【作者】 刘喆；

【导师】 季晓平；

【作者基本信息】 山东大学 ， 内科学（心血管病）（专业学位）， 2021， 硕士

【摘要】 研究背景:心力衰竭是心血管事件链的终点,近年来在国内外患病率呈现持续升高趋势。无论是在欧美发达国家还是我国,心衰都是一个亟待解决的难题。随着心衰治疗和管理的越发规范化和结构化,心衰患者的生存率已经有所改善,但是其出院后短期再住院率和长期的心血管死亡率仍然非常高。神经内分泌系统激活导致了心肌的重构,是目前公认的心衰发生发展机制。近30年来开展的一系列大规模随机对照试验(randomized controlled trial,RCT),更是统一了人们的心衰治疗理念。在充分的循证医学证据下,“金三角”心衰药物治疗为各国的指南、共识高级别推荐为目前临床上慢性心衰的基本治疗方案。ARNI作为国内外随机对照研究的热点,正在广泛地积累和丰富临床应用的经验。心房颤动,简称房颤,是心脏生理功能退化的临床表现之一,发作持续时间>7天者定义为持续性房颤。年龄是房颤发生最主要的危险因素。此外,房颤还经常并发出现于一些导致心房扩大的器质性心脏病。持续性房颤特别是快心室率房颤会引起血流动力学异常,减少接近1/4的心排出量,诱发患者心功能不全。心衰和房颤具有共同的危险因素,二者同时存在提示病情更重、治疗难度更大、死亡风险更高。β-受体阻滞剂不仅是在慢性心衰的治疗药物中被视作基石,同时也是房颤患者控制心室率以改善症状的首选药物。2015年一项由多国学者联合完成的荟萃分析提出,β-blocker并不降低慢性心衰合并房颤患者的全因死亡率。但直到现在,针对心衰合并房颤的患者而设计试验开展的大规模研究仍然为数不多,这方面的循证医学证据仍不够充分。这让我们又一次回到起点,关注是否合并有房颤对心衰患者药物疗效的影响。研究目的:1.比较慢性心衰不合并持续性房颤、慢性心衰合并持续性房颤两组患者在接受规范化心衰治疗后β受体阻滞剂和RAAS抑制剂的使用情况以及用量达到指南推荐目标剂量的比率。2.比较慢性心衰不合并持续性房颤、慢性心衰合并持续性房颤两组患者在接受规范化心衰治疗后的心功能恢复及再住院情况。资料和方法1.入组患者:确定入选及排除标准,收录2010年1月1日至2020年9月30日期间就诊于山东大学齐鲁医院心内科门诊的慢性心衰患者并纳入分析。2.随访管理:通过门诊随访、电话随访相结合的形式建立随访体系。每次随访、登记均有专人负责完成。在易损期(首次确诊心衰后的3个月内),应定期至门诊复诊、调药,每次复诊间隔至少为2周,最长不超过1个月。指导患者在随访间期规范、规律地监测血压、心率并记录。门诊随访时根据患者症状、体征,家庭自测血压、心率水平调整β受体阻滞剂和RAAS抑制剂的用量,以《中国心衰诊治指南2014》、《中国心衰诊治指南2018》为依据,从小剂量开始,逐渐滴定至指南推荐的目标剂量,或者是达到患者所能耐受的最大剂量。部分患者由于调药进度的个体化差异,调药窗口可适当延长,最长不超过6个月。在患者调药完成的3个月以后,门诊随访并复查患者的心脏彩超、NT-pro BNP以评估患者治疗的有效性;复查肝肾功、血生化等检验以评估治疗安全性。完成调药后,患者应在病情稳定的前提下按该剂量长期服用。3.资料收集和统计分析:所收集患者基本数据包括其性别、年龄、病因、合并疾病、生活方式、基本生命体征(收缩压、舒张压、静息心率)、心功能情况(NYHA心功能分级、左室射血分数、左室舒张末内径、N端前脑钠肽)、肝肾功能、血生化水平、用药情况等。患者每次随访的血压、静息心率(以家庭自测血压心率为准)、症状(并以NYHA心功能分级体现)、体征,用药及药物剂量的调整以及辅助检查结果均详细记录于当日门诊病历,并及时录入电子随访档案。建立数据库,采用SPSS 24.0统计分析软件对本研究获取的计数资料和计量资料进行数据分析。结果:1.基本情况:共237例患者完成了至少6个月的随访。其中非房颤组193例,平均年龄为51.0±14.4岁,男性患者74.1%,主要心衰病因为非缺血性心肌病(53.9%),其次为缺血性心肌病(45.1%)。合并有冠心病(56.9%)、高血压(52.3%)的患者占总体的一半以上。房颤组患者44例,平均年龄60.9± 12.3岁,男性患者72.7%,主要病因为非缺血性心肌病(54.6%)。两组患者在年龄上[(51.0±14.4)岁vs(60.9±12.3)岁,P<0.01]具有显著差异。性别构成(P=0.852)上差异不明显。心衰病因方面,心脏瓣膜病与心衰合并房颤具有明显的相关性(P<0.01)。合并疾病方面,非房颤组合并高血压(P=0.025)、冠心病(P=0.008)、频发室性早搏(P=0.016)的机会要高于房颤组,而两组患者合并糖尿病(P=0.214)和OSAS(P=0.090)的几率差别不大。生活方式方面,吸烟(P=0.230)、饮酒(P=0.172)、肥胖(P=0.760)是两组患者共同的危险因素,在非房颤组中有更多的患者作息不规律(P=0.022)。在基本生命体征[SBP(P=0.248)、DBP(P=0.862)、RHR(P=0.514)]和心脏结构功能[NYHA心功能分级(P=0.408)、LVEF(P=0.138)、LVEDD(P=0.202)]上基线一致。2.主要终点事件:本研究总死亡率1.6%(4/250)。非房颤组随访期内再住院率26.9%,心衰再住院率18.7%;房颤组再住院率31.8%,心衰再住院率22.7%。比较两组患者的随访期内再住院率(P=0.515)和心衰再住院率(P=0.537)差异均无统计学意义。3.心衰药物使用情况:所有患者均使用了 β-blocker和RASS抑制剂治疗。非房颤组患者β-blocker的用量达标率为64.8%,RAAS抑制剂的用量达标率75.7%,药物双达标率50.8%。房颤组患者β-blocker的用量达标率为68.2%,RAAS抑制剂的用量达标率72.7%,药物双达标率54.6%。两组患者β-blocker达标率(P=0.667)、RAAS抑制剂达标率(P=0.686)、上述两种药物双达标率(P=0.652)均无统计学差异。4.患者治疗前后心脏结构和功能变化:非房颤组患者治疗后:LVEF(%)显著升高[(43.4±11.9%)vs(33.6±8.8%),P<0.01],LVEDD(mm)明显减小[(58.0±8.2mm)vs(62.1±8.2mm),P<0.01]。房颤组患者治疗后:LVEF(%)显著升高[(43.7± 11.3%)vs(35.7±8.2%),P<0.01],LVEDD(mm)明显减小[(57.2±7.8mm)vs(60.1±8.4mm),P<0.01]。非房颤组患者首次诊断时NYHA心功能分级以Ⅲ～Ⅳ级为主(60.6%),经过至少6个月治疗,心功能以NYHA Ⅰ～Ⅱ级为主(75.6%)。房颤组患者首诊时以NYHA ⅲ～ⅳ级为主(70.4%),经过至少6个月治疗,NYHA i～ii级的占比明显增加(63.7%)。5.患者治疗前后心功能恢复和症状改善情况:经至少6个月规范化心衰治疗后,非房颤组心功能有效恢复率44.6%,症状改善率81.9%;房颤组心功能有效恢复率38.7%,症状改善率79.5%。与非房颤组患者相比,房颤组患者经过规范化心衰治疗后,心功能有效恢复率(P=0.474)、症状改善率(P=0.721)均无明显差异。6.患者治疗前后生命体征变化:非房颤组经过6个月规范化治疗,SBP、DBP、RHR.均有明.显降低。治疗后RHR 63.2±9.3次/分,RHR达标率为50.8%(98/193)。房颤组经过6个月规范化治疗,SBP明显降低,DBP、RHR较前无显著变化。