Chronic obstructive pulmonary disease (COPD) is a chronic, progressive lung disease resulting from exposure to cigarette smoke, noxious gases, particulate matter, and air pollutants. COPD is exacerbated by acute inflammatory insults such as lung infections (viral and bacterial) and air pollutants which further accelerate the steady decline in lung function. The chronic inflammatory process in the lung contributes to the extrapulmonary manifestations of COPD which are predominantly cardiovascular in nature. Here we review the significant burden of cardiovascular disease in COPD and discuss the clinical and pathological links between acute exacerbations of COPD and cardiovascular disease.
Chronic obstructive pulmonary disease (COPD) is characterized by emphysema, small airways disease, and bronchitis, associated with pulmonary hypertension. The chronicity of COPD is well documented, characterized by a progressive decline in lung function associated with airway narrowing due to inflammation, fibrosis and mucus plugging, and parenchymal destruction with a loss of elasticity, gas exchange surface area, and airway support with subsequent early airway closure [
The close association between COPD and cardiovascular disease has received significant attention in the last fifteen years in a concerted effort to improve our understanding of the systemic consequences of COPD. It is estimated that the diagnosis of COPD increases the risk of cardiovascular disease by an OR of 2.7 (95% CI 2.3–3.2) [
Mortality from cardiovascular disease is similarly increased in the COPD population. The 45,966 patients with COPD in the Northern California Kaiser Permanente Medical Care Program had an adjusted RR for mortality for all cardiovascular endpoints of 1.68 (95% CI 1.50–1.88), ranging from 1.25 (stroke) to 3.53 (heart failure) [
COPD patients do not tolerate cardiac injury or intervention as well as those without airways obstruction. Bursi et al. determined that COPD subjects with an acute myocardial infarction have a five-year survival rate of 46% (95% CI 41–52%) as compared to those without COPD (survival rate 68%, 95% CI 66–70%), with an adjusted hazard ratio of 1.30, 95% CI 1.10–1.54 [
The difference in mortality after a cardiovascular event may relate to a difference in management of COPD patients with cardiovascular disease. Those with coexisting cardiac disease and COPD are more likely to have less aggressive treatment with cardiac medications and/or coronary angiography [
COPD contributes to cardiovascular risk, so it is important to understand whether other cardiovascular risk factors are associated with COPD as well. There are a multitude of studies linking classical cardiovascular risk factors [
Interestingly, the metabolic syndrome phenotype is commonly present in COPD patients [
The presence of peripheral vascular disease is very common in COPD patients, and there are multiple variables that contribute to this disease process including the systemic inflammatory response induced by the inhalation of cigarette smoke, diesel exhaust particles, and other air pollutants [
Cerebrovascular disease, as a manifestation of severe vascular disease, is increased in the COPD population, both in the presence of acute inflammation and in chronic disease [
The emphysematous component of COPD is characterized by destruction of alveolar walls and pulmonary capillaries, hyperinflation with resultant positive alveolar pressure throughout inspiration, hypoxic vasoconstriction, and pulmonary vascular endothelial dysfunction, with subsequent pulmonary hypertension. Depending on the definition used, 25 to 70% of COPD patients have pulmonary hypertension [
Left heart dysfunction in COPD patients can be a challenge to recognize clinically and has recently been shown to be associated with significant morbidity and increased mortality in the COPD population. Many of the early studies looking at cardiac dysfunction and COPD lacked objective parameters defining reproducible echocardiographic measures and spirometric criteria [
COPD patients with co-existing heart failure experience similar mortality, hospitalization for cardiovascular events, and frequency of pulmonary events, regardless of whether they have a preserved or reduced ejection fraction [
Arrhythmias associated with airflow obstruction are relatively common and have been a long-standing research interest. Hudson et al. in 1973 report a variety of arrhythmias noted in those with airflow obstruction, as defined by ATS guidelines in the 1970’s [
An increased risk of supraventricular arrhythmia has also been reported, most commonly atrial fibrillation and multifocal atrial tachycardia. A higher risk of irregular heartbeats [
While numerous factors have been associated with poor outcomes from AECOPD, cardiovascular disease is being increasingly recognized as an important predictor of in-hospital mortality. Cardiovascular risk factors and cardiac comorbidities that correlate with in-hospital mortality include age [
The cardiovascular morbidity of the population admitted with AECOPD is often underappreciated and underdiagnosed at the time of admission, as it is in stable disease. As an example, a high frequency (55%) of those with AECOPD have systolic or diastolic left ventricular dysfunction; more than are accounted for by known comorbid disease [
There is much interest in the prevention of repeated or prolonged hospitalizations for AECOPD as recurrent admissions are associated with a higher all-cause mortality [
