Cardiopulmonary Risk in Chronic Obstructive Pulmonary Disease　― A Perspective for Reducing Mortality ―

Michihiro Yoshimura; Shigeo Muro; Koichiro Kuwahara; Hisatoshi Sugiura; Koichi Fukunaga; Ryoko Sorimachi; Munehiro Seki; Toyoaki Murohara

doi:10.1253/circj.CJ-24-1025

Abstract

Chronic obstructive pulmonary disease (COPD) and cardiovascular disease (CVD) show a relationship through the sharing of several risk factors, and the prevalence of each disease increases in an age-related manner. Therefore, clinicians are very likely to encounter patients with both diseases. Importantly, the risk of death in patients with CVD is even greater in those with coexisting COPD. Cardiopulmonary risk, defined as “the risk of serious respiratory and/or cardiovascular events in patients with COPD,” is a concept whereby COPD exacerbations (characterized by worsening of COPD symptoms over a short period of time) and/or CVD events may increase the risk of death due to these events in patients with COPD. Lowering cardiopulmonary risk requires appropriate treatment to prevent COPD exacerbations. Inhalation therapies can prevent COPD exacerbations and may reduce mortality rates. Research to investigate whether inhaled therapies can lower cardiopulmonary risk is ongoing. There is a need for early COPD diagnosis and timely, effective treatment that prevents COPD exacerbations while also considering cardiopulmonary risk. We propose an urgent call to action for cardiology and respirology societies to address cardiopulmonary risk and reduce COPD and CVD deaths.

Importance of COPD in Cardiovascular Care

Cardiovascular disease (CVD) is becoming increasingly prevalent worldwide,¹^,² affecting approximately 56 million people globally.³ The global prevalence of heart failure (HF) has prompted the concept of a “HF pandemic.”⁴ The prevalence of HF in Japan may be as high as 6.5%,⁵ and is expected to increase owing to population aging.⁶^–⁸

When treating patients with CVD, it is necessary to consider the patient holistically, including other conditions or contributing factors. Discussion of CVD (including HF) from the perspective of the cardiopulmonary system, with consideration of related conditions such as chronic obstructive pulmonary disease (COPD), is a timely topic that has been raised in some recent reviews.⁹^,¹⁰

COPD Comorbidity in CVD

COPD is also becoming increasingly prevalent, affecting an estimated 480 million patients, and prevalence is expected to increase to 600 million patients worldwide in 2050.¹¹ COPD is a chronic and progressive lung disease characterized by airflow obstruction, which is mainly caused by long-term exposure to toxic inhalants, such as tobacco smoke.¹² The Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2025 report added a section highlighting cardiovascular risk in COPD, which included the impact of stable and exacerbated COPD on cardiovascular risk.¹²

Because COPD and CVD share several risk factors, including their age-related prevalence,¹³^,¹⁴ they are considered syndemic, a term that refers to synergistic interactions among diseases that contribute to an increased disease burden and an increased prevalence of each disease. In a study of Japanese patients aged ≥40 years, airflow obstruction was observed in 27.0% (269/995) of patients with a history of smoking who routinely visited the hospital for CVD.¹⁵ Airflow obstruction was also frequently found in patients with chronic HF (30.1% of patients), arrhythmia (29.5%), and myocardial infarction (25.9%).¹⁵ Additionally, the prevalence of airflow obstruction increased with age, affecting approximately 20% of patients aged 50–69 years and 40% of patients aged >70 years.¹⁵

COPD Complications and Mortality in the Context of CVD

Japanese studies have reported a higher mortality rate in patients with HF and moderate COPD than in patients without COPD,¹⁶ and that patients with ischemic heart disease and COPD have a greater risk of cardiac death or non-cardiovascular death.¹⁷ As Japan’s population ages, the number of patients with COPD and CVD (especially HF) will increase.⁷^,¹³^,¹⁴ Therefore, we expect that discussions of COPD in the cardiovascular field will increase and become more central to patient management.

