patients and occult vascular disease. New risk prediction models that combine traditional risk factors for CAD with the prudent use of new screening methods will allow clinicians to target proven risk reduction therapies at high-risk patients before they experience a cardiac event.

Thienopyridines or aspirin to prevent stroke and other serious vascular events in patients at high risk of vascular disease? A systematic review of the evidence from randomized trials.

Aspirin is the most widely studied and prescribed antiplatelet drug for patients at high risk of vascular disease. We aimed to establish how the thienopyridines (ticlopidine and clopidogrel) compare with aspirin in terms of effectiveness and safety. We did a systematic review of all unconfounded randomized trials comparing either ticlopidine or clopidogrel with aspirin for patients at high risk of vascular disease. The primary outcome was vascular events (stroke, myocardial infarction, or vascular death). Adverse outcomes were intracranial and extracranial hemorrhage, upper and lower gastrointestinal disturbances, neutropenia, thrombocytopenia, and skin rash. In 4 trials among 22 656 patients (including 9840 presenting with a transient ischemic attack/ischemic stroke), the thienopyridines reduced the odds of a vascular event by 9% (odds ratio 0.91, 95% CI 0.84 to 0. 98; 2P=0.01), preventing 11 (95% CI 2 to 19) events per 1000 patients treated for approximately 2 years. The thienopyridines produced significantly less gastrointestinal hemorrhage and upper gastrointestinal upset (indigestion/nausea/vomiting) than did aspirin. Both thienopyridines increased the odds of skin rash and of diarrhea (ticlopidine by approximately 2-fold and clopidogrel by approximately one third). Only ticlopidine increased the odds of neutropenia. The thienopyridines appear modestly more effective than aspirin in preventing serious vascular events in high-risk patients. Clopidogrel appears to be safer than ticlopidine and as safe as aspirin, making it an appropriate, but more expensive, alternative antiplatelet drug for patients unable to tolerate aspirin. However, there is insufficient information to determine which particular types of patients would benefit most, and which least, from clopidogrel instead of aspirin.

Aspirin-associated intracerebral hemorrhage: clinical and radiologic features.

To identify the clinical and radiologic features of intracerebral hemorrhage (ICH) in aspirin users. Although the benefits of aspirin outweigh its hemorrhagic risks for patients at high risk of vascular diseases, prolonged use of aspirin is associated with an increased risk of ICH. The authors enrolled consecutive patients with acute stroke who were admitted to a regional hospital from 1993 to 1998 into a stroke registry. From this registry, they identified all stroke patients who had ICH confirmed by CT scan and then selected those taking regular aspirin before ICH as the study group. For each study patient, they selected the immediate next two patients with ICH but not taking aspirin as controls. The authors identified 58 aspirin users and 1193 nonusers among all patients hospitalized for ICH. From the group of nonusers, they selected 116 patients as controls. The locations of the hematoma were different (p = 0.002), with more lobar hematoma in the aspirin group (32.8%) than in the control group (10.3%). Prior cerebrovascular disease was the reason for taking aspirin in 37 (64%) patients but five patients had prior ICH. The propensity for lobar hematoma in aspirin-associated ICH suggests its pathology may be somewhat different from spontaneous ICH among nonaspirin users. Further research to examine the risks and benefits of aspirin use in certain subgroups at risk of both thrombotic and hemorrhagic events is needed.

Hyperhomocysteinaemia

Homocysteine is a sulphur-containing amino acid that is derived primarily from protein of animal origin. Classical homocystinuria is an inherited metabolic disorder that arises from defects in either the re-methylation or trans-sulphuration pathways of homocysteine metabolism and leads to skeletal abnormalities, mental retardation and a high risk of vascular disease. In contrast, moderate hyperhomocysteinaemia is associated with an increased risk of both arterial and venous thrombotic disease but no other abnormalities. This increased risk appears to be independent of other conventional risk factors. Many cases of hyperhomocysteineaemia have been attributed to defects in the enzyme cystathionine-β-synthase (CBS) but this accounts for less than 1·5% of cases. A thermolabile variant of the enzyme methylenetetrahydrofolate reductase (MTHFR) arises from a C→T transition at nucleotide 677 in the MTHFR gene resulting in an alanine-to-valine substitution. While the mutation does not appear to be associated with an increased risk of vascular disease, it results in excessively high homocysteine levels in response to a low or low–normal serum folate. Supplementation of the diet with folate, B6and B12can reduce homocysteine levels and this is the mainstay of treatment. Supplementation of grain with folate is undertaken in the USA to reduce the risk of neural tube defects in pregnant women. However, by reducing plasma homocysteine levels, it is estimated that this will save up to 50000 lives per annum.

Prevalence of the mutation C677 --> T in the methylene tetrahydrofolate reductase gene among distinct ethnic groups in Brazil.

Vascular disease is a serious public health problem in the industrialized world, and is a frequent cause of death among the adult population of Brazil. Mild hyperhomocysteinemia has been identified as a risk factor for arterial disease, venous thrombosis, and neural tube defects. Individuals homozygous for the thermolabile variant of methylenetetrahydrofolate reductase (MTHFR-T) are found in 5-15% of the general population and have significantly elevated plasma homocysteine levels which represent one of the genetic risk factors for vascular diseases. We have analyzed the prevalence of individuals homozygous for the MTHFR-T in 327 subjects representing the three distinct ethnic groups in Brazil. The prevalence of homozygotes for the mutated allele MTHFR-T was high among persons of Caucasian descent (10%) and considerably lower among Black (1.45%) and Indians persons populations (1.2%). These data suggest that screening for the MTHFR-T allele should help in identifying individuals with a high risk of vascular disease among populations with a heterogeneous background.

