Continuous Positive Airway Pressure Therapy On Recovery Of Left Ventricular Remodeling And Function In Patients With Heart Failure

BackgroundHeart failure with reduced ejection fraction(HFrEF)is a complex clinical syndrome characterized by impaired systolic and/or diastolic function caused by numerous etiologies.The myocardial remodeling is the hallmark of HFrEF.Furthermore,HFrEF is the decompensated and end stage of various cardiovascular diseases,which caused serious financial burden and distress.Compared with the estimated prevalence of 1-2%of worldwide adult population,in a recent Chinese population-based study conducted in 2019,the morbidity of heart failure was 0.97%,which had increased by 44%since 2004.For the huge population size and the aging of population,the prevalence of HFrEF will escalate steadily and the mortality will also increase continuously.Thus,early identification and timely intervention is relatively crucial for HFrEF to improve prognosis and reduce mortality.The most common cause and the high risk factors of HFrEF is ischemic heart disease,while arrhythmia,cardiomyopathies and valvular heart diseases are other still common etiologies.For HFrEF,multifactorial compensatory mechanisms,such as activation of the neurohumoral system(including sympathetic nervous system and renin-angiotensin-aldosterone system),participate in myocardial remodeling which is the basic concept of the pathogenesis.Obstructive sleep apnea(OSA),one of the independent risk factors and prevalent comorbidities for HFrEF,can aggravate the impairment of myocardial contractility and exacerbate left ventricle(LV)remodeling,leading to the deterioration of cardiac function and worse prognosis.The underlying pathogenesis is complex and multifactor etiologies,including intermittent hypoxia,increased oxidative stress and systemic inflammation,over-activated sympathetic nerve activity and elevated blood pressure,which may participate in this pathological process.The continuous positive airway pressure(CPAP)is a type of non-invasive respiratory support technique which uses mild air pressure to keep the upper airways open and to ameliorate the episodic reduction(hypopnea)or cessation(apnea)of airflow.Based on this mechanical effect,the arousal from sleep,oxidative stress,sympathetic nerve activity and concomitant hypercapnia will be attenuated.Thus,symptoms of OSA,including unrefreshing sleep,fatigue and tiredness,will be relieved.Thus,CPAP has been proposed as the first-line therapy for OSA.In HFrEF patients combined with OSA,2022 AHA/ACC/HFSA HF guideline notes that CPAP may be reasonable to improve sleep quality and decrease daytime sleepiness(Class of Recommendation 2a),however,the evidence of its influence on cardiac structure and function was not mentioned.Lack of evidence of large-scaled multi-central clinical study may be the critical issue.Mild-to-moderate improvement of LV systolic function and reversion of the LV remodeling was detected in previous scattered small-scale researches during their limited follow-up period(several weeks to 6 months).However,no increase of left ventricle ejection fraction(LVEF)at least 10 absolute points and no complete recovery of LV function,which refers to the increase of LVEF up to the normal limit of 50%,was observed in previous studies.Whether complete recovery of LV function can be accomplished and what benefits can be obtained from continuous CPAP therapy are still ambiguous.Based on the current situations,we performed the cohort study to explore long-term effects of CPAP therapy on LV function improvement as well as LV remodeling reversion for HFrEF patients with OSA receiving guide directed medical therapy(GDMT).Objectives1.To explore whether CPAP therapy can facilitate the recovery of cardiac function in HFrEF patients with OSA.2.To explore the impact of CPAP therapy on LV remodeling for HFrEF patients with OSA.3.To illustrate long-term effects of CPAP therapy on LV function improvement as well as LV remodeling reversion for HFrEF patients with OSA receiving GDMT.Methods1.Study populationThis was a single center non-randomized control study,which was approved by the Ethics Committee of Qilu hospital of Shandong University(KYLL-202011-086).All patients provided informed written consent.Participants were consecutively recruited from specialist HF clinic of cardiology department of Qilu hospital from June 2018 to June 2021.1.2 Inclusion criteria included:(1)Ages range from 20 to 75 years old,(2)Validated heart failure with reduced ejection fraction(HFrEF)which refers to LVEF<40%determined by using transthoracic echocardiography,(3)New York Heart Association(NYHA)functional class Ⅱ to Ⅲ,clinically stable for at least one month,(4)GDMT given following the ESC HF guidelines,(5)Confirmed OSA validated by polysomnography(PSG),overnight sleep studies or STOP-BANG and Epworth Sleepiness Scale(ESS)questionnaires combining with portable sleep monitoring deceives(PSMDs).1.3 Exclusion criteria included:(1)recent instability of hemodynamic status and/or assistant device implantation,such as implantable