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  • 1.
    Lindberg, Anne
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Linder, Robert
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Backman, Helena
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Eriksson Ström, Jonas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Frølich, Andreas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Nilsson, Ulf
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Rönmark, Eva
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Johansson Strandkvist, Viktor
    Behndig, Annelie F
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Blomberg, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    From COPD epidemiology to studies of pathophysiological disease mechanisms: challenges with regard to study design and recruitment process2017In: European Clinical Respiratory Journal, ISSN 2001-8525, Vol. 4, article id 1415095Article in journal (Refereed)
    Abstract [en]

    Background: Chronic obstructive pulmonary disease (COPD) is a largely underdiagnosed disease including several phenotypes. In this report, the design of a study intending to evaluate the pathophysiological mechanism in COPD in relation to the specific phenotypes non-rapid and rapid decline in lung function is described together with the recruitment process of the study population derived from a population based study.

    Method: The OLIN COPD study includes a population-based COPD cohort and referents without COPD identified in 2002–04 (n = 1986), and thereafter followed annually since 2005. Lung function decline was estimated from baseline in 2002–2004 to 2010 (first recruitment phase) or to 2012/2013 (second recruitment phase). Individuals who met the predefined criteria for the following four groups were identified; group A) COPD grade 2–3 with rapid decline in FEV1 and group B) COPD grade 2–3 without rapid decline in FEV1 (≥60 and ≤30 ml/year, respectively), group C) ever-smokers, and group D) non-smokers with normal lung function. Groups A–C included ever-smokers with >10 pack years. The intention was to recruit 15 subjects in each of the groups A-D.

    Results: From the database groups A–D were identified; group A n = 37, group B n = 29, group C n = 41, and group D n = 55. Fifteen subjects were recruited from groups C and D, while this goal was not reached in the groups A (n = 12) and B (n = 10). The most common reasons for excluding individuals identified as A or B were comorbidities contraindicating bronchoscopy, or inflammatory diseases/immune suppressive medication expected to affect the outcome.

    Conclusion: The study is expected to generate important results regarding pathophysiological mechanisms associated with rate of decline in lung function among subjects with COPD and the in-detail described recruitment process, including reasons for non-participation, is a strength when interpreting the results in forthcoming studies.

  • 2.
    Nilsson, Ulf
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Cardiovascular aspects on chronic obstructive pulmonary disease: with focus on ischemic ECG abnormalities, QT prolongation and arterial stiffness2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background

    Chronic Obstructive Pulmonary disease (COPD) is an under-diagnosed disease with a prevalence of approximately 10%, highly dependent on age and smoking habits. Comorbidities are common in COPD and of these, cardiovascular diseases (CVD) are the most common. COPD is the fourth leading cause of death globally, and CVD probably contribute to the high mortality. Within CVD, Ischemic Heart Disease (IHD) is the most common. It is highly clinically relevant to identify signs of ischemic heart disease, other cardiac conditions, and risk factors for CVD in COPD. Electrocardiogram (ECG) is a simple but still major diagnostic tool in clinical cardiology, including disturbances in the electric conduction system and ischemia. Due to the under-diagnosis of COPD, there is limited knowledge regarding the prevalence and prognostic impact of ECG abnormalities in COPD. Arterial stiffness is a risk factor for CVD, which has raised an increased interest, however not evaluated in population based studies of COPD.

    Aim

    The overall aim was to describe cardiovascular aspects on COPD, with a specific focus on arterial stiffness, prevalence and prognostic impact of ischemic ECG abnormalities and prolonged QT interval, by comparing subjects with and without obstructive lung function impairment in a population-based cohort.

