Effect of an aggressive lipid-lowering strategy on progression of atherosclerosis in the left main coronary artery from patients in the post coronary artery bypass graft trial.

BACKGROUND: The Post Coronary Artery Bypass Graft Trial, designed to compare the effects of two lipid-lowering regimens and low-dose anticoagulation versus placebo on progression of atherosclerosis in saphenous vein grafts of patients who had had CABG surgery, demonstrated that aggressive lowering of LDL cholesterol levels to a mean yearly cholesterol level from 93 to 97 mg/dL compared with a moderate reduction to a level of 132 to 136 mg/dL decreased the progression of atherosclerosis in saphenous vein grafts. Low-dose anticoagulation did not affect progression. This secondary analysis tested the hypothesis that a similar decrease in progression of atherosclerosis would also be present in native coronary arteries as measured in the left main coronary artery (LMCA). METHODS AND RESULTS: A sample of 402 patients was randomly selected from 1102 patients who had baseline and follow-up views of the LMCA suitable for analysis. Patients treated with the aggressive lipid-lowering strategy had less progression of atherosclerosis in the LMCA as measured by changes in minimum (P=0.0003) lumen diameter or the maximum percent stenosis (P=0.001), or the presence of substantial progression (P=0.008), or vascular occlusion (P=0.005) when compared with the moderate strategy. CONCLUSIONS: A strategy of aggressive lipid lowering results in significantly less atherosclerosis progression than a moderate approach in LMCAs.

Cerebrovascular reactivity in normal pregnancy and preeclampsia.

OBJECTIVE: To compare cerebrovascular reactivity in normotensive and preeclamptic pregnant women. METHODS: Transcranial Doppler ultrasound was used to measure peak, end-diastolic, and mean velocities in the middle cerebral arteries of 45 normotensive and 36 preeclamptic women in the third trimester. All measurements were done in the left lateral position at baseline, during 5% carbon dioxide (CO2) inhalation, and during an isometric hand-grip test. Blood pressure (BP), heart rate, oxygen (O2) saturation, and end-tidal partial pressure of carbon dioxide (pCO2) were recorded with each Doppler measurement. The mean pulsatility index (PI), resistance index (RI), and cerebral perfusion pressure at each time was compared using two-way repeated measures analysis of variance. Cerebrovascular reactivity, calculated as the percentage change in response to each maneuver, was also compared using analysis of covariance. A post hoc power analysis was performed to evaluate the primary measures of the study (middle cerebral artery PI and RI). Using alpha error of 5%, the statistical power to identify a difference in PI and RI in women with preeclampsia compared with normotensive women was 90% and 67%, respectively. The statistical power to identify a difference in PI and RI in response to the two maneuvers was 69% and 53%, respectively. Statistical significance was set at P <.05. RESULTS: Preeclamptic women had higher baseline cerebral perfusion pressure (90.4 compared with 61.9 mmHg, P <.05) and lower PI (0.64 compared with 0.76, P <.05) and RI (0.46 compared with 0.51, P <.05) than normotensive pregnant women. In normotensive patients, both 5% CO2 inhalation and isometric hand-grip test caused a significant decrease in PI (-9.5% and -6.1%, respectively) and RI (-6.5% and -4.2%, respectively). In contrast, in preeclamptic patients there was no change in any of the middle cerebral artery parameters in response to either maneuver. CONCLUSION: Normotensive pregnant women had normal middle cerebral artery responses to both 5% CO2 inhalation and isometric hand-grip test. Preeclamptic patients had elevated baseline cerebral perfusion pressure and reduced vasodilatory responses to both tests. These findings are consistent with a state of vasoconstriction in preeclamptic women that is unresponsive to stimuli that under normal circumstances result in vasodilation.

The hemostatic effects of warfarin titration in post CABG patients in comparison to placebo treatment.

