COPD and Cardiovascular Disease: Mechanistic Links and Implications for Practice

Abstract

Purpose of review:

Chronic obstructive pulmonary disease (COPD) and cardiovascular disease (CVD) are both significant burdens on the healthcare system and often coexist. Mechanistic links between the two conditions and their clinical impact are increasingly understood.

Recent findings:

Recent studies demonstrate multiple mechanisms by which the pathobiology of COPD may have negative effects on the cardiovascular system. These include extrapulmonary consequences of the COPD inflammatory state, cardiac autonomic dysfunction, which has been recently implicated in worsening respiratory symptoms and exacerbation risk, and mechanical effects of lung hyperinflation on left ventricular diastolic function.

Clinical studies have consistently shown a high prevalence of CVD in COPD patients and worsened outcomes (and vice versa). Exacerbations of COPD have also been demonstrated to dramatically increase the risk of cardiovascular events. While some safety concerns exist, medications for COPD and cardiovascular disease should be used in accordance with respective guidelines. However, real-world data show suboptimal management for patients with COPD and CVD.

Summary:

COPD and cardiovascular disease have complicated interrelationships. Further mechanistic studies may lead to defining better targets for interventions. Education for medical professionals and implementation of novel screening protocols should be encouraged to fill in the gaps in clinical care for these patients.

Introduction

Chronic obstructive pulmonary disease (COPD) and cardiovascular (CV) disease (CVD) are both common and pose significant burden on affected individuals as well as healthcare systems. There are several important links between COPD and CVD, including shared risk factors, common pathobiological pathways, and the impact of abnormal lung physiology and COPD medications on CVD (and vice versa). Because the presence of one condition increases the risk of the other, clinicians should be vigilant when evaluating these patients. However, real-world data show that current clinical practice is suboptimal [1]. We review recently published studies that further advance our understanding of the interrelationship between COPD and CVD. We avoided a detailed summary of prior work.

Mechanistic relationships

Aging, tobacco smoking, poor nutrition, physical inactivity and air pollution are well-recognized risk factors for both COPD and CVD [including heart failure (HF), ischemic heart disease (IHD) and arrhythmias]. Structural changes to the lungs including emphysema and small airway mucus occlusion and fibrosis are associated with a persistent inflammatory state which may accelerate vascular pathology independent of those shared risk factors. Further, hypoxemia and vascular dysregulation in advanced COPD can lead to pulmonary hypertension (PH) and increase the risk of adverse CV events, and lung hyperinflation can result in left ventricular (LV) diastolic dysfunction [i.e., HF with preserved ejection fraction (HFpEF)] [2]. Another recently investigated link between COPD and CVD is cardiac autonomic dysfunction, mediated by damage or impaired function of the intrathoracic autonomic nerve fibers in COPD lungs.

Inflammation and systemic vascular effects

Inflammation is a major pathobiological factor linking COPD and CVD, in part by way of endothelial dysfunction and elastin degradation. Fuhr et al. performed a prospective cohort study measuring biomarkers of systemic inflammation [C-reactive protein (CRP) and interleukin (IL)-6], endothelial function [reactive hyperemia index (RHI)] and arterial stiffness [pulse wave velocity (PWV)] in patients experiencing exacerbation of COPD (ECOPD) as compared to non-exacerbating controls. While CRP and RHI were significantly worse in ECOPD patients compared to stable COPD controls, IL-6 and PWV were not different between groups. These data provide new insights into the specific measures that can be used to assess the mechanistic pathways by which ECOPD influences CV risk [3]. Thrombotic phenomena often result from endothelial dysfunction and in both the CLEAN AIR and CURE COPD cohorts, increased level of urinary 11-dehydro-thromboxaone B2 (a marker of platelet activation) was found to be associated with worse respiratory symptoms, health status and quality of life; however, the other two measured markers of platelet activity (soluble CD40L and soluble P-selectin) did not demonstrate an association [4].

