The Effect of Sleep Quality on Coronary Lesion Severity and Prognosis in the Young Acute Coronary Syndrome Population

This study aimed to explore the effect of long-term (≥1 year) sleep quality on coronary lesion complexity and cardiovascular prognosis in young acute coronary syndrome (ACS) patients. We consecutively recruited young patients aged from 18 to 44 years old with first-episode ACS and significant epicardial stenosis on coronary angiography from January 2016 to January 2017. Coronary lesion complexity was evaluated based on SYNTAX scores. Long-term sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI) (PSQI ≤ 5 and PSQI > 5 groups). The primary endpoints were major adverse cardiovascular events (MACEs). A total of 466 young ACS patients (93.13% male; median age, 41 years) were included. Poor sleepers (PSQI > 5) had higher SYNTAX scores. After adjusting for confounders, PSQI scores (continuous variables, OR: 1.264; 95%CI: 1.166–1.371; p < 0.001) and PSQI grade (binary variable, OR: 3.864; 95%CI: 2.313–6.394; p = 0.001) were significantly associated with an increased risk of complex coronary lesions. During a median follow-up of 74 months, long-term poor sleep quality (PSQI > 5) was significantly associated with an increased risk of MACEs (HR: 4.266; 95%CI: 2.274–8.001; p < 0.001). Long-term poor sleep quality was a risk factor for complex coronary lesions and has adverse effects on cardiovascular prognosis in the young ACS population.


Introduction
With economic and social development and changes in people's lifestyles, the incidence of acute coronary syndrome (ACS) among young adults is increasing year by year [1].The World Health Organization uses a special classification to define coronary artery disease (CAD) occurring before the age of 45 years as youth CAD.It has different characteristics than elderly coronary heart disease; the lesions occur earlier, and the disease progresses more rapidly [2].For young patients, increased risks of major adverse cardiovascular events (MACEs) have been observed after ACS.Thus, it is essential to identify the editable risk factors of ACS and to carry out early intervention to delay its incidence.The development of ACS is always associated with inflammation [3,4].Thus, it has been demonstrated that male sex, hypertension, diabetes, hyperlipidemia, obesity, smoking, and insufficient sleep are risk factors for cardiovascular disease mortality in the young population [5][6][7].
As an important neurobehavioral state, sleep has been an essential topic in abundant genetic, epigenetic, and proteomic studies.Robust evidence has revealed that poor sleep quality may cause adverse immunological and metabolic changes, including increased susceptibility to infectious disease, decreases in growth hormone, and increases in sympathetic activation [8].Moreover, poor sleep quality could also increase the risk of cognitive impairments and other chronic diseases, such as stroke, type 2 diabetes [9], calcification of the coronary arteries [10], and death [11,12].Growing evidence indicates that sleep duration and sleep disorder are also associated with a higher risk of ACS and MACEs [13,14].However, clinical evidence on the effect of sleep quality on coronary lesion complexity and cardiovascular prognosis in youth ACS is inadequate and warrants further study.Therefore, we conducted this prospective cohort study to investigate the effect of sleep quality on coronary lesion severity and cardiovascular prognosis in young ACS patients.

