M.Heikki Frick

Helsinki Heart Study. New perspectives in the prevention of coronary heart disease.

SummaryThe Helsinki Heart Study tested the effect of modifying plasma low density lipoprotein (LDL)- and high density lipoprotein (HDL)-cholesterol on the primary prevention of coronary heart disease in middle-aged men with non-HDL-cholesterol ⩾ 5.2 mmol/L (200 mg/dl). One group (2046 men) received 600mg of gemfibrozil twice daily, and the other (2035 men) received placebo. Averaged over the 5-year trial period, gemfibrozil induced mean decreases of 11% in LDL-cholesterol and 35% in triglycerides and a mean increase of 11% in HDL-cholesterol compared with placebo. These changes were accompanied by a 34% reduction (number of end-points; 56 vs 84) in the incidence of coronary heart disease. The reduction was largest in subjects with type IIB hyperlipoproteinaemia and smallest in subjects with type IIA hyperlipoproteinaemia. The changes in serum HDL-and LDL-cholesterol during the trial were associated (p < 0.02 and p < 0.05, respectively) with the risk of coronary heart disease in the gemfibrozil group, but not in the placebo group.

Adrenal androgens and testosterone as coronary risk factors in the Helsinki Heart Study

We investigated the role of adrenal androgens, cortisol, testosterone and sex-hormone binding globulin (SHBG) as coronary risk factors using a nested case-control design. The study population consisted of 62 cases with cardiac end-points and 97 controls on placebo during the last 4 years in the Helsinki Heart Study. Serum concentrations of dehydroepiandrosterone, dehydroepiandrosterone sulfate (DHEAS), androstenedione, androstanediol glucuronide, cortisol, testosterone, and SHBG at the first annual visit of the 5-year study period were determined by radioimmunoassays. The only significant difference was found in DHEAS, with cases having higher levels than controls (P < 0.04). DHEAS levels were positively associated with smoking (P < 0.001), alcohol consumption (P < 0.04) and triglyceride levels (P < 0.002) and with systolic (P < 0.04) and diastolic (P < 0.006) blood pressures, and negatively associated with age (P < 0.01) and HDL-cholesterol (P < 0.03). The association between DHEAS and the CHD risk was studied using logistic regression analyses with the classical risk factors--age, smoking, blood pressure, and lipid levels--as covariates in the models. Studies of the joint effects of age and DHEAS disclosed that the risk associated with elevated DHEAS was confirmed to older men (odds ratio (OR) 7.3, 95%, CI 2.3-23.3). A similar analysis with smoking revealed that the DHEAS-related risk was mainly found in smokers (OR 3.4, 95% CI 1.5-8.2). One possible explanation for these results is that some form of mild steroid biosynthetic defect of the adrenals or functional adrenal hyperplasia associated with high DHEAS levels increases the CHD risk in this population.

Relation between baseline lipid and lipoprotein values and the incidence of coronary heart disease in the Helsinki Heart Study

A 34% reduction in the incidence of definite coronary heart disease events was observed in dyslipidemic men treated with gemfibrozil in the Helsinki Heart Study, a controlled 5-year, double-blind primary prevention trial for coronary heart disease. Over the entire study period, gemfibrozil therapy induced mean decreases of 10% in serum total cholesterol levels, 11% in low-density lipoprotein (LDL) cholesterol, 35% in triglyceride levels, and a mean increase of 11% in high-density lipoprotein (HDL) cholesterol level, compared with placebo. The differences in percentage changes in LDL cholesterol between gemfibrozil- and placebo-treated men varied among Fredrickson hyperlipoproteinemia types; after 1 year of treatment the difference was greatest for type IIA hyperlipoproteinemia (14 percentage units) and smallest for IIB hyperlipoproteinemia (3 percentage units). The treatment-associated changes in HDL cholesterol and triglycerides did not differ materially between the 3 hyperlipoproteinemia types, when calculated in the same way. The gemfibrozil-associated reduction in incidence of definite coronary events varied among Fredrickson types and among tertiles of baseline HDL cholesterol and triglycerides. The greatest rate reductions were seen in subjects with type IIB hyperlipoproteinemia, low initial HDL level or high initial triglycerides. These results suggest that subjects with low HDL cholesterol and type IIB hyperlipoproteinemia (and possibly type IV hyperlipoproteinemia) would benefit from treatment with gemfibrozil.

