Impact of Pulmonary Ventilation Dysfunction on Prognosis of Patients with Coronary Artery Disease: A Single-Center, Observational Study

Background: Patients with coronary artery disease (CAD) often experience pulmonary ventilation dysfunction following their initial event. However, there is insufficient research exploring the relationship between this dysfunction and CAD prognosis. Methods: To address this gap, a retrospective observational study was conducted involving 3800 CAD patients without prior pulmonary ventilation disease who underwent cardiopulmonary exercise testing (CPET) during hospitalization between November 2015 and September 2021. The primary endpoint was a composite of major adverse cardiovascular events (MACE), such as death, myocardial infarction (MI), repeat revascularization, and stroke. Propensity score matching (PSM) was used to minimize selection bias between the two groups, with a subgroup analysis stratified by smoking status. Results: The results showed that patients were divided into normal (n = 2159) and abnormal (n = 1641) groups based on their pulmonary ventilation function detected by CPET, with 1469 smokers and 2331 non-smokers. The median follow-up duration was 1237 (25–75% interquartile range 695–1596) days. The primary endpoint occurred in 390 patients (10.26%). 1472 patients in each of the two groups were enrolled in the current analysis after PSM, respectively. However, pulmonary function was not associated with MACE before (hazard ratio (HR) 1.20, 95% confidence interval (95% CI) 0.99–1.47; Log-rank p = 0.069) or after PSM (HR 1.07, 95% CI 0.86–1.34; Log-rank p = 0.545) among the entire population. Nonetheless, pulmonary ventilation dysfunction was significantly associated with an increased risk of MACE in smoking patients (HR 1.65, 95% CI 1.25–2.18; p < 0.001) but not in non-smoking patients (HR 0.81, 95% CI 0.60–1.09; p = 0.159). In addition, there was a significant interaction between current smoking status and pulmonary ventilation dysfunction on MACE (p for interaction < 0.001). Conclusions: Pulmonary ventilation dysfunction identified through CPET was independently associated with long-term poor prognosis in smoking patients with CAD but not in the overall population.


Introduction
Dyspnea is a common occurrence after index events in patients with coronary artery disease (CAD) [1,2], and is associated with increased mortality [3,4].However, it is important to note that objective measures are necessary to confirm the presence of pulmonary ventilation dysfunction in cases of dyspnea.Cardiopulmonary exercise testing (CPET) is a common procedure for assessing the cardiopulmonary function of patients [5], which objectively identify symptoms such as dyspnea.However, the impact of pulmonary ventilation function on the prognosis of CAD patients is still an open issue.
Previous studies showed that cigarette smoke exposure is a risk factor result in the pulmonary dysfunction [6,7].Simultaneously, as an independent risk factor of CAD, smoking is associated with a poor prognosis of car-diovascular disease [8,9].However, the link of smoking, pulmonary dysfunction, and the prognosis of patients with CAD is unknown.
Therefore, we conducted an observational study to hypothesize that pulmonary ventilation dysfunction may play a significant role in major adverse cardiovascular events (MACE) in the CAD population.We also further explored whether smoking was associated with an increased likelihood of MACE in CAD patients with pulmonary ventilation dysfunction.

Study Design and Population
We performed a retrospective analysis of MACE within a cohort of CAD patients without lung disease, who received coronary angiography and post-procedure CPET during hospitalization between November 2015 and September 2021.Exclusion criteria were as follows: (i) combined with myocarditis, pericarditis, myocardiopathy, congenital heart disease, valvular heart disease or other structural heart diseases; (ii) with a history of pulmonary disease; (iii) mental impairment with limited ability to co-operate; (iv) unwillingness to participate or incomplete information.Categories of lung disease were defined based on forced expiratory volume in one second (FEV 1 ) and forced vital capacity (FVC), which can be measured during CPET in our cardiac rehabilitation center.Normal pulmonary ventilation function was defined as FEV 1 /FVC ≥70%.Abnormal pulmonary ventilation function was classified as obstructive (FEV 1 /FVC <70% or <92% of predicted), restrictive (FEV 1 /FVC ≥70% and FVC <80% of predicted), or mixed (FEV 1 /FVC <70%) according to the American Thoracic Society/European Respiratory Society guidelines [10][11][12][13].Abnormal pulmonary ventilation function of any type diagnosed in the CPET report will be enrolled in the abnormal group, while normal pulmonary ventilation function will be enrolled in the normal group.
A total of 3800 patients were eligible for our study criterion, including 2159 normal pulmonary ventilation function CAD patients and 1641 abnormal pulmonary venti-lation function CAD patients (Fig. 1).After performing propensity score matching (PSM), 1472 patients were included in each of the two groups for analysis.Additionally, to further investigate the effect of smoking status on MACE and pulmonary ventilation dysfunction, participants were divided into two groups based on smoking status, with 1469 smokers and 2331 non-smokers in the overall population.This study was approved by the Ethics Committee of General Hospital of Northern Theater Command, and an exemption for informed consent was approved simultaneously.

