Evidence suggests that the prevalence of CVD among COPD patients demonstrates considerable variability, ranging from 20% to 70% [12]. The pathophysiological mechanisms underlying increased CVD risk in COPD are multifactorial (Figure 2). First, COPD and CVD share several established risk factors, such as a history of smoking, exposure to air pollution, and advancing age. Soumagne et al. [13] found that smoking enhances arterial stiffness, thereby precipitating early cardiovascular impairment in individuals with COPD. Chen et al. [14] demonstrated that with every 10 μg/m3 increase in PM2.5 (fine particulate matter ≤2.5 μm) concentration, the mortality due to respiratory and CVDs increased by 0.29% and 0.27%, respectively. Second, systemic inflammation and oxidative stress associated with COPD promote progression of atherosclerosis, endothelial dysfunction, and thrombotic events, thereby amplifying CVD risk [15,16]. Finally, hyperinflation of the lungs in COPD can induce chronic hypoxemia and pulmonary hypertension, which further increase cardiac workload. Research conducted by Olsson et al. [17] and Tarry and Powell [18] underscored that hypoxemia and pulmonary vasculopathy are significant contributors to right ventricular dysfunction, while Funk et al. [19] and Cheyne et al. [20] showed that lung hyperinflation detrimentally affects cardiac performance by decreasing left ventricular filling and by increasing pulmonary vascular resistance.

The association between COPD and a higher prevalence of cardiovascular comorbidities has been comprehensively established in earlier studies. A systematic review by Chen et al. [21] demonstrated that individuals with COPD face a significantly elevated risk of CVD when compared to the general population (odds ratio [OR], 2.46; 95% confidence interval [CI], 2.02 to 3.00). Another systematic review indicated that the rate ratio for overall CVD in patients with COPD compared to those without COPD varied widely, ranging from 1.6 to 2.7 [22]. Despite this, there is a lack of extensive research regarding the link between COPD phenotypes and cardiovascular risk. A recent study by Cobb et al. [23], published in 2024, utilized data from the National Health and Nutrition Examination Survey (NHANES), overseen by the Centers for Disease Control and Prevention from 1999 to 2018. This analysis included 31,560 United States adults aged ≥40 years, among whom 2,504 were classified as having COPD. The COPD group was subdivided into 1,690 with chronic bronchitis, 491 with emphysema, and 323 exhibiting concurrent COPD (both chronic bronchitis and emphysema). The findings further showed that patients with COPD had a markedly increased risk of CVD, encompassing coronary heart disease, heart failure, myocardial infarction (MI), and stroke, relative to individuals without COPD. In detail, the odds of CVD were 1.76 times higher in chronic bronchitis (95% CI, 1.41 to 2.20; p<0.001), 2.31 times higher in emphysema (95% CI, 1.80 to 2.96; p<0.001), and 2.98 times higher in concurrent COPD (95% CI, 2.11 to 4.21; p<0.001). The respective prevalence rates of CVD were 17.5% for chronic bronchitis, 37.2% for emphysema, and 36.1% for concurrent COPD, versus 9.2% in individuals without COPD. Importantly, this investigation was the first to examine CVD prevalence and risk across different COPD phenotypes, identifying the highest risk in those with combined phenotypes. Nevertheless, as the study did not assess the chronology between COPD and CVD, and utilized self-reported NHANES data, there are ongoing concerns about misclassification and difficulties in establishing causality. Future research employing validated clinical diagnoses and prospective cohort designs is necessary to substantiate these relationships [23].

CVD events occur more frequently among individuals with COPD who experience exacerbations. Laribi et al. [24] found that concurrent elevation of high-sensitivity troponin I and copeptin—biomarkers that reflect systemic stress and myocardial injury—was linked to a mortality rate exceeding 20% in patients hospitalized for COPD exacerbations, indicating considerable myocardial damage. Kunisaki et al. [25] showed a markedly increased risk of CVD following acute COPD exacerbations, with the highest risk occurring within the initial 30 days (hazard ratio [HR], 3.8; 95% CI, 2.7 to 5.5), and the elevated risk extending up to 1 year. Hospitalized exacerbations conferred an even greater risk (HR, 9.9; 95% CI, 6.6 to 14.9) [25]. Nevertheless, few studies have directly investigated the long-term CVD risk associated with both the frequency and severity of past exacerbations.