cardioverter-defibrillator(ICD)and cardiac resynchronization therapy with a defibrillator(CRT-d),less than one month,(2)Central sleep apnea(CSA)defined as central apnea index(CAI)>50%of the Apnea index(AI),(3)a history of stroke with neurologic deficit,(4)structural heart diseases,chronic serious respiratory or end-stage renal diseases on continuous renal replacement therapy,(5)the presence of known untreated neoplasms with a life expectancy less than 1 year,(6)follow-up period less than 10 months.1.3 GroupingAccording to the intention-to-treat of patients,tolerance of CPAP and economic condition,the participants were divided into CPAP+GDMT group and GDMT group2 Data collection2.1 Baseline data collectionThe following data,including gender,age,Body Mass Index(BMI),systolic blood pressure,diastolic blood pressure,heart rate,history of smoking and drinking and important complications(including coronary heart disease,hypertension,diabetes,chronic kidney disease and atrial fibrillation),were collected at baseline.2.2 Echocardiogram examinationTwo-dimensional(2-D)echocardiography was performed by Phillip EPIQ7C system(Philips Ultrasound,Bothell,WA,USA)to evaluate the cardiac function and status of LV remodeling at the baseline and follow-up period.The echocardiographic parameters,such as LVEF,left ventricular end diastolic diameter(LVEDD),left atrial diameters(LAD)、interventricular septum dimension(IVS),left ventricular posterior wall dimension(LVPW),and the ratio of early diastolic mitral in flow velocity(E)to early diastolic TDI annular velocityle’s(e)(E/e’),were performed following the American Society of Echocardiography and the European Association of Cardiovascular Imaging guidelines.LVEF was measured according to biplane method according to modified Simpson’ s rule.LVMI was calculated by dividing LV mass by body surface area.2.3 Pharmacotherapy interventionGDMT pharmacotherapies,including angiotensin-converting enzyme inhibitor(ACE-I),angiotensin-receptor blocker(ARB),angiotensin receptor-neprilysin inhibitor(ARNI),beta-blocker,mineralocorticoid receptor antagonist(MRA)and sodium-glucose co-transporter 2 inhibitor(SGLT2i),were initiated once the patient is hemodynamically stabilized and gradually up-titrated to target dose or maximum tolerated recommended doses according to the ESC HF guideline.2.4 Sleep studiesThere were three manageable diagnostic tools of OSA in our study,including PSG study,overnight sleep studies or STOP-BANG and ESS questionnaires combining with PSMDs.The diagnosis and subtype of sleep-disordered breathing(SDB)was confirmed at baseline,while the AHI would be recorded and the STOP-BANG and ESS questionnaires would be reevaluated at 3-,6-and 12-month follow-up to assess the effectiveness of CPAP therapy and severity of OSA.3 Study outcomes3.1 The primary endpoints were the absolute change from baseline in LVEDD,LVMI and LVEF,as well as the rate of the complete recovery of cardiac structure and function.Annotations:Percentage of LVEF change=(LVEF-baseline LVEF)/baseline LVEF.Percentage of LVEDD change=(LVEDD-baseline LVEDD)/baseline LVEDD.Percentage of LVMI change=(LVMI-baseline LVMI)/baseline LVMI.(1)Complete recovery of LV function and reversion of LV remodeling need met both three echocardiographic criteria,which referred to LVEF≥ 50%,LVEDD≤55mm(for male)or≤50mm(for female)and LVMI<125 g/m2(for male)or<110 g/m2(for female).(2)Patrial recovery of LV function was defined as that LVEF increased at least 10 absolute points but did not reach the limit of 50%.Besides,LEVF≥50%with unnormal LVEDD and/or LVMI was also regarded as partial recovery.(3)No recovery of LV function referred to that LVEF increased fewer than 10 absolute points and did not reach the limit of 50%.Worsening LVEF was also included in the category.3.2 Secondary outcomes were defined as the change in NT-proBNP and E/e’,as well as the relief of HF symptoms,which was measured by NYHA function class,and other parameters related to cardiac structure and function.4 Follow-upAll participants would be re-evaluated at 3,6 and 12 months after baseline study.The echocardiography and laboratory tests,such as N-terminal B-type natriuretic peptide(NT-proBNP),were performed at programmed follow-up.Besides,the monitoring and usage data of CPAP device was recorded to assess the compliance and efficacy of CPAP therapy.Necessary adjustment of parameters of CPAP and up-titration of drugs were also conducted during follow-up.Statistical analysisStatistical analyses were performed on the software package SPSS version 24(SPAA Inc,Chicago,IL).Descriptive variables were expressed as medians and interquartile ranges(IQR),or percentages,as appropriate.For quantitative variables,a non-parametric Mann-Whitney U test were used to compare each two groups.For categorical variables,the χ2 test or Fisher exact test was used as appropriate.Proportional changes in LVEF,LVEDD,LVMI,e/e’ and NT-proBNP were calculated and compared between subgroups.Cox proportional hazards analysis was performed to evaluate the CPAP treatment effect among subgroups.Hazard ratios(HRs)with 95%confidence intervals