Homocysteine levels in patients with risk factors for atherosclerosis

BACKGROUND: Abundant epidemiological evidence has demonstrated that the presence of mild to moderate hyperhomocysteinemia is an independent risk factor for atherosclerosis in the coronary, cerebral, and peripheral vasculature, and for vascular disease, including coronary disease. It has been demonstrated that plasma total homocysteine level is a strong predictor of mortality in patients with angiographically confirmed coronary artery disease. HYPOTHESIS: The study was undertaken to determine the extent of homocysteine levels in patients without documented coronary artery disease, but with at least one risk factor for atherosclerosis. METHODS: Fasting blood samples were collected prospectively from 160 consecutive patients (50 women and 110 men, mean age 65+/-7 years) who had at least one risk factor for atherosclerosis, but had no documented coronary artery disease. Homocysteine levels were measured by an immunoassay method. RESULTS: Of the patients studied, 78 (48.75%) with at least one risk factor for atherosclerosis had high homocysteine levels; 62 patients had mild hyperhomocysteinemia (15-30 micromol/l); and 16 patients had moderate hyperhomocysteinemia (30-100 micromol/l). CONCLUSIONS: Our data suggest that hyperhomocysteinemia is highly prevalent in patients with risk factors for atherosclerosis. Homocysteine level (an independent convertible risk factor to atherosclerosis) should be measured routinely in patients with risk factors for atherosclerosis and treated appropriately.     

Homocysteine, a risk factor for cardiovascular disease

Fasting hyperhomocysteinemia is an independent risk factor for coronary artery disease, stroke, peripheral vascular atherosclerosis, and for arterial and venous thromboembolism. The risk for cardiovascular disease with homocysteine is similar to conventional risk factors. The interaction of hyperhomocysteinemia with hypertension and smoking is strong and the combined effect is more than multiplicative. The combined effect of homocysteine and cholesterol is additive. Homocysteine produces atherosclerosis, thromboembolism, and vascular endothelial cell injury. Vascular dysfunction produced by homocysteine may be due to endothelial cell damage. Homocysteinemia-induced atherosclerosis is probably due to various factors including endothelial cell injury, inability to sustain S-nitroso-homocysteine formation because of imbalance between production of nitric oxide by dysfunctional endothelium and homocysteine, smooth muscle cell proliferation, and thromboembolism. There is strong evidence that endothelial cell injury is associated with oxidative stress produced by homocysteine. Hyperhomocysteinemia is associated with numerous conditions, including coronary disease, stroke, peripheral vascular disease (carotid artery and cerebrovascular atherosclerosis), venous thrombosis, renal disease, diabetes mellitus, and organ transplant. Folic acid, vitamin B₁₂ and B₆ have been shown to be beneficial in reducing plasma homocysteine levels. Folic acid is specifically very effective, safe and inexpensive.     

Absence of association between serum homocysteine levels and coronary artery disease in south Indian males.

BACKGROUND: Asian Indians are reported to have a very high prevalence of premature coronary artery disease. However, traditional risk factors do not explain this excess of coronary artery disease. Elevated levels of homocysteine are reported to be associated with coronary artery disease among Europeans. This study looked at the association of serum homocysteine levels with coronary artery disease in South Indians. METHODS AND RESULTS: Four groups of patients were studied: Group 1 consisted of healthy nondiabetic subjects without coronary artery disease (n=18): Group 2 consisted of nondiabetic subjects with coronary artery disease (n=21); Group 3 consisted of type 2 diabetic patients without coronary artery disease (n=18) and Group 4 consisted of type 2 diabetic patients with coronary artery disease (n=20). The mean homocysteine value was 12.4+/-3.4 micromol/L in Group 1; 12.6+/-4.6 micromol/L in Group 2; 10.1+/-4.4 micromol/L in Group 3; and 10.4+/-3.9 micromol/ L in Group 4. There was no significant difference in the homocysteine levels between the groups studied. The prevalence of hyperhomocysteinemia, defined as a level of 17.1 micromol/L (the 95th percentile for serum homocysteine in the control group) was not significantly different among the groups. CONCLUSIONS: Elevated serum homocysteine levels are not associated with coronary artery disease in South Indian male subjects with or without diabetes. However, the results must be interpreted with caution because of the small numbers studied.     