Current COPD Care in Japan

The number of deaths in Japan due to COPD has exceeded 15,000/year for the past decade.¹⁸ Two key aspects need to be considered regarding COPD deaths in Japan.

First, COPD may be underdiagnosed. Challenges exist regarding diagnosis rates globally, with underdiagnosis rates ranging from 12% (USA) to 95% (Austria).¹⁹ Japan is no exception to this. Approximately 362,000 patients receive ongoing COPD care in Japan,²⁰ but an epidemiological study revealed that 5.3 million people aged ≥40 years met the clinical definition of COPD,²¹ indicating that only 6.8% of Japanese patients with COPD actually receive care. Although direct comparisons are not possible, the proportion of patients receiving medical care for COPD is far lower than the proportion treated for other chronic diseases (Figure 1).²⁰^–²⁴ A recent database study reported that only 8.4% of patients with airflow obstruction were diagnosed with COPD, despite undergoing spirometry performed in annual health examinations.²⁵ Another study reported that approximately 27% of patients with CVD and a history of smoking had airflow obstruction, but only 12% of these patients were diagnosed with COPD.¹⁵ Taken together, these studies indicate that many Japanese patients are not diagnosed with COPD, despite meeting the clinical definition, thus contributing to the absence of COPD care.

Figure 1.

Estimated prevalence and total number of patients in Japan with COPD, hypertension, diabetes mellitus, and dyslipidemia.²⁰^–²⁴ The percentages of patients with medical care are also shown. Derived data for the estimated number of patients with COPD,²¹ hypertension,²³ diabetes mellitus,²⁴ or dyslipidemia,²⁴ and the number of patients with medical care.²²^,²³ COPD, chronic obstructive pulmonary disease.

In patients with CVD, several factors may contribute to underdiagnosis of COPD. Patients with CVD often experience similar symptoms to patients with COPD, such as worsening shortness of breath, which may be misattributed to HF instead of COPD.²⁶^,²⁷ Blood test results cannot always distinguish between COPD and CVD because some markers can be elevated in both diseases, such as elevated B-type natriuretic peptide (BNP) and N-terminal pro-BNP.²⁸^,²⁹ COPD diagnosis requires spirometry, which may be incorrectly performed or not performed at all.³⁰ Moreover, some cardiovascular-related diseases (including acute coronary syndromes, coronary spastic angina with frequent attacks, dissecting aortic aneurysms, aortic aneurysms with a risk of rupture, acute cerebrovascular disorders, severe hypertension, dangerous arrhythmias, and severe HF) could preclude spirometry because of the potential risks associated with these conditions.³¹

Second, patients with COPD may be undertreated. In a Japanese real-world study (January 2005–December 2018), only 13.0% (29,501/227,451) of patients diagnosed with COPD had ≥1 dispensed prescription for any inhaled therapy.³² Additionally, patients who are initially treated for COPD might not continue treatment, as demonstrated by a French study in which only 18–30% of patients were continuing their inhaler treatment after 1 year.³³

Cardiopulmonary Risk: COPD Exacerbations and/or CVD Events Causing Death in Patients With COPD

Causes of Death in Patients With COPD

Cardiopulmonary risk is a concept whereby COPD exacerbations and/or CVD events may increase the risk of death.⁹^,¹⁰ In a Japanese study, 40% (45/112) of patients with COPD died from respiratory diseases and 11% (12/112) died from CVD events.³⁴ Of note, 14% of patients with mild airflow obstruction and 18% of patients with moderate airflow obstruction died from CVD events.³⁴

COPD Exacerbations and Increased CVD Events

The GOLD 2025 report¹² defines COPD exacerbations as “an event characterized by increased dyspnea and/or cough and sputum that worsens in <14 days which may be accompanied by tachypnea and/or tachycardia and is often associated with increased local and systemic inflammation caused by infection, pollution, or other insult to the airways.” Patients with COPD exacerbations are at increased risk of future cardiopulmonary events, including COPD exacerbations³⁵^,³⁶ and CVD events.³⁷ Even among patients with mild exacerbations requiring short-acting β-agonists, who are likely to be encountered by cardiologists, the risk of moderate-to-severe exacerbation increases following each exacerbation.³⁸ Additionally, repeated COPD exacerbations are associated with a higher all-cause mortality rate vs. that in patients without COPD exacerbations.³⁹ Thus, exacerbations are an important predictor of worse outcomes, including death.