Study Procedures and Population
This cohort study consecutively enrolled young patients aged 18 to 44 years old with suspected ACS who were admitted to Beijing Anzhen Hospital from January 2016 to January 2017.Participants were excluded if they refused coronary angiography (CAG) or had a history of myocardial infarction (MI), percutaneous coronary intervention (PCI), coronary artery bypass graft surgery (CABG), severe heart failure (New York Heart Association classes III-IV or Killip classes III-IV), severe renal insufficiency (estimated glomerular filtration rate < 30 mL/min/1.73m 2 ), severe valvular heart disease, malignant arrhythmia (ventricular tachycardia, ventricular fibrillation, high atrioventricular block, etc.), congenital heart disease, myocarditis, cardiomyopathy, heart transplantation, secondary hypertension, or severe wasting disease (malignant tumor, liver disease, severe infection, etc.).We took complete medical histories and performed fasting blood tests and electrocardiograms (ECGs) on all included patients.In addition, sleep questionnaires and CAG were also completed.Based on the results of CAG, the cardiologist recommends an individualized treatment to the patient, including PCI, CABG, or conservative treatment.According to the guidelines [15] and combined with auxiliary examinations, patients who had significant epicardial stenosis after CAG and who were diagnosed with ACS were included in this study.For the enrolled patients, clinical follow-up was performed semiannually, ending in August 2022, to record data on their sleep changes, clinical status, all interventions received, and outcome events.
A total of 743 young patients with suspected ACS were consecutively enrolled between January 2016 and January 2017.After excluding 237 patients according to the criteria, the PSQI questionnaires were administered and SYNTAX scores were recorded in the remaining 506 patients.During the research process, 17 patients were removed because of incomplete questionnaire content, and 23 patients were lost during the follow-up.The missing outcomes were less than 5% of the total.Finally, 466 patients were included and divided into a PSQI ≤ 5 group (n = 202) and a PSQI > 5 group (n = 264) (Figure 1).The study was approved by the Ethics Committee of Beijing Anzhen Hospital, Capital Medical University (No. 2016044X).All enrolled patients provided written informed consent.

Diagnostic Criteria
Hypertension was diagnosed when it was consistent with 2 or more systolic blood pressures ≥ 140 mmHg or diastolic blood pressures ≥ 90 mmHg [16].Diabetes mellitus was diagnosed when it was consistent with fasting glucose ≥ 7.0 mmol/L or non-fasting glucose ≥ 11.10 mmol/L [17], and hyperlipidemia was diagnosed when it was consistent with fasting total cholesterol > 5.18 mmol/L or triglyceride > 1.72 mmol/L [18].Smoking included all former and current smokers.Patients were also classified as hypertensive, diabetic, or hyperlipidemic if they had been clearly diagnosed and/or were taking medication.

Coronary and Sleep Assessment
Coronary lesion complexity was assessed using the SYNTAX score (SS) [19], which was recorded by two experienced cardiologists based on CAG images with the assistance of a senior cardiovascular imaging specialist if there was a discrepancy between the scores.According to the guidelines [20], coronary lesion complexity was divided into a low-complexity group with SS ≤ 22 and a high-complexity group with SS > 22.
Sleep quality was assessed with the Pittsburgh Sleep Quality Index (PSQI) questionnaire based on the participants' sleep habits over the past year before CAG.The investigators were highly trained and unaware of the patient's diagnoses or coronary angiography findings.PSQI is one of the most widely used standardized measures to evaluate sleep quality and has shown good internal reliability and validity in a variety of samples

Diagnostic Criteria
Hypertension was diagnosed when it was consistent with 2 or more systolic blood pressures ≥ 140 mmHg or diastolic blood pressures ≥ 90 mmHg [16].Diabetes mellitus was diagnosed when it was consistent with fasting glucose ≥ 7.0 mmol/L or non-fasting glucose ≥ 11.10 mmol/L [17], and hyperlipidemia was diagnosed when it was consistent with fasting total cholesterol > 5.18 mmol/L or triglyceride > 1.72 mmol/L [18].Smoking included all former and current smokers.Patients were also classified as hypertensive, diabetic, or hyperlipidemic if they had been clearly diagnosed and/or were taking medication.

Coronary and Sleep Assessment
Coronary lesion complexity was assessed using the SYNTAX score (SS) [19], which was recorded by two experienced cardiologists based on CAG images with the assistance of a senior cardiovascular imaging specialist if there was a discrepancy between the scores.According to the guidelines [20], coronary lesion complexity was divided into a lowcomplexity group with SS ≤ 22 and a high-complexity group with SS > 22.
Sleep quality was assessed with the Pittsburgh Sleep Quality Index (PSQI) questionnaire based on the participants' sleep habits over the past year before CAG.The investigators were highly trained and unaware of the patient's diagnoses or coronary angiography findings.PSQI is one of the most widely used standardized measures to evaluate sleep quality and has shown good internal reliability and validity in a variety of samples [21,22].This questionnaire can be used for different continents, countries, genders, and ages, and in patients with sleep disorders, psychiatric disorders, or cancer [23][24][25].It is composed of 18 individual items, comprising 7 "component" scores: subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medication, and daytime dysfunction [26].Each component has a score scale of 0 to 3 with '0' indicating no difficulty and '3' indicating great difficulty [26].The seven components were added together to form a 'PSQI score' ranging from 0 to 21 with '0' indicating no difficulty and '21' indicating severe difficulty in all areas.Grades of PSQI ≤ 5 and PSQI > 5 are used to represent good and poor sleep quality according to the original paper [26], and this has been confirmed with known-group validity in many studies [24,27].