The graded effect of hyperhomocysteinemia on the severity and extent of coronary atherosclerosis

It is not clear to what extent methylenetetrahydrofolate reductase (MTHFR) gene and hyperhomocysteinemia effect the severity and extent of coronary atherosclerosis in Asian populations. We examined the MTHFR genotypes and plasma homocysteine (HCY) concentrations in 192 Taiwanese and investigated their relationship with coronary artery disease (CAD), and the severity and extent of coronary atherosclerosis. The distribution of MTHFR genotypes was similar in 116 CAD patients and 76 non-CAD subjects. Homozygosity was noted in 8% of CAD patients and 13% of non-CAD subjects (P=0.33; 95% CI, 0. 2-1.6). The geometric mean of HCY values was higher in CAD patients (11.10+/-1.51 micromol/l) than in non-CAD subjects (9.21+/-1.55 micromol/l) (P=0.003). HCY levels were higher in patients with multi-vessel disease (P<0.05) or in patients with > or = 90% stenotic lesions (P=0.005), compared with non-CAD subjects. The CAD risks in the top two HCY quartiles (> or = 14.0 and 10.1-13.9 micromol/l) were 4.0 (95% CI, 1.7-9.2) and 3.2 (95% CI, 1.4-7.4) times higher than in the lowest quartile (< or = 7.9 micromol/l) (P=0.001 and 0.007, respectively). Linear regression analysis showed significant correlations between HCY concentrations and the severity and extent of atherosclerosis (P=0.0001 for both). In conclusion, hyperhomocysteinemia appears to have a graded effect on the risk of CAD as well as the severity and extent of coronary atherosclerosis. Our findings do not support the homozygous genotype of MTHFR as a genetic risk factor for CAD in this Taiwanese population. Perhaps a further study including assessment of vitamin status is needed to better clarify the relationship between MTHFR genotypes and CAD.     

Methylene tetrahydrofolate reductase genotype and the risk and extent of coronary artery disease in a population with low plasma folate

OBJECTIVE: To determine the effects of the thermolabile methylene tetrahydrofolate reductase (MTHFR) mutation on the presence and extent of coronary atherosclerosis in a population with low plasma folate. METHODS: 242 consecutive patients undergoing coronary angiography were prospectively evaluated for conventional risk factors, plasma homocysteine, vitamin B-12, and folate, and MTHFR genotype. The severity of coronary atherosclerosis was determined by the Leaman score. RESULTS: Mean (SD) plasma homocysteine was 15.6 (10) micromol/l in controls and 18.5 (11) micromol/l in patients with coronary artery disease (p > 0.05). Plasma homocysteine concentrations above 15 micromol/l were a risk factor for coronary artery disease (p = 0.03, risk ratio 2.1, 95% confidence interval (CI) 1.07 to 4.4). Homocysteine remained an independent risk factor on multivariate analysis when conventional risk factors were taken into account (p = 0.04). Homocysteine concentrations above 15 micromol/l were correlated with the extent of atherosclerosis (p = 0. 04, risk ratio 3.2, 95% CI 1.3 to 8.2). Homocysteine had no effect on other lipid variables (p > 0.05). Plasma folate was 15.8 (7.2) nmol/l in controls and 11.5 (2.9) nmol/l in patients with coronary artery disease. Plasma folate concentrations below 12.9 nmol/l (5.7 ng/ml) conferred a risk for coronary artery disease (p = 0.03, risk ratio 2.42, 95% CI 1.05 to 5.59). When the MTHFR genotype was determined, the TT genotype was present in 7.4% of patients and 5.2% of controls (p > 0.05). The prevalence of alleles was within the Hardy-Weinberg equilibrium (TT 7, CT 40, CC 53, chi2 = 2.3, p = 0.3). The highest homocysteine concentrations were found in patients with the TT genotype and folate below the median of the population (p = 0. 01). The extent of coronary atherosclerosis judged by the Leaman score was significantly higher in patients with the TT genotype (p = 0.03). CONCLUSIONS: Plasma homocysteine over 15 micromol/l was a significant risk factor for the presence and extent of coronary artery disease. The mean plasma folate of the population was low and correlated negatively with homocysteine. Although TT genotype was not an independent predictor of coronary artery disease, it was an important predictor of the extent of coronary atherosclerosis and plasma homocysteine, especially in the presence of plasma folate values below the median of the population. These findings may have important implications for folate replacement in patients with the TT genotype.     