BACKGROUND: Since coronary artery bypass graft patients remain at risk of coronary artery and bypass graft occlusion after successful surgery, adjunct treatment regimens are under investigation. In a study of the patients of the multicenter Post Coronary Artery Bypass Graft (Post CABG) Trial, 1 mg warfarin was found to have no important effect on coagulation parameters. STUDY DESIGN: The effects of 1, 2 and 3 mg warfarin were evaluated at six-week intervals in 20 Post CABG Trial patients receiving titrated dose increases in comparison to 20 patients of similar age, gender and time from CABG treated with placebo. RESULTS: International normalized ratio (INR) values increased with warfarin dose increments for 1, 2, and 3 mg, respectively (0.95+/-0.16, 1.08+/-0.19, and 1.34+/-0.39) and in comparison to placebo treated patients (dosextreatment p<0.001). Factor VII coagulant activity decreased with warfarin titration (1 mg, 119.0+/-18.3 %; 2 mg, 100.6+/-32.8 %; 3 mg, 95.0+/-27.8 %) and in comparison to placebo (dosextreatment p=0.008). Levels of prothrombin fragment F1.2, tissue plasminogen activator, fibrinogen and von Willebrand factor were unchanged with warfarin dose increments and in comparison to placebo. CONCLUSIONS: At doses up to 3 mg, warfarin acts on the INR through a reduction of factor VII with no effect on the fibrinolytic system, fibrinogen or von Willebrand factor. At these doses F1.2 did not document reduced coagulation activity. The observations of this study were consistent with the decision in the Post CABG Trial to increase the warfarin dose above 1 mg to achieve a distinct effect of warfarin that was less than full anticoagulation.

Changes in flow velocity, resistance indices, and cerebral perfusion pressure in the maternal middle cerebral artery distribution during normal pregnancy.

BACKGROUND: There are few longitudinal data currently available detailing the normal changes in maternal cerebral hemodynamics during human pregnancy. This lack of information limits the study of pregnancy-associated cerebrovascular adjustments and, in particular, preeclampsia, where the brain appears to be especially susceptible to ischemic and encephalopathic injury. Our objective was to define the hemodynamic changes, specifically velocity, resistance indices, and cerebral perfusion pressure, in the middle cerebral artery (MCA) distribution of the brain during normal pregnancy. METHODS AND MATERIALS: Transcranial Doppler ultrasound was used to determine the systolic, diastolic and mean blood velocities in the middle cerebral arteries in non-laboring women studied longitudinally during normal gestation. The resistance index (RI), pulsatility index (PI), and cerebral perfusion pressure (CPP) were calculated using the velocity and blood pressure data. Data were analyzed using a longitudinal statistical model incorporating random patient effects and a homoscedastic (compound symmetric) variance-covariance structure over time (gestational age). The predicted mean value (Least Squares Mean), and the 5th and 95th percentiles, were defined for normal pregnancy. RESULTS: MCA systolic velocity decreased (24%) as did the mean velocity (17%). The diastolic velocity did not change significantly. The MCA RI decreased by 19% and the PI decreased by 25%. The MCA CPP increased by 52% between 12 and 40 weeks of gestation. CONCLUSIONS: The normative ranges for MCA velocity, RI, and CPP have been defined in normal human pregnancy using longitudinally collected data. By having a defined normal range, identification of abnormalities in cerebral hemodynamics during pregnancy is now possible, and this may help researchers and clinicians to elucidate etiologies and treatments for pregnancy-related pathophysiologic states such as preeclampsia

Lessons from the post coronary artery bypass graft study in evaluating and controlling technical variability in angiographic trials. Post CABG Investigators.

Although many investigators have evaluated the technical variability of quantitative angiographic techniques used to study atherosclerosis regression in native coronary arteries, few have studied the variability inherent in repeated studies of atherosclerotic saphenous vein grafts. This study describes 2 studies performed during the course of the Post Coronary Artery Bypass Graft (CABG) Clinical Trial that were designed to assess the reproducibility of: (1) repeated angiographic views within a short time period; and (2) reproducibility of the total process of quantitative analysis of saphenous vein graft angiograms. Statistical methods are described that provide a more meaningful assessment of the impact of measurement variability in the analytic process versus the variability related to changes induced by pharmacologic interventions. One such method, the increase in standard deviation (SD) among patients (ISDP), showed that repeated angiographic views increased the variability of calculation of lesion minimal diameter by 1.5%, whereas the ISDP for repetition of the entire process of quantitative angiographic readings increased variability 6.4%. These data from the Post CABG trial reveal that technical variability is small and has negligible impact on the conclusions of the study.

Pregnant women with chronic hypertension and superimposed pre-eclampsia have high cerebral perfusion pressure.