治疗后RHR 69.8±9.6次/分,70.5%的患者RHR控制在61～80次/分,RHR达标率仅为20.5%(9/44)。7.患者治疗前后实验室检查结果变化:非房颤组治疗后 NT-proBNP[849.0(376.5-2267.5)pg/ml vs 424.0(211.3-768.2)pg/ml,P<0.01]明显降低,K+水平[(4.2±0.3)mol/L vs(4.4±0.4)mmol/L,P<0.01]升高,ALT、AST、ALB、Cr、Na+治疗前后无明显变化。房颤组治疗后K+水平[(4.3±0.4)mmol/L vs(4.6±0.5)mol/L,P<0.01]升高,NT-proBNP、ALT、AST、ALB、Cr、Na+治疗前后无明显变化。8.房颤组除外的射频消融术后患者分析:9例患者在随访期内接受了射频消融手术治疗,且随访期内未再复发。规范治疗后有其中8例患者心功能得到了有效恢复(88.89%)。结论:1.经过规范化的药物治疗和门诊随访管理后,慢性心衰不合并持续性房颤与慢性心衰合并持续性房颤两组患者均能达到较高的药物达标率。2.在规范化的药物治疗下,持续性房颤在短期内对慢性心衰患者药物疗效的影响并不显著。更多还原

【Abstract】 BackgroundHeart failure is a group of complex clinical syndromes in which the structure and/or function of the heart is abnormal due to various reasons,and then the systolic and/or diastolic dysfunction is impaired,leading to the reduction of ventricular pumping function.The main symptoms are dyspnea,fatigue,and fluid retention.As a serious manifestation or late stage of various cardiovascular diseases,the prevalence of heart failure at home and abroad is showing a continuous upward trend.It is a problem that needs to be solved urgently both at home and abroad.Most patients with acute heart failure have partial relief of symptoms after treatment,which can lead to chronic heart failure.The prognosis of patients with chronic heart failure is comparable to that of malignant tumors.As the treatment and management of heart failure become more standardized and structured,the survival rate of patients with heart failure has improved,but the short-term rehospitalization rate and long-term cardiovascular mortality rate after discharge are still very high.Therefore,heart failure is also called"the last battlefield of cardiovascular disease in the 21st century."The activation of the neuroendocrine system leads to the remodeling of the myocardium,which is currently recognized as a mechanism for the development of heart failure,A series of large-scale randomized controlled trials(RCT)carried out in the past 30 years have unified people’s heart failure treatment concepts.The"golden triangle" composed of β blockers,RAAS inhibitors and aldosterone receptor antagonists(MRA)has been highly recommended as the basic treatment for chronic heart failure in clinical practice.As a hot spot of randomized controlled research at home and abroad,ARNI is accumulating and enriching clinical application experience extensively.Atrial fibrillation,a common arrhythmia,is one of the clinical manifestations of degeneration of cardiac physiological function and those whose onset lasts longer than 7 days are called persistent atrial fibrillation(Pe AF).Age is the most important risk factor for atrial fibrillation.The incidence of atrial fibrillation increases with age.Otherwise,atrial fibrillation is often complicated by some organic heart diseases that cause atrial enlargement.Persistent atrial fibrillation,especially fast ventricular rate atrial fibrillation,can cause abnormal hemodynamics and reduce cardiac output.If not intervened in time,it will further induce cardiac insufficiency in patients.There is a common risk factor for heart failure and atrial fibrillation,both at the same time there is prompted sicker,treatment is more difficult and higher risk of death.Beta-blockers are not only regarded as the cornerstone in