Plasma homocysteine levels and the left ventricular systolic function in coronary artery disease patients

BACKGROUND: Numerous studies have shown a relationship between hyperhomocysteinemia, atherothrombosis and cardiovascular mortality. However, an association between hyperhomocysteinemia and the extent of coronary artery disease (CAD) remains controversial whereas its relationship with left ventricular systolic function has not been established. METHODS: One hundred and fifty-seven patients with angiographically defined CAD were included. The relationships between hyperhomocysteinemia, severity of CAD and left ventricular systolic function were studied. Left ventricular systolic function was determined primarily by ventriculography. The severity of CAD was determined through coronary angiography using the Gensini score and the number of vessels with > or = 50% stenosis. RESULTS: The mean fasting plasma homocysteine level was 13.4 mumol/l+/-0.5 SE. Elevated levels of homocysteine correlated significantly with increased severity of CAD both by the Gensini scores (r-value = 0.344, P < 0.0005) and the total number of diseased vessels (r-value = 0.387, P < 0.0005). The patients with hyperhomocysteinemia were found to have significantly reduced left ventricular ejection fraction (r-value = -0.382, P < 0.0005). A multivariate regression analysis revealed homocysteine level to be an independent predictor of left ventricular systolic function. In addition, adjusted analysis revealed hyperhomocysteinemia to be associated with global left ventricular dysfunction. CONCLUSION: In patients with CAD, homocysteine levels correlate independently with left ventricular systolic function. The mechanism of this association between homocysteine and left ventricular systolic function is unknown but may be due to a direct effect of homocysteine on myocardial function separate from its effects on coronary atherosclerosis.     

Homocysteine: Role and implications in atherosclerosis

Hyperhomocysteinemia promotes atherosclerosis and is most commonly caused by B-vitamin deficiencies, especially folic acid, B₆, and B₁₂; genetic disorders; certain drugs; and renal impairment. Elevated homocysteine promotes atherosclerosis through increased oxidant stress, impaired endothelial function, and induction of thrombosis. Prospective studies have shown that elevated plasma homocysteine concentrations increase risk of cardiovascular disease by twofold and risk of cerebrovascular disease to a lesser degree. Hyperhomocysteinemia should be identified in patients with progressive or unexplained atherosclerosis and treated appropriately. Treatment of hyperhomocysteinemia is primarily through vitamin supplementation; folic acid and vitamins B₆ and B₁₂ are the mainstay of therapy. Betaine and 5-methyl tetrahydrofolate are also effective in lowering homocysteine levels. Treatment of moderately elevated plasma homocysteine in patients without atherosclerosis should be deferred until the completion of randomized outcome trials.     

Plasma homocysteine level and the angiographic extent of coronary artery disease

Recent epidemiologic studies have shown that moderately elevated plasma homocysteine concentrations are associated with an increased risk for the development of atherosclerotic cardiovascular diseases. But, it is not known whether moderate hyperhomocysteinemia is associated with the angiographic extent of atherosclerotic cardiovascular disease in patients with coronary artery disease (CAD). A possible relationship was investigated between admission plasma homocysteine level and the angiographic extent of coronary artery disease in patients with CAD. In this study, 156 consecutive patients presenting with coronary artery disease (group 1) and control group (group 2) of 35 age-matched persons with normal coronary angiography were enrolled. Blood samples for homocysteine were obtained on admission. Plasma homocysteine concentration was measured with high-performance liquid chromatography with fluorescence detection. Radiographs from coronary angiography were viewed and scored using Sullivan's method to assess the atherosclerotic involvement of coronary artery disease. There were significant elevations in homocysteine level in group 1 compared to group 2 (15.59 +/-5.7 micromol/L, 9.24 +/-1.50 micromol/L; respectively, p < 0.001). All scores (demonstrated angiographic extension of CAD) correlated significantly with plasma homocysteine levels; however, the Sullivan's extent score correlated more closely (r = 0.68, p < 0.001) than both the stenosis score (r = 0.44, p < 0.01) and vessel score (r = 0.35, p < 0.05). Elevated homocysteine levels in patients with coronary artery disease correlated with the angiographic extent of atherosclerotic disease.     