OBJECTIVE: To determine any differences in cerebral perfusion pressure in patients with chronic hypertension compared with those with chronic hypertension and superimposed pre-eclampsia. DESIGN: A prospective observational study. SETTING: University hospital clinic and labour and delivery suite. PARTICIPANTS: Fifteen women with chronic hypertension and 15 with superimposed pre-eclampsia. METHODS: Transcranial Doppler ultrasound was used to measure blood velocity in the middle cerebral arteries of the patients. Systemic blood pressure in the brachial artery was measured simultaneously. Middle cerebral artery. resistance index, pulsatility index, and cerebral perfusion pressure were calculated and plotted on the same axes as data from normal pregnant women. Cerebral perfusion pressure values outside of the 5th and 95th centiles were regarded as abnormal. Cerebral perfusion pressure data from the chronic hypertension and superimposed pre-eclampsia groups were also expressed in terms of the number of normative standard deviations from the mean value for normal pregnancy (Multiples of the Standard Deviation: MOS). All studies were conducted before labour, under similar conditions, and before volume expansion or treatment. Statistical analysis was by Student's t test and Fisher's exact test as appropriate with significance set at a two-tailed P<0.05. RESULTS: Patient demographics and blood pressure were not significantly different between the two groups. The resistance index and pulsatility index were not significantly different (neither absolute nor multiples of the standard deviation values). The absolute cerebral perfusion pressure was significantly higher in the patients with superimposed pre-eclampsia. The group of women with superimposed pre-eclampsia had a significantly higher mean value of cerebral perfusion pressure measured as multiples of the standard deviation from the mean value for normal pregnancy, despite there being no blood pressure difference. CONCLUSIONS: Superimposed pre-eclampsia is associated with significantly higher cerebral perfusion pressure measurements compared with women with uncomplicated chronic hypertension. This is not directly related to a higher blood pressure. The difference in cerebral perfusion pressure may be used to speculate upon the pathophysiology of the increased risk for eclampsia seen in patients with superimposed pre-eclampsia.

Evaluation of a noninvasive transcranial Doppler and blood pressure-based method for the assessment of cerebral perfusion pressure in pregnant women.

OBJECTIVE: We have developed a Doppler method for the estimation of cerebral perfusion pressure (CPP) using noninvasive techniques. Our objective was to evaluate our new method in pregnant women. METHODS AND MATERIALS: Laboring women with a lumbar epidural in situ had transcranial Doppler interrogation of the maternal middle cerebral artery (MCA) to measure systolic, diastolic, and mean velocities. A pressure transducer was connected to the epidural catheter and pressure was recorded. Systolic (SBP), diastolic (DBP), and mean (MAP) blood pressure were taken with a Dinamap monitor. Doppler estimated CPP (mm Hg) = [V(mean)/(V(mean) - V(diastolic)](MAP - DBP) and directly measured CPP = MAP - Epidural pressure data were plotted on a Bland-Altman graph with limits of agreement. The mean difference (the mean of the sum of both positive and negative differences) and absolute difference (the mean of the sum of the absolute differences) were calculated. In addition, linear and polynomial regression analyses were performed. RESULTS: Twenty laboring women were studied. All had normal pregnancies. The mean maternal age was 28 +/- 7 years and the mean gestational age was 39 +/- 2 weeks. The mean maternal MAP was 77 +/- 12 mm Hg. The Bland-Altman plot showed a mean difference of 2.2 mm Hg at a mean CPP of 65 +/- 12 mm Hg; with a standard deviation of 4.8 mm Hg, the absolute difference was 3.9 +/- 3.0 mm Hg at a mean CPP of 65 +/- 12 mm Hg. The regression analysis showed an r = 0.92, r(2) = 0.86, and p < 0.0001. CONCLUSIONS: Our formula allows the estimation of CPP using a simple calculation and noninvasively acquired data. This method may be of use for frequent, easy, and accurate CPP and intracranial pressure estimation and may, as such, have significant research and clinical applications.

Apolipoprotein E genotypes and response of plasma lipids and progression-regression of coronary atherosclerosis to lipid-lowering drug therapy.