    Methods

    The thesis is based on the Obstructive Lung Disease in Northern Sweden (OLIN) COPD study; a population-based longitudinal cohort study. During the years 2002-2004, all participants in clinical examinations from previously recruited large population-based cohorts were invited to re-examination including spirometry and a structured interview. All subjects with obstructive lung function impairment (n=993) were identified, together with 993 age and sex-matched referents without airway obstruction. The study population (n=1986) has been invited to annual examinations since 2005 including spirometry and structured interview. Papers I-III are based on data from 2005 when electrocardiogram (ECG) was recorded in addition to the basic program. All ECGs were Minnesota coded and QT-time was measured. Paper IV is based data from 2010 when non-invasive measurements of arterial stiffness, assessed as pulse wave velocity (PWV), was added to the program. Spirometric data were classified as normal lung function (NLF), restrictive spirometric pattern (RSP) and airway obstruction (COPD). The following spirometric criteria for COPD were used: post-bronchodilator FEV1/VC<0.70 (papers I-IV, in paper III labelled GOLD-COPD) and lower limit of normal, LLN (LLN-COPD) (paper III). Spirometric classification of COPD severity was based on FEV1 % predicted as a continuous variable or according to the Global Initiative for Obstructive Lung Disease (GOLD), divided into GOLD 1-4.

    Results

    The prevalence of ischemic heart disease (IHD), both self-reported and assessed as probable and possible ischemic ECG abnormalities (I-ECG) according to the Whitehall criteria, was similar among subjects with NLF and COPD. The prevalence of both self-reported and probable (I-ECG) according to Whitehall increased by GOLD grade.  Among those with COPD, self-reported IHD was associated with disease severity, assessed as FEV1 % predicted also after adjustment for age and sex (paper I).

    In both COPD and NLF, those with I-ECG had a higher cumulative mortality over 5 years than those without I-ECG (29.6 vs. 10.6%, p<0.001 and 17.1 vs. 6.3 %, p=0.001). When analysed in a multivariate model, the Mortality Risk Ratio (MRR, 95%CI) was increased for subjects with COPD and I-ECG (2.4, 1.5-3.9), and non-significantly so for NLF with I-ECG (1.65, 0.94-2.90), when compared to NLF without I-ECG.  When analyzed separately among subjects with COPD, the increased risk for death associated with I-ECG persisted independent of age, sex, BMI-class, smoking habits and disease severity assessed as FEV1 % predicted (1.89, 1.20-2.99). The proportion without reported IHD was high among those with I-ECG; 72.4% in NLF and 67.3% in COPD. The pattern was similar also among them; I-ECG was associated with an increased risk for death in COPD and non-significantly so in NLF (paper II).

    Mean corrected QT-time (QTc) and prevalence of QTc prolongation was higher in RSP than NLF but similar in NLF and GOLD-COPD. The prevalence of borderline as well as prolonged QTc increased by GOLD grade (test for trend p=0.012 for both groups). Of those with GOLD-COPD, 52% fulfilled the LLN-criterion (LLN-COPD). When comparing LLN-COPD and NLF, the pattern was similar as when comparing NLF and GOLD-COPD. The cumulative mortality over 5 years was higher among subjects with borderline and prolonged QTc than those with normal QTc in subjects with GOLD-COPD and LLN-COPD but not in NLF and RSP (paper III).

    Arterial stiffness, assessed as PWV, was higher in GOLD 3-4 compared to non-COPD (10.52 vs. 9.13 m/s, p=0.042). Reported CVD and age >60 were both associated with significantly higher PWV in COPD as well as in non-COPD. In a multivariate model, GOLD 3-4 remained associated with higher PWV when compared with non-COPD, also when adjusted for sex, age group, smoking habits, blood pressure, reported CVD and pulse rate (paper IV).

    Conclusion

    In this population-based study, the prevalence of ischemic ECG abnormalities was similar among subjects with normal lung function and COPD, but increased by disease severity among subjects with COPD. Ischemic ECG abnormalities were associated with an increased mortality among subjects with COPD, independent of common confounders and disease severity, also among those without known heart disease. Whilst the prevalence of QTc prolongation was similar in NLF, COPD and LLN-COPD, it was associated with an increased mortality only in the COPD-groups. ECG is a simple non-invasive method and seems to identify findings of prognostic importance among subjects with COPD. Central arterial stiffness, a known risk factor for cardiovascular disease, was increased among subjects with severe and very severe COPD when compared to subjects without COPD independent of common confounders.