Study Endpoints
The primary endpoints were MACEs, which were defined as the composite of allcause death, MI, and target-vessel revascularization (TVR).Secondary endpoints included all-cause death, cardiac death, MI, and TVR.
All deaths were considered to be due to cardiac causes unless a non-cardiac cause could be identified.MI was defined as symptoms, ECG changes, or abnormal imaging with a creatine kinase MB fraction above the upper normal limits or a troponin T/I level above the 99th percentile of the upper normal limit [28].TVR was defined as a repeat PCI/CABG in the target vessel either with the presence of ischemic symptoms or a positive stress test and ≥50% stenosis of the vessel diameter or with the absence of ischemic symptoms or a negative stress test and ≥70% stenosis of the vessel diameter [29].Cardiac death was defined as death due to MI, cardiac perforation, or pericardial tamponade; arrhythmia within 30 days of the procedure or related to the procedure; death due to a procedural complication; or any case of death in which a cardiac cause was not excluded by a clinical event committee [30].If >1 event occurred during follow-up (death > MI > TVR), the most severe endpoint event was selected for the primary endpoint analysis.

Statistical Analyses
Normally distributed continuous variables were expressed as mean ± standard deviation, and non-normally distributed variables were expressed as the medians and interquartile range (IQR) (Q25-Q75).Categorical variables are presented as numbers (percentages).Differences in continuous variables were analyzed with Student's t-test or the Mann-Whitney U test, and differences in categorical variables were analyzed with the chi-square test or Fisher's exact test, as appropriate.Multifactorial logistic regression was used to analyze the association between sleep quality, as a dichotomous variable ("PSQI grade") and a continuous variable ("PSQI score"), and coronary lesion complexity.In addition, the relationship between time to sleep and sleep duration, as independent variables, and SYNTAX scores were listed separately.On this basis, subgroup analyses were performed to determine the interaction between sleep quality and other risk factors.Cox proportional hazard regression was used to assess the association between PSQI grade (dichotomous variable) and MACEs, while the Kaplan-Meier method (log-rank test) was used to determine the cumulative incidence of MACEs.Clinically significant confounders and variables with statistical significance (p < 0.15) from univariate analysis were included in the model after being checked for collinearity.All statistical analyses were performed with R version 4.1.3(R Foundation for Statistical Computing, Vienna, Austria) and IBM SPSS Statistics version 26.0 (IBM Corporation, Chicago, IL, USA).Two-tailed p-values of < 0.05 were considered statistically significant.
Compared with patients with good sleep quality (PSQI ≤ 5), patients with poor sleep quality (PSQI > 5) had higher SYNTAX scores (p < 0.001).The proportion of stenosis was higher in the left main (LM) and left circumflex (LCX) (all p < 0.05).We also found that patients with poor sleep quality had higher hypersensitive c-reactive protein (hs-CRP) (p = 0.049) and were more likely to use aspirin (p = 0.013) and statins (p = 0.031).There were no significant differences in other clinical, laboratory, or medication history characteristics between the two groups (Tables 1 and 2).