OBJECTIVES: We sought to examine the association of apolipoprotein (apo) E genotypes with baseline plasma lipid levels and severity of coronary artery disease (CAD), as well as the response to treatment with fluvastatin in the Lipoprotein and Coronary Atherosclerosis Study (LCAS). BACKGROUND: Apo E genotypes have been associated with plasma lipid levels and CAD. However, the influence of apo E genotypes on the response of plasma lipids and CAD progression or regression to statin treatment in patients with mildly to moderately elevated cholesterol remains unknown. METHODS: Apo E genotypes were determined by polymerase chain reaction and restriction mapping. Plasma lipids were measured at baseline and 12 weeks after therapy with fluvastatin or placebo in 320 subjects. In 287 subjects, quantitative coronary angiography was performed at baseline and after 2.5 years of treatment. RESULTS: Subjects with the 3/3 genotype had greater reductions in total cholesterol (20.4% vs. 15.4%, p = 0.01) and low density lipoprotein (LDL) cholesterol (28.8% vs. 22.7%, p = 0.03) than did the subjects with the 3/4 or 4/4 genotype. In contrast, subjects with the 2/3 genotype (n = 10) had a greater increase in high density lipoprotein cholesterol (19.1%) than did the subjects with the 3/3 genotype (4.3%, p = 0.002) and those with the 3/4 or 4/4 genotype (7.0%, p = 0.02). Subjects with the 3/4 or 4/4 genotype had an increased frequency of previous angioplasty, but other measures of baseline CAD severity and baseline lipids did not differ significantly among the genotypes, nor did CAD progression or clinical events. CONCLUSIONS: Although subjects with the epsilon4 allele had less reduction in LDL cholesterol with fluvastatin, they had similar benefit in terms of CAD progression.

Effective and safe modification of multiple atherosclerotic risk factors in patients with peripheral arterial disease.

BACKGROUND: Patients with peripheral arterial disease (PAD) are at an increased risk of cardiovascular mortality and morbidity and thus are an excellent group in whom to evaluate the feasibility and the effect of an aggressive multifactorial intervention on atherosclerotic vascular disease risk factors. The Arterial Disease Multiple Intervention Trial (ADMIT) was designed to determine the efficacy, safety, and compliance of an multifactorial therapy on selected atherosclerotic disease risk factors in patients with PAD. METHODS: By a 2 x 2 x 2 factorial design, eligible participants (N = 468) were randomly assigned to low-dose warfarin, antioxidant vitamins, and niacin or its corresponding placebo, and followed up for 1 year. All participants were encouraged to use aspirin. Pravastatin was added to the drug regimen for those who needed to reduce LDL cholesterol to recommended levels. RESULTS: Niacin increased HDL cholesterol levels by 30%, with the majority of effect achieved at a dosage of 500 mg twice daily. Warfarin had an anticoagulant effect. The antioxidant vitamins resulted in a significant increase in vitamin E, C, and beta-carotene plasma levels. Overall, compliance was high and few adverse effects were reported. CONCLUSIONS: ADMIT demonstrates that it is both feasible and safe to modify multiple atherosclerotic disease risk factors effectively with intensive combination therapy in patients with PAD.

Effect of niacin, warfarin, and antioxidant therapy on coagulation parameters in patients with peripheral arterial disease in the Arterial Disease Multiple Intervention Trial (ADMIT).

BACKGROUND: Patients with peripheral arterial disease (PAD) have high rates of cardiovascular morbidity and mortality, including that caused by associated coronary heart disease and cerebrovascular disease. Previous studies have shown that coagulation parameters are altered in PAD and that altered coagulation may play a critical role in the susceptibility to cardiovascular complications in PAD. It is therefore important to assess the effect of secondary prevention measures on coagulation in patients with PAD. The Arterial Disease Multiple Intervention Trial (ADMIT), a multicenter, randomized, placebo-controlled trial, was conducted to determine the feasibility of a combined lipid-modifying, antioxidant, and antithrombotic treatment regimen in patients with PAD. The objective of this study was to assess the effect of the ADMIT interventions on coagulation. METHODS: ADMIT participants were randomly assigned to low-dose warfarin, niacin, and antioxidant vitamin cocktail or corresponding placebos in a 2 x 2 x 2 factorial design. Specialized coagulation studies were performed in a subset of 80 ADMIT participants at baseline and after 12 months of treatment. RESULTS: Low-dose warfarin (1 to 4 mg/d) resulted in a significant decrease in factor VIIc (P <.001) and in plasma F1.2 (P =.001). Unexpectedly, niacin treatment also resulted in significant decrease in both fibrinogen (48 mg/dL; P <.001) and F1.2 (P =.04). von Willebrand factor increased after antioxidant vitamin treatment (P =.04). CONCLUSIONS: A regimen of low-dose warfarin effectively modifies coagulation in patients with PAD. Niacin also favorably modifies fibrinogen and plasma F1.2. Niacin, in addition to its lipid effects, modifies abnormal coagulation factors that accompany PAD.