Wallstrom et al. [26] conducted a large, register-based cohort study using data from the Swedish National Airway Register to assess the long-term risk of MI and pulmonary embolism (PE) in COPD patients according to the number and severity of previous exacerbations. Patients aged ≥30 years with a COPD diagnosis were followed for 8 years and categorized into five groups: no exacerbation; one moderate; ≥2 moderate; one severe; and ≥2 severe exacerbations. Findings demonstrated that MI risk increased with exacerbation burden, with a sub-distribution HR of 1.57 (95% CI, 1.38 to 1.78) for those with ≥2 moderate exacerbations, and 1.82 (95% CI, 1.36 to 2.44) for ≥2 severe exacerbations. Risk of PE similarly rose from 1.33 (95% CI, 1.11 to 1.60) in patients who had one moderate exacerbation to 2.62 (95% CI, 1.77 to 3.89) for those with ≥2 severe exacerbations. Notably, both MI and PE risk were highest during the first year after an exacerbation, but these risks remained above baseline for up to 5 years. Overall, both exacerbation frequency and severity serve as meaningful predictors of future cardiovascular events among individuals with COPD [26].

Similarly, Yang et al. [27] examined data from the prospective, multicenter, longitudinal COPDGene cohort and showed that frequent exacerbation (≥1 exacerbation per year) was associated with a significantly higher HR for cardiovascular events compared with infrequent exacerbation (<1 exacerbation per year), regardless of baseline CVD status. This relationship held across all COPD stages in the overall study population (without CVD: HR, 1.81; 95% CI, 1.47 to 2.22; with CVD: HR, 1.92; 95% CI, 1.51 to 2.44), as well as in patient subgroups with moderate to very severe COPD (Global Initiative for Chronic Obstructive Lung Disease [GOLD] 2-4). These results further underline the relevance of exacerbation frequency as a clinically meaningful predictor of cardiovascular risk, underscoring the importance of implementing proactive management strategies focused on preventing exacerbations in individuals with COPD [27].

A study by Graul et al. [28] assessed the effect of COPD exacerbation severity on nonfatal cardiovascular events using data from the UK Clinical Practice Research Datalink. The cohort consisted of patients aged ≥40 years with COPD and no history of cardiovascular events during the year prior to the index date. The primary endpoint was the initial occurrence of a nonfatal cardiovascular event, encompassing acute coronary syndrome (MI, unstable angina), arrhythmias, heart failure, ischemic stroke, and pulmonary hypertension. The results indicated that COPD exacerbations substantially increased the risk of nonfatal cardiovascular events (adjusted HR, 1.84; 95% CI, 1.79 to 1.90). Furthermore, this risk rose with increasing exacerbation severity, with patients who experienced severe exacerbations facing greatly elevated risk compared to those with moderate exacerbations (moderate exacerbation: adjusted HR, 1.67; 95% CI, 1.62 to 1.72; severe exacerbation: adjusted HR, 3.18; 95% CI, 3.06 to 3.29). A key strength of this investigation was its detailed time-stratified analysis of cardiovascular risk following exacerbations, which demonstrated that the elevated risk was highest within the first 1 to 14 days post-exacerbation and persisted for more than 9 months. These results emphasize the importance of exacerbation severity as a significant risk factor for cardiovascular events in patients with COPD. Additionally, they demonstrate that cardiovascular risk is not evenly distributed over time but is concentrated in specific high-risk intervals following exacerbation. This shows the need for both prompt cardiovascular risk assessment and sustained post-exacerbation monitoring and intervention in this population [28].

Lung cancer remains the most frequently diagnosed malignancy and is the primary cause of cancer-related mortality globally. According to the latest global data from the International Agency for Research on Cancer, nearly 2.5 million new lung cancer cases were identified in 2022, and more than 1.8 million deaths (18.7% of all cancer deaths) were attributed to this disease [29]. COPD is recognized as one of the most significant risk factors for lung cancer. Individuals diagnosed with COPD have at least double the risk of developing lung cancer in comparison to those without COPD [30-32].

Low-dose computed tomography (LDCT) screening for lung cancer is advised for adults aged 50 to 80 years with a considerable history of smoking [33]. In 2024, Nielsen et al. [34] utilized data from the 2022 Behavioral and Risk Factors Surveillance Survey in the United States to evaluate the prevalence of LDCT screening among individuals with COPD, asthma-COPD overlap (ACO), asthma, and healthy controls. The results showed that 31.9% of patients with COPD and 25.6% with ACO had received screening in the previous year, reflecting higher screening rates than the general population. However, despite this increase, overall lung cancer screening uptake remains low [34].

