Killian Robinson

Hyperhomocysteinemia: an independent risk factor for vascular disease.

BACKGROUND Hyperhomocysteinemia arising from impaired methionine metabolism, probably usually due to a deficiency of cystathionine beta-synthase, is associated with premature cerebral, peripheral, and possibly coronary vascular disease. Both the strength of this association and its independence of other risk factors for cardiovascular disease are uncertain. We studied the extent to which the association could be explained by heterozygous cystathionine beta-synthase deficiency. METHODS We first established a diagnostic criterion for hyperhomocysteinemia by comparing peak serum levels of homocysteine after a standard methionine-loading test in 25 obligate heterozygotes with respect to cystathionine beta-synthase deficiency (whose children were known to be homozygous for homocystinuria due to this enzyme defect) with the levels in 27 unrelated age- and sex-matched normal subjects. A level of 24.0 mumol per liter or more was 92 percent sensitive and 100 percent specific in distinguishing the two groups. The peak serum homocysteine levels in these normal subjects were then compared with those in 123 patients whose vascular disease had been diagnosed before they were 55 years of age. RESULTS Hyperhomocysteinemia was detected in 16 of 38 patients with cerebrovascular disease (42 percent), 7 of 25 with peripheral vascular disease (28 percent), and 18 of 60 with coronary vascular disease (30 percent), but in none of the 27 normal subjects. After adjustment for the effects of conventional risk factors, the lower 95 percent confidence limit for the odds ratio for vascular disease among the patients with hyperhomocysteinemia, as compared with the normal subjects, was 3.2. The geometric-mean peak serum homocysteine level was 1.33 times higher in the patients with vascular disease than in the normal subjects (P = 0.002). The presence of cystathionine beta-synthase deficiency was confirmed in 18 of 23 patients with vascular disease who had hyperhomocysteinemia. CONCLUSIONS Hyperhomocysteinemia is an independent risk factor for vascular disease, including coronary disease, and in most instances is probably due to cystathionine beta-synthase deficiency.

Low Circulating Folate and Vitamin B6 Concentrations Risk Factors for Stroke, Peripheral Vascular Disease, and Coronary Artery Disease

BACKGROUND A high plasma homocysteine concentration is a risk factor for atherosclerosis, and circulating concentrations of homocysteine are related to levels of folate and vitamin B6. This study was performed to explore the interrelationships between homocysteine, B vitamins, and vascular diseases and to evaluate the role of these vitamins as risk factors for atherosclerosis. METHODS In a multicenter case-control study in Europe, 750 patients with documented vascular disease and 800 control subjects frequency-matched for age and sex were compared. Plasma levels of total homocysteine (before and after methionine loading) were determined, as were those of red cell folate, vitamin B12, and vitamin B6. RESULTS In a conditional logistic regression model, homocysteine concentrations greater than the 80th percentile for control subjects either fasting (12.1 micromol/L) or after a methionine load (38.0 micromol/L) were associated with an elevated risk of vascular disease independent of all traditional risk factors. In addition, concentrations of red cell folate below the lowest 10th percentile (<513 nmol/L) and concentrations of vitamin B6 below the lowest 20th percentile (<23.3 nmol/L) for control subjects were also associated with increased risk. This risk was independent of conventional risk factors and for folate was explained in part by increased homocysteine levels. In contrast, the relationship between vitamin B6 and atherosclerosis was independent of homocysteine levels both before and after methionine loading. CONCLUSIONS Lower levels of folate and vitamin B6 confer an increased risk of atherosclerosis. Clinical trials are now required to evaluate the effect of treatment with these vitamins in the primary and secondary prevention of vascular diseases.