Discussion
To the best of our knowledge, the young population represents a special cohort that deserves more attention regarding the prevention of ACS and its malignant outcomes.This prospective study with a 5-year follow-up investigated the role of poor sleep quality on coronary lesion complexity and MACEs in young ACS patients and elicited three main findings.First, high PSQI scores, which usually represent poor sleep quality, were positively correlated with coronary lesion complexity.Second, after adjustment for confounding factors, long-term poor sleep quality (PSQI > 5) was found to be an independent risk factor for MACEs, especially TVR.In addition, our subgroup analysis showed no significant interaction relationships between PSQI scores and hypertension, diabetes mellitus, hyperlipidemia, or smoking status in the process of ACS.Taken together, this is the first study to show that a high PSQI score is a predictor of coronary lesion complexity and is

Discussion
To the best of our knowledge, the young population represents a special cohort that deserves more attention regarding the prevention of ACS and its malignant outcomes.This prospective study with a 5-year follow-up investigated the role of poor sleep quality on coronary lesion complexity and MACEs in young ACS patients and elicited three main findings.First, high PSQI scores, which usually represent poor sleep quality, were positively correlated with coronary lesion complexity.Second, after adjustment for confounding factors, long-term poor sleep quality (PSQI > 5) was found to be an independent risk factor for MACEs, especially TVR.In addition, our subgroup analysis showed no significant interaction relationships between PSQI scores and hypertension, diabetes mellitus, hyperlipidemia, or smoking status in the process of ACS.Taken together, this is the first study to show that a high PSQI score is a predictor of coronary lesion complexity and is significantly associated with the occurrence of MACEs in young ACS patients.This might provide new information about the prevention and rehabilitation of ACS.
In recent years, the incidence of ACS among the young population (under the age of 45) has significantly increased [1,31].Compared with those in the elderly, the risk factors of ACS in young people have different characteristics, which are closely related to abnormal living habits such as smoking, less physical activity, excessive stress, and sleep disorders [32,33].As our literature review illustrated, short sleep duration, shift work, and poor sleep quality could all promote adverse health, including headache, stroke, gastrointestinal disorders, and cardiovascular disease [34][35][36][37].Zhao et al. demonstrated that shift work can increase myocardial infarction reperfusion injuries and the incidence of heart failure in mouse, ovine, and human models after acute MI, which might be associated with an elevated risk of MACEs [13].Post-ACS patients with a history of overnight shift work were found to be at increased risk of MACEs in a long-term follow-up period in [38].Moreover, in the Sleep Heart Health Study, short sleep duration (<7.5 h per night) was predictive of incident stroke or MI (with HR = 1.68) [39].Compared with normal sleep duration, all-cause death has been illustrated to be higher in short-duration (≤5 h per night) sleep and prolonged-duration (>9 h) sleep in post-ACS patients [40].In addition, Barger et al. demonstrated that obstructive sleep apnea (OSA) is underrecognized as a predictor of adverse outcomes after ACS [14].Furthermore, a systematic review and metaanalysis involving 122,501 subjects found that the sleep disorder insomnia could also lead to an increased risk of developing MACEs or death from cardiovascular disease during the follow-up period (RR 1.45, 95%CI 1.29-1.62,with p < 0.01) [41].However, although abundant research has discussed how shift work, sleep duration, and disorders affect cardiovascular health, few studies have focused on poor sleep quality using specific scores.
In the present study, we used a variety of approaches to analyze data from a youth population cohort.Thus, we are the first to unveil the association between sleep quality and cardiovascular prognosis in young ACS patients.We demonstrated that poor sleep quality is positively correlated with high coronary lesion complexity and adverse prognosis in young ACS patients in a long-term follow-up period.Unlike the studies mentioned above, our study focused on poor sleep quality evaluated with the PSQI.High PSQI scores (usually > 5) have been considered to show poor subjective sleep quality in previous research [25].After using different models of multivariate logistic regression analysis, the results showed that there was a significant association between PSQI scores and elevated SYNTAX scores, which also represented the complexity of coronary lesions [42].Thus, we concluded that long-term poor sleep quality is an independent risk factor for highcomplexity coronary lesions in youth ACS, which is consistent with the results of previous studies.Another important finding of the current study is that poor long-term sleep quality is one of the factors that influences poor prognosis in young ACS patients.Based on a five-year follow-up, we demonstrated that patients with higher PSQI scores were more likely to suffer from TVR.The results were clearly driven by TVR, so although sleep quality is related to a higher SYNTAX score, it is likely that worse outcomes are related to more complex coronary disease.Of note, there was no significant difference in the rate of MI, all-cause death, or cardiac death because of the limited number of positive cases.Further research needs to be carried out to identify young ACS patients at high risk of MACEs.In addition, unlike previous studies, we did not find an association between hypertension, diabetes, hyperlipidemia, smoking, and sleep quality in subgroup analyses, which may be related to our small sample size.In our study, 93.13% of young ACS patients were male.The reason may be that male patients have more high-risk factors such as smoking, alcohol abuse, obesity, and high-fat diets.In addition, young women are protected by estrogen.
The pathophysiology underlying the relationship between sleep quality and youth ACS has been reported both in epidemiologic and experimental studies but is still not completely clear.It has been demonstrated that poor-quality sleep, as well as short-duration sleep or the presence of non-restorative sleep [39], can lead to sympathetic activation or increased levels of inflammatory cytokines in the plasma [41], both of which are associated with metabolic, endocrine, and cardiovascular diseases [43,44].Meanwhile, evidence indicates that chronic hyperarousal and long-term stress responses caused by sleep disorders can motivate both the hypothalamic-pituitary-adrenal axis and the autonomic nervous system [45][46][47]; further increase the metabolic rate [48] and heart rate; and decrease heart rate variability [49].These physiological processes may have an association with vascular endothelial dysfunction and atherosclerosis, which are responsible for the development of cardiovascular events in young ACS patients in later life.
Poor sleep quality may be one of the risk factors for young ACS patients and their disease's adverse outcomes.Therefore, it is of great clinical significance to explore the association between sleep quality and coronary lesion complexity.The studies above indicate the importance of improving overall sleep quality for young ACS patients.However, the potential mechanism between sleep duration and youth ACS needs further exploration regarding the use of more drug-assisted therapy.Furthermore, health education about adjusting sleep habits and improving sleep should be carried out to promote public health in the future.A previous trial demonstrated that sleep quality can be improved by treating depressive symptoms in ACS patients [50], which could be applied to cardiac rehab programs for youth ACS patients.
This study has some limitations.First, the study was based on a single center, enrolling patients of East Asian heritage, and needs to be validated in diverse groups.Second, our sample size was relatively small, with a predominance of male patients, and we had a small number of outcome events with predominant TVR, which might affect the accuracy of the results to some extent.Third, compared with polysomnography, sleep quality questionnaires cannot provide objective data, and there could be a recall bias in self-reported PSQIs.