Serum lipid changes in a one-year, multicenter, double-blind comparison of doxazosin and atenolol for mild to moderate essential hypertension

Proatherogenic changes in serum lipid concentrations have been implicated as one of the major risk factors in the development of coronary artery disease. In a double-blind study, the new alpha 1-adrenoceptor inhibitor, doxazosin, was compared with atenolol for effects on the serum lipid profile. Ninety-six hypertensive patients were treated for up to 1 year with either doxazosin or atenolol once daily. There were statistically significant differences (p less than or equal to 0.01) between doxazosin and atenolol after 20 to 52 weeks of treatment in changes from baseline total triglyceride levels, high density lipoprotein (HDL) cholesterol levels and HDL/total cholesterol ratio. The percentage of change from baseline and the statistical significance of the difference between treatment groups were: total triglycerides, doxazosin -5.9%, atenolol +32.4% (p = 0.01); HDL cholesterol, doxazosin +7.2%, atenolol -5.6% (p = 0.007) and HDL/total cholesterol ratio: doxazosin +8.7%, atenolol -6.2% (p = 0.006). All mean changes were in favor of doxazosin therapy. In addition, doxazosin treatment beneficially decreased total serum cholesterol levels (-1.6%) compared with atenolol (+0.6%), although not to a significant degree. The differences were maintained in the cohort of 67 patients treated for a full year. The favorable change exerted by doxazosin on the lipid profile suggests that it may have a beneficial influence on the lipid risk factor. These results, together with the sustained decrease in blood pressure achieved for up to 1 year of therapy, suggest that doxazosin may reduce the risk of coronary artery disease in susceptible patients.

Effects of physical training on circulation at rest and during exercise

Abstract Fourteen young men with sedentary habits were studied before and after a two-month hard training period to obtain data on the changes in hemodynamics, explored both at rest and during supine leg exercise. The physical working capacity of the subjects was markedly improved, paralleled by an increase in the heart volume. The cardiac output at rest was slightly higher after training, due to a significant increase in the stroke volume. The change in the total peripheral resistance was inversely commensurate to that of the cardiac output. The heart rate was reduced at rest in eleven of the subjects. Left heart work was unchanged, but this work was performed with a smaller oxygen cost after training, as assumed from the changes in the tension-time index. This sequence of events was even more evident in the circulatory adjustment during exercise, characterized by a larger stroke volume and a significantly lower heart rate than before training.

Progression of coronary artery disease in randomized medical and surgical patients over a 5-year angiographic follow-up

Progression of coronary artery disease (CAD) was assessed prospectively in a randomized series of 36 medically treated and 42 surgically treated patients with angina pectoris. The medical patients were reexamined after 5 years and the surgical patients 3 weeks, 1 year and 5 years after operation. Sixty-seven percent of the medical patients and 69% of the surgical patients had progression. The frequency of new lesions in initially normal segments after 5 years in the medical group was 6.7%, versus 4.1% in ungrafted normal segments in the surgical group (p = 0.05 less than 0.010). The frequency of progression in abnormal arteries was 24.1% in the medical group, versus 22.6% in the ungrafted arteries of the surgical group (p = 0.90 less than 0.95). The rate of progression of obstructed segments proximal to the graft over 5 years was 43%, versus 27% of the corresponding segments in the medical group (p less than 0.01). Progression took place in 11.6% of normal segments proximal to the graft, versus 2% of the corresponding segments in the medical group (p less than 0.05); 69% of progression occurring in segments proximal to the graft had reached total occlusion, versus 38% of the corresponding segments in the medical group (p less than 0.01). Progression developed in 3.9% of segments distal to the graft, versus 3.1% of the corresponding segments in the medical group. Progression takes place at identical rates in medically treated patients and in ungrafted arteries and segments distal to the graft in surgical patients. Proximal to the graft the rates differ and total occlusions appear as early as 3 weeks after operation.

