Simulating CSF flow dynamics in the normal and the Chiari I subarachnoid space during rest and exertion.

BACKGROUND AND PURPOSE: CSF fluid dynamics in healthy subjects and patients with Chiari I have been characterized during rest with phase-contrast MR imaging and CFD. CSF flow velocities and pressures in the nonresting state have not been adequately characterized. We used computer simulations to study CSF dynamics during increased heart rates in the normal and Chiari I subarachnoid space. MATERIALS AND METHODS: Cyclic CSF flow was simulated for multiple cycles in idealized 3D models of the subarachnoid space for normal and Chiari I malformation subarachnoid spaces, with flow cycles corresponding to 80 or 120 heart beats per minute. Flow velocities and pressures were computed by the Navier-Stokes equations. Synchronous bidirectional flow and flow patterns were displayed in Star-CD and inspected visually. Peak velocities and pressure differences in the 2 models were compared for the 2-cycle frequencies. RESULTS: Elevating the cycle rate from 80 to 120 cpm increased peak superior-inferior pressure gradients (top-bottom) by just 0.01% in the normal model and 2% in the Chiari model. Corresponding average pressure gradients increased by 92% and 100%, respectively. In addition, in both models, the range of synchronous bidirectional flow velocities increased. Systolic velocities had smaller increases with faster cycling. For each cycle rate, peak and average pressure gradients in the Chiari model were greater than in the normal model by 11%-16%. CONCLUSIONS: Raising the cycle rate from 80 to 120 cpm increased superior-inferior average pressure gradients and the range of synchronous bidirectional flow velocities in the normal and Chiari I models.

Effect of tonsillar herniation on cyclic CSF flow studied with computational flow analysis.

BACKGROUND AND PURPOSE: The Chiari I malformation, characterized by tonsils extending below the foramen magnum, has increased CSF velocities compared with those in healthy subjects. Measuring the effect of tonsillar herniation on CSF flow in humans is confounded by interindividual variation. The goal of this study was to determine the effect of herniated tonsils on flow velocity and pressure dynamics by using 3D computational models. MATERIALS AND METHODS: A previously described 3D mathematic model of the normal subarachnoid space was modified by extending the tonsils inferiorly. The chamber created was compared with the anatomy of the subarachnoid space. Pressures and velocities were calculated by CFA methods for sinusoidal flow of a Newtonian fluid. Results were displayed as 2D color-coded plots and 3D animations. Pressure gradients and flow velocities were compared with those in the normal model. Velocity distributions were also compared with those in clinical images of CSF flow. RESULTS: The model represented grossly the subarachnoid space of a patient with Chiari I malformation. Fluid flow patterns in the Chiari model were complex, with jets in some locations and stagnant flow in others. Flow jets, synchronous bidirectional flow, and pressure gradients were greater in the Chiari model than in the normal model. The distribution of flow velocities in the model corresponded well with those observed in clinical images of CSF flow in patients with Chiari I. CONCLUSIONS: Tonsillar herniation per se increases the pressure gradients and the complexity of flow patterns associated with oscillatory CSF flow.

Correlates of blood pressure change in middle-aged male mild hypertensives: results from the untreated control group in the Oslo hypertension trial. The Oslo Study.

The never-treated control group in the Oslo Study hypertension trial of middle-aged men 40-49 years old at entry (n = 379) was studied with respect to five-year change in blood pressure and its correlates. The study began in 1972 and ended in 1979, and each patient was followed for five years. Both baseline and rate of change of correlates were analyzed as independent variables versus rate of change in blood pressure as the dependent variable. Rate of change in serum triglycerides were found to be the strongest correlate of rate of change in blood pressure in this population of healthy mild hypertensives. In addition, rate of change in serum cholesterol and body weight made significant contributions in some analyses, but to a lower degree than did rate of change in triglycerides. The model predicts a substantial decrease in blood pressure if lipids and body weight are reduced. Rate of change in sodium, uric acid, and chloride concentrations were also associated with blood pressure change, but total degree of explanation of all explaining variables only accounted for 11-15% of total variation in annual blood pressure change.

The influence of atenolol and prazosin on serum lipids and atherosclerosis in minipigs fed a hyperlipidemic diet.

1. The effect of the adrenergic blockers prazosin and atenolol were tested in hypercholesterolemic Göttingen minipigs. 2. After 1 yr there was a significant reduction of plasma triglycerides and total cholesterol in the medicated animals as compared to untreated ones. 3. No significant difference in atherosclerotic lesions was observed.

Oslo study: treatment of mild hypertension. A five-year controlled drug study.