the treatment of chronic heart failure,but also the first choice for patients with atrial fibrillation to control the ventricular rate to improve symptoms.In 2015,a meta-analysis conducted by scholars from many countries published in Lancet magazine proposed that β-blockers do not reduce the all-cause mortality of patients with chronic heart failure and persistent atrial fibrillation.But until now,large-scale research trials conducted in patients with heart failure and atrial fibrillation for the design still few in number,evidence-based medical evidence in this regard is still inadequate.This brings us back to the starting point again and pays attention to the impact of atrial fibrillation on the drug efficacy of patients with heart failure.Objective1.To compare the use of β-blockers and RAAS inhibitors and the ratio of the dosage reached the target dose recommended by the guidelines after the two groups of patients,CHF without PeAF group and CUF with PeAF group,received standardized heart failure treatment.2.To compare the recovery of cardiac function and rehospitalization rate of the two groups of patients after receiving standardized treatment of heart failure.Methods1.Collecting patients:The selection and exclusion criteria were determined,and patients with chronic heart failure who attended the Cardiology Department of Shandong University Qi Lu Hospital from January 1,2010 to September 30,2020 were included and included in the analysis.2.Outpatient follow-up management:Establish a follow-up system through a combination of outpatient follow-up and telephone follow-up.Every follow-up and registration will be completed by a dedicated person.In the vulnerable period(within 3 months after the first diagnosis of heart failure),patients should go to the outpatient clinic for follow-up and adjust the medicine regularly.The interval between each adjustment is at least 2 weeks,and the longest is no more than 4.Guide patients during follow-up norms,regular monitoring of blood pressure,heart rate and record.During the outpatient follow-up,adjust the dosage ofβ-blockers and RAAS inhibitors according to the patient’s symptoms,signs,family self-tested blood pressure and heart rate levels.To heart failure treatment guidelines as the basis,start small dose and gradually titrated to the target dose,or the maximum dose that can be tolerated by the patient.For some patients,due to the individual differences in the progress of the medication adjustment,the medication adjustment window can be appropriately extended,and the longest period is no more than 6 months.3 months after the patient’s β-blockers and RAAS inhibitors have reached the target dose or the maximum tolerated dose,follow up in the outpatient clinic and review the patient’s echocardiography,NT-proBNP,liver and kidney function,and electrolytes,and evaluate the patient’s treatment effect.After the adjustment is completed,the patient should take this dose for a long time under the premise of stable disease.3.Data acquisition and analysis:The basic data collected from patients include their genderage,etiology,comorbid diseases,lifestyle(smoking,drinking,obesity,irregular work and rest),basic vital signs(SBP,DBP,RHR),cardiac function(NYHA cardiac