In 2024, Metwally et al. [35] conducted a study investigating the prevalence of COPD among older adults with lung cancer in the United States, with a specific focus on the timing of COPD diagnosis and its influence on lung cancer stage at diagnosis. The study evaluated data from 159,542 lung cancer patients, 73.5% of whom had COPD. Importantly, 34.4% of the cohort received a COPD diagnosis within 3 months of their lung cancer diagnosis, which categorized them as having ‘concurrent COPD.’ The results demonstrated that ‘preexisting COPD,’ defined as a diagnosis established more than three months before lung cancer detection, was significantly associated with increased odds of early-stage lung cancer at diagnosis (prevalence ratio, 1.27; 95% CI, 1.23 to 1.30). These findings suggest that prompt identification and diagnosis of COPD could promote earlier detection of lung cancer, underlining the importance of optimizing lung cancer screening and diagnosis within the broader context of COPD management [35].

COPD and bronchiectasis are two respiratory diseases that share similar clinical presentations, such as chronic cough, sputum production, breathlessness, and a heightened risk of exacerbations. A meta-analysis indicated that the mean prevalence of bronchiectasis among COPD patients was 54.3%, with individual studies reporting a range from 25.6% to 69% [36]. Moreover, another study demonstrated that individuals with COPD had a 1.9-fold increased risk of developing bronchiectasis in comparison to those without COPD (adjusted HR, 1.9; 95% CI, 1.75 to 2.05) [37]. Additionally, two review articles by Du et al. [38] and Ni et al. [36] reported that patients with both COPD and bronchiectasis are at increased risk for exacerbations, exhibit higher rates of isolation of potentially pathogenic microorganisms, and experience more profound airway obstruction compared to COPD patients without bronchiectasis. In addition, a recent multicenter study from South Korea found that the coexistence of bronchiectasis in patients with COPD was significantly linked to an increased prevalence of potentially drug-resistant (PDR) pathogens during acute exacerbations. Multivariate logistic regression identified coexisting bronchiectasis as an independent risk factor for PDR pathogen infection, emphasizing the clinical relevance of identifying and appropriately managing this overlapping phenotype [39]. These findings underscore the importance of recognizing bronchiectasis as a clinically significant comorbidity in COPD, due to its impact on risk of exacerbations, pathogen colonization, and therapeutic management.

Previous studies have indicated that individuals with both bronchiectasis and COPD face an elevated risk of COPD exacerbations as well as mortality. Nonetheless, the majority of earlier research was hindered by limited cohort sizes and inconsistent or unclear definitions of bronchiectasis, which may have reduced the applicability of the results to broader populations. Notably, in 2024, Polverino et al. [40] performed a large-scale prospective observational study utilizing data from the European Bronchiectasis Registry to evaluate the effects of concurrent COPD and bronchiectasis. This investigation incorporated 16,963 patients with computed tomography-confirmed bronchiectasis across 29 countries, among whom 4,324 (25.5%) had a clinician- reported diagnosis of COPD. Those with both diseases demonstrated greater comorbidity burden, more pronounced impairment in lung function, and a lower quality of life compared to patients with only bronchiectasis (all p<0.001). These individuals also exhibited higher rates of exacerbations (incidence rate ratio [IRR], 1.41; 95% CI, 1.35 to 1.47) and hospitalizations (IRR, 2.16; 95% CI, 2.04 to 2.28). To refine the identification of patients with overlapping bronchiectasis and COPD, the investigation introduced the ROSE criteria—Radiological bronchiectasis (R), Obstruction (FEV₁/FVC <0.7; O), Symptoms (S), and Exposure (≥10 pack-years of smoking; E)—as a standardized approach for delineating ‘true COPD’ within the bronchiectasis population. Of the 4,324 patients diagnosed with COPD by clinicians, only 2,130 fulfilled all elements of the ROSE criteria. Critically, patients who satisfied the ROSE criteria experienced significantly heightened risks of mortality (HR, 2.24; 95% CI, 1.9 to 2.64), hospitalization (HR, 3.09; 95% CI, 2.70 to 3.53), and exacerbation (HR, 1.55; 95% CI, 1.41 to 1.69) relative to those with bronchiectasis alone. Notably, among bronchiectasis patients without a clinical diagnosis of COPD, those meeting the ROSE criteria also had worse clinical outcomes, including greater risks of mortality (HR, 1.33; 95% CI, 0.99 to 1.78), hospitalization (HR, 1.46; 95% CI, 1.20 to 1.78), and exacerbation (HR, 1.17; 95% CI, 1.03 to 1.32). The ROSE criteria provide an objective framework for reliable identification of coexisting COPD in individuals with bronchiectasis. Using the ROSE criteria may enhance consistency in diagnosis and improve recognition of high-risk individuals, thereby supporting the development of more tailored and effective management approaches [40].