Cardiopulmonary Exercise Testing
CPET is a common method for assessing cardiovascular and pulmonary function in clinical practice, which has been routinely conducted in our center since 2015.Unlike general exercise and static lung function tests, CPET is an objective, quantitative, continuous, and non-invasive clinical detection method [14,15].Static pulmonary function parameters were measured in all patients and calibrated in a standardized manner using reference gases prior to each test.Following these mea-surements, dynamic pulmonary function indicators were measured using bicycle ergometers (SCHILLER, Baar, Switzerland) [16].
After a resting period of 1-2 minutes, a 2-3 minutes period of unloaded exercise was initiated at 60 revolutions per minute, followed by a continuous increase in load (gradually increased by 10% of the estimated exercise power based on patient age, height, and weight) until oxygen uptake and carbon dioxide excretion achieved equilibrium [17].The exercise lasted until test termination according to the scientific statement from the American Heart Association.In the recovery period, patients exercised for approximately 2-3 minutes while rehabilitation technicians recorded CPET test results, including maximum kilogram oxygen uptake, metabolic equivalent, anaerobic threshold, and other indicators.

Clinical Data Collection and Follow-up
Patient information was obtained directly from the hospital information system, including demographic and clinical characteristics for all patients, past medical history, clinical diagnosis, medication at discharge, left ventricular ejection fraction (LVEF), procedural information, laboratory indicators, and CPET parameters.The follow-up was performed via telephone interview at 1, 6, 12, 36, and 60 months.

Study Endpoints
The primary endpoint was a composite of MACE within 60 months after discharge, including all-cause death, myocardial infarction (MI), repeat revascularization, and stroke.The secondary endpoint included the incidence of events for individual components of MACE, rehospitalization, the Bleeding Academic Research Consortium (BARC) defined type 2, 3 and 5 bleeding events, and all bleeding events.
Death and repeat revascularization were defined according to the Academic Research Consortium criteria [18], MI was defined according to the Fourth Universal Definition of Myocardial Infarction (2018) [19], and bleeding was defined according to the BARC criteria [20].Stroke was defined as the sudden onset of vertigo, numbness, dysphasia, weakness, visual field defects, dysarthria, or other focal neurologic deficits due to vascular lesions of the brain such as hemorrhage, embolism, thrombosis, or a rupturing aneurysm that persists for >24 hours.

