Relationship between lung function impairment, hypertension, and major adverse cardiovascular events: A 10‐year follow‐up study

Abstract Lung function impairment and hypertension, especially hypertension, are risk factors of major adverse cardiovascular events (MACEs). However, the relationships among lung function impairment, hypertension, and MACEs have not been well‐reported. We aimed to investigate the association between lung function and hypertension and MACEs. We studied 6769 people who were a representative sample of the general population in Jiangsu Province using the multi‐stage stratified cluster sampling method. The average age was 51.54 years. Cox proportional hazards models were used to analyze the relationships between the blood pressure status and various types of lung function impairment related to MACEs. Over a follow‐up of 10 years, 236 MACEs occurred. After adjusting for age, sex, BMI, smoking, drinking, education, physical activity, diabetes mellitus, dyslipidemia, creatine and use of antihypertensive drugs, hypertension [hazard ratio (HR) = 2.154, 95% confidence intervals (CI): 1.565–2.966], and restrictive lung function impairment (RLFI) (HR = 1.398, 95% CI: 1.021–1.879) were independently associated with MACEs. Individuals with hypertension and RFLI had the highest risk for MACEs (HR = 2.930, 95% CI: 1.734–4.953) and stroke (HR = 3.296, 95% CI: 1.862–5.832). Moreover, when combined with hypertension, obstructive lung function impairment (OLFI) (HR = 2.376, 95% CI: 1.391–4.056) and mixed lung function impairment (MLFI) (HR = 2.423, 95% CI: 1.203–4.882) were associated with MACEs. There is a synergistic effect of lung function impairment (especially RLFI) and hypertension on MACEs. Therefore, more attention should be paid to the incidence of MACEs in individuals with impaired lung function, especially those who have hypertension.


BACKGROUND
Cardiovascular disease comprises heart and vascular disease and is the main cause of global mortality and disability. In developing countries, the social and economic burden due to major adverse cardiovascular events (MACEs) is increasing yearly. 1 In 2016, cardiovascular mortality was the main cause of death, accounting for more than 40% of deaths in the Chinese population, and its rate was higher than that of tumors and other diseases. 2 According to the China Cardiovascular Health and Disease Report in 2019, 330 million people suffer from MACEs, among which stroke ranked first with 13 million people. 3 Hypertension is a risk factor for MACEs. A previous study showed that when blood pressure exceeded 115/75 mmHg, the risk of MACEs would double with each increase of 20/10 mmHg. 4 Previous studies have shown that the risk of stroke among hypertensive patients was seven times more than those with normal blood pressure. 5 In addition, some cross-sectional studies have shown that reduced lung function is associated with an increased risk of MACEs. 6,7 In particular, several studies have shown a significant negative association between lung function and ischemic stroke. 8

Population
A multi-stage, stratified sampling method (

Data collection
A standardized questionnaire was used to collect demographic infor-  protocol. We conducted follow-up every 3 years after baseline for outcomes of MACEs, which comprised stroke, myocardial infarction, and heart failure, and the follow-up was completed by December 2018.

Definitions
Smoking was defined as a history of smoking and smoking at least one cigarette per day in the past year. 12 Drinking was defined as having alcohol more than once per month in the past year. 13 Physical activity levels were assessed with the International Physical Activity Questionnaire. 14,15 According to the types and frequency of physical activity in 1 week, we calculated the metabolic equivalent task (MET), and divided physical activity into three levels of low physical activity (< 600 MET min/week), moderate physical activity (physical activity ≥600 and < 3000 MET min/week) and high physical activity (≥3000 MET min/week). Hypertension was defined by self-reported or a measured blood pressure > 140/90 mmHg or taking antihypertensive drugs. Dyslipidemia was defined as TC ≥6.22 mmol/L, or HDL-C < 1.04 mmol/L, or LDL-C ≥4.14 mmol/L, or TG ≥2.26 mmol/L. 16