PRISm has been identified as the GOLD precursor condition to COPD [10], and is also described in the literature as an unclassified, restrictive, or nonspecific spirometric pattern [41,42]. Wan et al. [43] found that 25.1% of individuals with PRISm progressed to GOLD 1-4 COPD during a 5-year observation period, supporting the concept of PRISm as a form of pre-COPD—a high-risk group without spirometry-defined airflow obstruction [44].

In addition to its role in disease development, PRISm has been linked to higher mortality and greater comorbidity risk compared with individuals who have normal lung function. Wan et al. [45] demonstrated in a large retrospective cohort study that PRISm increased the risk of all-cause mortality (HR, 1.50; 95% CI, 1.42 to 1.59), respiratory-related mortality (HR, 1.95; 95% CI, 1.54 to 2.48), and mortality due to coronary heart disease (HR, 1.55; 95% CI, 1.36 to 1.77) compared to those with normal spirometry. These results were corroborated by a systematic review conducted by Yang et al. [11], which similarly reported elevated all-cause (HR, 1.71; 95% CI, 1.51 to 1.93), cardiovascular (HR, 1.57; 95% CI, 1.44 to 1.72), and respiratory mortality (HR, 1.97; 95% CI, 1.55 to 2.49) risks. In addition, Zhao et al. [44] identified small airway dysfunction as a central physiological feature in PRISm, which may result in reduced total lung capacity. Although its clinical significance is increasingly recognized, there is still a notable lack of comprehensive and stratified studies examining comorbidities in the PRISm population.

PRISm and restrictive spirometric pattern (RSP) are characterized by a preserved FEV₁/FVC ratio but are now acknowledged as separate conditions. PRISm is identified by reduced FEV₁, whereas RSP is defined by reduced FVC. Emerging research indicates that these patterns differ in both the extent and the distribution of FEV₁ and FVC reductions, often displaying asymmetric decline [46,47]. In 2024, based on the premise that asymmetry may influence morbidity profiles and clinical characteristics, Cestelli et al. [42] performed a prospective analysis using data from the Pneumoconiosis Survey of Western Norway cohort to explore morbidity and mortality differences between PRISm and RSP. Among 26,091 individuals, five groups were delineated: normal (82.4%), obstruction (11.0%), PRISm-alone (1.4%), RSP-alone (1.7%), and PRISm+RSP (3.5%). The analysis demonstrated that PRISm and RSP present distinguishable characteristics; PRISm-alone and obstruction groups exhibited comparable smoking behaviors, while the RSP-alone group had a higher prevalence of underweight participants and smoking habits largely resembling the normal group. Mortality results showed the PRISm+RSP group had the highest risk for all-cause (HR, 1.73; 95% CI, 1.45 to 2.05), cardiovascular (HR, 1.67; 95% CI, 1.20 to 2.33), and non-lung cancer mortality (HR, 1.61; 95% CI, 1.17 to 2.22). In contrast, diabetes-related mortality was greatest in the RSP-alone group (HR, 6.43; 95% CI, 1.88 to 21.97), and deaths due to respiratory conditions (HR, 6.61; 95% CI, 4.11 to 10.63) and lung cancer (HR, 1.85; 95% CI, 1.39 to 2.46) were most pronounced in the obstruction group. This study work is significant for being the first to directly analyze risk profiles, morbidity, and cause-specific mortality for PRISm and RSP in the same cohort, including comparison with normal and obstructive spirometric patterns. Nonetheless, certain limitations must be considered. The assessment focused solely on men aged 30 to 46 years, which restricts generalizability to women and older populations. In addition, lacking repeat spirometric evaluations precluded the ability to track lung function changes longitudinally. Consequently, future cohort studies involving both genders and a wider age spectrum are necessary to corroborate and expand on these results [42].

Yang et al. [27] conducted a subgroup analysis of individuals with PRISm using data from the COPDGene cohort. In this analysis, the incidence of composite cardiovascular events was significantly higher among those experiencing frequent exacerbations (≥1 exacerbation per year) compared with those with infrequent exacerbations (<1 exacerbation per year), independent of baseline CVD status (without CVD: HR, 1.81; 95% CI, 1.06 to 3.09; with CVD: HR, 2.03; 95% CI, 1.19 to 3.47). These findings indicate that, similar to patients with COPD, exacerbation frequency in individuals with PRISm may act as a significant predictor of cardiovascular risk. This underscores the importance of identifying and managing the burden of exacerbations, even in individuals who do not have overt airflow obstruction [27].

