Jacob Louis Marott

Lung-Function Trajectories Leading to Chronic Obstructive Pulmonary Disease.

BACKGROUND Chronic obstructive pulmonary disease (COPD) is thought to result from an accelerated decline in forced expiratory volume in 1 second (FEV1) over time. Yet it is possible that a normal decline in FEV1 could also lead to COPD in persons whose maximally attained FEV1 is less than population norms. METHODS We stratified participants in three independent cohorts (the Framingham Offspring Cohort, the Copenhagen City Heart Study, and the Lovelace Smokers Cohort) according to lung function (FEV1 ≥80% or <80% of the predicted value) at cohort inception (mean age of patients, approximately 40 years) and the presence or absence of COPD at the last study visit. We then determined the rate of decline in FEV1 over time among the participants according to their FEV1 at cohort inception and COPD status at study end. RESULTS Among 657 persons who had an FEV1 of less than 80% of the predicted value before 40 years of age, 174 (26%) had COPD after 22 years of observation, whereas among 2207 persons who had a baseline FEV1 of at least 80% of the predicted value before 40 years of age, 158 (7%) had COPD after 22 years of observation (P<0.001). Approximately half the 332 persons with COPD at the end of the observation period had had a normal FEV1 before 40 years of age and had a rapid decline in FEV1 thereafter, with a mean (±SD) decline of 53±21 ml per year. The remaining half had had a low FEV1 in early adulthood and a subsequent mean decline in FEV1 of 27±18 ml per year (P<0.001), despite similar smoking exposure. CONCLUSIONS Our study suggests that low FEV1 in early adulthood is important in the genesis of COPD and that accelerated decline in FEV1 is not an obligate feature of COPD. (Funded by an unrestricted grant from GlaxoSmithKline and others.).

Prediction of the Clinical Course of Chronic Obstructive Pulmonary Disease, Using the New GOLD Classification A Study of the General Population

RATIONALE The new Global Initiative for Obstructive Lung Disease (GOLD) stratification of chronic obstructive pulmonary disease (COPD) into categories A, B, C, and D is based on symptoms, level of lung function, and history of exacerbations. OBJECTIVES To investigate the abilities of this stratification to predict the clinical course of COPD. METHODS Two similar population studies were performed in an area of Copenhagen including 6,628 individuals with COPD. MEASUREMENTS AND MAIN RESULTS The patients were monitored for an average period of 4.3 years regarding COPD exacerbations, hospital admissions, and mortality. The percentages of individuals experiencing a COPD exacerbation during the first year of observation were 2.2% in group A, 5.8% in group B, 25.1% in group C, and 28.6% in group D. One- and 3-year mortality rates were 0.6 and 3.8%, respectively, in group A, 3.0 and 10.6% in group B, 0.7 and 8.2% in group C, and 3.4 and 20.1% in group D. Groups B and D, characterized by a higher degree of dyspnea than groups A and C, had five to eight times higher mortality from cardiovascular disease and cancer than did groups A and C. CONCLUSIONS The new stratification performs well by identifying individuals at risk of exacerbations. Surprisingly, subgroup B, characterized by more severe dyspnea, had significantly poorer survival than group C, in spite of a higher FEV(1) level. This subgroup warrants special attention, as the poor prognosis could be caused by cardiovascular disease or cancer, requiring additional assessment and treatment.

Inflammatory biomarkers and exacerbations in chronic obstructive pulmonary disease.

