Joint effect of self-reported sleep problems and three components of the metabolic syndrome on risk of coronary heart disease.

OBJECTIVE: This study explored the joint effect of two epidemics, sleep problems and metabolic syndrome (MetS), on the risk of coronary heart disease (CHD). METHODS: The study group is part of the Finnish middle-aged men who participated in the first screening for the Helsinki Heart Study (HHS) in 1981-1982. At that time, three components of MetS were measured: body mass index, HDL cholesterol, and blood pressure. Later, in 1986-1988, they were given a psychosocial questionnaire including items on sleep problems. Of the respondents, 2753 formed our study group and were followed up using population-based registers until 1995. The relative risks (RR) of CHD were estimated using Cox's regression models. RESULTS: When several sleep problems were present simultaneously, some increased CHD risk was observed. However, when considered jointly with MetS, insomnia or daytime fatigue approximately doubled the CHD risk and the presence of insufficient sleep more than tripled the risk. Among those who had MetS only, the RR was 2.55, and among those with both insufficient sleep and MetS the RR was 9.36 (95% confidence interval: 4.60-19.04; P for interaction 0.09) when compared to those with no insufficient sleep and no components of MetS. CONCLUSION: The interaction occurred when all three measured MetS components were present, suggesting that co-occurrence of these two epidemics may predict growing public health problems.

Chlamydia pneumoniae antibody levels before coronary events in the Helsinki Heart Study as measured by different methods.

The lack of specific tests for the diagnosis of chronic Chlamydia pneumoniae infection has led to the use of enzyme immunoassay (EIA) instead of the gold standard, that is, microimmunofluorescence (MIF), in the measurement of C. pneumoniae antibodies. We assessed the predictive values of C. pneumoniae antibody levels and seroconversions measured by MIF and EIA for coronary events in the prospective Helsinki Heart Study. Sera from 239 cases with coronary events and 239 controls were available at the baseline and data from 210 cases and 211 controls before and after the event. The agreement between MIF and EIA antibody levels was best in high antibody titers. In conditional logistic regression analysis, only high IgA MIF titers (>/=40) at the baseline predicted future coronary events, and the participants with MIF seroconversion between consecutive sera had a higher (nonsignificant) risk for coronary events than the controls. The difference in the kinetics of EIA and MIF antibodies demonstrated that MIF should remain the gold standard.

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 tryptase levels in acute coronary syndromes.

BACKGROUND: Mast cell accumulation and activation have been demonstrated in the vulnerable shoulder regions of atherosclerotic plaques and at the actual sites of plaque erosion and rupture. When activated and degranulated, mast cells release tryptase, a neutral protease, capable of activating matrix metalloproteinases and predisposing to plaque rupture. We tested the hypothesis that in acute coronary syndromes the levels of serum tryptase would reflect mast cell activation. METHODS AND RESULTS: The study population consisted of 183 patients admitted to the emergency room of 3 general hospitals because of acute chest pain of ischemic origin. Of these patients, 64 suffered from exertional angina presenting with acute chest pain, 60 had unstable angina, and 59 had acute myocardial infarction. Serum tryptase levels were analyzed from samples drawn, on average at 7 h, and also at 24 h after the onset of the chest pain. As controls served 41 patients admitted for surgical treatment of inguinal hernia or varicose veins. Serum tryptase levels remained stable within the observation period, and no differences were detected between the patient groups and controls. On the other hand, the differences in C-reactive protein levels reflected the extent of myocardial injury. CONCLUSIONS: In ACS, serum tryptase levels are normal and remain stable. Our results do not exclude the possibility of local activation of coronary mast cells, but suggest that the excess quantity of tryptase acutely released from mast cells in ACS, if any, is not sufficient to be detected by measuring tryptase concentration in the systemic circulation.

Prognostic usefulness of plasma monocyte/macrophage and T-lymphocyte activation markers in patients with acute coronary syndromes.

Macrophages and T lymphocytes accumulate and are activated in atherosclerotic plaques. We tested the hypothesis that plasma levels of the monocyte/macrophage and T-lymphocyte activation markers, monocyte chemoattractant protein-1 (MCP-1) and soluble interleukin-2 receptor (sIL-2r), respectively, can be used in acute coronary syndrome classification and risk prediction. Blood samples were collected at hospital admissions of 183 patients who had ischemic chest pain. Of these, 59 had acute myocardial infarction, 60 had unstable angina, and 64 had angina pectoris. No significant differences in the levels or proportions of subjects with increased levels of MCP-1 or sIL-2r were found across groups. During a mean follow-up of 13 months, 117 patients (64%) had a study end point (i.e., cardiac death, recurrent myocardial infarction, unstable angina, or revascularization). Increased levels (above median) of MCP-1 and sIL-2r were associated with increased risk, with odds ratios of 1.85 (95% confidence interval 0.92 to 3.73, p = 0.08) and 2.34 (95% confidence interval 1.16 to 4.71, p <0.02), respectively. In summary, in this unselected patient population with a very high rate of coronary events during follow-up, increased plasma levels of MCP-1 and sIL-2r were helpful for predicting new coronary events.

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.

Promise of combined low-molecular-weight heparin and platelet glycoprotein IIb/IIIa inhibition: results from Platelet IIb/IIIa Antagonist for the Reduction of Acute coronary syndrome events in a Global Organization Network B (PARAGON B).

BACKGROUND: Low-molecular-weight heparin (LMWH) has a more predictable anticoagulant effect than unfractionated heparin (UFH), is easier to administer, and does not require monitoring. Minimal data are available on LMWH combined with platelet glycoprotein (GP) IIb/IIIa inhibitors. METHODS: In the Platelet IIb/IIIa Antagonist for the Reduction of Acute Coronary Syndrome Events in a Global Organization Network B (PARAGON B) trial, patients with an acute coronary syndrome were randomized to receive the IIb/IIIa inhibitor lamifiban or a placebo. To rigorously explore the potential benefits of LWMH and GP IIb/IIIa inhibition, we analyzed the rates of ischemic complications and safety outcomes in PARAGON B. RESULTS: Approximately one fifth of the patients received LMWH (805 vs 4395 UFH). For the overall cohort, the incidence of death/myocardial infarction (MI)/severe recurrent ischemia (SRI) was 12.2%, and this composite end point was numerically lowest in the lamifiban with LMWH group (10.2%). Similarly, the incidence of death/MI was 11.0% for the entire cohort and lowest in the lamifiban and LMWH group (9.0%). The lower event rate for patients taking LMWH in the lamifiban group was sustained at 6 months, with a lower revascularization rate (51.5% vs 42.8%) and a lower composite of death/MI (13.8% vs 11.9%). Bleeding was comparable in the 2 heparin groups (1.4% with UFH vs 0.9% with LMWH). The propensity adjusted odds ratio for 30-day revascularization was significantly lower with LMWH (odds ratio 0.67, 95% CI 0.57-0.79, P <.001). There were no significant differences in death/MI/SRI at 30 days (P =.465), death/MI at 30 days (P =.264), and stroke at 30 days with the type of heparin use (P =.201) after propensity risk adjustment. CONCLUSIONS: In the PARAGON B trial, use of LMWH in conjunction with a GP IIb/IIIa inhibitor was safe and associated with a lower revascularization rate. These findings support the rationale and promise for combining GP IIb/IIIa blockers and LMWH for future management of acute coronary syndrome.

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

OBJECTIVE: Creatine 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. DESIGN: Open, noncomparative study. SETTING: Intensive and intermediary care units in a university hospital. PATIENTS: A 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. RESULTS: Myoglobin 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). CONCLUSION: Serum 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.

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.