Deciphering COPD and associated cardiovascular impairment

Characterising the cardiovascular risks associated with chronic obstructive pulmonary disease (COPD) is a substantial challenge. Despite adjustment for shared risk factors, patients with COPD are at increased risk for admissions to hospital and death due to heart failure, coronary artery disease, and other cardiovascular diseases.¹

Hyperinflation of the lungs caused by COPD increases the risk of cardiac dysfunction, as it leads to higher intrathoracic pressures, increased pulmonary vascular resistance, and abnormal cardiac haemo dynamics that ultimately reduce pulmonary venous return and increase myocardial transmural pressure gradients.^2–5 Such changes seem to have prognostic significance; a study showed that patients with COPD with greater left ventricular mass had poorer cardiovascular outcomes than those with no change in ventricular mass.⁶ Furthermore, successful lung deflation either via lung volume reduction surgery⁷ or the short-term use of combined inhaled corticosteroid and long-acting β₂-agonist (ICS–LABA) bronchodilators⁸ improved cardiac performance probably by increasing ventricular end-diastolic volumes and stroke volume. Such changes could ultimately explain the association between hyperinflation caused by COPD and poor cardiovascular outcomes.

In this issue of The Lancet Respiratory Medicine, Jens Hohlfeld and colleagues⁹ report important new data underscoring the cardiopulmonary interdependence seen in patients with COPD and hyperinflation. In a double-blind, randomised, placebo-controlled, crossover trial of 62 such patients, they assessed the use of indacaterol (110 μg)–glycopyrronium (50 μg), a dual long-acting β₂-agonist plus long-acting muscarinic antagonist (LABA–LAMA) bronchodilator versus placebo on cardiac performance and lung volume deflation. The investigators assigned patients to either treatment for 14 days, followed by a 14-day washout, then the other treatment for 14 days. Compared with placebo, there was a greater increase in the primary outcome of left-ventricular end-diastolic volume indexed to body surface area (measured on days 15 and 43) from baseline with indacaterol–glycopyrronium (least-squares means treatment difference 5·23 mL/m² [95% CI 3·22–7·25; p<0·0001]). LABA–LAMA therapy also improved lung function, reduced hyperinflation, and improved right ventricular filling volume and cardiac indices as measured by cardiac MRI. Additionally and not surprisingly, there were between-treatment improvements in patient-reported dyspnoea and COPD-related symptom burden, providing the clearest evidence to date linking lung deflation with improved haemodynamics and COPD symptom burden that represents an improvement compared with previous investigations that used combined ICS–LABA.⁸ The collective data from Hohlfeld and colleagues’ study⁹ showed that improved pulmonary physiology can in turn improve cardiac performance, and increases our understanding of the relationship between pulmonary and cardiac dysfunction in individuals with COPD and hyperinflation.

However, despite the study’s careful characterisation of cardiac function, the results did not confirm the long-postulated connection between hyperinflation and cardiovascular disease. Most notably, although patients showed improvement in COPD-related symptoms, there was no assessment for heart failure short of the measurement of ejection fraction. This assessment is crucial because there is a substantial clinical overlap between COPD and heart failure with preserved ejection fraction.¹⁰ The addition of patient-reported outcome measurements for heart failure would have provided some evidence of the benefit of dual bronchodilator therapy on any underlying symptoms associated with heart failure. More importantly, assessment of physical endurance through cardiopulmonary exercise might be necessary to help discern a clear cardiovascular benefit of lung deflation. These parameters might indeed improve with a combined LABA–LAMA treatment given the increase in cardiac index; however, clinical outcomes still need validation and rigorous examination before any clinical significance can be ascribed. Hence, it is premature to recommend dual bronchodilator therapy for lung deflation as a preventive strategy to reduce cardiovascular outcomes in patients with COPD.

Hohlfeld and colleagues’ study⁹ also raises the question of whether lung deflation and increased ventricular diastolic volumes represent meaningful surrogate markers for cardiovascular function in future COPD investigations. The use of combined ICS–LABA was not associated with a reduction in cardiovascular deaths in the TORCH trial,¹¹ nor were there associations between indacaterol–glycopyrronium use and cardiovascular outcomes in a pooled analysis of 14 studies,¹² suggesting no direct association between improvement in lung function and cardiovascular events. Albeit promising, the findings from Hohlfeld and colleagues⁹ do not provide the evidence needed to decipher these interconnected observations. However their findings, in addition to those by Stone and colleagues,⁸ provide the framework with which to investigate whether improved ventricular filling in COPD represents a clinically meaningful target, or merely an associated occurrence of effective bronchodilation.

Finally, we present a word of caution regarding the association of increasing ventricular filling volumes with LABA–LAMA therapies. Generally, the prevalence of hypertension, heart failure (both reduced and preserved ejection fraction), arrhythmias, coronary artery disease and valvular heart disease is substantial among individuals with COPD. Such patients with these potentially undiagnosed comorbidities might not inherently do better with increasing filling volumes or pressures. Hence, the potential to unmask silent cardiovascular disease is an important consideration that must be addressed before initiating dual bronchodilator therapy.¹³ Although Hohlfeld and colleagues did not observe such hazards in their short-term trial, prospective clinical trials are nonetheless needed before early or preventive intervention to reduce lung volumes and cardiovascular disease with dual LABA–LAMA therapies can be safely recommended.

Despite the aforementioned limitations, Hohlfeld and colleagues⁹ provide substantial evidence of an ever-present relationship linking pulmonary hyperinflation with altered cardiac haemodynamics. The results of their trial further substantiate calls for early interventions to reduce hyperinflation as a means of preventing related cardiac comorbidities. More importantly, their preliminary findings emphasise the need for continued prospective clinical trials to investigate novel strategies to reduce cardiovascular events in patients with COPD.