Length of stay in hospital for an acute exacerbation of COPD averages between 6 and 9 days [
There is mounting evidence that associates a higher frequency of acute cardiovascular disease with acute respiratory illness, such as pneumonia or AECOPD. In the general population, subjects with a respiratory tract infection are more likely to get an acute myocardial infarction within 1-2 weeks (OR 2-3) [
Increased vascular risk associated with infection can be more broadly defined as secondary to an acute inflammatory lung condition, as other inflammatory states within the lung are associated with vascular dysfunction as well. Diesel exhaust has been linked to exercise-induced ST-segment depression and surrogates for vascular endothelial dysfunction [
In any disease state, ECG analyses are used to identify predisposing risk for development of ischemia/arrhythmias or signs of underlying cardiac disease. In stable COPD patients, there are subtle changes in the ECG that are not present in the general population. Screening ECGs in patients with COPD have a low coefficient of variation of the RR interval that correlates with degree of hypoxemia [
Stable COPD patients (
In AECOPD, ECG changes are very common, and studies demonstrate a high frequency of finding a new abnormality on ECG from baseline. In a study by Harvey and Hancox, 8% had ST segment depression, 37% had T wave changes, 17% had conduction block, and 6% had a new change on their ECG from baseline (
Presence of an electrocardiogram (ECG) abnormality and length of stay (LOS) of subjects admitted with an AECOPD to St. Paul’s Hospital or Mount St. Joseph’s Hospital between 2007 and 2008. The presence of ECG abnormalities did not influence LOS (
AECOPD is associated with greater prolongation of P wave dispersion than in stable COPD [
The natriuretic peptides have an established role in differentiating amongst the causes of dyspnea in COPD patients presenting with AECOPD [
Similarly, NT-proBNP levels in patients with AECOPD and left heart failure were significantly higher than those with AECOPD without LV failure or stable controls [
The utility of BNP and NT-proBNP is well-proven in its ability to document heart failure, but clinicians are still challenged to predict whether the BNP is indicative of right heart dysfunction or left heart dysfunction. Several studies have attempted to correlate BNP and NT-proBNP with right heart and left heart pathology but have as yet not been able to discriminate between the two [
Elevated troponin levels are hallmarks of stress or ischemia affecting the myocardium. At baseline, COPD patients have been shown to have higher highly sensitive cTnT than the general population [
Summary of studies analyzing the prognostic and diagnostic importance of serum troponins in patients admitted to hospital for acute exacerbations of COPD.
Author | Study design | Sample size | Controls | Follow-up (months) | Associations with elevated troponin |
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Fruchter and Yigla [ |
Retrospective |
83 | 953 without troponins and 99 with low cTnI | ≤72 | Increased long-term mortality |
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Martins et al. [ |
Retrospective |
121 | 52 with undetectable cTnI | >18 | Age, heart failure, atrial arrhythmia, elevated BNP, need for NIPPV |
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Harvey and Hancox [ |
Retrospective |
47 | 147 with undetectable cTnI or cTnT | Until discharge | Older age, lower pulse oximetry, acidosis, hypercapnea |
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Brekke et al. [ |
Retrospective | 173 | 897 without troponins and 223 with undetectable cTnT | <66 | Increased all-cause mortality |
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Brekke et al. [ |
Retrospective |
321 | 120 with undetectable cTnT | Discharge | Neutrophilia, increased creatinine, cardiac infarction injury score, low hemoglobin, and tachycardia |
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Odigie-Okon et al. [ |
Prospective |
19 | 95 without an ischemic ECG and undetectable cTnT | First 24 hours from admission | Presence of acute coronary syndrome or marker of ischemia |
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Marcun et al. [ |
Prospective |
32 at admission |
95 admitted with |
6 | Increased risk of repeat hospitalization (HR 2.89, 95% CI 1.13–7.36) |
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Høiseth et al. [ |
Prospective | 73 | 26 with a low highly sensitive cTnT | <36 | Increased long-term mortality and higher mortality with tachycardia |
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Høiseth et al. [ |
Prospective |
49 | 50 with a low geometric mean of hs-cTnT | Discharge | Age, arterial hypertension, tachycardia, creatinine |
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Baillard et al. [ |
Prospective |
13 | 58 with normal troponins | Discharge | In-hospital mortality |
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Soyseth et al. [ |
Prospective |
50 | 124 stable COPD patients admitted to a rehabilitation hospital | Until discharge | No association between retrosternal chest pain or T wave inversions on ECG and elevated troponin |
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Chang et al. [ |
Prospective | 40 | 201 with undetectable cTnT | 12 | Increased 30-day mortality |
LOS: length of stay; LVH: left ventricular hypertrophy; cTnI: cardiac troponin I; cTnT: cardiac troponin T; AECOPD: acute exacerbation of COPD; ECG: electrocardiogram.