  • 3.
    Nilsson, Ulf
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Blomberg, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Johansson, Bengt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Backman, Helena
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Eriksson, Berne
    Lindberg, Anne
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Ischemic ECG abnormalities are associated with an increased risk for death among subjects with COPD, also among those without known heart disease2017In: The International Journal of Chronic Obstructive Pulmonary Disease, ISSN 1176-9106, E-ISSN 1178-2005, Vol. 12, p. 2507-2514Article in journal (Refereed)
    Abstract [en]

    Background: Cardiovascular comorbidity contributes to increased mortality among subjects with COPD. However, the prognostic value of ECG abnormalities in COPD has rarely been studied in population-based surveys.

    Aim: To assess the impact of ischemic ECG abnormalities (I-ECG) on mortality among individuals with COPD, compared to subjects with normal lung function (NLF), in a population-based study.

    Methods: During 2002–2004, all subjects with FEV1/VC <0.70 (COPD, n=993) were identified from population-based cohorts, together with age- and sex-matched referents without COPD. Re-examination in 2005 included interview, spirometry, and 12-lead ECG in COPD (n=635) and referents [n=991, whereof 786 had NLF]. All ECGs were Minnesota-coded. Mortality data were collected until December 31, 2010.

    Results: I-ECG was equally common in COPD and NLF. The 5-year cumulative mortality was higher among subjects with I-ECG in both groups (29.6% vs 10.6%, P<0.001 and 17.1% vs 6.6%, P<0.001). COPD, but not NLF, with I-ECG had increased risk for death assessed as the mortality risk ratio [95% confidence interval (CI)] when compared with NLF without I-ECG, 2.36 (1.45–3.85) and 1.65 (0.94–2.90) when adjusted for common confounders. When analyzed separately among the COPD cohort, the increased risk for death associated with I-ECG persisted after adjustment for FEV1% predicted, 1.89 (1.20–2.99). A majority of those with I-ECG had no previously reported heart disease (74.2% in NLF and 67.3% in COPD) and the pattern was similar among them.

    Conclusion: I-ECG was associated with an increased risk for death in COPD, independent of common confounders and disease severity. I-ECG was of prognostic value also among those without previously known heart disease.

  • 4.
    Nilsson, Ulf
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Blomberg, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Mills, Nicholas
    Rönmark, Eva
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Lindberg, Anne
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Elevated serum high-sensitivity cardiac troponin I is related to mortality in COPD2018In: European Respiratory Journal, ISSN 0903-1936, E-ISSN 1399-3003, Vol. 52Article in journal (Other academic)
    Abstract [en]

    Background: Cardiovascular diseases are the most common comorbid condition among subjects with COPD, but the predictive value of high-sensitivity cardiac troponin I (hs-cTnI) on prognosis has rarely been studied in population surveys.

    Aim: To assess the prevalence and impact of elevated serum hs-cTnI on mortality among subjects with COPD and normal lung function (NLF).

    Methods: In 2002-04, subjects with FEV1/VC <0.70 (COPD, n=993) and age- and sex-matched referents without COPD were identified from population-based cohorts. In 2005, structured interview, post-bronchodilator spirometry and blood sampling were performed in individuals with COPD (n=601) and referents (n=954), where 755 referents had NLF. Hs-cTnI was analysed in serum and values ≥5 ng/L were defined as elevated. Mortality data were collected until 2010.

    Results: The prevalence of elevated hs-cTnI was higher among COPD compared to NLF (31.1% vs. 24.9%, p=0.01). The 5-year cumulative mortality in individuals with elevated hs-cTnI was higher in COPD than in NLF (29.9% vs. 14.9%; p<0.001). In a cox-regression model adjusting for age, sex, pack-years and self-reported ischemic heart disease, elevated hs-cTnI was associated with an increased risk for death in COPD (HR 2.64, 95%CI 1.55-4.51), but not in those with NLF (HR 1.18, 95%CI 0.66-2.10). The increased risk in COPD remained after adjusting for disease severity.