Homocysteine and coronary atherosclerosis

Homocysteine is increasingly recognized as a risk factor for coronary artery disease. An understanding of its metabolism and of the importance of vitamins B6 and B12 and folate as well as enzyme levels in its regulation will aid the development of therapeutic strategies that, by lowering circulating concentrations, may also lower risk. Possible mechanisms by which elevated homocysteine levels lead to the development and progression of vascular disease include effects on platelets, clotting factors and endothelium. This review presents the clinical and basic scientific evidence supporting the risk and mechanisms of vascular disease associated with elevated homocysteine concentrations as well as the results of preliminary therapeutic trials.

Prospective Study of Hyperhomocysteinemia as an Adverse Cardiovascular Risk Factor in End-Stage Renal Disease

BACKGROUND Retrospective and case-control studies show that hyperhomocysteinemia is an independent risk factor for atherosclerosis in patients with end-stage renal disease. We studied prospectively the association between total homocysteine and cardiovascular outcomes. METHODS AND RESULTS In all, 167 patients (93 men, 74 women; mean age, 56.3+/-14.7 years) were followed for a mean duration of 17.4+/-6.4 months. Cardiovascular events and causes of mortality were related to total homocysteine values and other cardiovascular risk factors. Cox regression analysis was used to identify the independent predictors for cardiovascular events and mortality. Fifty-five patients (33%) developed cardiovascular events and 31 (19%) died, 12 (8%) of cardiovascular causes. Total plasma homocysteine values ranged between 7.9 and 315.0 micromol/L. Levels were higher in patients who had cardiovascular events or died of cardiovascular causes (43.0+/-48.6 versus 26.9+/-14.9 micromol/L, P=.02). The relative risk (RR) for cardiovascular events, including death, increased 1% per micromol/L increase in total homocysteine concentration (RR, 1.01; CI, 1.00 to 1.01; P=.01). CONCLUSIONS These prospective observations confirm that hyperhomocysteinemia is an independent risk factor for cardiovascular morbidity and mortality in end-stage renal disease, with an increased RR of 1% per micromol/L increase in total homocysteine concentration. Interventional studies are needed to evaluate the possible effects of modifying this risk factor in these patients.

Hyperhomocysteinemia confers an independent increased risk of atherosclerosis in end-stage renal disease and is closely linked to plasma folate and pyridoxine concentrations

BACKGROUND A high level of total plasma homocysteine is a risk factor for atherosclerosis, which is an important cause of death in renal failure. We evaluated the role of this as a risk factor for vascular complications of end-stage renal disease. METHODS AND RESULTS Total fasting plasma homocysteine and other risk factors were documented in 176 dialysis patients (97 men, 79 women; mean age, 56.3 +/- 14.8 years). Folate, vitamin B12, and pyridoxal phosphate concentrations were also determined. The prevalence of high total homocysteine values was determined by comparison with a normal reference population, and the risk of associated vascular complications was estimated by multiple logistic regression. Total homocysteine concentration was higher in patients than in the normal population (26.6 +/- 1.5 versus 10.1 +/- 1.7 mumol/L; P < .01). Abnormally high concentrations (> 95th percentile for control subjects, 16.3 mumol/L) were seen in 149 patients (85%) with end-stage renal disease (P < .001). Patients with a homocysteine concentration in the upper two quintiles (> 27.8 mumol/L) had an independent odds ratio of 2.9 (CI, 1.4 to 5.8; P = .007) of vascular complications. B vitamin levels were lower in patients with vascular complications than in those without. Vitamin B6 deficiency was more frequent in patients than in the normal reference population (18% versus 2%; P < .01). CONCLUSIONS A high total plasma homocysteine concentration is an independent risk factor for atherosclerotic complications of end-stage renal disease. Such patients may benefit from higher doses of B vitamins than those currently recommended.