Frailty is more commonly observed in individuals with impaired lung function and is linked to poor clinical outcomes. In patients with COPD, the prevalence and impact of frailty have been extensively documented. Roberts et al. [48] found that among individuals aged ≥65 years, frailty was observed in 23.1% of COPD patients compared to 9.4% of those without COPD, with mortality rates more than twice as high in the COPD group. Similarly, Verduri et al. [49] observed a 43% prevalence of frailty in COPD, which was associated with higher risks of mortality (pooled OR, 4.21; 95% CI, 2.99 to 5.93), hospital readmission, and exacerbations. In a systematic review, Wang et al. [50] demonstrated that frail COPD patients exhibited significantly reduced pulmonary function (mean difference in FEV₁%, −5.06%), poorer exercise capacity (6-minute walk distance, −90.23 m), and more severe dyspnea (mean differences in COPD assessment test score, 6.2; modified Medical Research Council dyspnea scale, 0.93). Despite the established importance of frailty in chronic lung disease, the majority of research to date has relied on cross-sectional designs and has primarily focused on established COPD. The relationship between PRISm and frailty, particularly the effect of PRISm status on the onset and progression of frailty, remains inadequately understood and warrants further investigation in longitudinal studies.

In 2024, He et al. [51] performed a study utilizing data from the English Longitudinal Study of Aging to examine the effect of pulmonary function on frailty progression in individuals aged ≥50 years. Among 5,901 participants, those with PRISm (frailty index [FI], 13.50) and COPD (FI, 10.38) demonstrated substantially higher FI values at baseline when compared to those with normal lung function (FI, 7.48; p<0.001). Both PRISm (β=0.301; 95% CI, 0.211 to 0.392; p<0.001) and COPD (β=0.172; 95% CI, 0.102 to 0.242; p<0.001) were linked to significantly greater increases in FI over time relative to individuals with normal pulmonary function. Severe PRISm presented with an elevated baseline FI (β=2.280; 95% CI, 1.476 to 3.083; p<0.001) and more rapid FI progression (β=0.308; 95% CI, 0.213 to 0.404; p<0.001), while COPD patients in GOLD stages 3-4 exhibited the highest baseline FI (β=2.381; 95% CI, 1.313 to 3.450; p<0.001) and the most rapid FI progression (β=0.279; 95% CI, 0.147 to 0.411; p<0.001). Furthermore, individuals transitioning from normal spirometry to PRISm showed higher baseline FI (β=3.110; 95% CI, 1.618 to 4.603; p<0.001) and more pronounced FI progression (β=0.242; 95% CI, 0.008 to 0.476; p=0.042), whereas those shifting from PRISm to normal spirometry did not show a significant increase in FI progression. This research offers important evidence on longitudinal pulmonary function changes and their connection to frailty progression, indicating that both PRISm and COPD comparably accelerate frailty deterioration over time [51].

Obstructive sleep apnea (OSA) is defined by recurring episodes of reduced airflow during sleep caused by upper airway obstruction. OSA is present in 3% to 66% of COPD patients, and their co-occurrence forms what is known as overlap syndrome [52,53]. This syndrome results in more severe clinical consequences compared to either condition alone, leading to further impairment of respiratory function, poorer sleep quality, and increased cardiovascular risks. Individuals affected by overlap syndrome exhibit elevated mortality risk, particularly related to cardiovascular complications, respiratory failure, pneumonia, and lung cancer. Prompt recognition and active intervention are critical due to the potentially fatal outcomes of overlap syndrome [54,55].

OSA is commonly associated with obesity [56] and increased cardiovascular morbidity [57]; notably, both conditions are also linked to PRISm [45]. However, there are currently no studies that have directly compared PRISm with OSA diagnostic findings. In 2024, Ogata et al. [58] performed an observational cross-sectional study evaluating the relationship between OSA and PRISm in 374 patients aged ≥40 years diagnosed with OSA by polysomnography. The investigators found that 9.4% of patients with OSA had PRISm, including a prevalence of 6.2% in mild/moderate OSA and 12.9% in severe OSA, suggesting an over 2-fold increase in severe cases (p=0.040). After adjusting for age, gender, and obesity, severe OSA remained significantly associated with PRISm (adjusted OR, 2.29; 95% CI, 1.08 to 4.86; p=0.030). Although the relatively large sample size strengthens the findings, their single-center study design may limit generalizability. Furthermore, while evidence suggests that continuous positive airway pressure therapy can improve FEV₁ [59], the dataset did not include information on OSA treatment. Future multicenter research that includes treatment data is necessary to fully elucidate the association between OSA and PRISm. Nonetheless, these results provide important evidence that severe OSA may represent an independent risk factor for PRISm, underscoring the need for comprehensive OSA management [58].