Statistical Analysis
Continuous variables were described as mean ± standard deviation (SD) for normally distributed measurement data and median (P 25 -P 75 ) for non-normally distributed measurement data; categorical variables were described as frequencies with percentages.Continuous data were compared using the Student's t-test and one-way analysis of variance (ANOVA), with correction for unequal variance when necessary.Chi-square tests or Fisher exact tests as appropriate for categorical variables.
To account for potential confounding attributable to such differences, a propensity score was used to match each patient in the abnormal group with a patient in the normal group with similar baseline characteristics, procedure information, and laboratory indicators.Greedy matching on propensity scores was performed with caliper of 0.2.
The Kaplan-Meier method was used to describe the cumulative incidence of endpoint events; comparisons were made with the Log-rank t-test.The association of smoking status with pulmonary ventilation function was evaluated using multivariable logistic regression analysis, and odds ratios (OR) with 95% confidence intervals (95% CI) were derived.The multivariate Cox regression analysis was performed specifically for smoking, and hazard ratios (HR) with 95% CI were derived.The interaction p-value was calculated to explore the interactive effect between smoking status and pulmonary ventilation dysfunction in the prognosis of CAD.A two-sided p-value < 0.05 was considered statistically significant.All statistical analyses were performed using R software (version 4.3.0;R Foundation for Statistical Computing, Vienna, Austria).
There was no significant difference in the incidence of MACE in different type of abnormal pulmonary ventilation function, both of before and after PSM (before PSM: p = 0.450; after PSM: p = 0.690; Table 5).The Kaplan-Meier analysis also showed there was no significant in different type of abnormal pulmonary ventilation function and MACE, before (HR 1.15, 95% CI 0.85-1.55;Log-rank p = 0.376; Fig. 3A) or after PSM (HR 1.08, 95% CI 0.78-1.51;Log-rank p = 0.637; Fig. 3B).Demographic characteristics, procedural information, laboratory indicators and CPET parameters of three groups before and after PSM were summarized in Supplementary Tables 1-3.

Secondary Endpoints
Patients in the abnormal group had a significantly higher rate of all-cause death compared with normal group before PSM (1.71% vs. 0.74%, p = 0.009, Table 4).After PSM, however, no significant difference was found in respect to the rate of all-cause death between the two groups (all p > 0.05).The Kaplan-Meier analysis also showed that, significant association was observed between two groups    Note: PCI, percutaneous coronary intervention; CKMB, creatine kinase MB; VE/VO 2 , the minute ventilationoxygen dioxide production; SYNTAX score, the synergy between percutaneous coronary intervention with taxus and cardiac surgery score; HR, hazard ratio; 95% CI, 95% confidence interval.