AHA Dietary Guidelines Revision 2000: A Statement for Healthcare Professionals From the Nutrition Committee of the American Heart Association

This document presents guidelines for reducing the risk of cardiovascular disease by dietary and other lifestyle practices. Since the previous publication of these guidelines by the American Heart Association,1 the overall approach has been modified to emphasize their relation to specific goals that the AHA considers of greatest importance for lowering the risk of heart disease and stroke. The revised guidelines place increased emphasis on foods and an overall eating pattern and the need for all Americans to achieve and maintain a healthy body weight (Table⇓). View this table: Table 1. Summary of Dietary Guidelines The major guidelines are designed for the general population and collectively replace the “Step 1” designation used for earlier AHA population-wide dietary recommendations. More individualized approaches involving medical nutrition therapy for specific subgroups (for example, those with lipid disorders, diabetes, and preexisting cardiovascular disease) replace the previous “Step 2” diet for higher-risk individuals. The major emphasis for weight management should be on avoidance of excess total energy intake and a regular pattern of physical activity. Fat intake of ≤30% of total energy is recommended to assist in limiting consumption of total energy as well as saturated fat. The guidelines continue to advocate a population-wide limitation of dietary saturated fat to <10% of energy and cholesterol to <300 mg/d. Specific intakes for individuals should be based on cholesterol and lipoprotein levels and the presence of existing heart disease, diabetes, and other risk factors. Because of increased evidence for the cardiovascular benefits of fish (particularly fatty fish), consumption of at least 2 fish servings per week is now recommended. Finally, recent studies support a major benefit on blood pressure of consuming vegetables, fruits, and low-fat dairy products, as well as limiting salt intake (<6 grams per day) and alcohol (no more than 2 drinks per day for men and …

Natural history of isolated bundle branch block

The purpose of this study was to determine the long-term outcome of patients with bundle branch block (BBB) who have no clinical evidence of cardiovascular disease. Among 110,000 participants in a screening program, 310 subjects with BBB without apparent of suspected heart disease were identified. Their outcome after a mean follow-up of 9.5 years was compared with that of 310 similarly screened age- and sex-matched controls. Among the screened population, isolated right BBB was more prevalent than isolated left BBB (0.18% vs 0.1%, respectively; p<0.001), and the prevalence of each abnormality increased with age (p<0.001). Total actuarial survival was no different for those with left BBB or right BBB and their respective controls. Cardiac mortality, however, was increased in the left BBB group when compared with their controls (p=0.01, log rank test). Left BBB, but not right BBB, was associated with an increased prevalence of cardiovascular disease at the follow-up (21% vs 11%; p=0.04). In the absence of clinically overt cardiac disease, the presence of left BBB or right BB is not associated with increased overall mortality. Isolated left BBB is associated with an increased risk of developing overt cardiovascular disease and increased cardiac mortality.

Occult and Frequent Transmission of Atherosclerotic Coronary Disease With Cardiac Transplantation Insights From Intravascular Ultrasound

BACKGROUND Transplant coronary artery disease is a major cause of morbidity and mortality after cardiac transplantation. However, limited data exist regarding the potential contribution of coronary atherosclerosis in the donor heart to cardiac-allograft vasculopathy. METHODS AND RESULTS We performed quantitative coronary angiography and intravascular ultrasound imaging in 50 of 62 consecutive heart-transplant recipients (40 men, 10 women, mean age, 53 +/- 9 years) 4.6 +/- 2.6 weeks after transplantation. The donor population consisted of 30 men and 20 women (mean age, 32 +/- 12 years). Ultrasound imaging visualized all three coronary arteries in 22 patients, two coronary arteries in 23, and one coronary artery in 5. Ultrasound imaging detected coronary atherosclerosis (intimal thickness > or = 0.5 mm) in 28 patients (56%). However, the angiography was abnormal in only 13 patients (26%). The sensitivity and specificity of coronary angiography were 43% and 95%, respectively. With ultrasound, the average atherosclerotic plaque thickness was 1.3 +/- 0.6 mm and the cross-sectional area narrowing was 34 +/- 16%. Atherosclerotic involvement frequently was focal (85%), eccentric (mean eccentricity index, 87 +/- 8), and near arterial bifurcations. Donors of the transplant recipients with coronary atherosclerosis were older than those without atherosclerosis (37 +/- 12 versus 25 +/- 10 years, P = .001). Maximal intimal thickness correlated with donor age (r = .54, P = .0001). Multivariate analysis demonstrated that donor age (P = .0001), male sex of donor (P = .0006), and recipient age (P = .03) were independent predictors of atherosclerosis. CONCLUSIONS Coronary atherosclerosis is frequently but inadvertently transmitted by means of cardiac transplantation from the donor to the recipient. Long-term outcomes of donor-transmitted coronary artery disease will require further evaluation.

