Treatable cardiac disease in hospitalised COPD exacerbations

Discussion

We report the first application of dynamic cardiopulmonary CT in a cohort of hospitalised patients with AECOPD. Severe, but treatable cardiac disease was detected in 42% of patients: severe CAD was found in about one-third of patients, and severely reduced LVEF and/or RVEF was found in approximately 10% of cases. Standard tertiary hospital care assessments, including cardiac biomarkers performed relatively poorly to diagnose severe CAD and HFrEF. Unsurprisingly, undertreatment with disease-modifying agents was common. Taken together these findings imply that targeted disease finding in hospitalised AECOPD may aid diagnosis, treatment and prevention of future cardiac morbidity and mortality.

Hospitalised AECOPD is associated with substantial mortality and an enriched risk of subsequent major adverse cardiovascular events [2, 3]. Hospitalisation therefore represents a favourable opportunity to diagnose and intervene in cardiac disease by implementing well-established treatment pathways with recognised treatment benefits [11–13]. The finding that 42% of patients exhibited one or more of severe CAD or HFrEF, indicates that abundant treatment opportunities exist in this population of hospitalised AECOPD. Importantly, our findings are likely to be an underestimate of cardiovascular involvement in an unselected hospitalised AECOPD population as we excluded patients with severe renal disease and those who were not in sinus rhythm.

Dynamic CT highlighted that standard clinical assessments often grossly underdiagnosed CAD and HFrEF. One-third of severe CAD and two-thirds of severe HFrEF was clinically unsuspected on standard history and examination and would have been overlooked in routine AECOPD management. ECGs were nonspecific for CAD, and chest radiographs were nonspecific for HFrEF, as were troponin and BNP. Combining standard clinical assessments could be useful as the presence of a normal ECG, troponin and BNP rendered HFrEF unlikely. This combination was not entirely reassuring as important CAD was still detected in many of these individuals and our observations require replication in other cohorts.

It is unsurprising that cardiac biomarkers were not associated with specific cardiac diagnoses since these biomarkers are sensitive but not specific for cardiovascular diagnoses. Numerous factors including exacerbation severity, effects of tachycardia, hypoxia, and chronic changes including pulmonary hypertension and diastolic dysfunction could result in biomarker elevation [2, 31]. Consequently, biomarkers cannot be relied upon to directly determine therapeutic strategies outside of defined circumstances such as dynamic troponin elevations, which might suggest acute coronary syndrome. However, biomarkers remain important sentinel markers of adverse outcomes including mortality [2]. Taken together, standard clinical assessments underdiagnosed cardiac disease and when abnormal, generally lacked the diagnostic accuracy required to institute disease-specific treatments.

The current studies show that 35% of patients had severe CAD, mirroring other cohorts including ECLIPSE, COPDGene and the Danish Lung Cancer Screening Trial [7, 8, 32]. In populations with COPD, CAD is associated with adverse outcomes, including higher dyspnoea, lower exercise capacity and greater mortality [7, 8, 32]. Further, the incidence of acute myocardial infarction increases at AECOPD [3] beyond a baseline of elevated risk [33]. In aggregate, diagnosing CAD during AECOPD represents an opportunity for cardiac risk mitigation not only during that episode, but also towards improved longer-term outcomes. This notion is supported by data from COPD populations suggesting that antiplatelet and lipid-lowering treatments may reduce dyspnoea, mortality and COPD exacerbations [1, 4]. A case-finding approach for CAD, such as that using CT, could define individuals with CAD and its severity, allowing targeted cardiac risk reduction.

HFrEF was less common in our cohort at about 10% prevalence, but this group may be of disproportionate clinical prominence since coexistent heart failure and COPD is associated with an increased frequency of hospitalisation [2, 4] and incipient heart failure may simulate AECOPD or even precipitate it [2, 4, 14]. Diagnosis and treatment of HFrEF appeared clinically difficult in our study. Two-thirds of those patients with HFrEF on dynamic CT related no clinical history or examination evidence of this diagnosis. Conversely, about half of patients with normal biventricular function received treatment for presumed heart failure. Identifying COPD patients with clear indications for HFrEF treatment such as angiotensin blockade and beta blockers would enhance the risk–benefit profile of these agents, as broader prescription may lead to adverse effects [34]. Finally, when HFrEF was detected, a higher burden of CAD was present, suggesting that CAD warrants consideration when HFrEF is detected.

