Antioxidant vitamins and the risk of carotid atherosclerosis. The Perth Carotid Ultrasound Disease Assessment study (CUDAS).

OBJECTIVES: This study examined whether dietary intake or plasma levels of antioxidant vitamins were independently associated with common carotid artery intima-media (wall) thickness (IMT) or focal plaque, or both, in a large, randomly selected community population. BACKGROUND: Oxidation of low-density lipoprotein (LDL) cholesterol is thought to be important in early atherogenesis. Antioxidant micronutrients may therefore protect against lipid peroxidation and atherosclerotic vascular disease. METHODS: We studied 1,111 subjects (558 men and 553 women; age 52 +/- 13 years [mean +/- SD], range 27 to 77). We measured dietary vitamin intake and fasting plasma levels of vitamins A, C and E, lycopene and alpha- and beta-carotene and performed bilateral carotid artery B-mode ultrasound imaging. RESULTS; After adjustment for age and conventional risk factors, there was a progressive decrease in mean IMT, with increasing quartiles of dietary vitamin E intake in men (p = 0.02) and a nonsignificant trend in women (p = 0.10). Dietary vitamin E levels accounted for 1% of the variance in measured IMT in men. For plasma antioxidant vitamins, there was an inverse association between carotid artery mean IMT and plasma lycopene in women (p = 0.047), but not in men. None of the other dietary or plasma antioxidant vitamins, nor antioxidant vitamin supplements, were associated with carotid artery IMT or focal carotid artery plaque. CONCLUSIONS: This study provides limited support for the hypothesis that increased dietary intake of vitamin E and increased plasma lycopene may decrease the risk of atherosclerosis. No benefit was demonstrated for supplemental antioxidant vitamin use.

Angiotensin-converting enzyme gene polymorphism and carotid wall thickening in a community population.

The insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene has been associated with an increased risk of coronary heart disease, but whether it is a risk factor for underlying atherosclerosis remains unclear. Therefore, we examined to see whether the ACE gene deletion polymorphism was associated with carotid wall thickening and atherosclerotic plaque formation in a large randomly selected community population. A total of 1111 subjects, aged 27 to 77 years, with an equal male:female ratio and equal numbers in each age decile, were randomly selected from the Perth community population. Mean common carotid intima-medial wall thickness (IMT) and focal plaque formation were assessed by high-resolution B-mode ultrasound. The ACE gene I/D polymorphism was detected by PCR. The distribution of the ACE genotypes conformed to the Hardy-Weinberg equilibrium (DD, 31.0%; ID, 48.4%; and II, 20.6%). The D allele was strongly correlated in a codominant fashion with plasma ACE activity (r(s)=0.53, P<0.0001), and accounted for 33% of the total variance in circulating ACE activity. No significant differences among the ACE genotypes were found with respect to age, sex, and conventional risk variables, including a history of hypertension and vascular disease. The average mean IMT and prevalence of increased IMT and focal plaque were not significantly different among genotypes in the overall population or in the subset (n=852) who were conventionally low risk by Framingham coronary heart disease risk score. Logistic regression analysis selected age, systolic blood pressure, pack-years of smoking, LDL cholesterol level, waist/hip ratio, and history of hypertension, but not the D allele, as multivariate predictors of increased IMT and carotid plaque formation. We conclude that, although the ACE I/D polymorphism is strongly related to ACE activity, it is not a risk predictor of carotid wall thickening or focal plaque formation when examined in a large randomly selected community population.

Hyperhomocysteinemia but not the C677T mutation of methylenetetrahydrofolate reductase is an independent risk determinant of carotid wall thickening. The Perth Carotid Ultrasound Disease Assessment Study (CUDAS)

BACKGROUND: Hyperhomocysteinemia has been identified as a potential risk factor for atherosclerosis. This study examined whether a modest elevation of plasma total homocysteine (tHcy) was an independent risk factor for increased carotid artery intimal-medial wall thickness (IMT) and focal plaque formation in a large, randomly selected community population. We also examined whether vitamin cofactors and the C677T genetic mutation of the methylenetetrahydrofolate reductase (MTHFR) enzyme were major contributors to elevated plasma tHcy and carotid vascular disease. METHODS AND RESULTS: In 1111 subjects (558 men, 553 women) 52+/-13 years old (mean+/-SD; range, 27 to 77 years) recruited from a random electoral roll survey, we measured fasting tHcy and performed bilateral carotid B-mode ultrasound. For the total population, mean tHcy was 12.1+/-4.0 micromol/L. Plasma tHcy levels were correlated with IMT (Spearman rank rs=0.31, P=0.0001). After adjustment for age, sex, and other conventional risk factors, subjects in the highest versus the lowest quartile of tHcy had an odds ratio of 2.60 (95% CI, 1.51 to 4.45) for increased IMT and 1.76 (95% CI, 1.10 to 2.82) for plaque. Serum and dietary folate levels and the C677T mutation in MTHFR were independent determinants of tHcy (all P=0.0001). The mutant homozygotes (10% of the population) had higher mean tHcy than heterozygotes or those without the mutation (14.2 versus 12.3 versus 11.6 micromol/L, respectively, P=0.0001). The inverse association of folate levels with tHcy was steeper in the mutant homozygotes. Despite this, the C677T MTHFR mutation was not independently predictive of increased carotid IMT or plaque formation. CONCLUSIONS: Mild hyperhomocysteinemia is an independent risk factor for increased carotid artery wall thickness and plaque formation in a general population. Lower levels of dietary folate intake and the C677T mutation in MTHFR are important causes of mild hyperhomocysteinemia and may therefore contribute to vascular disease in the community.