function classification,LVEF,LVEDD,NT-pro BNP),liver and kidney function,blood biochemical level,medication status,etc.The blood pressure,resting heart rate(based on family self-tested blood pressure and heart rate),symptoms(and reflected in NYHA heart function classification),physical signs,medication and drug dosage adjustments,and auxiliary examination results of each follow-up of the patient are recorded in the outpatient clinic of the day in detail Medical records,and enter the electronic follow-up file in time.Relying on electronic records to establish a database,using SPSS 24.0 statistical analysis software to count data and measurement data obtained in this study for data analysis.Result1.Basic state:A total of 237 patients completed at least 6 months of follow-up.Wherein the non-AF group 193 cases,mean age 51.0 ± 14.4 years,74.1%male patient.The main cause of heart failure was non-ischemic cardiomyopathy(53.9%),followed by ischemic cardiomyopathy(45.1%).Patients with coronary heart disease(56.9%)and hypertension(52.3%)accounted for more than half of the total.44 patients with AF group,mean age 60.9 ± 12.3 years old,72.7%male patients.The main cause was non-ischemic cardiomyopathy(54.6%).The two groups of patients had significant differences in age[(51.0± 14.4)vs(60.9± 12.3)years,P<0.01],but difference in gender composition is not obvious(P=0.852).Heart failure etiology aspect,valvular heart disease has significant correlation with heart failure combined with AF(P<0.01).In terms of complications,non-AF group combined with hypertension(P=0.025),coronary heart disease(P=0.008),and frequent ventricular premature beats(P=0.016)have higher chances than the AF group.While the probability of two groups with diabetes mellitus(P=0.214)and OSAS(P=0.090)is little different.Lifestyle,smoking(P=0.230),alcohol consumption(P=0.172),obesity(P=0.760)is the common risk factors for both groups of patients,more irregular schedule patients(P=0.022)in the non-AF group.The two groups in basic vital signs[SBP(P=0.248),DBP(P=0.862),RHR(P=0,514)]and cardiac structure function[NYHA cardiac function classification(P=0.408),LVEF(P=0.138),LVEDD(P=0.202)]have the same baseline.2.End event:In this study,overall mortality was 1.6%(4/250).Readmission rate of 26.9%follow-up period in non-AF group,and the heart failure rehospitalization rate was 18.7%;the atrial fibrillation group rehospitalization rate was 31.8%,and the heart failure rehospitalization rate was 22.7%.There was no significant difference in the rehospitalization rate(P=0.515)and heart failure rehospitalization rate(P=0.537)of the two groups during the follow-up period.3.The use of drugs for the heart failure treatment:All patients were treated with β-blockers and RASS inhibitors.The compliance rate of β-blockers in the non-atrial fibrillation group was 64.8%,and that of RAAS inhibitors was 75.7%.The double compliance rate was 50.8%.The compliance rate ofβ-blockers in the atrial fibrillation group was 68.2%,and that of RAAS inhibitors was 72.7%.The double compliance rate was 54.6%.There was no significant difference in the β-blocker compliance rate(P=0.667),RAAS inhibitor compliance rate(P=0.686),and double compliance rate of the above two