Matti Mänttäri

Joint effects of serum triglyceride and LDL cholesterol and HDL cholesterol concentrations on coronary heart disease risk in the Helsinki Heart Study. Implications for treatment.

BackgroundWe studied the joint effect of baseline triglyceride and lipoprotein cholesterol levels on the incidence of cardiac end points in the trial group (n = 4,081) of the Helsinki Heart Study, a 5-year randomized coronary primary prevention trial among dyslipidemic middle-aged men. The relative risks (RR) were calculated using Cox proportional hazards models with a dummy variable technique that allows simultaneous study of subgroup combinations from the placebo and treatment groups. Methods and ResultsIn the placebo group (n = 2,045), the low density lipoprotein cholesterol (LDL-C)/high density lipoprotein cholesterol (HDL-C) ratio was the best single predictor of cardiac events. This ratio in combination with the serum triglyceride level revealed a high-risk subgroup: subjects with LDL-C/HDL-C ratio >5 and triglycerides >2.3 mmol/1 had a RR of 3.8 (95% CI, 2.2-6.6) compared with those with LDL-C/HI)L-C ratio ≤5 and triglyceride concentration ≤2.3 mmol/1. In subjects with triglyceride concentration >2.3 mmol/l and LDL-C/H1)L-C ratio ≤5, RR was close to unity (1.1), whereas in those with triglyceride level ≤2.3 mmoVIl and LDL-C/HDL-C ratio >5, RR was 1.2. The high-risk group with LDL-C/HDL-C ratio >5 and triglyceride level >2.3 mmol/1 profited most from treatment with gemfibrozil, with a 71% lower incidence of coronary heart disease events than the corresponding placebo subgroup. In all other subgroups, the reduction in CHD incidence was substantially smaller ConclusionsSerum triglyceride concentration has prognostic value, both for assessing coronary heart disease risk and in predicting the effect of gemfibrozil treatment, especially when used in combination with HDL-C and LDL-C.

Anti-Cardiolipin Antibodies and Risk of Myocardial Infarction in a Prospective Cohort of Middle-Aged Men

BACKGROUND Data concerning the relation between antiphospholipid (aPL) antibodies and myocardial infarction in subjects without evidence of overt autoimmune disease are conflicting. All published studies have been performed on survivors of myocardial infarction or in patients with established coronary heart disease. The purpose of the present study was to determine whether the presence of aPL antibodies, namely, anti-cardiolipin (aCL) antibodies, carries a risk for myocardial infarction in a prospective cohort. METHODS AND RESULTS The sera to be studied were drawn at entry from middle-aged dyslipidemic men (non-high-density lipoprotein cholesterol, > or = 5.2 mmol/L) participating in the Helsinki Heart Study, a 5-year coronary primary prevention trial with gemfibrozil. Samples were tested for IgG-class antibodies to cardiolipin by an ELISA. The risk was estimated with logistic regression analysis using a nested case-control design with 133 patients (myocardial infarction or cardiac death) and 133 control subjects, matched for treatment (gemfibrozil/placebo) and geographical area. The aCL antibody level, as expressed in optical density units, was significantly higher in patients than in control subjects (0.417 versus 0.361; P < .005). Subjects with the antibody level in the highest quartile of distribution had a relative risk for myocardial infarction of 2.0 (95% confidence interval, 1.1 to 3.5) compared with the remainder of the population. This risk was independent of confounding factors, such as age, smoking, systolic blood pressure, low-density lipoprotein (LDL), and high-density lipoprotein. There was a correlation between the levels of aCL antibodies and antibodies to oxidized LDL (r = .40, P < .001), and their joint effect was additive for the risk. CONCLUSIONS In a prospective cohort of healthy middle-aged men, the presence of a high aCL antibody level is an independent risk factor for myocardial infarction or cardiac death. Antibodies to cardiolipin and oxidized LDL may, at least in part, represent cross-reactive antibody populations.

Lipoprotein (a) and coronary heart disease risk: a nested case-control study of the Helsinki Heart Study participants