Refining the risk-benefit equation for thrombolysis: how to identify the low risk patient before administering thrombolytic therapy.

In view of the relative risk of intracranial haemorrhage and major bleeding with thrombolytic therapy, it is important to identify as early as possible the low risk patient who may not have a net clinical benefit from thrombolysis in the setting of acute myocardial infarction. An analysis of 5434 hospital-treated patients with myocardial infarction in the Perth MONICA study showed that age below 60 and absence of previous infarction or diabetes, shock, pulmonary oedema, cardiac arrest and Q-wave or left bundle branch block on the initial ECG identified a large group of patients with a 28 day mortality of only 1%, and one year mortality of only 2%. Identification of baseline risk in this way helps refine the risk-benefit equation for thrombolytic therapy, and may help avoid unnecessary use of thrombolysis in those unlikely to benefit.

Natural history of vegetations during successful medical treatment of endocarditis.

Although initial morphologic features of vegetations have been related to the risk of early complications, there is little information about the natural history of the vegetations during medical treatment or the relation of morphologic changes in vegetation to late complications. To assess the evolution of valvular vegetations by echocardiography during treatment of infective endocarditis and to relate the morphologic changes in vegetation to late prognosis, serial echocardiograms of patients with successful medical treatment for native valve infective endocarditis were reviewed to assess the presence and morphologic features of valvular vegetations at the onset and at the end of therapy. The evolution of vegetation size, mobility, consistency, the extent of the disease, and the severity of valvular regurgitation were related to late complications such as embolism, valve replacement, or death occurring after the end of therapy. Forty-one vegetations were identified in 32 patients on initial echocardiograms. At the end of treatment, 29 vegetations were still present; 59% had no significant change in size and 52% appeared to be denser in consistency. Morphologic changes did not relate to late complications, but the presence of severe valvular regurgitations was associated with late valve replacement. The echocardiographic persistence of vegetations is common after successful medical treatment of infective endocarditis. In the absence of severe valvular dysfunction, however, persistent vegetations are not independently associated with late complications.

Effect of static pressure on the disappearance rate of specific echocardiographic contrast agents.

Contrast echocardiography has been applied to identify cardiac structures, shunts, and perfusion territories. Most recently, quantification of flow has been proposed based on disappearance of contrast intensity. This requires that contrast agents are stable and produce a predictable effect. To assess the possible effect of pressure on their stability, the rates of backscatter decay of four echocardiographic contrast agents (Albunex, Levovist, agitated Angiovist, and agitated saline solution) exposed to constant pressures (0, 50, 100, 150, and 200 mm Hg) were quantitated. Contrast was recorded by echocardiography and measured to construct time-intensity curves. The peak decay rate for each agent at each pressure was determined. For all four agents, contrast intensity (I) decreased over time and could be described by the sigmoid function: I = a [e-lambda(t-ts)/1 + e-lambda(t-ts)] + C. Peak decay rate was significantly affected by pressure (p < 0.005) in a proportionate fashion. At pressures of 0, 100, and 200 mm Hg, the rates increased for each agent in the following fashion: Albunex, 0.144 +/- 0.109 to 0.410 +/- 0.142 to 1.442 +/- 0.309; Levovist, 0.060 +/- 0.023 to 0.162 +/- 0.049 to 0.495 +/- 0.142; Angiovist, 0.089 +/- 0.028 to 0.166 +/- 0.057 to 0.224 +/- 0.027; and saline solution, 0.068 +/- 0.039 to 0.110 +/- 0.036 to 0.154 +/- 0.057. The effect of pressure on the peak rate of contrast disappearance (lambda) was significantly different among agents (p < 0.001). Thus attempts to quantitate blood flow with contrast agents must take into account the influence of pressure.

Valvular surgery in Western Australia: a 15-year review.

Between 1970 and 1984, 1138 patients underwent the insertion of 1300 prosthetic heart valves in Western Australia; 56% received an aortic-valve replacement; 34% received a mitral-valve replacement and 10% had more than one valve replaced. Mechanical valves were used in 93% of patients before 1977, in 20% of patients between 1978 and 1982 and in 70% of patients from 1983 onwards. The 30-day mortality was 18% before 1973 and has been below 6% since 1974. The over-all, 15-year actuarial survival rate was 67%; this was not affected by age, sex, race, valvular position or the type of prosthesis. Both the 30-day mortality and 15-year survival rates were significantly worse in patients who underwent multiple valvular replacements (13% and 54%, respectively) or reoperation (16% and 58%, respectively). The major causes of death were cardiac failure and myocardial infarction (65%); endocarditis (13%); cancer (6%); and thromboembolism and bleeding (6%). The hazard rate for reoperation was low and fairly constant in patients with mechanical valves, but increased markedly after four years in patients with tissue valves. Although our experience so far suggests that survival rates are not affected by the choice of prosthesis, this may not be so in the future, as more patients with tissue valves undergo reoperation and so become exposed to an increased risk of mortality.