    Conclusion: In this population-based study, elevated serum hs-cTnI concentrations were associated with increased risk for death among individuals with COPD, but not in those with NLF during a 5-year follow-up.

  • 5.
    Nilsson, Ulf
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Johansson, Bengt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Eriksson, Berne
    Göteborgs Universitet.
    Blomberg, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Lundbäck, Bo
    Göteborgs Universitet.
    Lindberg, Anne
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Ischemic heart disease among subjects with and without chronic obstructive pulmonary disease: ECG-findings in a population-based cohort study2015In: BMC Pulmonary Medicine, ISSN 1471-2466, E-ISSN 1471-2466, Vol. 15, article id 156Article in journal (Refereed)
    Abstract [en]

    Background: Cardiovascular comorbidity in COPD is common and contributes to increased mortality. A few population-based studies indicate that ischemic electrocardiogram (ECG)-changes are more prevalent in COPD, while others do not.

    The aim of the present study was to estimate the presence of ischemic heart disease (IHD) in a population-based COPD-cohort in comparison with subjects without COPD.

    Methods: All subjects with obstructive lung function (COPD, n = 993) were identified together with age- and sex-matched controls (non-COPD, n = 993) from population-based cohorts examined in 2002–04. In 2005, data from structured interview, spirometry and ECG were collected from 1625 subjects. COPD was classified into GOLD 1–4 after post-bronchodilator spirometry. Ischemic ECG-changes, based on Minnesota-coding, were classified according to the Whitehall criteria into probable and possible IHD.

    Results: Self-reported IHD was equally common in COPD and non-COPD, and so were probable and possible ischemic ECG-changes according to Whitehall. After excluding subjects with restrictive spirometric pattern from the non-COPD-group, similar comparison with regard to presence of IHD performed between those with COPD and those with normal lung-function did neither show any differences. There was a significant association between self-reported IHD (p = 0.007) as well as probable ischemic ECG-changes (p = 0.042), and increasing GOLD stage. In COPD there was a significant association between level of FEV1 percent of predicted and self-reported as well as probable ischemic ECG-changes, and this association persisted for self-reported IHD also after adjustment for sex and age.

    Conclusion: In this population-based study, self-reported IHD and probable ischemic ECG-changes were associated with COPD disease severity assessed by spirometry.

  • 6.
    Nilsson, Ulf
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Kanerud, Isabel
    Diamant, Ulla-Britt
    Blomberg, Anders
    Eriksson, Berne
    Lindberg, Anne
    The prevalence of prolonged QTc by spirometric classification in a populationbased cohort: normal lung function, restrictive pattern and airway obstructionManuscript (preprint) (Other academic)
    Abstract [en]

    Background Prolonged QT (corrected for heart rate, QTc) is associated with malignantarrhythmias. Cardiovascular comorbidity contributes to the increased mortality in COPD, butthe role of QTc is unclear.

    Aim The aim of this population-based study was to estimate the prevalence of QTcprolongation among subjects with normal lung function (NLF), airway obstruction (fixedratio, GOLD-COPD and Lower Limit of Normal, LLN-COPD) and restrictive spirometricpattern (RSP). Furthermore, to evaluate the prognostic impact of QTc prolongation.

    Method After re-examination of population-based cohorts in 2002-04, all individuals (n=993)with airway obstruction were identified together with age and sex-matched referents withoutairway obstruction. In 2005, the study-population was invited to examination includingspirometry, structured interview and 12-lead ECG, and QTc was calculated. Mortality datawere collected until December 31st, 2010.

    Results The study-population included NLF (n=734), RSP (n=175) and GOLD-COPD(n=571) whereof 299 LLN-COPD. RSP had longer mean QTc and higher prevalence ofprolonged QTc than NLF. GOLD-COPD, LLN-COPD and NLF had similar mean QTc andprevalence of prolonged QTc. In GOLD-COPD and LLN-COPD, the prevalence of prolongedQTc increased by GOLD-grade (test for trend p=0.002 and 0.043) and the cumulativemortality was higher in subjects with borderline and prolonged QTc in both groups, comparedto normal QTc. This was not the case in NLF or RSP.