To prospectively assess the role of lipoprotein(a) (Lp(a)) as a risk factor for coronary heart disease, the serum Lp(a) concentration was determined in 130 subjects without coronary events and in 138 patients in whom coronary events (i.e. fatal and non-fatal myocardial infarction and cardiac death) occurred during the 5-year Helsinki Heart Study. The participants of this study (n = 4081) were 40-55-year-old men who were devoid of coronary heart disease at the beginning of the trial; half were randomized to gemfibrozil and the other half to placebo treatment. In patients with coronary events blood pressure and total cholesterol were not significant predictors of the events but their LDL cholesterol was higher than compared to the control group in this cohort (P less than 0.05). The serum Lp(a) concentration was determined by immunoassay from samples obtained 3 months after the beginning of the trial and then stored at -20 degrees C until analysed. Studies on the effect of long term storage at -20 degrees C on serum Lp(a) levels did not reveal significant changes in Lp(a) concentration in sera stored for up to 8.5 years. The distribution of Lp(a) concentrations were similar in the men with coronary events and the controls. Nor did the mean or median levels of Lp(a) differ significantly between the two groups. Measurements of Lp(a) levels in fresh samples using 2 different immunoassays did not reveal any significant difference between the participants who had survived a myocardial infarction or participants without cardiac events. Thus, we conclude that in the Helsinki Heart Study cohort the serum Lp(a) level was not a predictor of future coronary events.

Infections, Inflammation, and the Risk of Coronary Heart Disease

BACKGROUND The role of infections and inflammation in the pathophysiology of coronary heart disease is emerging. We studied the independent and joint effects of these 2 components on coronary risk. METHODS AND RESULTS We measured baseline levels of C-reactive protein (CRP) and antibodies to adenovirus, enterovirus, cytomegalovirus, and herpes simplex virus as well as to Chlamydia pneumoniae (Cpn) and Helicobacter pylori in 241 subjects who suffered either myocardial infarction or coronary death during the 8.5-year trial in the Helsinki Heart Study, a coronary primary prevention trial. The 241 controls in this nested case-control study were subjects who completed the study without coronary events. Antibody levels to herpes simplex type I (HSV-1) and to Cpn were higher in cases than in controls, whereas the distributions of antibodies to other infectious agents were similar. Mean CRP was higher in cases (4.4 versus 2.0 mg/L; P<0.001), and high CRP increased the risks associated with smoking and with high antimicrobial antibody levels. The odds ratios in subjects with high antibody and high CRP levels were 25.4 (95% CI 2.9-220.3) for HSV-1 and 5.4 (95% CI 2.4-12.4) for Cpn compared with subjects with low antibody levels and low CRP. High antibody levels to either HSV-1 or to Cpn increased the risk independently of the other, and their joint effect was close to additive. CONCLUSIONS Two chronic infections, HSV-1 and Cpn, increase the risk of coronary heart disease. The effect is emphasized in subjects with ongoing inflammation, denoted by increased CRP levels.

Some Coronary Risk Factors Related to the Insulin Resistance Syndrome and Treatment With Gemfibrozil Experience From the Helsinki Heart Study

BACKGROUND Coronary risk factors related to the insulin resistance syndrome tend to cluster in the same individual. Our previous studies have shown that the dyslipidemia characteristic of this syndrome--low HDL cholesterol and high triglyceride (TG) levels--responds well to treatment with gemfibrozil. Most factors related to insulin-resistance syndrome decrease fibrinolytic capacity, whereas a recent study showed that gemfibrozil improves it and thus may attenuate thrombotic events. To discover whether subjects with clustering of factors related to this resistance might in particular benefit from gemfibrozil, we reanalyzed the Helsinki Heart Study data. METHODS AND RESULTS We used Cox regression models to explore the effects of gemfibrozil among overweight subjects with additional coronary risk factors in this hypercholesterolemic male population of 2046 subjects randomized to gemfibrozil and 2035 to placebo. The effect of gemfibrozil was largely confined to overweight subjects: among those with body mass index (BMI) > 26 kg/m2, the net difference in cardiac end points between gemfibrozil and placebo groups was 21 (25 of 1119 versus 46 of 1081), and in those with BMI < or = 26 kg/m2, it was 7 (31 of 927 versus 38 of 954). The risk reduction with gemfibrozil was 78% (P = .002) among those with BMI > 26 kg/m2 and dyslipidemia (TG > or = 2.3 mmol/L and HDL cholesterol < 1.08 mmol/L). Among those with BMI > 26 kg/m2 and three or four of the following factors present--smoking, sedentary lifestyle, blood pressure > or = 140/90 mm Hg, or blood glucose > 4.4 mmol/L--the risk reduction was 68% (P = .03). CONCLUSIONS Gemfibrozil reduced the coronary risk mainly in overweight subjects with additional risk factors known to contribute to the insulin-resistance syndrome or predispose to it.