IMPORTANCE Exacerbations of respiratory symptoms in chronic obstructive pulmonary disease (COPD) have profound and long-lasting adverse effects on patients. OBJECTIVE To test the hypothesis that elevated levels of inflammatory biomarkers in individuals with stable COPD are associated with an increased risk of having exacerbations. DESIGN, SETTING, AND PARTICIPANTS Prospective cohort study examining 61,650 participants with spirometry measurements from the Copenhagen City Heart Study (2001-2003) and the Copenhagen General Population Study (2003-2008). Of these, 6574 had COPD, defined as a ratio between forced expiratory volume in 1 second (FEV1) and forced vital capacity below 0.7. MAIN OUTCOMES AND MEASURES Baseline levels of C-reactive protein (CRP) and fibrinogen and leukocyte count were measured in participants at a time when they were not experiencing symptoms of exacerbations. Exacerbations were recorded and defined as short-course treatment with oral corticosteroids alone or in combination with an antibiotic or as a hospital admission due to COPD. Levels of CRP and fibrinogen and leukocyte count were defined as high or low according to cut points of 3 mg/L, 14 μmol/L, and 9 ×10(9)/L, respectively. RESULTS During follow-up, 3083 exacerbations were recorded (mean, 0.5/participant). In the first year of follow-up, multivariable-adjusted odds ratios for having frequent exacerbations were 1.2 (95% CI, 0.7-2.2; 17 events/1000 person-years) for individuals with 1 high biomarker, 1.7 (95% CI, 0.9-3.2; 32 events/1000 person-years) for individuals with 2 high biomarkers, and 3.7 (95% CI, 1.9-7.4; 81 events/1000 person-years) for individuals with 3 high biomarkers compared with individuals who had no elevated biomarkers (9 events/1000 person-years; trend: P = 2 × 10(-5)). Corresponding hazard ratios using maximum follow-up time were 1.4 (95% CI, 1.1-1.8), 1.6 (95% CI, 1.3-2.2), and 2.5 (95% CI, 1.8-3.4), respectively (trend: P = 1 × 10(-8)). The addition of inflammatory biomarkers to a basic model including age, sex, FEV1 percent predicted, smoking, use of any inhaled medication, body mass index, history of previous exacerbations, and time since most recent prior exacerbation improved the C statistics from 0.71 to 0.73 (comparison: P = 9 × 10(-5)). Relative risks were consistent in those with milder COPD, in those with no history of frequent exacerbations, and in the 2 studies separately. The highest 5-year absolute risks of having frequent exacerbations in those with 3 high biomarkers (vs no high biomarkers) were 62% (vs 24%) for those with Global Initiative for Chronic Obstructive Lung Disease (GOLD) grades C-D (n = 558), 98% (vs 64%) in those with a history of frequent exacerbations (n = 127), and 52% (vs 15%) for those with GOLD grades 3-4 (n = 465). CONCLUSIONS AND RELEVANCE Simultaneously elevated levels of CRP and fibrinogen and leukocyte count in individuals with COPD were associated with increased risk of having exacerbations, even in those with milder COPD and in those without previous exacerbations. Further investigation is needed to determine the clinical value of these biomarkers for risk stratification.

Cardiac Dysfunction Assessed by Echocardiographic Tissue Doppler Imaging Is an Independent Predictor of Mortality in the General Population

Background— Tissue Doppler imaging (TDI) detects left ventricular dysfunction in patients with heart failure and normal ejection fraction, but the prognostic significance of left ventricular dysfunction by TDI in the general population is unknown. Methods and Results— Within the Copenhagen City Heart Study, a large community-based population study, cardiac function was evaluated in 1036 participants by both conventional echocardiography and TDI. Averages of peak systolic (s′), early diastolic (e′), and late diastolic (a′) velocities from 6 mitral annular sites were used. TDI was furthermore quantified by a combined index (eas index) of diastolic and systolic performance: e′/(a′×s′). During follow-up (median, 5.3 years), 90 participants died. Left ventricular dysfunction by TDI, in terms of low s′ (hazard ratio, 1.23 per 1-cm/s decrease; P<0.05) and a′ (hazard ratio, 1.20 per 1-cm/s decrease; P=0.001), were significant predictors of death in Cox proportional-hazards models adjusted for clinical variables (age, sex, body mass index, heart rate, hypertension, diabetes mellitus, and ischemic heart disease) and conventional echocardiography. The adjusted hazard ratio for death in the third tertile compared with the first tertile of the combined index of systolic and diastolic performance by TDI was 2.5 (P<0.005). Conclusions— In the general population, in which most are free of left ventricular systolic dysfunction and restrictive diastolic filling using conventional echocardiographic parameters, left ventricular dysfunction by TDI is a powerful and independent predictor of death, especially when systolic performance and diastolic performance are considered together, recognizing their interdependency and their complex relation to deteriorating cardiac function.