Long-term effects on clinical outcomes of aggressive lowering of low-density lipoprotein cholesterol levels and low-dose anticoagulation in the post coronary artery bypass graft trial. Post CABG Investigators.

BACKGROUND: The Post Coronary Artery Bypass Graft Trial, designed to compare the effects of 2 lipid-lowering regimens and low-dose anticoagulation versus placebo on progression of atherosclerosis in saphenous vein grafts of patients who had had CABG surgery, demonstrated that aggressive lowering of LDL cholesterol (LDL-C) levels to <100 mg/dL compared with a moderate reduction to 132 to 136 mg/dL decreased the progression of atherosclerosis in grafts. Low-dose anticoagulation did not significantly affect progression. METHODS AND RESULTS: Approximately 3 years after the last trial visit, Clinical Center Coordinators contacted each patient by telephone to ascertain the occurrence of cardiovascular events and procedures. The National Death Index was used to ascertain vital status for patients who could not be contacted. Vital status was established for all but 3 of 1351 patients. Information on nonfatal events was available for 95% of surviving patients. A 30% reduction in revascularization procedures and 24% reduction in a composite clinical end point were observed in patients assigned to aggressive strategy compared with patients assigned to moderate strategy during 7.5 years of follow-up, P=0. 0006 and 0.001, respectively. Reductions of 35% in deaths and 31% in deaths or myocardial infarctions with low-dose anticoagulation compared with placebo were also observed, P=0.008 and 0.003, respectively. CONCLUSIONS: -The long-term clinical benefit observed during extended follow-up in patients assigned to the aggressive strategy is consistent with the angiographic findings of delayed atherosclerosis progression in grafts observed during the trial. The apparent long-term benefit of low-dose warfarin remains unexplained.

Ethnicity affects the postprandial regulation of glycogenolysis.

We investigated the effect of nutrient intake on glucose metabolism in normal Mexican-Americans (n = 6) and European-Americans (n = 6). Subjects were studied after an 18-h fast and after 5-6 h of ingestion of hourly meals that supplied 6.35 or 12.75 micromol glucose. kg(-1). min(-1). Endogenous glucose production (EGP), gluconeogenesis (GNG), and glycogenolysis (GLY) were estimated by mass isotopomer analysis with [U-(13)C]glucose infusions. Fasting EGP, GNG, and GLY did not differ between the groups. Food ingestion lowered the molar rate of GNG by only 31%. However, while consuming the lower quantity of nutrients, Mexican-Americans had higher plasma glucose (P < 0.05), a 39% higher rate of EGP (P < 0.05), and a 68% (P < 0.025) higher rate of GLY than the European-Americans. At the higher intake, EGP and GLY were suppressed completely in both groups. There was a linear relationship between insulin concentrations, EGP, and GLY in both groups, but the slope of the line was significantly (P < 0.05) greater in the European-Americans. We conclude that the sensitivity of GLY to nutrient intake differs between ethnic groups and that this may play a role in the increased predisposition of Mexican-Americans to type II diabetes.

A new pharmacological treatment for intermittent claudication: results of a randomized, multicenter trial.