Discussion
In our daily work, patients were often anxiety about abnormal pulmonary ventilation function in CPET reports.Meanwhile, the association between pulmonary ventilation dysfunction and CAD prognosis was inconclusive.Thus, we performed the present study, which firstly examined the association between pulmonary ventilation dysfunction measured by CPET and the prognosis of CAD.Present data showed that: (i) there was no difference in the incidence of MACE in CAD stratified by pulmonary ventilation func-tion; (ii) before PSM, a higher mortality was found in patients with pulmonary ventilation dysfunction, while there was no difference after PSM; (iii) among the smoking patients, pulmonary ventilation dysfunction was an independent risk factor of MACE.
Dyspnea is a subjective symptom of CAD patients, but the existence of pulmonary ventilation dysfunction is uncertain.Parameters of pulmonary ventilation function measured by CPET provide more objective and reliable results than self-reported symptoms.The present study, which analyzed a cohort of 3800 CAD patients undergoing CPET, demonstrated that the impact of MACE was similar among patients with normal or abnormal pulmonary ventilation function.This is consistent with the findings of the CON-FIRM registry study, which reported that the presence of dyspnea did not increase the long-term risk for MACE in obstructive CAD [21].However, other studies have reported conflicting results, indicating that dyspnea is associated with worse clinical outcomes among CAD patients [21][22][23][24].This phenomenon may be due to enrollment variety in different studies.The present study included patients without history of pulmonary dysfunction, but contradictory studies enrolled patients with pulmonary symptoms such as dyspnea [21][22][23][24][25] who may already had pulmonary ventilation dysfunction before had symptoms of CAD.As numerous known, the presence of pulmonary dysfunction prior to the occurrence of CAD may impact the clinical outcomes.
Consistent with previous research [26,27], the present study showed that the overall all-cause mortality was higher in patients with pulmonary ventilation dysfunction before  PSM.However, after adjustment by PSM, the difference was not significant.Founded on the present findings, considering that some patients with pulmonary ventilation dysfunction may be transient or compensatory in some patients, leading to pulmonary ventilation dysfunction had no impact on the prognosis of CAD patients.Moreover, pulmonary ventilation dysfunction determined before discharge had limited value of predicting long-term prognosis of CAD patients.Therefore, the periodic inspection of pulmonary ventilation function may be required for CAD patients, which confirm whether pulmonary ventilation dysfunction still exists identify the impact on long-term prognosis of CAD.Previous studies have found that dyspnea is commonly associated with ticagrelor therapy [28][29][30].In most previous studies, the subjective feelings of patients with dyspnea had been used as an endpoint.However, patients with pulmonary ventilation dysfunction may not have symptom of dyspnea.In the present study, 30% of both groups were on ticagrelor, but there was no difference.Therefore, pulmonary dysfunction was not associated with ticagrelor therapy.
Smoking is a risk factor to the progression and adverse prognosis of cardiovascular and pulmonary disease [31,32].The present data demonstrated that pulmonary ventilation dysfunction is an independent risk factor for MACE in smoking patients.A study of 3103 smoking patients with ischemic heart disease also reported similar results [33].However, in non-smoking participants, there was no significant correlation between pulmonary venti-lation dysfunction and MACE, which is consistent with the overall study population.Previous studies have confirmed that cigarette smoke exposure has been associated with vasodilator dysfunction and atherosclerotic pathological changes, which impaired blood flow reconstruction and deteriorated the prognosis of patients with coronary artery disease [9].Additionally, cigarette smoke exposure disrupted the epithelial barrier, leading to the development of upper respiratory tract infections that may further exacerbate dyspnea [6].The present data also showed the interaction between current smoking status and pulmonary ventilation dysfunction.Pathological changes in the lungs caused by smoking may deteriorate the prognosis of CAD patients, compared with non-smoking patients.In considering the results of this study, pulmonary ventilation function may be an important factor in evaluating the outcomes of smoking patients with CAD.
There are some limitations of the present study which should be considered.First, this study was a single-center retrospective analysis, with possible selection bias, despite PSM was conducted.The prospective multicenter study is needed to further support the conclusions.Second, pulmonary ventilation function might be relative to the prognosis of CAD, while no pulmonary ventilation function endpoints were followed up in present study.Although the mortality of the group with abnormal pulmonary ventilation function was nearly twice that of the normal group, there was no statistically significant difference.That may be due to insufficient sample size.A larger sample size may reveal differences in further analysis.Third, the CPET is unable to assess the severity of the prognosis of pulmonary ventilation function.Therefore, the detailed clinical assessment by the respiratory physician may be better.Fourth, only the hard endpoints such as MACE and all-cause death were analyzed in this study.Functional status and quality of life were not evaluated due to the insufficiency of follow-up.We intend to focus on this issue in another prospective observational study.Finally, our analysis included smoking status as a subgroup analysis to investigate the role of pulmonary ventilation dysfunction on MACE in CAD patients, which need further research to validate.

Conclusions
No association was observed between pulmonary ventilation dysfunction detected by CPET and long-term MACE in the entire population of patients with CAD.However, in the subgroup analysis including smoking patients, pulmonary ventilation dysfunction may be an independent risk factor of poor prognosis of CAD.

Table 3 . Comparison CPET parameters before and after PSM in groups with normal and abnormal pulmonary ventilation function.
Note: CPET, cardiopulmonary exercise testing; PSM, propensity score matching; FVC, forced vital capacity; FEV 1 , forced expiratory volume in one second; VCmax, maximum vital capacity; MVV, maximal voluntary ventilation; MET, metabolic equivalent; AT, anaerobic threshold; VO 2 , oxygen consumption; VE, minute ventilation volume; VE/VO 2 , the minute ventilation-oxygen dioxide production; VE/VCO 2 , the minute ventilation-carbon dioxide production; HRR, heart rate reserve; BR, breathing reserve.

Table 4 . Clinical outcomes before and after PSM in groups with normal and abnormal pulmonary ventilation function.
Note: PSM, propensity score matching; MACE, major adverse cardiovascular events, including all-cause deaths, MI, strokes, and repeated revascularizations; MI, myocardial infarction; BARC, bleeding academic research consortium.

Table 5 . Clinical outcomes before and after PSM in different type of abnormal pulmonary ventilation function.
Note: PSM, propensity score matching; MACE, major adverse cardiovascular events; MI, myocardial infarction; BARC, bleeding academic research consortium.