Erik Kjøller

High serum YKL-40 concentration is associated with cardiovascular and all-cause mortality in patients with stable coronary artery disease

AIMS Macrophages in atherosclerotic plaques secrete YKL-40. We tested the hypothesis if high serum YKL-40 concentration predicts coronary events and death of patients with stable coronary artery disease (CAD). METHODS AND RESULTS During the 2.6 years follow-up period (median 2.77 year, interquartile range 0.23 year), 270 patients among the 4298 patients with stable CAD in the CLARICOR trial suffered myocardial infarction (MI) and 377 died (187 classified as cardiovascular death). Serum YKL-40 transformed as Y=log[max(82, serum YKL-40/microg/L)] was significantly associated with cardiovascular death [hazard ratio (HR) = 1.88, 95% confidence interval (CI) = 1.54-2.31, P < 0.001], all-cause mortality (HR = 2.01, 95% CI = 1.75-2.31, P < 0.001), and MI (HR = 1.38, 95% CI = 1.13-1.68, P = 0.002). Following multivariable adjustment for cardiovascular risk factors (age, sex, previous MI, smoking status, hypertension, diabetes mellitus) and selected medical treatments Y contributed significantly to prediction of all-cause mortality (P < 0.001) and cardiovascular mortality (P = 0.001), but not MI (P = 0.25). CONCLUSION High serum YKL-40 is associated with MI, cardiovascular and all-cause mortality in patients with stable CAD.

Chronic obstructive pulmonary disease in patients admitted with heart failure

Objective.  Chronic obstructive pulmonary disease (COPD) is an important differential diagnosis in patients with heart failure (HF). The primary aims were to determine the prevalence of COPD and to test the accuracy of self‐reported COPD in patients admitted with HF. Secondary aims were to study a possible relationship between right and left ventricular function and pulmonary function.

The prognostic importance of lung function in patients admitted with heart failure

The purpose of the present study was to determine the prognostic importance for all‐cause mortality of lung function variables obtained by spirometry in an unselected group of patients admitted with heart failure (HF).

Importance of chronic obstructive pulmonary disease for prognosis and diagnosis of congestive heart failure in patients with acute myocardial infarction.

To evaluate the importance of chronic obstructive pulmonary disease for prognosis and diagnosis of congestive heart failure in patients with acute myocardial infarction.

Clarithromycin for 2 Weeks for Stable Coronary Heart Disease: 6-Year Follow-Up of the CLARICOR Randomized Trial and Updated Meta-Analysis of Antibiotics for Coronary Heart Disease

Objectives: We have reported increased 2.6-year mortality in clarithromycin- versus placebo-exposed stable coronary heart disease patients, but meta-analysis of randomized trials in coronary heart disease patients showed no significant effect of antibiotics on mortality. Here we report the 6-year mortality of clarithromycin- versus placebo-exposed patients and updated meta-analyses. Methods: Centrally randomized, placebo controlled multicenter trial. All parties were blinded. Analyses were by intention to treat. Meta-analyses followed the Cochrane Collaboration methodology. Results: We randomized 4,372 patients with stable coronary heart disease to clarithromycin 500 mg (n = 2,172) or placebo (n = 2,200) once daily for 2 weeks. Mortality was followed through public register. Nine hundred and twenty-three patients (21.1%) died. Six-year mortality was significantly higher in the clarithromycin group (hazard ratio 1.21, 95% confidence interval 1.06–1.38). Adjustment for entry characteristics (sex, age, prior myocardial infarction, center, and smoking) did not change the results (1.18, 1.04–1.35). Addition of our data to that of other randomized trials on antibiotics for patients with coronary heart disease versus placebo/no intervention (17 trials, 25,271 patients, 1,877 deaths) showed a significantly increased relative risk of death from antibiotics of 1.10 (1.01–1.20) without heterogeneity. Conclusions: Our results stress the necessity to consider carefully the strength of the indication before administering antibiotics to patients with coronary heart disease.

Pregnancy associated plasma protein-A as a marker for myocardial infarction and death in patients with stable coronary artery disease: A prognostic study within the CLARICOR Trial

OBJECTIVE Pregnancy associated plasma protein-A (PAPP-A) is a potential new marker for vulnerable plaques in the coronary arteries only examined in stable coronary disease (CAD) in patients undergoing coronary angiography. Here we address the prognostic value of serum PAPP-A in unselected stable CAD patients. METHOD Blood samples were drawn at study entry. Serum PAPP-A values ≥4mIU/L were considered elevated. Mortality and non-fatal myocardial infarction was prospectively registered. The primary outcome was the composite outcome of myocardial infarction and all-cause mortality, secondary outcomes were all-cause mortality and myocardial infarction. RESULTS Patients (n=4243) were followed for a median of 2.8 years. In a Cox analysis, elevated PAPP-A was significantly related to the composite outcome of myocardial infarction and death (HR 1.99, 95% CI 1.62-2.45, p<0.0005), all-cause mortality (HR 2.42, 1.92-3.06, p<0.0005), and myocardial infarction (HR 1.40, 1.01-1.94, p=0.046). After Holms correction, the latter significance disappeared. After adjustment for risk factors and medication at entry, elevated PAPP-A remained significantly related to the composite outcome (HR 1.51, 1.22-1.86, p<0.0005) and all-cause mortality (HR 1.68, 1.32-2.13, p<0.0005). CONCLUSION In patients with stable CAD elevated serum PAPP-A seems promising as aid in identifying patients at high risk for death.