Plasma homocysteine and the extent of atherosclerosis in patients with coronary artery disease

Homocysteine is a graded risk factor for the incidence of stroke and for the degree of carotid atherosclerosis. Homocysteine is also a graded risk factor for the incidence of myocardial infarction but we do not know its precise relations to the severity of atherosclerosis in coronary patients. Seventy five symptomatic coronary patients were recruited for the study. Fifty of these patients had coronary artery disease only and were compared in a case-control manner to 50 healthy controls matched for age and sex. The 25 other coronary patients had also symptoms in another atherosclerotic territory (cerebral, peripheral or both) and were also compared to 25 matched controls. Mean plasma homocysteine level was significantly higher in coronary patients than in controls (11.7±0.7μmol l⁻¹, n=50 versus 9.9±0.5μmol l⁻¹, n=50, p<0.05). Homocysteine in patients with symptomatic atherosclerosis in two or three arterial sites was 15.7±1.5μmol l⁻¹ which differed significantly from matched controls and from patients with coronary artery disease only (p=0.01). The extent of coronary atherosclerosis evaluated by an angiographic coronary score correlated weakly to plasma homocysteine levels (r=0.25, p<0.05). The patients with both hypertension and high levels of homocysteine (>11.3μmol l⁻¹, median value) had more severe coronary atherosclerosis (coronary score of 16.3±2.3 versus 11.9±0.9, p<0.05) and more diffuse atherosclerosis (number of atherosclerotic territories of 1.5±0.2 versus 1.2±0.7, p=0.08) than the coronary patients without this association. There were no other high risk association when considering the other classical risk factors.

Thus, the highest levels of homocysteine were present in patients with coronary disease and another symptomatic localisation of atherosclerosis. A small gradient in the extent of coronary atherosclerosis was found with increasing levels of homocysteine. The presence of both hypertension and hyperhomocysteinemia was associated with more severe coronary atherosclerosis.     

Homocysteine: A new cardiac risk factor?

Elevated plasma homocysteine levels have recently been implicated as a new risk factor for coronary artery disease. In this article, homocysteine metabolism, secondary causes of elevated plasma homocysteine, and the potential mechanism of vascular damage in hyperhomocysteinemia are briefly reviewed. The current clinical evidence implicating hyperhomocysteinemia as a risk factor for coronary artery disease, as well as the data regarding the effects of B vitamin supplementation on homocysteine concentrations, are also reviewed. The current recommendation of the authors is to treat patients with known coronary artery disease or those who are considered to be at high risk for coronary artery disease with 400 microg of folate supplementation. Until prospective clinical trial data become available, this approach appears to be a safe and effective way to approach this patient population.     

The association of homocysteine and coronary artery disease

Hyperhomocysteinemia has been associated with increased risk of atherosclerosis and myocardial infarction by a number of prospective case-control studies. A variety of genetic mutations, nutritional deficiencies, disease states, and drugs can elevate homocysteine concentrations. Treatment with folic acid with or without B-complex vitamins effectively lowers homocysteine levels. Whether therapy corresponds with decreased risk of coronary events is unknown, but may be promising. This article reviews the biochemistry of homocysteine metabolism, pathogeneisis, and etiology of hyperhomocysteinemia, along with its association with coronary artery disease, screening, and treatment.     

Borderline peripheral arterial disease

Peripheral arterial disease (PAD), along with coronary artery disease and cerebrovascular disease, is a manifestation of systemic atherosclerosis. These cardiovascular diseases (CVDs) are the leading cause of death in the world, representing 30% of all global deaths. Although population-based studies indicate that PAD has a relatively benign course in the legs, patients with PAD show more cardiovascular comorbidity and have at least twofold risk of fatal coronary artery disease and cerebrovascular accidents compared with the general population. These studies suggest that noninvasive testing using the ankle-brachial index (ABI) is also an accurate marker of subclinical CVD and thus may hold promise for early identification of individuals at the greatest risk for major CVD events.The Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II) defines a cutoff ABI value of 0.90 or less for diagnosing PAD at rest. This threshold value has been reported to be 95% sensitive in detecting angiogram-positive PAD and almost 100% specific in identifying apparently healthy individuals. In persons without PAD, arterial pressures increase with greater distance from the heart, resulting in higher systolic blood pressures at the ankle than at the the brachial arteries. Thus, persons without atherosclerosis typically have an ABI greater than 1.00. But what is the significance of ABI values between 0.91 to 1.00, which are conventionally regarded as ‘no disease’? The present article gives an overview of current knowledge of borderline PAD (ie, an ABI of 0.91 to 1.00).     