The EXACOS-CV program is an international (10 countries) observational database study that is examining the risk of serious CVD events following COPD exacerbations in patients with COPD aged ≥40 years.⁴⁰ CVD events and deaths (all-cause or CVD) increased following COPD exacerbations in Japan⁴¹ and other Western countries, including Canada⁴² and the UK,⁴³ with a substantially increased risk after the exacerbation, from 1 week to 1 month, that remained elevated for the subsequent year after the exacerbation. The EXACOS-CV Japan study reported that the risk of serious CVD events or death from the events was greatest within the first 30 days after a moderate or severe COPD exacerbation, increasing by 44%, and this effect persisted over the following 6–12 months (Figure 2).⁴¹ When categorized by the type of CVD event, similar results were observed for the risk of HF, acute coronary syndrome, and arrhythmia.⁴¹ These results were confirmed in patients with COPD regardless of comorbid CVD. Likewise, the longitudinal COPDGene study reported that patients with COPD and frequent COPD exacerbations had an increased risk of CVD events, regardless of the presence or absence of CVD.⁴⁴

Figure 2.

Serious cardiovascular events following exacerbation of COPD in Japan.⁴¹ (A) Risk of cardiovascular events by severity of COPD exacerbation and (B) risk of serious cardiovascular events (by event category) at each timepoint after COPD exacerbation. COPD, chronic obstructive pulmonary disease. (Reproduced with permission from Matsunaga et al.⁴¹)

Factors Contributing to CVD Events in Patients With COPD

The syndemic nature of COPD and CVD means that they share overlapping risk factors, including increased age, smoking, air pollution, and infection⁶^–⁸^,¹³^,¹⁴^,⁴⁵^,⁴⁶ (Figure 3).⁴⁷^–⁵⁶ Several potential mechanisms underlying this syndemic nature have been proposed, including inflammation, hyperinflation of the lung, hypoxemia, and sympathetic hyperactivity (Figure 3).⁴⁷^–⁵⁶

Figure 3.

Mechanism involved in cardiovascular events in patients with COPD.⁴⁷^–⁵⁶ COPD, chronic obstructive pulmonary disease.

Inflammation can contribute to worse outcomes, including CVD events,⁵²^,⁵⁴ and patients with COPD and elevated levels of high-sensitivity C-reactive protein have a greater risk of major adverse cardiovascular events.⁵⁴ Additionally, systemic inflammation is often more pronounced and transient during exacerbations than in the stable phase,⁵⁷ accompanied by worsened dyspnea and oxygenation.⁵⁸ Chronic and transient inflammation in patients with COPD can damage vascular endothelial cells⁵⁹ and result in pulmonary hypertension,⁵³ which may also lead to thrombus formation and atherosclerosis.⁶⁰^–⁶²

In COPD, air is trapped within the lung causing lung hyperinflation.⁶³^,⁶⁴ An increase in lung size and a subsequent decrease in heart size impair cardiovascular functioning.⁵⁶ Additionally, lung hyperinflation can impede blood–gas transfer, resulting in hypoxemia.⁶⁵^,⁶⁶ Exacerbations can lead to transient hyperinflation.⁶⁷ Damage to vascular endothelial cells can also contribute to hypoxemia.⁶⁸ Hypoxemia can cause pulmonary hypertension,⁶⁹ HF,⁵⁵^,⁷⁰ constricted pulmonary blood vessels (hypoxic pulmonary vasospasm), and decreased pulmonary blood vessels, thus increasing the right atrial load.⁴⁹^,⁶⁹^,⁷¹ The increased right atrial load and pulmonary hypertension can lead to edema and HF.⁷²^,⁷³