Current AECOPD treatment paradigms [25] are dominantly aimed at pulmonary, rather than cardiac parameters, despite COPD populations demonstrating a 2.5-fold increased risk of cardiac disease [33]. Paradoxically, COPD management recommendations emphasise a thorough ‘precision medicine’ approach, in which characteristics are defined and treated [35]. We found that some form of cardiac involvement at AECOPD was extremely common, with only 28% of patients not exhibiting one or more of severe CAD, HFrEF or abnormal cardiac biomarkers. Without knowledge of influential cardiac diagnoses, a precision medicine strategy is difficult to fully implement, and treatable cardiac diseases could be routinely overlooked. Overall, accurately diagnosing and treating cardiac comorbidities at an opportune occasion such as AECOPD could not only alter mortality and morbidity [1, 4, 11–13] but could also ensure tailored pulmonary treatments that will minimise adverse cardiac effects. Our data demonstrated, however, that FEV₁ was the parameter most strongly associated with 30-day readmission, implying that optimising airway management may be the correct approach to preventing short-term readmission for many patients.

The current study has caveats. Severely unwell patients, including those with arrhythmias and with poor renal function, were excluded from the study. It is possible that results may not apply outside the study population of hospitalised AECOPD. However, findings are broadly consistent with previous global reports of under-diagnosis and undertreatment of coronary disease and systolic heart failure in COPD populations [1, 7, 36–38]. For example, the quantitative coronary calcium burden in our patients was comparable with that in the ECLIPSE cohort [7], who also only received statins about one-quarter of the time; beta blocker under-prescription for HFrEF is also commonly reported [1, 37, 39].

Diastolic dysfunction, and the clinical entity of heart failure with preserved ejection fraction are key comorbidities in patients with COPD that may explain cardiac biomarker elevation in some patients. However, methodologies to ascertain and quantify diastolic dysfunction on dynamic CT are not yet well established. Additionally, there is currently limited evidence that specific pharmacotherapies alter the course of heart failure with preserved ejection fraction, in contradistinction to HFrEF and CAD. Examining diastolic dysfunction therefore merits further study but was outside the scope of this work.

A limitation of this work is that multiple assays were used for both troponin and BNP. Because there are no validated ways to interchange values between assays, we were unable to draw inferences based on absolute biomarker levels. In addition, blood lipids were not measured and so could not be used to apply standard cardiovascular risk estimators.

A key strength is the use of dynamic CT to accurately assesses important cardiac parameters in a single, rapid imaging session requiring only one breath hold [21]. Coronary calcium was quantified using the gold-standard technique of prospective ECG-gated CT [15, 22]. For left and right ventricular parameters, dynamic CT is extremely precise and accurate, exhibiting near-perfect correlation (Pearson r 0.9 to 0.99) with the gold-standard of magnetic resonance imaging [16, 17, 19, 20]. CT however does require radiation exposure, adequate renal function and cannot directly measure pressures or vascular resistance.

The detection of coronary artery calcium reflects late-stage subclinical coronary atherosclerosis, and scores are proportionate to the area and volume of plaque [15, 22, 40]. Although we used the term severe CAD to refer to Agatston scores ≥400 based on precedent [27], and worse outcomes when scores ≥400 [8, 41], it is a limitation that we did not conclusively demonstrate that these were associated with specific disease entities such as ischaemic heart disease.

During AECOPD, dynamic CT affords substantial pragmatic advantages in comparison with other cardiac imaging modalities. In many patients with COPD, transthoracic echocardiography parameters cannot even be obtained due to hyperinflation and poor acoustic windows [2, 21]. In addition to overcoming this practical disadvantage, dynamic CT is more accurate than echocardiography [16]. Magnetic resonance imaging requires prolonged acquisitions in a claustrophobic environment, an arduous and potentially dangerous undertaking during acute breathlessness. Neither echocardiography nor magnetic resonance imaging can quantitate CAD. Conversely, dynamic CT was practicable and well tolerated during hospitalised AECOPD, revealing two significant, treatable cardiac diseases.

Future studies could answer whether the HFrEF abnormalities observed are persistent or transient, and clarify associations between outcomes and other CT-derived measurements. Key unresolved questions are identifying a subpopulation who would benefit from an invasive angiographic approach, and whether routine implementation of a CT-based case-finding strategy would be cost-efficient and improve long-term outcomes.

In conclusion, detection of cardiac disease employing dynamic cardiopulmonary CT is feasible during AECOPD with approximately 40% of patients having severe, but treatable cardiac disease. The ability to accurately delineate cardiac pathologies has potential to guide treatment and improve prognosis in people with COPD.