    Conclusion The prevalence of prolonged QTc was higher in RSP than NLF, while it wassimilar in COPD and NLF, but increased by GOLD-grade in COPD. QTc prolongation wasassociated with increased mortality in GOLD-COPD and LLN-COPD but not in NLF or RSP.

  • 7.
    Nilsson, Ulf
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Kanerud, Isabel
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Diamant, Ulla-Britt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Blomberg, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Eriksson, Berne
    Lindberg, Anne
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    The prevalence of prolonged QTc increases by GOLD stage, and is associated with worse survival among subjects with COPD2019In: Heart & Lung, ISSN 0147-9563, E-ISSN 1527-3288, Vol. 48, no 2, p. 148-154Article in journal (Refereed)
    Abstract [en]

    Background: The role of QTc-prolongation, in relation to the increased mortality in COPD, is unclear.

    Objectives: To estimate the prevalence and prognostic impact, assessed as mortality, of QTc-prolongation in COPD, restrictive spirometric pattern (RSP), and normal lung function (NLF), respectively.

    Methods: All individuals (n = 993) with COPD and age- and sex-matched non-obstructive referents were identified from well-defined population-based cohorts examined in Northern Sweden in 2002–04. In 2005, the study-sample was invited to re-examination including ECG; QTc was calculated and mortality data collected until 31st December 2010.

    Results: The prevalence of QTc-prolongation was higher among people with RSP than among those with NLF and, although similar in NLF and COPD, the prevalence increased by COPD-severity. Among participants with COPD, those with QTc prolongation had higher mortality than those with normal QTc, while no such differences were found among participants with NLF or RSP.

    Conclusion: Among participants with COPD, the prevalence of QTc-prolongation increased by disease-severity and was associated with mortality.

  • 8.
    Qvist, Linnea
    et al.
    Stockholm, Sweden.
    Nilsson, Ulf
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Johansson, Viktor
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Larsson, Kjell
    Stockholm, Sweden.
    Rönmark, Eva
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Langrish, Jeremy
    Edinburgh, United Kingdom.
    Blomberg, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Lindberg, Anne
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Central arterial stiffness is increased among subjects with severe and very severe COPD: report from a population-based cohort study2015In: European Clinical Respiratory Journal, ISSN 2001-8525, Vol. 2, article id 27023Article in journal (Refereed)
    Abstract [en]

    Introduction: Cardiovascular disease (CVD) is common in chronic obstructive pulmonary disease (COPD) and is, as productive cough, related to poorer prognosis in COPD. Central arterial stiffness is a marker of early atherosclerosis, but the association between COPD, productive cough, and arterial stiffness as a possible indicator of CVD is unclear.

    Objectives: To compare both arterial stiffness among subjects with and without COPD and the impact of productive cough in a population-based cohort.

    Methods: A population-based cohort, including 993 COPD and 993 non-COPD subjects, has been invited to annual examination since 2005. In 2010, 947 subjects, of which 416 had COPD (according to the GOLD spirometric criteria), participated in examinations including structured interview, spirometry, and measurements of central arterial stiffness as pulse wave velocity (PWV).

    Results: PWV was higher in GOLD 3–4 compared to non-COPD (10.52 vs. 9.13 m/s, p=0.042). CVD and age ≥60 were both associated with significantly higher PWV in COPD as well as in non-COPD. In COPD, those with productive cough had higher PWV than those without, significantly so in GOLD 1 (9.59 vs. 8.92 m/s, p=0.024). In a multivariate model, GOLD 3–4 but not productive cough was associated with higher PWV, when adjusted for sex, age group, smoking habits, blood pressure, CVD, and pulse rate.

    Conclusions: GOLD 3–4, age ≥60, and CVD were associated with increased arterial stiffness, and also increased in COPD subjects with productive cough compared to those without. Of importance, GOLD 3–4 but not productive cough remained associated with increased central arterial stiffness when adjusted for confounders.

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