Prevalence Of Sleep-disordered Breathing In Patients With Heart Failure And The Mechanism Of Intermittent Hypoxia On Left Cardiac Function

Ⅰ.Prevalence and risk factors of sleep-disordered breathing in patients with heart failureObjective:Sleep-disordered breathing(SDB)is closely related to heart failure(HF)and is an independent risk factor for HE.It is mainly divided into obstructive sleep apnea(OSA)and central sleep apnea(CSA).The purpose of this study was to investigate the prevalence and risk factors of SDB in patients with HF.Methods:Patients with stable HF who were hospitalized in the Department of Cardiology,Zhongda Hospital affiliated to Southeast University from January 2021 to October 2021 were consecutively enrolled.All the enrolled patients underwent portable overnight cardiorespiratory polygraphy,and were divided into No-SDB,OS A and CSA groups according to sleep study results.The prevalence of SDB,OS A,and CSA in patients with HF was analyzed.The clinical data of the three groups were compared and logistic regression analysis was used to explore the risk factors of OSA and CSA in patients with HF.Results:A total of 252 patients with HF were enrolled according to inclusion and exclusion criteria.The prevalence of SDB in HF was 69.8%,of which OSA was 47.6%and CSA was 22.2%.Logistic regression analysis revealed that age and BMI were independent risk factors for OSA in HF patients,while LUEF and smoking were independent risk factors for CSA in HF patients.Conclusions:SDB has a high prevalence in patients with HF,and patients with SDB,especially those with CSA,have more severe HF.Age and BMI are risk factors for OSA,while LVEF and smoking are risk factors for CSA in patients HF.According to the clinical characteristics and echocardiography data of patients with HF,the risk of SDB in patients with HF can be initially screened.Ⅱ.Prevalence and clinical characteristics of sleepdisordered breathing in heart failure patients with different left ventricular ejection fractionsObjective:The prevalence of sleep-disordered breathing(SDB)is high in patients with heart failure(HF),while the prevalence of SDB in HF patients with different left ventricular ejection fractions(LVEF)has rarely been reported.We aimed to explore the prevalence and clinical characteristics of SDB in HF patients with different LVEF.Methods:Patients with stable HF who were hospitalized in the Department of Cardiology,Zhongda Hospital affiliated to Southeast University from January 2021 to October 2021 were consecutively enrolled.All patients underwent portable overnight cardiorespiratory polygraphy and echocardiography.According to their LVEF,the patients were divided into the HFrEF(HF with reduced EF,EF<40%),HFmrEF(HF with mid-range EF,40 ≤EF<50),and HFpEF groups(HF with preserved EF,EF≥50%).The prevalence and clinical data of SDB among the 3 groups were then compared.Results:A total of 252 patients,including 134 men and 118 women were enrolled in the study.The prevalence of SDB in the HFrEE,HFmrEF,and HFpEF groups was 86.1%,86.0%,and 62.4%,respectively(P=0.001).The prevalence of OSA among the 3 groups was 41.7%,46.5%,and 49.1%,respectively(P=0.708),while the prevalence of CSA among the 3 groups was 44.4%,39.5%,and 13.3%(P<0.001).Correlational analyses revealed that LVEF was negatively correlated with apnea-hypopnea index(AHI)(r=-0.309,P<0.001)and central apnea index(CAI)(r=-0.558,P<0.001),while there was no significant correlation with obstructive apnea index(OAI).The ROC curve revealed that LVEF could predict the occurrence of CSA and SDB,with AUC=0.683(95%CI:0.600-0.767,P<0.001)and AUC=0.630(95%CI:0.559-0.702,P=0.001),but not of OSA.Conclusions:SDB was highly common in HF,and the prevalence of SDB was different in HF with different LVEF,mainly due to the difference in cardiac functions.The prevalence and severity of SDB in HFrEF and HFmrEF were significantly higher than those in HFpEF,which was mainly related to the increase of CSA.When HFmrEF was similar to HFrEF in other cardiac function indexes,the prevalence,types,and severity of SDB were similar between the two groups.Changes in LVEF had a significant impact on CAI,but not on OAI.LVEF can predict the occurrence of CSA and SDB to a certain extent.Ⅲ.Sleep-disordered breathing in heart failure patients with different etiologiesObjective:The prevalence of sleep-disordered breathing(SDB)is closely related to the severity of heart failure(HF),and the severity of HF is different in HF patients with different etiologies.This study aimed to explore the prevalence of SDB in patients with HF of different etiologies.Methods:Patients with stable HF who were hospitalized in the Department of Cardiology,Zhongda Hospital affiliated to Southeast University from January 2021 to October 2021 were consecutively enrolled.All patients underwent portable overnight cardiorespiratory polygraphy and echocardiography.Patients were divided into five groups according to the etiology of HF:ischemic,hypertensive,myocardial,valvular,and arrhythmic.The prevalence of SDB and clinical data were compared among the five groups.Results:In total,248 patients were enrolled in this study.Patients were divided into five groups:ischemic,hypertensive,myocardial,valvular and arrhythmic.The prevalence of SDB among the five groups was 75.3%,81.4%,77.8%,51.9%,and 58.5%(P=0.014),respectively.The prevalence of OSA among the five groups was 42.7%,72.1%,36.1%,37.0%,and 49.1%(P=0.009),whereas the CSA was 32.6%,9.3%,41.7%,14.8%,and 9.4%(P<0.001),respectively.Conclusions:SDB is common in HF patients.The prevalence and types of SDB varied in HF with different etiologies.SDB was highly prevalent in patients with ischemic,hypertensive,and myocardial HF.Hypertensive HF patients were mainly complicated with OSA,while myocardial HF patients were mainly complicated with CSA.Both conditions were highly prevalent in ischemic HF patients,but OSA was higher.The prevalence of SDB was relatively low in valvular and arrhythmic HF patients,and OSA was the main type.