Effects of Hypertension and Dyslipidemia on the Decline in Renal Function

Experimental evidence suggests that in addition to hypertension, serum lipids might also accelerate the decline in renal function. We tested this hypothesis in 2702 dyslipidemic middle-aged men without renal disease participating in the Helsinki Heart Study, a coronary primary prevention trial. The decline in renal function was estimated from linear regression slopes based on reciprocals of 10 serum creatinine determinations over the study period. Renal function deteriorated 3% on average during the 5-year study, and hypertension accelerated this change. Subjects with an elevated ratio of low- to high-density lipoprotein cholesterol ( > 4.4) had a 20% faster decline than those with a ratio less than 3.2. Both the contribution of the lipoprotein ratio and the protective effect of high-density lipoprotein cholesterol alone remained significant in multiple regression analyses. In the study of joint effects the contribution of lipids was confined to subjects with simultaneous elevation of blood pressure and lipids. The results suggest that in addition to hypertension, blood lipids also modify the decline in renal function.

Apolipoprotein E polymorphism influences the serum cholesterol response to dietary intervention

The association between apolipoprotein (apo) E polymorphism and the response of serum cholesterol to dietary counseling and to gemfibrozil treatment was investigated in 230 dyslipidemic middle-aged participants of the Helsinki Heart Study. Baseline lipid levels were not significantly different between subjects with or without the epsilon 4 allele. Following dietary counseling, participants with the epsilon 4 allele exhibited a greater reduction in serum total cholesterol (P less than .01) and low-density lipoprotein (LDL)-cholesterol (P less than .02) than those without the epsilon 4 allele, while the changes in high-density lipoprotein (HDL)-cholesterol and triglycerides were similar in the two groups. The alterations observed in total cholesterol, HDL-cholesterol, and triglycerides during treatment with gemfibrozil were not different between subjects with or without the epsilon 4 allele. The presence of the epsilon 4 allele and baseline serum cholesterol independently predicted the degree of cholesterol reduction following dietary counseling.

Efficacy of Gemfibrozil in Dyslipidaemic Subjects with Suspected Heart Disease. An Ancillary Study in the Helsinki Heart Study Frame Population

During screening in the Helsinki Heart Study (HHS), a 5-year coronary primary prevention trial with gemfibrozil, some 600 dyslipidaemic individuals were detected who exhibited symptoms and signs of possible coronary heart disease (CHD). These subjects were excluded from the primary study. To secure successful conduct in the HSS, an ancillary protocol was developed for the treatment of these individuals. Three-hundred and eleven subjects were randomized to receive gemfibrozil 600 mg twice daily and 317 subjects to receive a matching placebo over 5 years in a double-blind fashion. The end-point rate, consisting of fatal and non-fatal myocardial infarction and cardiac death, did not differ significantly between the placebo and gemfibrozil groups. The same was true for total mortality. Missing key prognostic factors, e.g. true prevalence of CHD, extent of coronary artery obstructions, degree of left ventricular dysfunction, and their distribution in the groups render the results less reliable and hence the data cannot be used to refute the thesis that treatment of dyslipidaemia in manifest CHD in successful.

The Helsinki Heart Study: Central Findings and Clinical Implications

This paper describes the central findings and discusses the clinical implications of the Helsinki Heart Study. This was a controlled primary prevention trial to test the hypothesis that using gemfibrozil to lower the concentrations of serum low density lipoprotein (LDL) and very low density lipoprotein (VLDL) and to raise that of high density lipoprotein (HDL) protects subjects against coronary heart disease.

Elimination kinetics of myoglobin and creatine kinase in rhabdomyolysis: implications for follow-up.

ObjectiveCreatine kinase and myoglobin are markers of muscular damage in rhabdomyolysis. Whereas myoglobin is considered to be the principal compound causing tubular damage, serum creatine kinase level is presently guiding therapeutic interventions in clinical practice to prevent acute renal failure. Because differences in elimination kinetics of these two compounds may influence therapeutic decisions, we studied elimination kinetics of myoglobin and creatine kinase in patients with rhabdomyolysis. DesignOpen, noncomparative study. SettingIntensive and intermediary care units in a university hospital. PatientsA total of 13 consecutive patients with rhabdomyolysis whose baseline serum creatine kinase exceeded 5000 IU/L. Ten of 13 patients were treated with forced alkaline diuresis, and none were dialyzed. ResultsMyoglobin had faster elimination kinetics than creatine kinase (p < .01), and the average times to reach the 50% level of initial values were 12 hrs for myoglobin and 42 hrs for creatine kinase. Elimination of myoglobin was not affected by glomerular filtration rate. Compared with creatinine clearance (mean, 102 mL/min), myoglobin clearance was low (mean, 3 mL/min), both in patients with preserved renal function (n = 11) and in those with acute renal failure (n = 2). ConclusionSerum myoglobin has faster elimination kinetics than creatine kinase in patients treated with forced alkaline diuresis for rhabdomyolysis. Considering the etiologic role of myoglobin, our data suggest that serum myoglobin level, rather than that of creatine kinase, should be used to guide therapy in patients with rhabdomyolysis.