Plasma homocysteine levels in patients with isolated coronary artery ectasia

OBJECTIVE: Hyperhomocysteinemia is recognized as an independent risk factor for arterial disease including coronary artery disease, cerebrovascular disease and peripheral vascular disease. Previously, an association between increased plasma homocysteine level and peripheral arterial aneurysms has been reported. However, the relationship between coronary artery ectasia (CAE) and plasma homocysteine level has not been investigated. Accordingly, this study was designed to investigate plasma homocysteine level in patients with isolated CAE. METHODS: Thirty-two patients with isolated CAE without significant stenosis and 30 control subjects with angiographically normal coronary arteries were included in this study. Fasting plasma homocysteine concentrations were measured by Fluorescence Polarization Immunoassay method using homocysteine kids. Hyperhomocysteinemia is defined as plasma homocysteine levels above the 95th percentile of the control subjects (13.6 mumol/l). RESULTS: According to the definition of hyperhomocysteinemia, 19 (59%) of patients with isolated CAE had elevated levels of plasma homocysteine compared to 2 (7%) in the control subjects with angiographically normal coronary arteries (p<0.001). In addition, patients with isolated CAE had significantly higher levels of plasma homocysteine compared to control subjects (14.9+/-4.5 micromol/l vs. 8.6+/-1.9 micromol/l respectively, p<0.001). Besides, we detected a significant positive correlation between the number of ectasic segment and plasma homocysteine level (r=0.537, p=0.002). CONCLUSION: We have shown for the first time an association between elevated plasma homocysteine level and isolated CAE. Larger prospective studies are needed to confirm the role of hyperhomocysteinemia in CAE and to evaluate the usefulness of homocysteine-lowering therapies.     

Elevated plasma homocysteine levels in patients with isolated coronary artery ectasia

OBJECTIVE: Coronary artery ectasia is a variant of coronary atherosclerosis. Hyperhomocysteinemia has emerged as a major, independent risk factor for cardiovascular diseases. The purposes of this study were to determine plasma hyperhomocysteine levels in patients with coronary artery ectasia, and to compare patients with coronary artery ectasia, coronary artery disease, and controls with normal coronary angiogram. METHOD: The study population included 37 patients with coronary artery ectasia and 36 patients with coronary artery disease. The control group consisted of 32 patients with angiographically proven normal coronary arteries. Plasma hyperhomocysteine levels were measured in all study patients with an enzyme-linked immunosorbent assay. RESULTS: Plasma homocysteine levels were significantly higher in patients with both coronary artery ectasia and coronary artery disease than in the controls (14.8+/-1.1 and 15.9+/-0.8 vs. 2.5+/-0.6 micromol/l; P<0.001 and P<0.001, respectively). No significant differences in plasma homocysteine levels were found among CAE and CAD groups (P>0.05). CONCLUSIONS: We have demonstrated that patients with coronary artery ectasia and coronary artery disease have increased plasma hyperhomocysteine levels compared with the controls. These findings suggest that hyperhomocysteinemia may play an important role in the pathogenesis of coronary artery ectasia as in coronary artery disease.     

Vascular multimorbidity in patients with a documented coronary artery disease

Atherosclerotic artery disease is a systemic vascular disorder typically involving multiple vascular territories in the same patient. To assess the prevalence and the topographic distribution of non-coronary peripheral artery disease (PAD), cerebrovascular (CVD) and renal artery disease (RAD) in patients with an angiographically confirmed coronary artery disease (CAD) a cross-sectional survey among inpatients admitted for symptoms of CAD was performed. The relationship between CAD and multiterritory vascular disease, and the major risk factors were also assessed. A total of 1855 consecutive patients, mean age 65 +/- 10.6 years (18-92 years), 1184 (63.8%) men and 671 (36.2%) women with an angiographically confirmed CAD were studied. The patients were divided into four age groups: group A < 35 years of age, group B 35 to 54 years, group C 55 to 74 years and group D > or =75 years of age. While 1265 (68.2%) had no evidence of a relevant non-coronary artery disease, in 590 (31.8%) a significant non-coronary artery disease in at least one additional major vascular territory was documented. CAD was most frequently associated with PAD in n = 176 (9.5%) patients. In 22 (1.2%), all four studied vascular territories were significantly diseased. The prevalence of the multi-territory artery disease increased with age: lowest in group A and highest in the group D. However, the data analysis by gender revealed the highest prevalence of CAD associated with PAD and RAD, respectively, in women 35 to 54 years of age. Using the multivariant logistic regression model, type II diabetes was the only major risk factor for a multi-territory expression of atherosclerosis.     

