Gemfibrozil in the treatment of dyslipidemia: an 18-year mortality follow-up of the Helsinki Heart Study.

BACKGROUND: The Helsinki Heart Study was a double-blind, placebo-controlled primary prevention trial among 4081 dyslipidemic middle-aged men to test the efficacy of gemfibrozil in the prevention of coronary heart disease (CHD). After the 5-year trial, the participants were notified of their treatment group and invited to continue or start gemfibrozil therapy free of charge through 1995. Approximately two thirds of participants in both groups chose gemfibrozil therapy. In this 18-year follow-up through 2000, we compared the CHD, cancer, and all-cause mortality among subjects in the original gemfibrozil (OG) group (n = 2046) with those in the original placebo (OP) group (n = 2035). METHODS: To provide an overview of the absolute risks in the 2 treatment groups as well as risk differences between them, we calculated crude mortality rates and presented Kaplan-Meier plots of survival with log-rank tests. We also estimated the relative risks (RRs) using Cox proportional hazards models with and without covariates. RESULTS: During the follow-up until 1995, subjects in the OG group had a 32% lower RR of CHD mortality (P = .03) compared with those in the OP group, and when followed up until 2000, the RR was 23% lower (P = .05). Overall, there were no differences in all-cause or cancer mortality. However, those in the OG group with both body mass index and triglyceride level in the highest tertiles had a 71% lower RR of CHD mortality (P<.001), a 33% lower RR of all-cause mortality (P = .03), and a 36% lower RR of cancer mortality (P = .22) compared with those in the OP group. CONCLUSION: Long-term mortality follow-up showed that patients with dyslipidemia benefited from beginning treatment with gemfibrozil early, especially if their dyslipidemia entailed factors related to the metabolic syndrome.

Serum iron, infection and inflammation; effects on coronary risk.

OBJECTIVES: To explore the potential pathways of association between serum iron and coronary heart disease, with major emphasis on factors related to infections and inflammation. DESIGN: A nested case-control study with 215 cases (myocardial infarction or coronary death) and 215 matched controls over 8.5 years. Logistic regression analyses were used to compare relative risks in various serum iron-high sensitive CRP-total leucocyte count-herpes simplex virus-1 antibody categories. RESULTS: Participants with low iron (< 17 micromol/l) had increased coronary risk with Odds Ratio (OR) of 2.1 (95% CI 1.1-3.8). Simultaneous elevation of hs-CRP and leucocyte count increased the risk substantially in those with low iron, OR 9.8 (95% CI 3.9-24.4). A combination of high herpes simplex virus-1 antibody level and low iron increased the risk modestly (OR 1.2), but when hs-CRP level was high simultaneously, the OR was 13.1 (95% CI 2.9-60.1). CONCLUSIONS: Our data suggest an association between low serum iron level and coronary risk. The association is not independent, but is related to the fact that chronic infections and inflammation are accompanied with low serum iron.

Antibodies to human heat shock protein 60, hypertension and dyslipidemia. A study of joint effects on coronary risk.

OBJECTIVE: High IgA-class (but not IgG-class) Anti-Heat-shock-protein 60 antibody level is a predictor of coronary risk in dyslipidemic middle-aged men. In this paper we studied the joint effects of high Anti-Hsp60-antibody level and the classical coronary risk factors. METHODS: We used nested case-control design and logistic regression analyses. The cases consisted of 233 middle-aged men with myocardial infarction or coronary death during 8.5-year follow-up in Helsinki Heart Study, a coronary primary prevention study with gemfibrozil. The controls were subjects without coronary events, matched for drug treatment and the geographical area. RESULTS: The relative coronary risks (Odds Ratios (ORs); 95% confidence interval) were 1.41 (0.96-2.05) for high IgA-class Anti-Hsp60 antibody level and 1.98 (1.35-2.90) for hypertension, defined as mean arterial pressure >114 mmHg. With simultaneous occurrence of high Anti-Hsp60 antibody level and hypertension, the ORs were 2.32 (1.26-4.27) for systolic and 2.99 (1.63-5.48) for diastolic hypertension. Similar patterns of joint effects were found between high Anti-Hsp60 antibody and lipoprotein cholesterol levels as well as antibodies against oxidized low-density lipoprotein. CONCLUSIONS: Our results suggest that, while high IgA-class Anti-Hsp60 antibody level predicts coronary risk, the effect is modest without simultaneous occurrence of other classical risk factors.

Synergistic effect of persistent Chlamydia pneumoniae infection, autoimmunity, and inflammation on coronary risk.