Ⅳ.Effects of chronic intermittent hypoxia on left cardiac function in young and aged miceObjective:Sleep-disordered breathing(SDB)is an independent risk factor for cardiovascular disease that is characterized by chronic intermittent hypoxia(CIH),and its impact is related to age.This study aims to assess the age-related impact of CIH on cardiac function and to further explore the mechanism.Methods:Three-month-old(young)and 22-to 24-month-old(aged)female C57BL/6 mice were obtained from the Animal Experiment Center of Southeast University.The mice were divided into the young group(n=20),young+CIH group(n=20),aged group(n=20),and aged+CIH group(n=20).To simulate the CIH that occurs in patients with severe SDB,the intermittent hypoxia device was used to construct CIH mouse model.Echocardiography was performed to assess cardiac function at 0,4,and 8 weeks.Masson’s triple staining and hematoxylin-eosin(HE)staining were used to assess fibrosis and cardiomyocyte area after 8 weeks.RT-PCR was used to determine the transcription level of type I collagen.The ultrastructural changes in the mitochondria were examined by transmission electron microscopy(TEM)after CIH exposure.The membrane potential of cardiac mitochondria was measured by JC-1 staining.Mitochondrial respiratory function evaluated by oxygen consumption rate(OCR)was assessed using a Seahorse XF 24 analyzer with the Seahorse XF Cell Mito Stress Test Kit.The DCFH-DA and MitoSOX Red reagent were respectively used to detect the level of cellular reactive oxygen species(ROS)and mitochondrial ROS.The mitochondrial DNA(mtDNA)copy number was detected by PCR.Western blotting(WB)was used to determine the expression of superoxide dismutase 2(SOD 2),nuclear respiratory factor 1(NRF 1),nuclear respiratory factor 2(NRF 2),peroxisome proliferator-activated receptor γ coactivator 1α(PGC-1α),mitochondrial transcription factor A(TFAM),sirtuin 1(SIRT1)and sirtuin 3(SIRT 3).Results:After 8 weeks of CIH exposure,compared with the young group,the mice in the young+CIH group showed a slight increase in the left ventricular internal diameter at end diastole(LVIDd)and left ventricular posterior wall at end diastole(LVPWd),a decrease in E/A,and the left ventricular ejection fraction(EF)and left ventricular fractional shortening(FS)did not decrease.However,compared with the aged group,the mice in the aged+CIH group showed an obviously decrease in EF,FS and E/A.Masson’s triple staining and HE staining results showed that interstitial collagen deposition,perivascular collagen deposition and cardiomyocyte size in the hearts of young+CIH mice increased compared with the young group.There was no significant difference in collagen deposition or the cardiomyocyte size in the hearts of mice in the aged group and the aged+CIH group.The RT-PCR results showed that the mRNA level of collagen I in the hearts of the mice in the young+CIH group was significantly increased.Under TEM,the hearts of young group,young+CIH group and aged group all exhibited healthy mitochondria with cristae with normal appearances.However,the cardiac mitochondria in the aged+CIH group exhibited blurred cristae and vacuoles,mitochondrial fragmentation,disruption of mitochondrial dynamics and a reduction in the mitochondrial fusion process.The membrane potential of cardiac mitochondria results showed a decrease in the mitochondrial membrane potential of cardiomyocytes in the aged+CIH group.Cardiac mitochondrial respiratory function detection showed that the OCR of basal respiration,maximum respiration,and ATP production did not decrease in the young+CIH group compared with the young group,but decreased in the aged+CIH group compared with the aged group.We continued to measure the levels of ROS in cardiomyocytes and mitochondria.The results showed that CIH exposure caused a slight increase in cellular ROS and mitochondrial ROS,but this increase seemed to be physiological in the hearts of young mice.In contrast,the levels of cellular ROS and mitochondrial ROS were significantly increased in the cardiomyocytes of aged mice after CIH exposure.Western blotting analysis showed that SOD2 protein expression in the hearts of mice in the young+CIH group increased,whereas the increase in SOD2 expression in the hearts of mice in the aged+CIH group was not obvious.PCR results showed CIH exposure caused the mtDNA copy number increased and the integrity of mtDNA was good in the hearts of the young mice,whereas the mtDNA copy number decreased and the integrity of mtDNA in the hearts of the aged mice was impaired after CIH exposure.WB was used to assess the mitochondrial-related proteins expression and the results showed that the expression of NRF1,NRF2,PGC1α,TFAM,SIRT1 and SIRTI3 was upregulated in the hearts of young mice to maintain mtDNA stability after CIH exposure,whereas these transcription of these genes and the regulation of related genes were not increased in the hearts of aged mice after CIH exposure and the expression of TFAM and SIRT1 was downregulated.Conclusions:After 8 weeks of CIH stimulation,there were differences in remodeling and mitochondrial function between the hearts of young and aged mice.In the hearts of young mice,the expression of PGC-1α,NRF1/2,SIRT1/3,TFAM,and SOD2 was adaptively increased after CIH exposure,the integrity of mtDNA was maintained,excess ROS was eliminated,and normal heart function was preserved.However,exposure to CIH caused an increase in collagen deposition in the hearts of young mice,which promoted premature aging of the heart.In contrast,CIH exposure caused maladaptation of the hearts of aged mice,which resulted in the inhibition of TFAM and SIRT1 expression,accumulation of ROS,disruption of mtDNA homeostasis,and dysfunction of mitochondria,ultimately leading to decreased heart function.