Risk stratification in stable coronary artery disease is possible at cardiac troponin levels below conventional detection and is improved by use of N-terminal pro-B-type natriuretic peptide

Aims Low prevalence of detectable cardiac troponin in healthy people and low-risk patients previously curtailed its use. With a new high-sensitive cardiac troponin assay (hs-cTnT), concentrations below conventional detection may have prognostic value, notably in combination with N-terminal pro-B-type natriuretic peptide (NT-pro-BNP). Methods and results Biomarker concentrations were determined from serum obtained at enrolment in the CLARICOR trial involving 4197 patients with stable coronary artery disease (CAD) followed for 2.6 years. Serum hs-cTnT was detectable (above 3 ng/l) in 78% and above the conventional 99th percentile (13.5 ng/l) in 23%. Across all levels of hs-cTnT there was a graded increase in the risk of cardiovascular death after adjustment for known prognostic indicators: hazard ratio (HR) per unit increase in the natural logarithm of the hs-cTnT level, 1.49; 95% confidence interval (CI), 1.23–1.81; similarly for all-cause mortality (HR 1.48, 95% CI 1.29–1.70) and myocardial infarction (HR 1.37, 95% CI 1.13–1.67). Increasing values of hs-cTnT were associated with increased mortality across all values of NT-pro-BNP, but this was particularly prominent when NT-pro-BNP >400 ng/l. Conclusions In patients with stable CAD, any detectable hs-cTnT level is significantly associated with all-cause mortality, cardiovascular death, and myocardial infarction after adjustment for traditional risk factors and NT-pro-BNP. Excess mortality is particularly pronounced in patients with NT-pro-BNP >400 ng/l.

Serum YKL-40 predicts long-term mortality in patients with stable coronary disease: A prognostic study within the CLARICOR trial

OBJECTIVE We investigated whether the inflammatory biomarker YKL-40 could improve the long-term prediction of death made by common risk factors plus high-sensitivity C-reactive protein (hs-CRP) and N-terminal-pro-B natriuretic peptide (NT-proBNP) in patients with stable coronary artery disease (CAD). BACKGROUND Non-hospitalized CAD patients are usually followed in general practice. There is a need for identify biomarkers which could help to foresee the prognoses of these patients. Elevated serum YKL-40 is a short-term predictor for myocardial infarction, cardiovascular mortality and all-cause mortality in patients with stable CAD. METHODS Serum YKL-40, hs-CRP, and NT-proBNP were measured in 4265 (97.6%) of the 4372 patients with stable CAD included in the CLARICOR trial, and death was registered in a 6-years follow-up period. RESULTS The median serum YKL-40 was 110 μg/L [IQR=93], hs-CRP 2.8 mg/L [IQR=4.74], and NT-proBNP 203 ng/L [IQR=407]. During 6 years follow-up period 923 (21.1%) patients died. After adjustment for type of intervention, risk factors (age, sex, hypertension, diabetes, smoking status, and previous myocardial infarction) and medical treatment (diuretics, digoxin, and statin) serum YKL-40 (transformed as ln(max(82, YKL-40/μg/L)) was significantly associated with all-cause mortality [hazard ratio (HR)=1.55, 95% CI=1.39-1.73, p<0.001]. After additional adjustment for ln(hs-CRP) and ln(NT-proBNP) this was still true [HR=1.38, 95% CI=1.21-1.53, p<0.001]. CONCLUSIONS Serum YKL-40 is a predictor of long-term mortality in patients with stable CAD independent of common risk factors and ln(hs-CRP) and ln(NT-proBNP). Serum YKL-40 can be used for prognostication in these patients.

The Prognostic Importance of Smoking Status at the Time of Acute Myocardial Infarction in 6676 Patients

Smoking is an important risk factor for atherosclerotic heart disease, but several studies have shown smoking to be associated with a favourable prognosis in patients who have suffered an acute myocardial infarction (AMI). We studied a large group of consecutive patients admitted alive to hospital with an infarction in order to further study the prognostic importance of smoking status at the time of myocardial infarction. The study cohort comprised 6676 patients with an enzyme-confirmed myocardial infarction admitted to 27 Danish hospitals over a 26-month period between 1990 and 1992. Smoking status was determined at the time of hospitalisation and complete follow-up was obtained in October 1996. Smokers were on average 10 years younger, had fewer concomitant cardiac risk factors, and were more likely to be male and to receive thrombolytic therapy more frequently than non-smokers. In univariate analysis, smoking was associated with reduced 30-day and long-term mortality (risk ratio at 30 days 0.55, P<0.001, risk ratio long-term 0.59, P< 0.001). When age only was included in a multivariate analysis, smoking was no longer of importance in short- or long-term mortality (risk ratio 0.92, P=0.4 at 30 days and long-term risk ratio 0.98, P = 0.7). Inclusion of further variables did not change this picture. In conclusion, smoking contributes to the occurrence of AMI at a younger age. The more favourable prognosis in smokers at the time of AMI is a result of more favourable baseline characteristics, especially their lower age.

Excess Sudden Cardiac Deaths after Short-Term Clarithromycin Administration in the CLARICOR Trial: Why Is This So, and Why Are Statins Protective?

Objectives: To elucidate potential mechanisms for the clarithromycin-induced excess mortality observed in the CLARICOR trial during 2.6 year follow-up of patients with stable coronary artery disease. Methods: Cox analyses using out-of-hospital death as a proxy for sudden death compared to in-hospital (nonsudden) death. Result: In 100 of 189 (53%) cardiovascular (CV) deaths in which it was possible to examine the question, there was a strong association between place of death and the classification of CV death as sudden or not-sudden. The excess mortality in the clarithromycin group was confined to sudden CV death in patients not on statins at trial entry (HR: 2.61, 95% CI: 1.69–4.05, p < 0.0005). Other categories of deaths showed no marked drug-placebo difference. Conclusions: Short-term clarithromycin administration was significantly associated with increased risk of sudden CV death in stable coronary heart disease patients not using statins.