drugs(P=0.652)between the two groups.4.Changes in the structure and function of the heart before and after treatment:Patients with non-AF group at least 6 months after treatment LVEF(%)was significantly higher[(43.4±11.9%)vs(33.6±8.8%),P<0.01],and LUEDD(mm)is significantly reduced[(58.0±8.2mm)vs(62.1 ±8.2mm),P<0.01].Patients in the atrial fibrillation group had a significant increase in LVEF(%)after at least 6 months of treatment was significantly increased[(43.7±11.3%)vs(35.7±8.2%),P<0.01],LUEDD(mm)was significantly reduced[(57.2±7.8mm)vs(60.1±8.4mm),P<0.01].Non AF patients before treatment to NYHA class NYHA Ⅲ～Ⅳ main stage(60.6%),after at least six months of treatment,cardiac function to the main stage NYHA Ⅰ～Ⅱ(75.6%).Atrial fibrillation group before treatment to NYHA class NYHA ⅲ～ⅳ main stage(70.4%),at least 6 months after treatment,NYHA i～ii level significantly increased the proportion(63.7%).5.The patient’s heart function recovery and symptom improvement before and after treatment:After at least 6 months of standardized treatment of heart failure,the effective recovery rate of heart function in the non-atrial fibrillation group was 44.6%,and the symptom improvement rate was 81.9%;the effective recovery rate of heart function in the atrial fibrillation group was 38.7%,and the symptom reduction rate was 79.5%.We can find little difference in the cardiac function effective recovery(P=0.474)and the symptom improvement rate(P=0.721)between the AF group with non-AF group patients after standardized heart failure treatment.6.Changes in patient’s vital signs before and after treatment:After treatment in the non-AF group,SBP,DBP,and RHR were significantly reduced,RHR after treatment 63.2±9.3 beats/min,and the RHR compliance rate was 50.8%(98/193).After treatment in the atrial fibrillation group,SBP was significantly reduced,DBP and RHR were not statistically different from before,RHR after treatment 69.8±9.6 beats/min,70.5%of patients’ resting heart rate is controlled at 61～80 beats/min and the RHR compliance rate was 20.5%(9/44).7.Changes in laboratory test results before and after treatment:After treatment in the non-AF group,NT-pro BNP was obviously reduced[849.0(376.5-2267.5)pg/ml vs 424.0(211.3-768.2)pg/ml,P<0.01],K+level was obviously increased[(4.2±0.3)mmol/L vs(4.4±0.4)mmol/L,P<0.01],and there was no significant change in ALT,AST,ALB,Cr,and Na+before and after treatment.AF group after treatment K+levels[(4.3± 0.4)mmol/L vs(4.6±0.5)mmol/L,P<0.01]increased obviously,NT-pro BNP,ALT,AST,ALB,Cr,Na+before and after the treatment had no significant Variety.8.Analysis of patients after radiofrequency ablation:Nine patients received radiofrequency ablation surgery in follow-up period,no recurrence till now.After standard treatment,8 patients had effective recovery of cardiac function(88.89%).Conclusion1.Standardized treatment and management of chronic heart failure do not merge persistent atrial fibrillation and chronic heart failure with persistent atrial fibrillation patients,two groups can reach a higher drug compliance rate.2.Under standardized drug treatment,persistent atrial fibrillation has no significant effect on the efficacy of drugs in patients with chronic heart failure in the short term.更多还原