Statistical analysis
The population was divided into eight groups according to their blood pressure and lung function status, and baseline characteristics in each group in relation to MACEs were analyzed. The mean with standard deviation was used to represent quantitative data. Analysis of variance was used to compare differences between groups using individuals with hypertension and normal lung function as the reference group.
The frequency and the percentage were used to represent qualitative data. The χ 2 test was used to compare differences between groups using individuals with no hypertension and normal lung function as the reference group. The crude incidence rate (per 1000 person-years) of MACEs (stroke, myocardial infarction, and heart failure) during followup were calculated. When calculating the incidence, we recorded two or more MACEs (stroke, myocardial infarction, or heart failure) events in the same person as two or more MACEs. The Cox proportional hazard model was used to analyze the effect of hypertension only, lung function impairment status only in two models (Model 1 was adjusted for age and sex. Model 2 was adjusted for age, sex, BMI, smoking, drinking, education, physical activity, diabetes mellitus, dyslipidemia, creatine, and use of antihypertensive drugs), and the combination of these two factors on MACEs and stroke after adjusting for age, sex, BMI, smoking, drinking, education, physical activity, diabetes mellitus, dyslipidemia, creatine, and use of antihypertensive drugs. The single factor of stroke was selected because it has the highest morbidity and mortality rates among MACEs in China, and the number of stroke cases in our study also accounted for the largest proportion of MACEs. In the Cox model, we counted the participants' first MACE as the outcome of concern. Hazard ratios (HRs) and 95% confidence intervals (CIs) were used to indicate the hazard of MACE in different lung impairment and hypertension status. In order to eliminate the effect of antihypertensive drugs on lung function, COX regression was carried out again after excluding the subjects taking antihypertensive drugs.

MACEs Stroke
Non-hypertension, normal lung function Note: hazard ratios are presented after adjusting for age, sex, BMI, smoking, drinking, education, physical activity, diabetes mellitus, dyslipidemia, and creatine. Individuals without hypertension and normal lung function were the reference group.

HRs of MACEs and stroke according to the presence of hypertension and lung function impairment status
The lung function impairment status and hypertension were com-  Table 4.

DISCUSSION
In this prospective study, the main findings were an association between hypertension or RLFI and MACEs or stroke. After adjusting for potential confounders, individuals who had high blood pressure and RLFI had the highest risk for MACEs. However, there was no significant association between only OLFI or only MLFI and MACEs.
In 2016, there were 4.34 million deaths from MACEs in China, including 2.10 million deaths from stroke, which was the main cause of death. 15,19 The prevalence of MACEs continues to rise, with more than 290 million cases of MACEs in China. 2 The high prevalence and mortality rates of MACEs impose a great economic and social burden. Therefore, there is an urgent need to examine cardiovascular risk factors and to control and prevent them.
Our study showed that hypertension was associated with an increased risk of major MACEs and stroke. Hypertension is a recognized risk factor for MACEs and is independent of other risk factors.
The risks of myocardial infarction, stroke and heart failure increase with an increase in blood pressure. 4 A review of 15 clinical trials showed that antihypertensive therapy reduced the risk of stroke, myocardial infarction and heart failure by 35% to 40%, 20% to 25%, and > 50%, respectively. 20 The current study also showed that lung function impairment, espe- This study showed an increased risk of MACEs in individuals with both hypertension and lung function impairment, regardless of the type of lung function impairment, which has rarely been reported. 10,11 This study also showed that the HRs of MACEs and stroke in individuals with only hypertension were 2.344 and 2.300, respectively, which were higher than the HR in individuals with only RLFI. Additionally, although OLFI or MLFI was not significantly associated with the occurrence of MACEs or stroke, the HR of these two types of lung function impairment with hypertension was higher than that in individuals with only hypertension. This finding suggested an association between blood pressure and lung function. Previous studies have shown that low lung function was associated with a high future blood pressure and the occurrence of MACEs. 31,32 The prospective study results of Sparrow 33 and Tockman 34 showed that baseline FVC was significantly negatively correlated with the risk of hypertension, and was independent of alcohol consumption, smoking, salt addiction, and other factors. FVC is an important predictor of hypertension and may affect the morbid-ity and mortality of MACEs through hypertension. Therefore, hypertension may be an important link between lung function and MACEs.
On the other hand, hypertension affects the structure and function of the lungs and pulmonary circulation. The important pathological feature of hypertension is the increase of peripheral vascular resistance, which leads to the decrease of blood supply, small airway injury, muscle endurance in the region under its jurisdiction, and the decrease of lung function through the influence of small airway ventilation. 35 Hypertension and lung function impairment interact with each other, and their association with MACEs may be based on systemic inflammation and endothelial dysfunction. 36 Our study has some strengths, which were its prospective nature with a large sample, and the follow-up was long. Additionally, we classified lung function impairment and combined it with hypertension to investigate the outcome of MACEs in different types of lung function impairment. However, this study also has some limitations. We did not identify the sequence of hypertension and lung function impairment, and lack evidence to establish a clear association between hypertension and lung function impairment. Therefore, the role of lung function impairment and hypertension in the occurrence of MACEs, as well as the mechanism of changes in lung function affecting the occurrence of cardiovascular events, require further research.
In conclusion, in this cohort study, hypertension and RLFI were asso- Technical or material support: Zhang Yuqing, Zhang Yongqing, and Qin Yu.

DATA AVAILABILITY STATEMENT
The authors can provide the data on request.