were calculated.Multivariable analyses were adjusted for age,gender and BMI.Kaplan-Meier curves was used to describe the probability of non-recovery of cardiac function and non-reversion of left ventricle myocardial remodeling.P values<0.05 were considered statistically significant and all tests were 2-sided.ResultsFrom June 2018 to June 2021,a total of 120 HFrEF patients with OS A were screened at initial period,while 75 patients were excluded after screening.Forty-five eligible patients were finally enrolled in our analysis.According to whether effective CPAP therapy was provided,the participants were categorized into GDMT+CPAP group(N=21)and isolated GDMT group(N=24).During follow-up period,3 patients were loss to follow-up and 12 patients did not accomplish programmed follow-up.A total of 30 patients(15 cases in CPAP+GDMT group and 15 cases in GDMT group)were included in the final statistical analysis.1.Patient characteristicsNo statistically significant difference was observed in age,gender,BMI,blood pressure,heart rate and medication between two groups.Besides,echocardiogram parameters(including LVEF、LVEDD、LAD、LVMI and E/e’)and sleep studies was also similar between groups.Compared with GDMT group,CPAP+GDMT group showed higher serum NT-proBNP levels and AHI.2.CPAP intervention and efficacyThe compliance CPAP treatment was satisfying which was reflected by CPAP use for at least 4 hours per night for at least 5 nights per week.Compared with baseline,AHI,STOP-BANG and ESS questionnaires scores in CPAP+GDMT group were all decreased at 3-,6-and 12-month follow-up,while no statistical significant change was observed in GDMT group.3.Pharmacotherapy titrationThe pharmacotherapy was administered following the ESC HF guideline and the up-titration protocol.For both groups of medication,the rate of reaching target dose increased continuously and no statistical difference was observed at baseline and during follow-up period.4.Effect of CPAP therapy to cardiac function and LV remodelingThe improvement of LVEF,the indicator of left ventricle systolic function,were significantly greater in CPAP+GDMT group than isolated GDMT group at 3-month,6-month and 12-month follow-up.LVEDD decreased dramatically and continuously in CPAP+GDMT groups,while no statistically significant change of LVEDD was observed in GDMT group at 3-,and 6-month follow-up.Furthermore,the reduction of LVMI,the important parameter of LV remodeling,were also more evident for patients on CPAP therapy than those without at 3-month,6-month and 12-month programmed follow-up.However,other echocardiographic parameters reflecting LV remodeling(including LCPW and IVS)had no statistically significant difference during the whole follow-up period.5.Effect of CPAP therapy to LA remodelingCPAP+GDMT group showed mild but statistically significant reduction of LAD at 3-month follow-up,and the improvement remained at 6-and 12-month follow-up.Compared with individuals without CPAP treatment,smaller LAD was observed in patients on CPAP therapy(median=45mm,IQR 41-48mm,vs median=40mm,IQR 36-45mm,p=0.041)at 12-month follow-up.However,this tendency was not observed in GDMT group.6.Primary outcomesThe primary endpoints were the absolute change from baseline in LVEDD,LVMI and LVEF,as well as the rate of the complete recovery of cardiac structure and function.Higher rate of complete LV recovery and reversion of LV remodeling was observed in patients on CPAP therapy than those without(80.0%vs 33.3%,p=0.010).After adjusted by age,gender and BMI,Cox proportional hazards analysis also indicated that CPAP therapy significantly facilitated the improvement of LV systolic function and reversion of LV remodeling(HR=3.186,95%CI:1.101-9.223,p=0.033).Patients without CPAP therapy had higher probability of non-complete recovery of LV function at 1-year follow-up(66.7%vs 20%,p=0.010).Besides,compared to GDMT group,the degree of improvement of LVEF and LVMI was higher in CPAP+GDMT group.For the degree of reduction of LVEDD,no statistically significant difference was detected between two groups.7.Secondary outcomesFor the secondary outcomes,the proportion changes in the plasm NT-proBNP concentrations and E/e’ differed indistinctively between GDMT+CPAP group and isolated GDMT group.However,higher proportion of NYHA function class Ⅰ/Ⅱ was observed in CPAP group(93.3%vs 26.7%,p=0.024)at 1-year follow-up.Despites no statistically significant difference of blood pressure,heart rate and BMI was observed between two groups,patients on CPAP group showed persistent but no statistically significant reduction of SBP,which was not detected in GDMT group.Conclusion1.For HFrEF(chronic heart failure with reduced ejection fraction)patients with OSA on GDMT,improvement of cardiac function and reversion of LV remodeling could occur at early period(3 months)after CPAP therapy.Moreover,CPAP could bring persistent and enduring cardiac benefits to HFrEF patients with OSA.2.Long-term CPAP therapy could mildly facilitate the reversion of left atrium.3.Compared with GDMT alone,long-term CPAP therapy could further relieve HF symptoms.