BACKGROUND: Effective medication is limited for the relief of intermittent claudication, a common manifestation of arterial occlusive disease. Cilostazol is a potent inhibitor of platelet aggregation with vasodilation effects. OBJECTIVE: To evaluate the safety and efficacy of cilostazol for the treatment of intermittent claudication. METHODS: Thirty-seven outpatient vascular medicine clinics at regional tertiary and university hospitals in the United States participated in this multicenter, randomized, double-blind, placebo-controlled, parallel trial. Of the 663 screened volunteer patients with leg discomfort, a total of 516 men and women 40 years or older with a diagnosis of moderately severe chronic, stable, symptomatic intermittent claudication were randomized to receive cilostazol, 100 mg, cilostazol, 50 mg, or placebo twice a day orally for 24 weeks. Outcome measures included pain-free and maximal walking distances via treadmill testing, patient-based quality-of-life measures, global assessments by patient and physician, and cardiovascular morbidity and all-cause mortality survival analysis. RESULTS: The clinical and statistical superiority of active treatment over placebo was evident as early as week 4, with continued improvement at all subsequent time points. After 24 weeks, patients who received cilostazol, 100 mg, twice a day had a 51% geometric mean improvement in maximal walking distance (P<.001 vs placebo); those who received cilostazol, 50 mg, twice a day had a 38% geometric mean improvement in maximal walking distance (P<.001 vs placebo). These percentages translate into an arithmetic mean increase in distance walked, from 129.7 m at baseline to 258.8 m at week 24 for the cilostazol, 100 mg, group, and from 131.5 to 198.8 m for the cilostazol, 50 mg, group. Geometric mean change for pain-free walking distance increased by 59% (P<.001) and 48% (P<.001), respectively, in the cilostazol, 100 mg, and cilostazol, 50 mg, groups. These results were corroborated by the results of subjective quality-of-life assessments, functional status, and global evaluations. Headache, abnormal stool samples or diarrhea, dizziness, and palpitations were the most commonly reported potentially drug-related adverse events and were self-limited. A total of 75 patients (14.5%) withdrew because of any adverse event, which was equally distributed between all 3 treatment groups. Similarly, there were no differences between groups in the incidence of combined cardiovascular morbidity or all-cause mortality. CONCLUSION: Compared with placebo, long-term use of cilostazol, 100 mg or 50 mg, twice a day significantly improves walking distances in patients with intermittent claudication.

The effect of aggressive and moderate lowering of LDL-cholesterol and low dose anticoagulation on plasma lipids, apolipoproteins and lipoprotein families in post coronary artery bypass graft trial.

The reported results (The Post Coronary Artery Bypass Graft Trial Investigators. The effect of aggressive lowering of low-density lipoprotein cholesterol levels and low-dose anticoagulation on obstructive changes in saphenous-vein coronary-artery bypass grafts. New Engl J Med 1997;336:153-162) of the Post Coronary Artery Bypass Graft (Post CABG) trial have shown that aggressive lowering was more effective than moderate lowering of low density lipoprotein (LDL) cholesterol in reducing the progression of atherosclerosis in saphenous-vein grafts (27 vs. 39%; P < 0.001); low dose warfarin had no effect on the progression of atherosclerosis. The present report describes the effect of long-term (an average of 4.3 years) aggressive treatment with high (40-80 mg/day) and moderate treatment with low (2.5-5 mg/day) doses of lovastatin on lipids, apolipoproteins (apo) and apoA- and apoB-containing lipoprotein families. To achieve the target LDL-cholesterol levels (60-85 mg/dl for aggressive group and 134-140 mg/dl for moderate group), cholestyramine (8 g/day) was given to 25% of subjects on aggressive and 5% of subjects on moderate treatment. Although with both treatment strategies there were significant decreases (P<0.001) in the levels of total cholesterol, LDL-cholesterol, apoB, LDL-apoB and cholesterol-rich Lp-B family, percent changes in the levels of these variables were greater in the aggressive- than in the moderate-treatment groups. These treatments had only marginal effects in increasing the levels of high density lipoprotein cholesterol, apoA-I and Lp-A-I and Lp-A-I:A-II families. The long-term aggressive treatment exerted no effect on the concentrations of triglycerides, apoC-IlI, apoC-III in VLDL + LDL and triglyceride-rich Lp-Bc families. Neither treatment affected the levels of Lp(a). The potentially modifying influence of warfarin and apoE phenotypes on lovastatin-induced changes in lipoprotein variables was found to be of little significance. It is likely that the beneficial effect of lovastatin in reducing the progression of atherosclerosis in grafts is mediated through its specific lowering effect on cholesterol-rich Lp-B particles.

Association of cerebral perfusion pressure with headache in women with pre-eclampsia.