Reduction of homocysteine levels in coronary artery disease by low-dose folic acid combined with vitamins B6 and B12 ☆

An increased plasma homocysteine concentration is a risk factor for atherosclerosis. Folic acid lowers homocysteine but the optimal dose in patients with coronary artery disease (CAD) is unclear. This placebo-controlled, single-blind, dose-ranging study evaluates the effect of low-dose folic acid on homocysteine levels in 95 patients aged 61 +/- 11 years (mean +/- SD) with documented CAD. Patients in each group were given either placebo or 1 of 3 daily supplements of folic acid (400 microg, 1 mg, or 5 mg) for 3 months. Each active treatment arm also received 500 microg vitamin B12 and 12.5 mg vitamin B6. Total plasma homocysteine levels were measured after 30 and 90 days. Folic acid 400 microg reduced homocysteine levels from 13.8 +/- 8.8 to 9.6 +/- 2.0 micromol/L at 90 days (p = 0.001). On 1- and 5-mg folic acid, levels decreased from 13.0 +/- 6.4 to 9.8 +/- 4.0 micromol/L (p = 0.001) and from 14.8 +/- 6.9 to 9.7 +/- 3.3 micromol/L (p < 0.001), respectively. The decrease was similar in all treatment groups. There was no significant change with placebo. Although the sample size is small, these findings suggest that daily administration of 400 microg/day folic acid combined with vitamin B12 and vitamin B6 may be equivalent to higher doses in reducing homocysteine levels in patients with CAD.

High homocysteine, low folate, and low vitamin B6 concentrations: prevalent risk factors for vascular disease in heart transplant recipients.

BACKGROUND A high plasma homocysteine concentration is a risk factor for atherosclerosis and thrombosis, which are major causes of morbidity and mortality in heart transplant patients. High homocysteine concentrations may be caused by lower folate and vitamin B6 levels. We hypothesized that these patients might have high homocysteine concentrations and low levels of folate and vitamin B6, which could contribute to the development of vascular complications. METHODS Total fasting plasma homocysteine was measured in 189 cardiac transplant recipients and in healthy controls, as were concentrations of folate, vitamin B12, vitamin B6, and creatinine. RESULTS Homocysteine concentrations were higher in recipients than controls (19.1+/-13.0 vs. 11.0+/-3.0 micromol/L, P<0.01), and hyperhomocysteinemia (>90th percentile for controls, 14.6 micromol/L) was seen in 68% of recipients (P<0.01). Folate and vitamin B6 concentrations were lower (5.9+/-4.2 vs. 7.9+/-4.2 pmol/L and 40+/-25 vs. 84+/-77 nmol/L, respectively; P<0.01 for both). Folate and vitamin B6 deficiencies were seen in 10.8% and 17.91% of recipients, respectively (P<0.01). Hyperhomocysteinemia was more frequent in patients with vascular complications after transplantation than in those without (79.2% vs. 63.8%, P<0.05). CONCLUSIONS Elevated plasma homocysteine and deficiencies of folate and vitamin B6 are common in transplant recipients. A high homocysteine concentration was more common in patients with vascular complications. Prospective studies are now required to evaluate the role of these abnormalities as risk factors for the atherothrombotic complications of transplantation.