Dose of Jogging and Long-Term Mortality : The Copenhagen City Heart Study

BACKGROUND People who are physically active have at least a 30% lower risk of death during follow-up compared with those who are inactive. However, the ideal dose of exercise for improving longevity is uncertain. OBJECTIVES The aim of this study was to investigate the association between jogging and long-term, all-cause mortality by focusing specifically on the effects of pace, quantity, and frequency of jogging. METHODS As part of the Copenhagen City Heart Study, 1,098 healthy joggers and 3,950 healthy nonjoggers have been prospectively followed up since 2001. Cox proportional hazards regression analysis was performed with age as the underlying time scale and delayed entry. RESULTS Compared with sedentary nonjoggers, 1 to 2.4 h of jogging per week was associated with the lowest mortality (multivariable hazard ratio [HR]: 0.29; 95% confidence interval [CI]: 0.11 to 0.80). The optimal frequency of jogging was 2 to 3 times per week (HR: 0.32; 95% CI: 0.15 to 0.69) or ≤1 time per week (HR: 0.29; 95% CI: 0.12 to 0.72). The optimal pace was slow (HR: 0.51; 95% CI: 0.24 to 1.10) or average (HR: 0.38; 95% CI: 0.22 to 0.66). The joggers were divided into light, moderate, and strenuous joggers. The lowest HR for mortality was found in light joggers (HR: 0.22; 95% CI: 0.10 to 0.47), followed by moderate joggers (HR: 0.66; 95% CI: 0.32 to 1.38) and strenuous joggers (HR: 1.97; 95% CI: 0.48 to 8.14). CONCLUSIONS The findings suggest a U-shaped association between all-cause mortality and dose of jogging as calibrated by pace, quantity, and frequency of jogging. Light and moderate joggers have lower mortality than sedentary nonjoggers, whereas strenuous joggers have a mortality rate not statistically different from that of the sedentary group.

Resting heart rate is associated with cardiovascular and all-cause mortality after adjusting for inflammatory markers: The Copenhagen City Heart Study

Aims: To investigate the association between resting heart rate (RHR) and markers of chronic low-grade inflammation. Also, to examine whether elevated resting heart rate is independently associated with cardiovascular and all-cause mortality in the general population, or whether elevated RHR is merely a marker of chronic low-grade inflammation. Methods and results: A group of 6518 healthy subjects from the the Danish general population were followed for 18 years during which 1924 deaths occurred. Subjects underwent assessment of baseline RHR, conventional cardiovascular risk factors, high-sensitivity C-reactive protein (hsCRP), and fibrinogen. RHR was associated with hsCRP and fibrinogen in uni- and multivariate models (p < 0.0001). A 10 beats per minute increase in RHR was associated with increased cardiovascular and all-cause mortality in univariate models – HR (95%CI) (1.21 (1.14–1.29) and 1.15 (1.11–1.19); multivariate models adjusted for conventional risk factors – 1.16 (1.09–1.24) and 1.10 (1.06–1.14); multivariate models including hsCRP – 1.14 (1.07–1.22) and 1.09 (1.05–1.14); fibrinogen – 1.15 (1.07–1.22) and 1.09 (1.05–1.14); and both hsCRP and fibrinogen – 1.14 (1.07–1.22) and 1.09 (1.05–1.14). Conclusion: RHR was associated with markers of chronic low-grade inflammation. However, RHR remained associated with both cardiovascular and all-cause mortality after adjusting for markers of chronic low-grade inflammation. This suggests that RHR is an independent risk factor for cardiovascular and all-cause mortality, and not merely a marker of chronic low-grade inflammation.

Leptin, Not Adiponectin, Predicts Hypertension in the Copenhagen City Heart Study

BACKGROUND Leptin and adiponectin are hormones secreted by adipose tissue, and both hormones are candidate intermediaries between adipose tissue and overweight-related diseases. So far, no prospective study has been published where the independent effects of these two hormones on the development of hypertension have been directly compared. The objective of this study was to investigate the relationships between plasma levels of leptin and adiponectin and new-onset hypertension in the Copenhagen City Heart Study (CCHS). METHODS In a prospective study design, we examined new-onset hypertension in 620 women and 300 men who were normotensive in the third CCHS examination, which was performed in 1991-1994. RESULTS Between the third and the fourth CCHS examination, which was performed in 2001-2003, 254 had developed hypertension, defined as systolic blood pressure (SBP) > or = 140 mm Hg, or diastolic blood pressure (DBP) > or = 90 mm Hg, or use of antihypertensive medication. Using logistic regression analysis, adjusting for age, sex, estimated glomerular filtration rate, triglycerides, high-density lipoprotein cholesterol (HDL-C), fibrinogen, and glucose, and with leptin and adiponectin included in the same model, leptin was significantly associated with new-onset hypertension with an odds ratio (95% confidence interval) of 1.28 (1.08-1.53; P < 0.005) for 1 s.d. higher level of log-transformed leptin, whereas adiponectin was not significantly associated with new-onset hypertension having an odds ratio of 1.02 (0.84-1.24; P = 0.83) for 1 s.d. higher level of log-transformed adiponectin. CONCLUSIONS In the CCHS, leptin, but not adiponectin, was a significant independent predictor of new-onset hypertension.