During 1972-1973, 785 symptom-free men, aged 40-49, with mild hypertension, were randomly assigned to a 5-year controlled drug treatment study, 406 in the treatment group and 379 in the control group. The basic drug was hydrochlorothiazide, in addition methyldopa or propranolol if necessary. The mean observation time was 66 months (range 60-78). At 5 years' follow-up there was no difference in total mortality between treated and controls, nor in cardiovascular mortality. There was a good prevention of cerebrovascular disease (0 vs. 7). Regarding coronary heart disease, however, there was an opposite trend (20 vs. 13, p greater than 0.10). During the trial, different drug-induced changes were observed in serum lipids, glucose and uric acid. The importance of these changes are still uncertain.

Enalapril, atenolol, and hydrochlorothiazide in mild to moderate hypertension. A comparative multicentre study in general practice in Norway.

Enalapril, atenolol, and hydrochlorothiazide were compared in a double-blind randomised parallel study in general practice. 436 patients with mild to moderate hypertension were included at 76 centres. A two-week placebo run-in period was followed by 16 weeks of monotherapy. The initial doses were: enalapril 20 mg; atenolol 50 mg; and hydrochlorothiazide 25 mg. These were doubled if treatment was not effective after 4 weeks. Adverse reactions were the main reason for withdrawal from the study (9 on enalapril, 19 on atenolol, and 8 on hydrochlorothiazide). Systolic and diastolic blood pressures were significantly reduced in all three groups. The reduction in systolic blood pressure was greater on enalapril than on atenolol. Serum potassium was reduced and uric acid increased on hydrochlorothiazide. Fasting blood sugar rose on atenolol but fell on enalapril. The frequency of adverse reactions was acceptable in all three groups. After 16 weeks on treatment significantly more adverse reactions were recorded in the atenolol group than in the enalapril group. Enalapril is effective and well tolerated in patients with mild to moderate hypertension.

Coronary heart disease and treatment of hypertension. Some Oslo Study data.

The Oslo Hypertension Study began in 1972; patients were followed for an average of 66 months (range: 60 to 78). A total of 785 healthy men, aged 40 to 49, with mild hypertension was randomly assigned to either a drug-treated group or to an untreated control group. Hydrochlorothiazide was used alone in 36 percent of patients, in combination with propranolol in 26 percent, and with methyldopa in 20 percent. Other drugs, including combinations with hydrochlorothiazide, were used in 18 percent. A total of 95 percent of patients in the drug-treated group received hydrochlorothiazide. Complications of hypertension such as stroke and aneurysm occurred only in the control group. Coronary events were more numerous in the drug-treated group; thus, the total incidence of cardiovascular complications did not significantly differ between the treated and untreated groups. After five and 10 years, total mortality was the same in both groups. However, the coronary heart disease mortality rate at 10 years was significantly greater in the drug-treated group than in the untreated control group (14 versus three, p less than 0.01). This article presents possible reasons for the failure of antihypertensive drug therapy to prevent coronary heart disease. The adverse effect of diuretics and beta-adrenergic blockers, both on lipid and carbohydrate metabolism, is contrasted with the effect of the alpha-adrenergic blocker prazosin, which has been shown to have no adverse effect on the blood lipid profile. In a short-term trial that was part of the Oslo Study, prazosin was found to reduce total serum cholesterol by 9 percent, low-density lipoprotein and very-low-density lipoprotein cholesterol by 10 percent, and total triglycerides by 16 percent. All these changes are statistically significant.

Oslo Hypertension Study.

The Oslo Hypertension Study started in 1972 and lasted for 66 (range 60-78) months. A total of 785 healthy men, aged 40 to 49 years, with mild hypertension were randomised to a drug-treated group and to an untreated, control group. The drugs used for treatment were hydrochlorothiazide alone in 36%, hydrochlorothiazide and propranolol in 26%, hydrochlorothiazide and methyldopa in 20%, and other drugs in 18%. A total of 95% in the drug-treated group received hydrochlorothiazide. Pressure complications, such as stroke and aneurysms, only occurred in the control group. Coronary events were more numerous in the drug-treated group, so that the total incidence of cardiovascular complications did not significantly differ between the treated and untreated groups. After 5 and 10 years, total mortality was found to be the same in both groups. However, the 10-year coronary heart disease mortality was significantly higher in the drug-treated group than in the untreated controls (14 v 3, p less than 0.01). Possible reasons for the failing effect of drug treatment of hypertension on coronary heart disease is discussed, and attention is drawn to the adverse effect of diuretics and beta-adrenergic blockers, both on lipid and carbohydrate metabolism. This is in contrast to the alpha-adrenergic blocker, prazosin, which has been shown to improve the blood lipid profile.

Therapeutic traditions in Northern Ireland, Norway and Sweden: I. Diabetes. WHO Drug Utilization Research Group (DURG).