Revisiting the frequency of peripheral arterial disease in patients with coronary artery disease: is there a difference between diabetic and non-diabetic patients?

BACKGROUND: The aim of this study was to investigate whether frequency of concomitant peripheral arterial disease (PAD) is associated with angiographic severity of coronary artery disease (CAD), as well as to ascertain if diabetic patients differ from those without diabetes in the association between these two manifestations of atherosclerosis. PATIENTS AND METHODS: This study included 302 patients (229 men, mean age 62.2 +/- 11.5 years) with documented CAD, divided into groups I-III, according to the angiographic severity of coronary atherosclerosis. Group I comprised 140 patients (104 men) with severe CAD, group II comprised 63 patients (48 men) with moderate CAD and group III comprised 99 patients (77 men) with mild CAD. Each of the groups I-III was further divided into the subgroups of diabetic and non-diabetic patients. Included were also 88 patients (42 men, mean age 61.7 +/- 9.5 years) without CAD and a control group of 60 healthy volunteers (30 men), aged 18-40 years. PAD was diagnosed by means of a Doppler apparatus. RESULTS: Frequency of PAD was associated with angiographic severity of CAD (p = 0.0001). This association was shown both in diabetic (p = 0.012) and in non-diabetic patients (p = 0.0041). Significantly (p < or = 0.01) higher frequency of PAD among diabetic patients was found in each of the groups I-III. CONCLUSIONS: Among patients with CAD, frequency of concomitant PAD is associated with angiographic severity of coronary atherosclerosis. This association is demonstrated both in diabetic and in non-diabetic patients. Finally, PAD is significantly more frequent in diabetic patients, irrespective of the angiographic severity of CAD.     

Carotid intima-media thickness and brachial-ankle pulse wave velocity in patients with and without coronary artery disease

BACKGROUND: Carotid intima-media thickness and pulse wave velocity are non-invasive markers of atherosclerosis and have been shown to reliably predict presence and extent of atherosclerotic vascular disease. However, studies examining their association with each other have shown inconsistent results. Hence it was sought to assess correlation between carotid intima-media thickness and pulse wave velocity in patients with and without coronary artery disease. METHODS AND RESULTS: Sixty-four patients with angiographically proven coronary artery disease and 84 age-matched individuals without coronary artery disease but having one or more conventional cardiovascular risk factors were included in the study. Individuals with established cerebrovascular disease and peripheral vascular disease were excluded from the study. Carotid intima-media thickness of far wall was measured at three predefined sites (distal common carotid, carotid bifurcation and proximal internal carotid artery) on each side. Brachial-ankle pulse wave velocity was measured non-invasively using VP 1000 (Colin Corporation) automated ABI/ PWV analyzer. There was no significant difference in gender and presence of cardiovascular risk factors in the two groups. Mean and maximum carotid intima-media thickness and brachial-ankle pulse wave velocity were all significantly higher in coronary artery disease patients as compared to patients without coronary artery disease (0.842 v. ( 0.657 mm, p <0.0001; 1.076 v. 0.795 mm, p <0.0001; 1708.63 v. 1547.26 cm/s, p <0.0004 respectively). There was a significant correlation between brachial-ankle pulse wave velocity and both mean and maximum carotid intima-media thickness in patients with coronary artery disease (r = 0.47, p <0.0001 and r=0.41, p < 0.0008 respectively) but not in individuals without coronary artery disease (r=0.01 and -0.1 respectively). CONCLUSIONS: Presence of significant correlation between carotid intima-media thickness and brachial-ankle pulse wave velocity in patients with coronary artery disease but absence of the same in individuals without major atherosclerotic vascular disease suggests that the correlation between carotid intima-media thickness and brachial-ankle pulse wave velocity becomes stronger with increasing extent of atherosclerosis.     

Total serum homocysteine--a predictor of extracranial carotid artery stenosis in male patients with symptomatic peripheral arterial disease.