The complex vascular effects of inflammation in COPD has also been studied in animal models and emphasize the complexity of the processes involved. Very recently, Desplanche et al. performed a study with a rat model of COPD/emphysema exacerbation where rats were treated with intratracheal instillation of porcine elastase and lipopolysaccharide. The exposed group had increased blood pressure and ratio of early diastolic mitral inflow velocity to early diastolic mitral annulus velocity (a major criterion for diagnosis of HFpEF), arterial hypotrophic remodeling, and a change in endothelial function (decreased contraction in response to potassium chloride and phenylephrine, and increased relaxation with acetylcholine), compared to the unexposed group. However, the response to nitric oxide did not differ from the unexposed group, which is inconsistent with endothelial dysfunction. In rats treated with the instillation of the same drugs plus bisoprolol (a cardioselective beta-blocker), such changes were not observed except for increased blood pressure. The authors concluded that the changes in arterial structure and endothelial function may be an adaptive response to the increased blood pressure, rather than the primary pathologic process [5].

Cardiac autonomic dysfunction

Data from clinical studies on heart rate variability (HRV: a measure of cardiac autonomic dysfunction) in COPD patients have been extensively reported in recent publications. Raju et al. demonstrated in the CLEAN AIR Heart study, where former smokers with moderate to severe COPD were randomized into portable air cleaner group vs placebo filter group, that an increase in indoor air pollution was associated with a decrease in HRV [6]. Decreased HRV was also associated with worse COPD symptoms and exacerbation risk [7]. A secondary analysis of the BLOCK COPD trial, which tested metoprolol (another cardioselective beta-blocker) in COPD patients, showed an association between decreased HRV and increased ECOPD risk but only in groups that did not receive metoprolol [8]. Data from a large multicenter prospective cohort study of Atherosclerosis Risk in Communities (ARIC) showed that decreased HRV and orthostatic hypotension were associated with COPD-related hospitalization over 26.9 years of follow up [9].

Lung hyperinflation

Lung hyperinflation has been linked to reduced right and left ventricular filling. A study on bronchoscopic lung volume reduction showed that right ventricular preload, cardiac contractility and cardiac output improved eight weeks following the treatment and that improvements in cardiac function were correlated with lung deflation [10]. Though additional studies are needed to demonstrate clear clinical benefits, lung hyperinflation may be an important and treatable contributor to cardiac dysfunction in COPD patients.

Hypoxemia

Hypoxemia is an important trigger of cardiac dysfunction in COPD including ischemia and arrhythmias. Recent data by Lodge et al. demonstrated that hypoxia augments neutrophil elastase secretion which results in vascular endothelial injury. This effect was greater in neutrophils from patients with COPD as compared to controls. These data suggest that hypoxic enhancement of neutrophil activity may contribute to the increased cardiovascular risk in patients with COPD and may point to new therapeutic targets [11].

Effect on pulmonary vasculature

PH occurs in chronic lung diseases including COPD and is driven by numerous factors including hypoxemia, loss of small vessels and endothelial dysfunction. Bhattarai et al. performed a study of pathologic specimens from lung cancer resection surgery and found that pulmonary artery pruning, decreased number of small pulmonary vessels, and increased intimal wall thickness were significantly more prevalent in smokers and patients with COPD (Fig. 1). In the COPD group, the intimal thickness and elastin deposition was inversely correlated with the ratio of forced expiratory volume in one second (FEV₁) to forced vital capacity (FVC) [12]. Alkhanfar et al. focused on radiographic detection of severe PH in chronic lung disease including COPD and found similar results with reduced pulmonary vessel volumes that correlated with the severity of PH and mortality. Both quantitative computed tomography (Fig. 2) [13] and a prediction model incorporating cardiac magnetic resonance imaging measurements [14] appear to be useful.

Figure 1.

Representative images of Movat’s pentachrome-stained pulmonary arteries (a–o) and parenchymal area (×4 magnification) (p–t) for never-smoker normal controls (NC), normal lung function smokers (NLFS), patients with small airway disease (SAD), current smokers with chronic obstructive pulmonary disease (COPD-CS) and ex-smokers with chronic obstructive pulmonary disease (COPD-ES). Arteries grouped by size as a–e) 100–300 μm (×20 magnification), f–j) 300–500 μm (×20 magnification) and k–o) 500–1000 μm (×10 magnification). In p–t, increased parenchymal tissue density and intimal thickening with luminal narrowing can be seen in the four pathological groups.