Patients with COPD sometimes exhibit autonomic nervous system dysregulation and sympathetic hyperactivity, which increases heart rate and blood pressure,⁵¹ exacerbating cardiac stress and mortality risk.⁵⁰^,⁷⁴^,⁷⁵ Activation of the sympathetic nervous system can also contribute to inflammation.⁷⁶

Significance of Spreading Awareness of Reducing Cardiopulmonary Risk in Patients With COPD

A proposed definition of cardiopulmonary risk is “the risk of serious respiratory and/or cardiovascular events in patients with COPD.”⁷⁷ These events include, but are not limited to, COPD exacerbations, myocardial infarction, stroke, HF decompensation, arrhythmia, and death due to any of these events (Figure 4).⁷⁷ Therefore, activities to raise awareness of cardiopulmonary risk among physicians treating COPD, including cardiologists, and appropriate COPD treatment in a timely manner are important. We anticipate that additional research will be conducted in Japan and overseas where there remains insufficient evidence.

Figure 4.

Cardiopulmonary risk in COPD.⁷⁷ Solid lines represent associations with accumulating evidence, and the dashed lines represent an association with initial evidence (purple), and a suspected association with no current available evidence (light-gray). COPD, chronic obstructive pulmonary disease. (Reproduced with permission from Singh et al.⁷⁷)

Effective Treatments for Reducing COPD Exacerbations

The recent emphasis on increasing awareness of cardiopulmonary risk stems from recent developments and treatment options that can prevent COPD exacerbations and may lower the risk of death.¹² Inhaled treatments, including long-acting anti-muscarinics (LAMA), LAMA/long-acting β₂-agonists (LABA), and inhaled corticosteroids (ICS)/LAMA/LABA, are widely used to manage COPD⁷⁸ and reduce the risk of COPD exacerbations.⁷⁹^–⁸² Their long-term use is recommended for the initial and follow-up treatment of patients diagnosed with COPD, depending on the severity of symptoms, number of exacerbations, and eosinophil count.¹² In patients at high risk of exacerbations, dual long-acting bronchodilator therapy (LABA+LAMA) reduces the risk of moderate-to-severe exacerbations relative to inhaled treatment with LAMA or LABA alone (network hazard ratio: 0.87 [95% credible interval: 0.78–0.99] and 0.70 [0.61–0.80], respectively).⁸⁰ Triple therapy (ICS+LABA+LAMA), relative to dual long-acting bronchodilator therapy, further reduces the risk of exacerbations (rate ratio: 0.73 [95% confidence interval (CI): 0.64–0.83]).⁸² Accumulating evidence shows that single-inhaler triple therapy, relative to dual long-acting bronchodilator therapy, reduces the risk of death (ETHOS trial: hazard ratio: 0.51 [95% CI: 0.33–0.80]; IMPACT trial: hazard ratio: 0.72 [95% CI: 0.53–0.99]).⁸³^,⁸⁴ Accordingly, the GOLD 2025 report states that the use of single-inhaler triple therapy can reduce the risk of death compared with dual long-acting bronchodilator therapy.¹²

Triple therapy may also reduce the risk of cardiovascular events and lower cardiopulmonary risk. A post hoc analysis of the ETHOS trial revealed that triple therapy reduced the frequencies of cardiovascular (hazard ratio: 0.63 [95% CI: 0.48–0.82]) and severe cardiopulmonary events (0.80 [0.67–0.95]) compared with dual therapy.⁸⁵ A post hoc analysis of the IMPACT trial also found that triple therapy reduced the risk of the cardiopulmonary events by 16.5% (95% CI: 5.0–26.7).⁸⁶ Further evidence is anticipated from ongoing prospective clinical trials (e.g., the THARROS study).⁸⁷

Role of Cardiology/HF and Respirology Societies

Beginning in April 2024, the third term of the Healthy Japan 21 policy of the Japanese Ministry of Health, Labour and Welfare aims to prevent the onset and progression of lifestyle-related diseases, including reducing the mortality rate of COPD.⁸⁸ The target mortality rate for 2032 is 10.0/100,000 people (down from 13.3/100,000 people in 2021).⁸⁸ To achieve this goal, early diagnosis and timely treatment are necessary, and cardiologists and primary care physicians, who are likely to manage patients with COPD or those with potential COPD, should understand the cardiopulmonary risks in COPD. Close collaboration between cardiology and respirology societies is critical to achieving this goal and addressing cardiopulmonary risk in COPD.