Conclusions
This study suggests that sleep quality is positively associated with coronary lesion complexity and that long-term poor sleep quality is a risk factor for complex coronary lesions.In addition, patients with poor sleep quality showed higher risks of MACEs and TVR compared with those with good sleep quality.Our findings could serve as a meaningful reference for preventing and rehabilitating ACS and its malignant outcomes in young people.More randomized controlled trials should be conducted in the future to further verify our conclusions.

Supplementary Materials:
The following supporting information can be downloaded at https: //www.mdpi.com/article/10.3390/jcdd11020068/s1,Supplementary Table S1.Univariate Logistic regression analysis between covariates and SYNTAX grades.Supplementary Table S2.The collinearity check between covariates in model 3 of logistic regression analysis.Supplementary Table S3.Univariate Cox proportional hazards regression analysis of covariates and clinical outcomes.Supplementary Table S4.The collinearity check between covariates in adjusted model of Cox proportional hazards regression analysis.

Figure 3 .
Figure 3. Kaplan-Meier curves of survival free of MACEs and PSQI grades.

Figure 3 .
Figure 3. Kaplan-Meier curves of survival free of MACEs and PSQI grades.

Table 1 .
The baseline clinical characteristics, laboratory parameters and angiographic findings of the patients according to PSQI score.

Table 2 .
Outcomes of the patients according to PSQI grades.

Table 3 .
Logistic regression analysis of association between sleep characteristics and coronary lesion complexity.