Published previously in: Bhattarai P, Lu W, Gaikwad AV, et al. Arterial remodelling in smokers and in patients with small airway disease and COPD: implications for lung physiology and early origins of pulmonary hypertension. ERJ Open Res. 2022;8(4). Copyright @authors 2022.

Figure 2.

Computed tomography small vessels and coronal images from patients with COPD/emphysema and ILD with no PH, mild to moderate and severe PH. Representative images from patients with COPD/emphysema and ILD with mean values for mPAP and SVV for each group.

COPD: chronic obstructive pulmonary disease; ILD: interstitial lung disease; PH: pulmonary hypertension; mPAP: mean pulmonary artery pressure; PVR: pulmonary vascular resistance; DLCO: diffusing capacity of the lung for carbon monoxide; SVV: small vessel volume of vessels <1.6 mm.

Published previously in: Alkhanfar D, Shahin Y, Alandejani F, et al. Severe pulmonary hypertension associated with lung disease is characterised by a loss of small pulmonary vessels on quantitative computed tomography. ERJ Open Res. 2022;8(2). Copyright @authors 2022.

Clinical Impact

Epidemiologic data showing increased prevalence and incidence, and worsened outcome of CVD in COPD patients have been reported from around the world and continue to accumulate.

Prevalence and Incidence

Studies of NHANES database in the United States, which includes participants with and without COPD and/or CVD, showed that those with COPD are significantly more likely to have multiple CV comorbidities (HF, IHD, diabetes and/or stroke) [15] and hypertension [16]. A global study on reported that the incidence of PH in COPD patients is nearly 40% [17]. On the other hand, COPD is present in one seventh of the included patients with HF with reduced ejection fraction (HFrEF) [18].

Regarding the incidence of CV events, Maclagan et al. found that in their primary prevention cohort of more than five million persons without established CVD in Ontario, Canada, the presence of physician-diagnosed COPD increases major adverse cardiac events (MACE; including acute myocardial infarction, stroke or cardiovascular death) by 25% (Table 1) [19]. This rate of MACE in patients with COPD is comparable to that in patients with more recognized CV risk factors and suggests that more aggressive preventive strategies are needed. Furthermore, a report from Brazil showed that patients with COPD had more severe coronary atherosclerotic lesions and increased risk of MACE [20]. Another observational study from the United Kingdom Biobank revealed similarly increased development of CVD in individuals with lower FEV₁ and/or FVC [21]. An analysis of the ARIC study data also showed heightened risk of sudden cardiac death, as the lung function decreases [22].

Table 1.

Sequential cause-specific hazards models for the impact of COPD on the development of major adverse cardiovascular events among persons with no previous CVD in Ontario, Canada.^#

	Unadjusted	Adjusted for COPD status, age and sex	Add traditional cardiovascular risk factors and comorbidities (except smoking)
COPD	3.31 (3.26-3.37)	1.65 (1.62-1.67)	1.50¶ (1.48–1.53)
Female		0.56 (0.55–0.56)	0.55 (0.54–0.55)
Age, years (continuous)		1.07 (1.07–1.07)	1.06 (1.06–1.06)
Hypertension			1.39 (1.38–1.41)
Diabetes			1.41 (1.40–1.42)
Chronic conditions, n+
0-1			1.00
2			1.12 (1.11–1.14)
3			1.26 (1.24–1.28)
4			1.41 (1.37–1.44)
5			1.64 (1.57–1.71)

Data are presented as hazard ratio (95% CI). After further adjusting for laboratory tests (HbA1c and cholesterol levels), income quintile, urban/rural residence and immigrant status, health service utilization and smoking, COPD remained to have significant association with CVD events [1.25 (1.23-1.27)].

^#:includes 5 626 596 individuals without COPD and 152 125 people with COPD (people with missing residence type (rural versus urban) or income quintile were excluded from the analysis; this accounted for 0.33% and 0.33% of people, respectively)

^¶:when additionally adjusted for chronic kidney disease, this value did not change

^+:includes number of chronic conditions other than COPD, CVD and CVD risk factors including asthma, arthritis (osteoarthritis, rheumatoid arthritis and other), cancer, dementia, inflammatory bowel disease, mood/anxiety/depression and other nonpsychotic disorders, other mental illnesses, osteoporosis, and chronic kidney disease.