Cigarette smoking is associated with elevated adrenal androgen response to adrenocorticotropin

Cigarette smoking alters the pattern of endogenous steroid levels. We examined this phenomenon in two separate male groups. Group A consisted of 189 dyslipidemic men participating in the Helsinki Heart Study and group B of 100 men including patients with heart disease and healthy controls. The subjects in the latter group underwent ACTH-testing. In group A, smokers had significantly higher basal androstenedione and dehydroepiandrosterone sulfate (DHEAS) levels and androstenedione/cortisol ratios than nonsmokers. Mean concentrations of cortisol, dehydroepiandrosterone (DHEA), androstanediol glucuronide, testosterone, and sex-hormone binding globulin (SHBG) did not differ between smokers and nonsmokers. In group B, smokers had lower high density lipoprotein (HDL)-cholesterol and apolipoprotein AI and higher triglyceride levels than nonsmokers. Basal androstenedione and ACTH stimulated androstenedione and DHEA concentrations were higher in smokers. No significant differences were found in basal insulin, SHBG, estrone, estradiol, testosterone, free testosterone, and dihydrotestosterone concentrations between smokers and nonsmokers. These results suggest that smoking decreases the activity of either 21- or 11 beta-hydroxylase in the adrenal cortex, which results in increased secretion of adrenal androgens.

Changes in native coronary arteries after coronary bypass surgery: Role of graft patency, serum lipids and hypertension☆

Sixty-seven patients were studied by coronary angiography early (mean 3 weeks) and late (mean 13 months) after coronary bypass surgery to assess changes in the native coronary vessels. Among the 208 nongrafted arteries progression of disease was found in 2.9 percent. In arteries that were normal before operation, the rate was 0.7 percent; in those with luminal obstructions the rate was 7.6 percent (P less than 0.05). Progression of disease occurred in 6 of the 67 patients (8.9 percent). In five bypassed arteries (5 percent), progression of disease occurred at or near the anastomotic site; in this subset the procedure was classified a technical failure. Progression of disease distal to graft insertion occurred in 2.4 percent of cases. The greatest incidence of progression took place proximal to graft insertion, in 24.2 percent of the grafted arteries. This rate differed significantly from the rate in non-grafted arteries (P less than 0.001) and in distal segments of grafted arteries (P less than 0.001). If the grafts were patent in the late control study, the progression of disease proximally occurred at a rate of 24 percent; if they were occluded, the rate was 25 percent. The data on timing of graft occlusion suggested that graft patency was related to the proximal progression. The prevalence of hyperlipidemia or hypertension did not correlate with progression of disease in any group.

Effect of gemfibrozil on the concentration and composition of serum lipoproteins A controlled study with special reference to initial triglyceride levels

We investigated the modulating effect of serum total triglycerides on the lipid composition of various lipoproteins, and on the response to gemfibrozil treatment. This placebo controlled study was conducted blind in 60 participants of the Helsinki Heart Study. An inverse relationship was observed between cholesterol content in all lipoprotein fractions and serum total triglyceride level. Gemfibrozil, in addition to changing the absolute amounts of lipoprotein lipids, also normalized the qualitative abnormalities associated with hypertriglyceridemia. Gemfibrozil increased the level of HDL-cholesterol with the main effect on HDL3-subfraction. The observed reduction in LDL-cholesterol was dependent on the initial triglyceride level.

Regional Myocardial Perfusion Abnormalities on Xenon-133 Imaging in Patients With Angina Pectoris and Normal Coronary Arteries

With use of semiselective xenon-133 injections and gamma camera recording, myocardial scintigrams were obtained in a series of 20 patients with angina pectoris, abnormal exercise electrocardiograms and normal coronary arteries. Ten patients (Group I) exhibited localized perfusion defects and the other 10 (Group II) a hjemogenous uptake of the tracer. Group I was characterized by more past myocardial infarctions and, most significantly, by male preponderance (P less than 0.001). Computer analysis of regional xenon-133 washout curves revealed that every patient in Group I had a reduced flow rate in the area of the perfusion defect (P less than 0.001). A comparison of this group with 26 patients with similarly abnormal scintigrams but coronary arterial obstruction revealed that myocardial perfusion was 16 to 18 percent greater in the group with normal coronary arteries. In three patients of this group, myocardial perfusion rates were not augmented by atrial pacing in contrast to the response in patients with coronary arterial obstruction. The data demonstrated localized perfusion abnormalities in half of the patients with angina pectoris and normal coronary arteries and constitute evidence that a metabolic disorder is not the sole mechanism for ischemia in this syndrome.