High total serum homocysteine (tHcy) concentrations are associated with an increased risk of carotid artery disease in the general population. Since patients with peripheral arterial disease (PAD) have a threefold risk of cerebrovascular morbidity compared to individuals free of PAD, and since the total neurological event rate is associated with a > or = 50% lumen reduction in extracranial carotid arteries, it was tested whether tHcy is a predictor of internal carotid artery stenosis in patients with symptomatic PAD. A total of 443 consecutive male PAD patients without previous carotid surgery/stenting were studied. In all, 100 patients with PAD had an internal carotid artery stenosis > or = 50%. Of the remaining 343 patients, 100 individuals matched for age (+/- 2 years) and diabetes served as controls. The extent of carotid stenosis was evaluated with color duplex measurement; tHcy was determined by high-performance liquid chromatography. Cases displayed a significantly higher median fasting tHcy level (17.0 micromol/l) than controls (13.7 micromol/l, p=0.001). Multivariate analysis showed that tHcy (p=0.036) was an independent predictor of internal carotid artery stenosis > or = 50% in PAD patients, representing an odds ratio of 1.32 (95% CI, 1.02-1.72) for an increment of 5 micromol/l. In the present study, high tHcy was an independent risk factor for an internal carotid artery stenosis > or = 50% in patients with PAD. Since PAD patients suffer a threefold risk of stroke compared to healthy individuals, a simple vitamin substitution in PAD patients may reduce the occurrence of internal carotid artery stenosis and therefore diminish the relatively high rate of cerebrovascular events in this population.     

Peripheral arterial disease: A growing problem for the internist

The atherothrombotic conditions, coronary artery disease, cerebrovascular disease and peripheral arterial disease (PAD), together account for almost one-half of all deaths in Europe each year; however, perception of the specific risks associated with PAD is generally poor compared with its related conditions. PAD is not just a localised disease — it has serious systemic effects, and affected individuals have a higher risk of serious cardiovascular sequelae or death within 1 year of diagnosis compared with those with coronary artery or cerebrovascular disease. PAD, which currently affects approximately 16% of the general population aged over 55 years, is increasing because of the population aging and the continuing rise in cardiovascular risk factors. The management of PAD is a multi-disciplinary approach, and while this can have its advantages, it can also mean that responsibility for patient care is unclear. Globally, almost one-third of all patients with PAD are under internist care. Internists are ideally placed to identify patients at risk of PAD and initiate prompt risk factor management because of their role in the continued care of elderly patients and those with diabetes, hypertension, dyslipidaemia, and chronic renal disease. Multi-disciplinary guidelines for the clinical management of PAD, based on consensus among international specialists in a number of fields, have been developed to create an informed, unified and proactive approach to the treatment of PAD. They stress the continuity of care, the use of office-based ankle–brachial index testing to aid early diagnosis, and prompt and aggressive risk factor management.     

Undertreatment of dyslipidemia in peripheral arterial disease and other high-risk populations: an opportunity for cardiovascular disease reduction

Atherosclerosis is a form of arterial disease that manifests in the coronary circulation as coronary artery disease (CAD), in the carotid arteries as cerebrovascular disease, and in the aorta and lower extremity arteries as peripheral arterial disease (PAD). The systemic nature of the disease is reflected in the fact that individuals with PAD or carotid artery disease are more likely to have CAD than those without. Since individuals with PAD are at markedly increased risk of cardiovascular ischemic events, early identification of this population and more aggressive medical interventions could substantially improve both morbidity and survival. The incidence of PAD in the general population is high, and currently affects 8-10 million Americans. The risk of developing PAD is predicted by both age and common atherosclerosis risk factors (e.g., smoking and diabetes). Efficient office-based PAD detection depends on the application of objective techniques to establish this diagnosis. Objective noninvasive tests, such as measurement of the ankle-brachial index (ABI), are known to be more sensitive than traditional clinical assessments. Since the major threat to patients with PAD is from secondary cardiovascular ischemic events, a primary therapeutic goal is to modify atherosclerotic risk factors. While national recommendations mandate aggressive lowering of serum low-density lipoprotein cholesterol (LDL-C) levels as a primary treatment goal in all patients with overt atherosclerosis, as 'coronary heart disease risk equivalent' syndromes, individuals with PAD are less intensively treated than those with CAD. Statins are the most effective of current treatments in lowering LDL-C, and have proven efficacy in secondary prevention among patients with established CAD. The use of statin medications in high-risk groups such as PAD patients could prove particularly beneficial in reducing cardiovascular morbidity and mortality and therefore merits prospective clinical investigation.