COPD: chronic obstructive pulmonary disease; CI: confidence interval; CVD: cardiovascular disease; HbA1c: glycosylated haemoglobin.

Previously published in and adapted from: Maclagan LC, Croxford R, Chu A, et al. Quantifying COPD as a risk factor for cardiac disease in a primary prevention cohort. Eur Respir J. 2023;62(2). Copyright @authors 2023.

The impact of ECOPD on CV risk should be highlighted. Post-hoc analyses of the IMPACT trial, which included patients with variable CV risks, revealed that risk of CV adverse events is significantly increased during a moderate (hazard ratio [HR]: 2.63, 95% confidence interval [CI]: 2.08–3.32) or severe (HR: 21.84, 95% CI: 17.71–26.93]) ECOPD and that the risk remains higher than baseline for 90 days [23]. This analysis also demonstrated that the risk of death was elevated during a severe ECOPD (HR, 41.22 [95% CI, 26.49–64.15]; p<0.001) [24]. Similar results were found in an observational study in Denmark of patients with COPD and stable CVD (Fig. 3) [25] and in a meta-analysis [26].

Figure 3.

Duration (days) from hospital discharge for the most recent COPD exacerbation to severe CV event (fatal/non-fatal) for (A) any exacerbations in a total of 197 patients, and for (B) severe exacerbations only in a total of 118 patients. Duration (days) from hospital discharge for the most recent COPD exacerbation. In both instances (A and B), fewer than three observations were not reported, and Day 0 indicates that both the COPD exacerbation and the CV event occurred during the same hospital stay. Duration (days) from hospital discharge for the most recent COPD exacerbation.

COPD: chronic obstructive pulmonary disease; CV: cardiovascular.

Published previously in: Lokke A, Hilberg O, Lange P, et al. Exacerbations Predict Severe Cardiovascular Events in Patients with COPD and Stable Cardiovascular Disease-A Nationwide, Population-Based Cohort Study. Int J Chron Obstruct Pulmon Dis. 2023;18:419-29. Copyright @authors 2023.

Prognosis

A Swedish cohort study reported that the presence of HF and/or IHD in COPD patients worsens their outcomes, mainly driven by cardiovascular rather than respiratory events [27]. Coexistent HF and COPD make the survival significantly shorter than for either disease alone [28]. Interestingly, the prognosis of patients with comorbid COPD and HFrEF is mainly determined by HFrEF, while in those with COPD and HFpEF, COPD dominates [29]. In PH associated with COPD, New York Heart Association functional class determined the overall prognosis [30].

Diagnosis

Clinical evaluation and management of CVD in patients with COPD is not straightforward due to the altered effectiveness of diagnostic tools, and underrecognition and undertreatment of the comorbidity. Laboratory tests like N-terminal prohormone of brain natriuretic peptide (NT-proBNP) are still useful but may need adjustment based on the severity of the underlying COPD [31]. In addition, patients often present with acute respiratory distress which could be due to ECOPD or exacerbation of CVD, causing significant diagnostic difficulty [32]. Lung ultrasound is an emerging diagnostic modality for the rapid evaluation of respiratory symptoms but the presence of B lines (consistent with interstitial thickening) did not prove useful in detecting concurrent decompensated HF in patients hospitalized with ECOPD [33].

Unfortunately, real-world data show that CVD are unrecognized in patients with COPD and, partly because of this, undertreated. This also applies to their CVD risk factors such as hypertension, diabetes, dyslipidemia and obesity [34]. Such missed opportunities for intervention may be disproportionally prevalent in underrepresented individuals [35]. The existing clinical prediction models for CVD do not recognize COPD as a CV risk factor and thus underestimate the risk of CV events. Newer clinical prediction, specifically applicable to COPD patients, have been constructed and their broader use should be considered [36]. Because the risk of CV events is clearly increased in this population, clinicians should be more aggressive about CVD screening in COPD patients than in those without.

Similarly, concomitant pulmonary disease should not be overlooked in patients with CVD. Van der Velden et al. published results of a screening protocol with handheld spirometry that was implemented in a cardiology clinic dedicated for atrial fibrillation catheter ablation. Their screening strategy detected airflow obstruction in 20% of the screened individuals and 59% of those patients who subsequently underwent pulmonology evaluation reached a definitive diagnosis of COPD or asthma [37]. Similar practice may be easily implemented in other outpatient offices and may significantly improve detection of COPD in patients at risk.

