In this study hs-cTnT was positively associated with age, history of arterial hypertension, tachycardia, creatinine, and follow-up time among patients hospitalised for AECOPD. The strength of this study is that the patients were followed prospectively, and that as many as 41% of the patients were investigated at two or more admissions. Consequently, the associations could be investigated longitudinally as well as cross-sectionally. We have also used the novel highly sensitive cardiac troponin T assay, allowing us to measure concentrations down to about 1/10 of what was previously possible, finding detectable cTnT in almost all samples.
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
]. 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 (≥0.04
]. 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
]. 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.
Although patients with confirmed PE were excluded from the study, the diagnosis was not systematically investigated, and unrecognised PE may have influenced the results.