Tachycardia has been shown to be an independent risk factor for cardiovascular mortality in the general population [
The Lung Health Study is a large prospective randomized control trial that looked at the benefits of intensified smoking cessation regimens and ipratropium. It found no significant difference in mortality or cardiovascular morbidity associated with ipratropium, although this study was not powered to examine this rigorously [
There are studies that suggest a possible contribution of inhaled bronchodilators to cardiovascular morbidity, but each study has inherent limitations and therefore more studies are needed. The Lung Health Study did not show a statistical difference between supraventricular arrhythmias in patients using ipratropium as compared to those using placebo or with usual care but did find that those with an arrhythmia were very compliant in their usage of ipratropium [
Noninvasive positive pressure ventilation (NIPPV), in the form of bilevel positive airway pressure, is a commonly used intervention in severely dyspneic or hypercarbic patients with AECOPD. Recently, 7.5 million admissions for AECOPD between 1998 and 2008 were reviewed documenting an increasing usage of NIPPV from 1% to 4.5% in all admissions for an AECOPD and a significant reduction in the number of patients who required mechanical ventilation [
Bilevel noninvasive ventilation has been shown to be beneficial in heart failure [
The impact that bilevel ventilation has on hemodynamics has been studied in stable COPD. Sin et al. performed a double-blind, parallel randomized control trial in 23 patients with advanced COPD to determine if bilevel noninvasive ventilation improves cardiac functioning by evaluating heart rate variability, functional performance, and serum markers of cardiac dysfunction after three months of treatment. Notably, use of bilevel positive pressure ventilation resulted in increased heart rate variability, which is a good prognostic marker and a surrogate for improved cardiac functioning as outlined previously [
The use of
COPD patients derive significantly less morbidity from respiratory disease when using
Recent work has focused on determining if there is an optimal
Several studies have documented a mortality benefit for COPD patients within the first 90 days following discharge from AECOPD who use ACEi and statins [
There has been an effort to determine whether ACE inhibitors may directly improve morbidity from COPD. The DD genotype of the angiotensin-converting enzyme (ACE) is associated with pulmonary hypertension and tissue oxygenation with exercise, raising questions as to whether it is associated with the phenotype of COPD [
Originally designed to lower cholesterol, the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, also called “statins,” are recognized as anti-inflammatory agents [
Statins are associated with improved mortality from COPD. A systematic review performed by Dobler and colleagues supports the mortality benefit of statins in COPD, but the data was predominantly based on observational and retrospective studies, with only the one randomized control trial by Lee et al. [
There are strong mechanistic links between acute and chronic lung injury, inflammation, peripheral vascular disease, acute vascular events [
Acute inflammatory events in the lungs provoke a cascade of systemic inflammation that starts in the lung, with hematologic spread to other organs, activating the systemic inflammatory response, and thereby promoting the development of atherosclerosis and vascular events.
Recent experimental evidence has shown that inflammatory mediators produced in the lung (following exposure to either lipopolysaccharide or particulate matter) directly translocate to the blood stream supporting the concept that inflammation in the lung directly contribute to the downstream systemic response [
AECOPD is associated with an acute lung injury initiating the local and systemic inflammatory pathways that cause endothelial injury and vascular dysfunction, a prothrombotic environment, and instability in vascular plaques that may predispose to coronary and cerebrovascular events.
COPD is a complex lung and systemic disease that is associated with a variety of cardiovascular diseases including coronary artery disease, peripheral vascular and cerebrovascular disease. COPD patients have frequent right and left ventricular dysfunction and an increase in sympathetic activation with high morbidity from arrhythmias. Acute exacerbations of COPD may trigger cardiac events but are also often precipitated by cardiac events. At the present time, many of these events are unrecognized, despite improved tools for diagnosis and assessment. The treatments we utilize for AECOPD have not been rigorously examined as to the effects they have on a vulnerable cardiovascular system and further studies are needed to explore this area. Finally, the association between lung inflammation (including that in COPD and AECOPD) and cardiac events may be due to consequences of the systemic inflammatory response and downstream microvascular changes in plaque stability, hypercoagulability, and endothelial cell dysfunction.
The authors declare that there is no conflict of interests regarding the publication of this paper.
This work was supported by the Heart and Stroke Foundation of Canada and the Canadian Institute for Health Research. Stephan van Eeden is an American Lung Association Career Investigator and the recipient of the William Thurlbeck Distinguish Research Award and is currently the GSK/CIHR Professor in Chronic Obstructive Pulmonary Disease.