Longevity in Male and Female Joggers: The Copenhagen City Heart Study

Since 1970, jogging has become an increasingly popular form of exercise, but concern about harmful effects has been raised following reports of deaths during jogging. The purpose of this study was to investigate if jogging, which can be very vigorous, is associated with increased all-cause mortality in men and women. Jogging habits were recorded in a random sample of 17,589 healthy men and women aged 20-98 years, invited between 1976 and 2003 to the Copenhagen City Heart Study. The expected lifetime was calculated by integrating the predicted survival curve estimated in the Cox model. In this study 1,878 persons (1,116 men and 762 women) were classified as joggers. During the 35-year maximum follow-up period, we registered 122 deaths among joggers and 10,158 deaths among nonjoggers. The age-adjusted hazard ratio of death among joggers was 0.56 (95% confidence interval: 0.46, 0.67) for men and 0.56 (95% confidence interval: 0.40, 0.80) for women. The age-adjusted increase in survival with jogging was 6.2 years in men and 5.6 years in women. This long-term study of joggers showed that jogging was associated with significantly lower all-cause mortality and a substantial increase in survival for both men and women.

Cardiovascular risk prediction in the general population with use of suPAR, CRP, and Framingham Risk Score

BACKGROUND The inflammatory biomarkers soluble urokinase plasminogen activator receptor (suPAR) and C-reactive protein (CRP) independently predict cardiovascular disease (CVD). The prognostic implications of suPAR and CRP combined with Framingham Risk Score (FRS) have not been determined. METHODS From 1993 to 1994, baseline levels of suPAR and CRP were obtained from 2315 generally healthy Danish individuals (mean [SD] age: 53.9 [10.6] years) who were followed for the composite outcome of ischemic heart disease, stroke and CVD mortality. RESULTS During a median follow-up of 12.7 years, 302 events were recorded. After adjusting for FRS, women with suPAR levels in the highest tertile had a 1.74-fold (95% confidence interval [CI]: 1.08-2.81, p=0.027) and men a 2.09-fold (95% CI: 1.37-3.18, p<0.001) increase in risk compared to the lowest tertile. Including suPAR and CRP together resulted in stronger risk prediction with a 3.30-fold (95% CI: 1.36-7.99, p<0.01) increase for women and a 3.53-fold (1.78-7.02, p<0.001) increase for men when both biomarkers were in the highest compared to the lowest tertile. The combined extreme tertiles of suPAR and CRP reallocated individuals predicted to an intermediate 10-year risk of CVD of 10-20% based on FRS, to low (<10%) or high (>20%) risk categories, respectively. This was reflected in a significant improvement of C statistics for men (p=0.034) and borderline significant for women (p=0.054), while the integrated discrimination improvement was highly significant (P≤0.001) for both genders. CONCLUSIONS suPAR provides prognostic information of CVD risk beyond FRS and improves risk prediction substantially when combined with CRP in this setting.

Occupational and leisure time physical activity: risk of all-cause mortality and myocardial infarction in the Copenhagen City Heart Study. A prospective cohort study

Objectives Men with low physical fitness and high occupational physical activity are recently shown to have an increased risk of cardiovascular disease and all-cause mortality. The association between occupational physical activity with cardiovascular disease and all-cause mortality may also depend on leisure time physical activity. Design A prospective cohort study. Setting The Copenhagen City Heart Study. Participants 7819 men and women aged 25–66 years without a history of cardiovascular disease who attended an initial examination in the Copenhagen City Heart Study in 1976–1978. Outcome measures Myocardial infarction and all-cause mortality. Occupational physical activity was defined by combining information from baseline (1976–1978) with reassessment in 1981–1983. Conventional risk factors were controlled for in Cox analyses. Results During the follow-up from 1976 to 1978 until 2010, 2888 subjects died of all-cause mortality and 787 had a first event of myocardial infarction. Overall, occupational physical activity predicted all-cause mortality and myocardial infarction in men but not in women (test for interaction p=0.02). High occupational physical activity was associated with an increased risk of all-cause mortality among men with low (HR 1.56; 95% CI 1.11 to 2.18) and moderate (HR 1.31; 95% CI 1.05 to 1.63) leisure time physical activity but not among men with high leisure time physical activity (HR 1.00; 95% CI 0.78 to 1.26) (test for interaction p=0.04). Similar but weaker tendencies were found for myocardial infarction. Among women, occupational physical activity was not associated with subsequent all-cause mortality or myocardial infarction. Conclusions The findings suggest that high occupational physical activity imposes harmful effects particularly among men with low levels of leisure time physical activity.