OBJECTIVE: To study estimated cerebral perfusion pressure and its relation to headache and scotomata in women with pre-eclampsia. DESIGN: Prospective, observational study. SETTING: University teaching hospitals. POPULATION: Seventy-nine pre-eclamptic women with (n = 42) and without (n = 37) headache. Patients with scotomata were also studied separately. METHODS: Transcranial Doppler ultrasound was used to estimate the resistance index, pulsatility index, and estimated cerebral perfusion pressure in the middle cerebral artery. eCPP data were plotted on the same axes as the mean (and 5th and 95th% prediction limits) eCPP data from 63 normal pregnant women followed longitudinally through pregnancy. Data outside of the 95% prediction limits were regarded as abnormal. Data from the pre-eclamptic women were also expressed in terms of the number of standard deviations from the mean value established for normal pregnancy (multiples of the standard deviation: MOS). All studies were prior to labour, under similar conditions, and before volume expansion or treatment. Analysis of data was performed using Student's t test, Mann-Whitney U test, ANOVA, and Fisher's exact test with two-tailed P < 0.05, and receiver operating characteristic curve analysis with a one-tailed P < 0.05. MAIN OUTCOME MEASURES: Resistance index, pulsatility index, and eCPP. RESULTS: Pre-eclamptic women with headache were much more likely to have abnormal eCPP (34/42; 88%) than those without headache (18/37; 49%), P = 0.004, OR 4.5 (95% CI 1.5 to 13.9). There were no differences in terms of MOS in the resistance index or pulsatility index between the two groups, but estimated perfusion pressure, expressed as multiples of the standard deviation in the group with headache, was significantly higher than in the women without. Headache was noted in both over-perfusion and under-perfusion states. Only women with headache had scotomata, and their presence was not related to the severity of the headache or any difference in resistance indices or eCPP. CONCLUSIONS: Headache in women with pre-eclampsia is strongly associated with the presence of abnormal cerebral perfusion pressure. This information may be of use in clinical management.

Change in estimated cerebral perfusion pressure after treatment with nimodipine or magnesium sulfate in patients with preeclampsia.

OBJECTIVE: Data are accumulating to suggest that cerebral perfusion pressure may be either abnormally high or low in preeclampsia and eclampsia. Little is known of the cerebral perfusion pressure effects of magnesium sulfate or nimodipine. Our objective in this study was to compare the change in cerebral perfusion pressure in patients with severe preeclampsia randomly selected to receive nimodipine or magnesium sulfate. STUDY DESIGN: Patients with severe preeclampsia were randomly selected to receive magnesium sulfate (6 g bolus and 2 g/hr intravenous infusion) or nimodipine (60 mg taken orally every 4 hours). Transcranial Doppler ultrasonography was used to measure flow velocities in the right and left middle cerebral arteries, and the results were averaged. Measurements were obtained before treatment (baseline) and 30 minutes after the magnesium sulfate bolus was completely infused or 30 minutes after the nimodipine was ingested. Studies were performed before any other intervention. The person performing the ultrasonography was unaware of the patient's group assignment. Estimated cerebral perfusion pressure was calculated with the following formula: Estimated cerebral perfusion pressure = Velocity(mean) x [(Blood pressure(mean ) - Blood pressure(diastolic ))/(Velocity(mean) - Velocity(diastolic ))]. The difference between estimated cerebral perfusion pressure at baseline and after treatment was compared between the 2 groups by means of the Mann-Whitney rank sum test. RESULTS: Nine patients were randomly selected to receive nimodipine and 12 to receive magnesium sulfate. Patient demographics and severity of condition were not significantly different between the 2 groups. The change in estimated cerebral perfusion pressure was significantly different between the groups. Estimated cerebral perfusion pressure increased after nimodipine use and decreased after magnesium sulfate use. CONCLUSION: Shortly after administration to patients with severe preeclampsia, nimodipine resulted in increased cerebral perfusion pressure in comparison with magnesium sulfate.

Lipoprotein lipase gene mutations, plasma lipid levels, progression/regression of coronary atherosclerosis, response to therapy, and future clinical events. Lipoproteins and Coronary Atherosclerosis Study.