A questionnaire survey was carried out to explore differences in the approach to treatment of patients with Type II diabetes between physicians in Northern Ireland, Norway and Sweden, and to discover to what extent it could account for the three-fold difference in drug use between the countries. A representative sample of 400 physicians in each country was asked to give their opinions on the choice of therapy for three model cases designed to cover the spectrum of treatment - from diet alone to insulin. Significantly more Swedish (65%) than Northern Irish (51%) and Norwegian (52%) doctors suggested diet alone for uncomplicated diabetes recently discovered in a middle aged, overweight man. For symptomatic diabetes in a 76 year old over-weight woman with few retinal microaneurysms, the majority of physicians in all three countries suggested treatment with sulphonylureas. Biguanides were here a more common alternative in Northern Ireland than in Scandinavia. For suspected secondary treatment failure in a 63 year old woman with no signs of complications, insulin was suggested by 71% of the Norwegian doctors but only by 44 and 49% of those in Northern Ireland and Sweden, respectively. General practitioners tended to suggest oral treatment earlier and to maintain it longer than hospital physicians. The study has demonstrated significant differences in the approach to treatment of Type II diabetes mellitus between physicians in the three countries. However, the differences were more prominent in the choice of drugs than in the threshold of drug treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Therapeutic traditions in Northern Ireland, Norway and Sweden: II. Hypertension. WHO Drug Utilization Research Group (DURG).

A questionnaire survey based on hypertension case histories was performed among a representative sample of 400 GP's and hospital doctors in Northern Ireland, Norway and Sweden, countries having markedly different utilization of antihypertensive drugs. We found a greater propensity to start antihypertensive drug treatment in Northern Ireland than in Norway and Sweden. This was true both in mild diastolic and isolated systolic hypertension. Yet the utilization of antihypertensive drugs in Sweden is about 60% higher than in Northern Ireland and 30% higher than in Norway. Swedish physicians preferred beta-blockers as their first choice to a greater extent than physicians in Northern Ireland and Norway who selected thiazides more often. In general, the choice of drugs agreed with the sales and prescribing patterns in the three countries. Besides providing more insight in therapeutic traditions the study indicates that the lower prescribing of antihypertensive drugs in Northern Ireland, and to some extent in Norway, compared to Sweden, might be due to differences in true or apparent morbidity.

Stenoses in the coronary arteries. Relation to atherosclerotic lesions, coronary heart disease, and risk factors. The Oslo Study.

Coronary heart disease is strongly associated with the presence of stenosis in the epicardial coronary arteries. This prospective autopsy study shows that the relationship between risk factors for coronary heart disease and the occurrence of stenosis is the same as between risk factors and coronary atherosclerotic lesions: serum cholesterol, systolic and diastolic blood pressure contribute to formation of coronary stenosis; high density lipoprotein cholesterol is inversely related to stenosis. None of the other risk factors for coronary heart disease, such as fasting triglycerides, smoking habits, social class, and physical activity at work and at leisure, was statistically associated with the occurrence of coronary stenosis. Additional statistical analyses show that these selected risk factors do not seem to have any independent influence on the development of coronary stenosis over and above that of the extent of raised atherosclerotic lesions.

The Oslo Study: diet and antismoking advice. Additional results from a 5-year primary preventive trial in middle-aged men.

In this randomized, primary prevention trial of 1,232 high-risk, middle-aged Oslo men, advice during 5 years about diet and smoking brought about a significant reduction (47%) in incidence of first major coronary heart disease (CHD) events in the intervention group compared with controls. Data are presented indicating that the net difference of 10% in serum cholesterol between groups was the main cause for this achievement and that the antismoking factor, due to a rather small net difference in quit rates (17 and 24% in control and intervention groups, respectively), contributed to a lesser degree. Analysis of social class reveals that the favorable results in the intervention group were present in all social strata, despite the unexpected finding that lower class men experienced a lower CHD incidence than men of higher socioeconomic status. Antismoking advice was especially effective in lower class intervention group men. Among cigarette quitters, lower social class men reduced their serum cholesterol more than higher social class men. However, for the total intervention group, higher status men had at least as great a reduction in serum cholesterol as did lower status men. With endpoint follow-up extended to 8.5-10 years, additional cases of CHD (nonfatal and fatal myocardial infarction and sudden death) numbered 7 and 10 in the intervention and control groups, respectively; CHD cases throughout the trial totaled 25 and 45 (P approximately equal to 0.02). Total deaths numbered 19 and 31, respectively (P approximately equal to 0.05).

Coronary risk factors and their pathway of action through coronary raised lesions, coronary stenoses and coronary death. Multivariate statistical analysis of an autopsy series: the Oslo Study.