Finally, though evidence for improved outcomes is limited, we and others have suggested that an interdisciplinary approach to complex patients with established COPD and CVD is needed to optimize care [38].

Treatment

The potential impact of COPD diagnosis on CVD treatment is important because of concerns about pharmacologic safety, particularly in case of beta-blockers. The above-mentioned BLOCK COPD trial showed that metoprolol was associated with an increase in severe ECOPD in the population with COPD but no CV indications for beta-blockers. A post-hoc analysis showed that metoprolol was associated with transient decrease in FVC, but that this change in lung function was not associated with the increased risk of ECOPD. The increase in severe ECOPD in the original trial remains unexplained [39]. Despite the concerns raised by the BLOCK COPD trial, the majority of published data (largely from observational studies) suggests that the benefits of beta-blockers outweigh the risks in COPD patients with established indications for the drugs such as HF and post myocardial infarction. Anderson et al. have studied the safety of bisoprolol and celiprolol (beta-1 selective beta-blocker with partial beta-2 agonist property) in COPD patients using measurements from cardiopulmonary exercise testing. Differences in lung function were not observed except increased airway resistance and reactance measured by impulse oscillometry in the celiprolol group compared to bisoprolol group and baseline [40].

Renin-angiotensin-aldosterone system (RAAS) blockers are also an important component of HF and IHD therapy. Losartan, an angiotensin receptor blocker (ARB), has effects on the transforming growth factor-beta signaling pathway and animal models suggested that it may prevent the development of emphysema. This was tested in the Losartan Effects on Emphysema Progression trial with the primary outcome being progression of emphysema, but no differences between losartan and placebo were observed [41]. A meta-analysis found that use of RAAS inhibitors was associated with better outcomes in COPD patients, but the benefits were lost when including only prospective trials, suggesting that study design significantly influenced findings [42]. Nevertheless, the use of these medications in patients with COPD and appropriate CV indications remains important [43]. Recent data continue to confirm the safety of other commonly used CVD medications in patients with COPD including mineralocorticoid receptor antagonists [18] and sodium-glucose cotransporter-2 inhibitors [44].

Another common concern in CVD patients with COPD is the safety of inhaled medications. While autonomic nervous function (including HRV) is not altered by the administration of LAMA or LABA [45], the increased metabolic demand and arrhythmogenic potential associated with these medications may increase the risk of CV events. A large observational study [46] and a meta-analysis [47] concluded that LAMA may increase risk of MACE especially in patients with high CV risk. Similar results were reported for LABA use in COPD but not asthma [48]. While benefit for COPD should outweigh CV risks in most cases, clinicians might need to be cautious in patients with very high CV risk. On the other hand, inhaled corticosteroids seem to have beneficial CV effects in some subgroup of patients [49].

There are few recent trials of non-pharmacologic interventions for COPD and their effect on CVD. A study by Kuhn et al. showed no significant change in QTc interval or incidence of clinically meaningful arrhythmias after physical activity in severe COPD patients [50]. Nevertheless, adequate exercise remains important for both COPD and chronic CVD. Overall, the recent studies suggest that clinicians should adhere to usual therapy for COPD and CVD.

Conclusions

COPD and CVD have complex interrelationships both pathobiologically and clinically. Recent advances in our understanding of the mechanistic links, such as the role of cardiac autonomic dysfunction and changes in vascular structure and function, may lead to new diagnostic and prognostic tools and potentially novel therapeutics for those with both conditions. Clinicians should recognize the clinical impact of the presence of one disease on the other and be encouraged to more proactively search for co-existent COPD and CVD. Education for medical professionals in multiple specialties including pulmonology and cardiology, and implementation of transdisciplinary protocols may facilitate optimization of clinical care for these patients.

Key Points:

• COPD and CVD have complex mechanistic interrelationships including inflammation, change in vascular structure and function, lung hyperinflation causing LV diastolic dysfunction, and cardiac autonomic dysfunction.

• The presence of COPD is associated with increased risk of CVD, and one condition worsens the outcomes of the other.

• Interdisciplinary efforts should be made to optimize diagnosis and treatment of both COPD and CVD.