Mutations in human lipoprotein lipase (LPL) gene are potential risk factors for susceptibility to coronary artery disease (CAD). The objectives of this study were to determine the influence LPL mutations Asn291Ser and Ser447Ter on plasma lipid levels, regression and progression of CAD, clinical events rate, and response to fluvastatin therapy in the Lipoprotein and Coronary Atherosclerosis Study (LCAS) population. LCAS is a double blind, randomized, placebo-controlled study designed to test the influence of fluvastatin on progression or regression of CAD. The Asn291Ser and Ser447Ter genotypes were determined by polymerase chain reaction (PCR) and restriction enzyme digestion. Fasting plasma lipid profiles were measured and quantitative coronary angiography was performed at baseline and 2.5 years following randomization. Fatal and non-fatal cardiovascular events during the follow-up period were recorded. A total of 4% (14/363) and 18% (62/352) of the subjects had the Asn291Ser and Ser447Ter mutations, respectively. Overall, there was no statistically association between the Asn291Ser and Ser447Ter mutations and the baseline or final mean plasma levels of lipids, number of coronary lesions, total occlusions, the mean minimal lumen diameter (MLD) stenoses and the clinical events rate. However, patients with the Ser447Ter variant had a slightly higher baseline high density lipoprotein-cholesterol (HDL-C) level (46.2 +/- 12 vs 43.2 +/- 11, P = 0.057), less increase in plasma HDL levels in response to fluvastatin therapy (3 vs 11%, P = 0.056) and a higher cardiovascular events rate (23 vs 13%, P = 0.056). Thus, the Ser447Ter variant had a modest influence on plasma HDL levels and the rate of cardiovascular events. These changes were of borderline statistical significance. Neither the Ser447Ter nor the Asn291Ser mutation had a major impact on susceptibility to CAD, progression or regression of CAD, clinical events rate or response to fluvastatin therapy in LCAS population.

Aggressive cholesterol lowering delays saphenous vein graft atherosclerosis in women, the elderly, and patients with associated risk factors. NHLBI post coronary artery bypass graft clinical trial. Post CABG Trial Investigators.

BACKGROUND: The NHLBI Post Coronary Artery Bypass Graft trial (Post CABG) showed that aggressive compared with moderate lowering of low-density lipoprotein-cholesterol (LDL-C) decreased obstructive changes in saphenous vein grafts (SVGs) by 31%.1 Using lovastatin and cholestyramine when necessary, the annually determined mean LDL-C level ranged from 93 to 97 mg/dL in aggressively treated patients and from 132 to 136 mg/dL in the others (P<0.001). METHODS AND RESULTS: The present study evaluated the treatment effect in subgroups defined by age, gender, and selected coronary heart disease (CHD) risk factors, ie, smoking, hypertension, diabetes mellitus, high-density lipoprotein cholesterol (HDL-C) <35 mg/dL, and triglyceride serum levels >/=200 mg/dL at baseline. As evidenced by similar odds ratio estimates of progression (lumen diameter decrease >/=0.6 mm) and lack of interactions with treatment, a similar beneficial effect of aggressive lowering was observed in elderly and young patients, in women and men, in patients with and without smoking, hypertension, or diabetes mellitus, and those with and without borderline high-risk triglyceride serum levels. The change in minimum lumen diameter was in the same direction for all subgroup categories, without significant interactions with treatment. CONCLUSIONS: Aggressive LDL-C lowering delays progression of atherosclerosis in SVGs irrespective of gender, age, and certain risk factors for CHD.

Rationale and design of the Arterial Disease Multiple Intervention Trial (ADMIT) pilot study.

The primary objectives of the pilot study were to: (1) evaluate the feasibility of recruiting patients with peripheral arterial disease (PAD); (2) measure the efficacy and safety of high-density lipoprotein (HDL)-raising treatment, low-density lipoprotein (LDL)-lowering therapy, antioxidant therapy, antithrombotic therapy, and their combinations; and (3) assess adherence to a complex multiple drug regimen. Secondary objectives included measurement of the effect of the interventions on prespecified biochemical markers, maintenance of therapy masking (in particular with niacin), and measurement of the intervention's impact on functional status and on quality of life. To date, no secondary prevention trial has been conducted specifically among patients with PAD. Intermittent claudication affects about 0.5% to 1.0% of persons aged >35 years. There is a striking increase in incidence of PAD with age, particularly among those aged >50 years in both sexes, although men are twice as likely as women to develop PAD. The Arterial Disease Multiple Intervention Trial was a double-blind randomized pilot trial of 468 participants with documented PAD. A 2 x 2 x 2 factorial design was used to evaluate the effect of 3 interventions. The pilot incorporated several major novel design features: first, the use of a simple noninvasive method (measurement of ankle brachial index) to identify a population with either symptomatic or asymptomatic PAD; and second, a lipid modifying strategy to increase HDL with nicotinic acid in the intervention group while lowering LDL levels equally with an hydroxymethylglutaryl-coenzyme A reductase inhibitor as needed in the intervention and control group. Two other arms, the antioxidant arm (consisting of beta-carotene and vitamins E and C) and the antithrombotic arm (using warfarin) were also added. Adherence to therapy was measured by pill count, and success in treatment was measured by the proportion of values in target range for HDL, LDL, and the international normalized ratio.