Hyperhomocysteinemia and atherosclerotic vascular disease: pathophysiology, screening, and treatment. off.

Hyperhomocysteinemia has recently been identified as an important risk factor for atherosclerotic vascular disease. This article reviews homocysteine metabolism, causes of hyperhomocysteinemia, the pathophysiological findings of this disorder, and epidemiological studies of homocysteine and vascular disease. Screening for hyperhomocysteinemia should be considered for patients at high risk for vascular disease or abnormalities of homocysteine metabolism. For primary prevention of vascular disease, treatment of patients with homocysteine levels of 14 micromol/L or higher should be considered. For secondary prevention, treatment of patients with homocysteine levels of 11 micromol/L or higher should be considered. Treatment is most conveniently administered as a folic acid supplement (400-1000 microg) and a high-potency multivitamin that contains at least 400 microg of folate. Higher doses of folic acid and cyanocobalamin supplements may be required in some patients. Until prospective clinical trial data become available, these conservative recommendations provide a safe, effective, and evidence-based approach to the diagnosis, evaluation, and management of patients with hyperhomocysteinemia.

2.P.256 Comparison of Brazilian men and women at high risk of vascular disease

2.P.256 Comparison of Brazilian men and women at high risk of vascular disease

Homocysteine Metabolism in Endothelial Cells of a Patient Homozygous for Cystathionine β-synthase (CS) Deficiency

Homocystinuria due to cystathionine beta-synthase (CS) deficiency is the most common inborn error of methionine metabolism. Patients with CS-deficiency have an extremely high risk of vascular disease. The underlying mechanism is still unsolved. Dysfunction of endothelial cells could be the trigger in the formation of atherosclerosis and thrombosis. Therefore, differences in cell function were studied between normal and CS-deficient human umbilical endothelial cells (HUVECs). Total homocysteine (tHcy) concentrations in culture media as a measure of homocysteine export increased in all cell lines, including the cell line with CS-deficiency, with constant amounts of approximately 2.5 microM every 24 h. von Willebrand factor (vWF), tissue plasminogen activator (tPA) and plasminogen activator inhibitor (PAI-1) in culture media were used as markers of endothelial function and increased also with progression of culture time. The effects of additions of folate, vitamin B6 and methionine to the culture medium were studied. The homocysteine export and the markers of endothelial function did not differ between the control and the CS-deficient HUVECs under various test conditions. These data show that CS-deficient endothelial cells have normal homocysteine export and normal endothelial cell function. In CS-deficient patients the very high blood levels of homocysteine, probably due to deficient CS function in liver and kidney, seems to be the hazardous factor to endothelial cells, thus promoting atherosclerosis and thrombosis in CS-deficient patients.

Acute effects of smoking cessation on antioxidant status

Smokers have a lower antioxidant status than nonsmokers which may contribute to their higher risk of vascular disease. To determine if antioxidant status improves 84 hr after smoking cessation, nine middle-aged fasting male smokers were studied. Six stopped smoking after the first day while three maintained their usual smoking pattern as ascertained by blood carboxyhemoglobin measurements. After smoking cessation, significant increases were seen in total plasma vitamin C levels (mean ± SEM, 19 ± 7%; P < 0.05) and in low density lipoprotein (LDL) α- and β-carotene. No change after smoking cessation was detected in other parameters including plasma lipids, α-tocopherol, and copper-induced LDL oxidizability. However, there was a 34 ± 13% (P < 0.05) increase in plasma γ-tocopherol after smoking cessation explicable by increases in LDL and high density lipoprotein (HDL) γ-tocopherol. That this increase was related to smoking status was supported by the correlation between the rise in plasma γ-tocopherol and the selfreported daily cigarette consumption at entry into the study (r = 0.874, P = 0.016). Moreover, plasma γ-tocopherol levels were significantly lower at baseline in the smokers studied (n = 9) when compared with a matched group of nonsmokers (1.43 ± 0.19 vs. 2.87 ± 0.51 μM). These results point to a special relation between γ-tocopherol and smoking status and indicate that increases in plasma antioxidant vitamins can be detected very soon after the cessation of smoking.

Alcohol, hypertension and cardiovascular disease--implications for management.

Regular alcohol consumption raises blood pressure and in drinking populations contributes significantly to the prevalence of hypertension. The effect of alcohol is additive to that of obesity. Reduction in alcohol intake leads to a lowering of blood pressure over 1-4 weeks. Acute alcohol ingestion in the evening may lower blood pressures overnight. Heavy weekend drinking may lead to a pressor effect for the succeeding 3 to 4 days. Certain personality types or heavy job strain increase susceptibility to pressor effects of alcohol. Alcohol consumption in the range of 1-3 standard drinks a day appears to have a protective effect against coronary disease and ischaemic stroke, which may be greater in those with a higher risk of vascular disease. At higher levels of consumption the risks of haemorrhagic stroke, cardiomyopathy and hypertension deaths predominate. Moderation of alcohol consumption to no more than two standard drinks a day can be an effective means of improving blood pressure control reducing drug requirements in treated hypertensives, and avoiding drugs in mild hypertensives. Moderating alcohol and reducing excess weight have additive effects in reducing overall cardiovascular risk.