We recently showed that myocardial injury, defined as high-sensitivity cardiac troponin T (hs-cTnT) above the 99^th percentile (i.e. 14ng/L), was present in 74% of patients admitted for acute exacerbation of COPD (AECOPD) and that such injury carried a markedly increased risk of subsequent mortality [13]. We proposed four possible mechanisms, that may occur in concert, leading to elevated hs-cTnT during AECOPD: Type 1 and 2 myocardial infarctions (MI), increased right heart afterload due to either AECOPD alone or pulmonary embolism, and concomitant left heart failure. The determinants of troponin elevation in AECOPD are, however, sparsely studied.

In a previous cross-sectional study among patients hospitalised for AECOPD, we found that cardiac troponin T measured with a 4^th generation assay was positively associated with increasing serum creatinine, blood neutrophil cell count, and cardiac infarction injury score (CIIS), whereas it was negatively associated with hemoglobin level [14]. In that retrospective study, troponins were measured at the discretion of the attending physician in selected patients, which may have introduced a selection bias. In the present study we prospectively obtained data from patients hospitalised for AECOPD one or more times during the study period, thereby providing the opportunity to study the association between hs-cTnT and relevant covariables within patients, and reducing the influence of inter-individual differences.

Serum and plasma from blood drawn on admission were stored at −80°C for subsequent analysis of creatinine and hs-cTnT (cobas e 411 immunoanalyser, Roche diagnostics). According to the manufacturer of the hs-cTnT assay, the lower limit of detection is 3.0ng/L, and the 99^th percentile in healthy volunteers was 14ng/L. The lowest hs-cTnT level with 10% coefficient of variation was 13ng/L. Glomerular filtration rate (GFR) was estimated by MDRD and Cockcroft-Gault formulae [15,16]. From the hospital records we recorded hemoglobin (Hb), leucocytes with neutrophil count, platelets, electrolytes, and C-reactive protein (CRP). Chest radiographs were examined by two physicians blinded for clinical data. Presence or absence of cephalisation, pneumonic infiltrates and pleural effusion in addition to the size of the heart and thoracic cavity in the frontal plane were recorded. ECGs recorded on admission were scored using CIIS. A score ≥20 has been shown to be a good indicator of prior MI [17], and to be associated with increased mortality in AECOPD patients [18]. Two physicians independently scored each ECG. When they disagreed on whether the CIIS was above or below 20, the score of a third physician was used. All three investigators were blinded to other data. ECGs were also analysed for the presence of arrhythmia, bundle branch block, left ventricular hypertrophy (LVH, assessed by Sokolow-Lyon criteria), signs of prior MI, or acute ischemia. We considered pathological Q-waves, loss of R-waves, T-wave inversion, and left bundle branch block to be signs of prior MI. ST-segment elevation or depression were recorded as signs of acute ischemia unless it was considered to be secondary to LVH.

Spirometry during stable phase was recorded when available. When several measurements were done, post bronchodilatation measurements prior to inclusion were preferred. Body mass index (BMI) was calculated from weight and height as recorded on the spirometry report or from the hospital records when spirometry was missing. Medical history was obtained by patient interview and hospital records. Patients were categorised as current, former (>1year abstinence) or never smokers. Further details regarding patient inclusion and data gathering are described in a previous paper [13].

The study was approved by the Data Inspectorate and reviewed by the Regional Committee for Research Ethics. All included patients provided written informed consent to the participation in the study.

Regarding the association between hs-cTnT and arterial hypertension, one might speculate that this was due to the development of LVH, as LVH have been found to be associated with troponin in other studies [20,21]. However, there was no significant association between troponin and electrocardiographic signs of LVH in the present study. An alternative explanation may be the established role of arterial hypertension as a risk factor for the development of CVD.