From 1972 to 1973, 16,202 Oslo men, aged 40 to 49 years, were examined for cardiovascular disease and coronary heart disease (CHD) risk factors. This report describes the results of autopsy examinations from 204 of 471 men who died in this cohort with regard to associations between selected risk factors and (1) raised coronary atherosclerotic lesions (RL), (2) coronary artery stenosis, and (3) CHD death. Total serum cholesterol and blood pressure levels were positively associated with all 3 measures of coronary atherosclerosis and its complications, both in univariate and multivariate analyses, whereas high-density lipoprotein (HDL) cholesterol was highly and inversely related. Triglyceride levels, cigarette smoking, social class and physical activity at work and at leisure were not significantly associated with either of the 3 measures. When RL was added to the model with stenosis as the dependent variable, the risk factors no longer appeared as independent; this is consistent with the hypothesis that these factors, when significant, work through the development of RL to produce stenosis. HDL cholesterol was the only risk factor independently and significantly associated with CHD death when RL or stenosis or both were put into the model for CHD. This points to the possibility of HDL cholesterol also working through mechanisms other than the prevention of RL and stenosis toward CHD death.

Serum glucose levels during long-term observation of treated and untreated men with mild hypertension. The Oslo study.

Serum glucose levels, triglyceride levels, and body weight are reported from a controlled drug trial in men, aged 40 to 49, with uncomplicated mild hypertension. The drug treatment started with hydrochlorothiazide alone, and methyldopa was added when necessary. If side effects occurred, methyldopa was replaced by propranolol. No detailed advice about diet, smoking, or weight reduction was given to any group. The untreated control subjects had a small increase in serum glucose levels during five years, from 6.08 to 6.21 mmol/liter. Those treated with hydrochlorothiazide alone and those treated with hydrochlorothiazide plus methyldopa had a small increase in serum glucose levels of the same order as that in the control subjects. However, those receiving the thiazide/propranolol combination experienced a sizeable increase in glucose levels, from 5.96 to 6.53 mmol/liter (p less than 0.001). This increase was significantly greater than the increase in the other groups (p less than 0.001). The thiazide/propranolol group also showed a significant increase in serum triglyceride levels (p less than 0.05). There was no difference in serum potassium levels in the different drug groups. The results indicate that moderate thiazide doses do not have significant effects on serum glucose levels in this age group. Propranolol in combination with thiazide seems to increase the level of serum glucose.

The influence of prazosin and propranolol on serum lipids and atherosclerosis in standard fed pigs.

The influence of prazosin and propranolol on serum lipids and atherosclerosis was evaluated in standard fed pigs during a nine months experimental period. The incidence and severity of atherosclerotic lesions was very low, and no difference could be observed neither between the two drugs nor between the drug groups and the placebo group. Prazosin and propranolol induced no marked change in the serum lipid profile. The results could be explained by the very low fat content, 3.6 per cent, in the present standard diet.

Treatment of mild hypertension with diuretics. The importance of ECG abnormalities in the Oslo Study and in MRFIT.

The Multiple Risk Factor Intervention Trial (MRFIT) showed that diuretic treatment of hypertensive men with certain ECG abnormalities at entry was associated with an increased coronary heart disease mortality in the special-intervention group as compared with the usual-care group. Following the same criteria for resting ECG abnormalities as in MRFIT, The Oslo Study trial of mild hypertension has been reanalyzed for similar effects. Although numbers of first coronary events are low in this study (20 cases in the treated group and 13 in the control group), similar trends are present in The Oslo Study. The excess of seven cases of coronary events in the Oslo treatment group can mainly be explained by introduction of the MRFIT ECG-Minnesota codes.

Changes in the lipoprotein profile during antihypertensive therapy.

In the Oslo study serum lipids have been studied during treatment with some of the most frequently used antihypertensive drugs. Hydrochlorothiazide induced no significant changes. However, those patients with the most marked increase in uric acid showed an increase of serum triglycerides. Total cholesterol was unchanged in these men. The beta-adrenoceptorblocking drugs propranolol, atenolol and oxprenolol caused a reduction of HDL cholesterol and an increase of total triglycerides. Total cholesterol remained unchanged. Pindolol induced no significant lipoprotein changes. Prazosin reduced total cholesterol and total triglycerides. HDL cholesterol remained unchanged. LDL + VLDL cholesterol was reduced.

The impact on serum lipids of combinations of diuretics and beta-blockers and of beta-blockers alone.

Treatment of hypertension with diuretics and beta-blockers is often associated with changes in lipids and uric acid levels. The clinical importance of these metabolic changes is still uncertain, but potentially they might counteract the beneficial effect of blood pressure reduction in some patients. As these drugs are widely used to prevent the cardiovascular complications of hypertension, it is imperative that we evaluate the effect of these drug-induced metabolic changes on the atherosclerotic process in humans.