The Japanese Respiratory Society (JRS) has begun several initiatives to support the Healthy Japan 21 policy and prevent COPD exacerbations, including creating a document that provides information on COPD diagnosis and treatment aimed at healthcare professionals beyond respiratory specialists.⁸⁹ The JRS also added a screening test, the COPD Population Screener (COPD-PS) to the “COPD Operational Diagnosis and Management Procedure”,⁹⁰ to help physicians diagnose COPD if spirometry equipment is unavailable or if it is difficult to perform spirometry. This screening test assigns scores according to the patient’s symptoms (such as shortness of breath, cough, and phlegm), smoking history, and age, and scores ≥4 are indicative of COPD.⁹¹ For patients diagnosed with COPD, the JRS has proposed procedures to prevent COPD exacerbations and an exacerbation screening questionnaire to regularly check for exacerbations.⁹² We believe that an increased understanding of COPD care among the cardiology community is key to addressing the complex needs of these patients.

Conclusions

Cardiopulmonary risk in patients with COPD is characterized by COPD exacerbations and/or CVD events, and deaths due to these events. Preventing COPD exacerbations through appropriate treatment is crucial to lowering cardiopulmonary risk. We propose that early COPD diagnosis and timely effective treatment that prevents COPD exacerbations represent an urgent call to action for cardiology and respirology societies to address cardiopulmonary risk and reduce COPD and CVD mortality rates.

Acknowledgments

The authors would like to thank Hannah Read, PhD, of Edanz, Japan, for medical writing support, which was funded by AstraZeneca K.K., Japan, through LESPEDEZA, a division of EMC K.K., Japan, in accordance with Good Publication Practice Guidelines (https://www.ismpp.org/gpp-2022).

Disclosures

M.Y. has received remuneration from AstraZeneca, Otsuka, Novartis, Daiichi Sankyo, Mochida, Astellas, Bayer, Viatris, and Novo Nordisk, and scholarship donations from Otsuka and Mochida. S.M. has received remuneration from AstraZeneca, GlaxoSmithKline, and Boehringer Ingelheim, and research funding from ROHTO. K.K. has received remuneration from Astellas, AstraZeneca, MSD, Otsuka, Ono, Kyowa Kirin, Kowa, Sanofi, Sumitomo Pharma, Mitsubishi Tanabe, Eli Lilly, Boehringer Ingelheim, Novartis, Novo Nordisk, Bayer, Pfizer, and Janssen; research funding from Kowa, AstraZeneca, Daiichi Sankyo, Novo Nordisk, Amgen, Janssen, Parexel, and Astellas; scholarship funds or donations from Otsuka, Mitsubishi Tanabe, Boehringer Ingelheim, and Kyowa Kirin; and is affiliated with a department endowed by Medtronic, Boston Scientific, Abbott, Japan Lifeline, BIOTRONIK, Terumo, Nipro, and Cordis. H.S. has received remuneration from AstraZeneca, Boehringer Ingelheim, Sanofi, and KYORIN. K.F. has received remuneration from Boehringer Ingelheim, Novartis, Sanofi, GlaxoSmithKline, AstraZeneca, and KYORIN. R.S. and M.S. are employees of AstraZeneca. T.M. has received remuneration from AstraZeneca, Boehringer Ingelheim, Novartis, Bayer, Eli Lilly, and Viatris. M.Y. is a member of the editorial board, K.K. is an associate editor, and T.M. is a Senior Advisory Editor for Circulation Journal.

IRB Information

Not applicable.

Data availability

Not applicable.

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