The association between hs-cTnT level and creatinine deserves some comment. In clinical practice, we often experience elevated levels of troponin in patients with renal failure, but without overt cardiac disease. It has been previously debated whether this is due to reduced renal elimination of troponin, but it may rather be a result of subclinical release of cTnT in these patients, as renal and cardiac atherosclerotic disease are pathophysiologically similar and partly overlapping. It may be worth noting that the majority of our patients had normal creatinine, an observation that favors the latter of the two theories. It may be argued that due to reduced muscle mass, patients with advanced COPD may have decreased renal function in spite of creatinine within the reference range. The finding that the addition of low BMI improves the fit of the final model, adds to this argument. We therefore estimated GFR, but still found that renal function was preserved in the vast majority of patients.

Although the cross-sectional analyses of the baseline data indicated an inverse association between tachycardia and hs-cTnT, longitudinal multivariable analysis showed a significant positive association between elevated hs-cTnT and tachycardia. This may be due to an effect of heart rate per se, but it may also reflect worsening of pulmonary hypertension and increased myocardial strain, undiagnosed pulmonary embolism, or a type 2 MI caused by insufficient oxygen delivery relative to the increased demand during tachycardia. Along this line of thinking, we would also expect an association between reduced PaO₂ and hs-cTnT. Although we found such an association in the univariable longitudinal analysis, it was not significant in the cross sectional or multivariable analyses. Hence, our data do not support that elevated hs-cTnT in these patients can be explained as a type 2 MI mediated hypoxemia. However, patients with normal arterial oxygen tension in the emergency room may have received oxygen therapy in the ambulance, yet have had severe arterial hypoxemia before admission to the hospital causing cTnT leakage from the cardiomyocytes. Thus, the lack of association between hypoxemia and elevated hs-cTnT should be interpreted with caution.

Our analyses are based on data from repeat admissions by applying the linear mixed model [19]. Among the strengths of the model is that it does not require the outcome variable to be independent between observations, so one can use repeat observations from the same individual. Moreover, by using an appropriate covariance structure, the model allows us to have unbalanced data with different number of observations per patient and different timing of these. Thus, the analyses are based not only on inter-individual differences, but also on intra-individual changes in covariables over time, effectively allowing patients with repeat admissions to serve as their own controls. Hence, the association between hs-cTnT and covariables (such as oxygen tension and creatinine changes) can be investigated intra-individually. Comparison of the results of these univariable analyses show that the associations with creatinine were highly significant in the cross-sectional as well as in the longitudinal models with the estimates being nearly identical. There is discrepancy regarding heart rate, with p-value <0.10 in the LMM only. Although the design of the study does not permit any conclusions to be drawn regarding cause and effect, this discrepancy may suggest that there is an association between tachycardia and cTnT release in susceptible individuals.

Our group has previously published results from a retrospective cohort study of 441 patients with AECOPD, identifying creatinine, hemoglobin, neutrophil count, heart rate and CIIS as independent predictors of elevated cTnT (≥0.04μg/L) [14]. In the present prospective study, we confirm that age, creatinine, and heart rate are independently associated with hs-cTnT level. In addition, we observed an association between hs-cTnT and history of arterial hypertension. CIIS and neutrophil count were not significantly associated in the present analyses, perhaps due to the relatively modest sample size. On the other hand, considerable intra-individual variation of neutrophil count was observed, thereby weakening the hypothesis of a relationship between neutrophils and cTnT. Other markers of inflammation than leucocytes, fibrinogen in particular, have been shown to be associated with COPD, its severity and exacerbation frequency [22-27]. Fibrinogen was not measured in this study, but one might speculate whether this inflammatory marker might be more closely associated with cTnT, as it may be a risk factor for the development of CVD.

Other limitations of this study include the modest size of the cohort, which may explain the inconsistency regarding tachycardia, and the nonsignificant association with hypoxemia. Nevertheless, we identify associations that are both statistically significant and physiologically plausible. The strengths of the associations may be unimpressive, with an estimated 44% increase in hs-cTnT in patients with hypertension as the strongest association. The range of hs-cTnT concentrations is small, however, so strong associations can not be expected. Moreover, in spite of this narrow range, relatively small changes in hs-cTnT are associated with markedly adverse prognosis in this group [13]. Thus, it is important to identify determinants of cTnT elevation in AECOPD.