BACKGROUND: Given the role of chronic infections, autoimmunity, and inflammation in atherosclerosis, we studied the joint effect of chronic Chlamydia pneumoniae infection, persistently elevated human heat-shock protein 60 (hHsp60) antibodies, and C-reactive protein (CRP) on coronary risk. METHODS AND RESULTS: The participants for this prospective nested case-control study were obtained from the Helsinki Heart Study, during which 241 nonfatal myocardial infarctions or coronary deaths occurred among 4081 dyslipidemic middle-aged men. Serum samples taken at baseline and 3 to 6 months before the coronary events that occurred during the 8.5-year period were analyzed for antibodies to C pneumoniae and hHsp60 and the CRP concentration. Compared with persistently low levels, the risk of coronary events was 2-fold for persistently elevated immunocomplex (IC)-bound and/or serum IgA antibodies to C pneumoniae (OR, 1.96; 95% CI, 1.14 to 3.36) and also for serum IgA antibodies to hHsp60 (OR, 2.11; 95% CI, 1.08 to 4.13). The risks associated with elevated antibodies were much higher when CRP was also elevated. Compared with low or transiently elevated levels, the risk of coronary events, with adjustment for age and smoking, was 4.5-fold for persistently elevated CRP and C pneumoniae IC/IgA antibodies together (OR, 4.47; 95% CI, 1.84 to 10.83) and was similar for CRP and hHsp60 IgA antibodies together (OR, 4.36; 95% CI, 1.53 to 12.39). CONCLUSIONS: Persistently but not transiently elevated C pneumoniae IC/IgA and hHsp60 IgA antibodies, especially when present together with an elevated CRP level, predicted coronary events.

Insulin sensitivity markers: predictors of accidents and suicides in Helsinki Heart Study screenees.

The purpose of this study was to evaluate whether elements signifying relative insulin sensitivity (IS) were prospectively linked to accidents and suicides in 14,976 Helsinki Heart Study (HHS) screenees. The main outcome measure was hospitalizations and deaths from accidents and suicide attempts determined from Finnish registries, in aggregate; and separating out suicides (and attempts). Cox proportional hazards regression was used to determine adjusted risk ratios (RR) relating IS characteristics (extreme quartiles of high HDL-C, low BMI, and low SBP), individually and conjointly, to subsequent accidents or suicides (including attempts), adjusted for age, alcohol use, smoking, and non-HDL cholesterol. Each IS element was related to combined hospitalization and death, from accidents and from suicide attempts; increasing numbers of these characteristics were associated with increased risk, an effect that was more powerful and statistically significant for suicide. For accidents, the presence of one and two to three IS characteristics provided RRs (95% confidence intervals (CI)) of 1.08 (0.97-1.20) and 1.14 (0.98-1.31), respectively. For suicides including attempts, RRs (95%CI) were 1.61 (1.09-2.38) for one IS factor, and 1.88 (1.18-2.98) for two to three IS factors, while for completed suicides, the figures were 2.01 (1.19-3.38) and 2.24 (1.20-4.17), respectively. We speculate that insulin sensitivity may relate to these outcomes through low central serotonin activity.

Autoimmunity to human heat shock protein 60, Chlamydia pneumoniae infection, and inflammation in predicting coronary risk.

Heat shock protein 60 (Hsp60) and Chlamydia pneumoniae infection have both been associated with cardiovascular diseases. Our aim was to study the role of Hsp60 antibodies as coronary risk predictors and their association with C pneumoniae infection and inflammation. This was a prospective, nested, case-control study. The cases consisted of 239 middle-aged Finnish men who developed myocardial infarction or coronary death during the follow-up. Baseline levels of IgA and IgG antibodies to human-specific and C pneumoniae-specific Hsp60 were measured by enzyme immunoassay. Human Hsp60 IgA, but not IgG or C pneumoniae Hsp60, antibodies were a significant risk factor for coronary events (odds ratio 2.0, 95% CI 1.1 to 3.6, when the fourth and first quartiles are compared). When an elevated human Hsp60 IgA antibody level (above the second quartile) was present simultaneously with a high C pneumoniae IgA antibody level (the third quartile) and an elevated C-reactive protein level (the second quartile), compared with all factors at low levels, the risk was 7.0 (95% CI 2.6 to 19.1) without adjustment and 5.0 (95% CI 1.8 to 14.2) when adjustment was made for age and smoking. In conclusion, an elevated human Hsp60 IgA antibody level was a risk factor for coronary events, especially when it was present together with C pneumoniae infection and inflammation.

Differing Effects of Two Angiotensin Converting Enzyme Inhibitors, Captopril and CI-906, on Diuresis and the Urinary Excretion of Kallikrein and Prostaglandins in Spontaneously Hypertensive Rats.

The effects of two angiotensin I convening enzyme inhibitors on the kallikrein-kinin system and prostanoids were studied in spontaneously hypertensive rats. The doses of captopril were 20, 50 and 100 mg/kg×day given twice daily, and those of CI-906 20 and 40 mg/kg once daily. Both drugs were equally effective in reducing the systolic blood pressure. Captopril increased urine volume dose-dependently (up to 3-fold with the largest dose). Only the larger dose of CI-906 was slightly diuretic. Captopril decreased the 24-h urinary excretion of kallikrein, while the excretion of the prostacyclin metabolite 6-keto-PGF1α was increased markedly and that of T × B2 to a lesser extent. CI-906 had no effect on the 24-h urinary excretion of kallikrein, 6-keto-PGF1α and T × B2. Both drugs tended to reduce PGE2 excretion. Captopril and CI-906 did not alter plasma kininogen levels. The marked renal effects of captopril may be caused by a strong local inhibition of converting enzyme in the kidneys. Captopril is mainly excreted unchanged in urine, and it is secreted actively by the proximal tubular cells. CI-906 is eliminated predominantly by biliary excretion. It is also possible that direct stimulation of prostacyclin formation by captopril may be involved in the diuretic action of the drug. However, as it was shown with CI-906, the increase in urine flow and the associated changes in urinary kallikrein and prostanoids are not necessary for the antihypertensive effect caused by the inhibition of converting enzyme.