医学交流课件：非抗心律失常药物的抗房颤作用

1、非抗心律失常药物的抗非抗心律失常药物的抗房颤作用房颤作用 心房颤动特点心房颤动特点 临床上最常见的需药物与非药物治临床上最常见的需药物与非药物治 疗的心律失常疗的心律失常 并非是一种良性心律失常并非是一种良性心律失常 慢性房颤多发生于器质性心脏病患慢性房颤多发生于器质性心脏病患 者，少数患者无心脏病证据者，少数患者无心脏病证据 发生率随年龄增加而增高发生率随年龄增加而增高 缺血性脑卒中的主要原因之一缺血性脑卒中的主要原因之一 快速心室率未能控制者，可发生心快速心室率未能控制者，可发生心 动过速性心肌病动过速性心肌病 心房颤动的流行病学心房颤动的流行病学 累积发生率男性为累积发生率男性为2.2%

2、、女性为、女性为 1.7 % 70左右的房颤发生在器质性心脏病左右的房颤发生在器质性心脏病 大约大约30的房颤无任何可发现的病因的房颤无任何可发现的病因 病死的最主要原因是缺血性脑卒中，其病死的最主要原因是缺血性脑卒中，其 发生率随年龄增加明显升高发生率随年龄增加明显升高 Atrial fibrillation accounts for 1/3 of all patient discharges with arrhythmia as principal diagnosis. 2% VF Data source: Baily D. J Am Coll Cardiol. 1992;19(3):41

3、A. 34% Atrial Fibrillation 18% Unspecified 6% PSVT 6% PVCs 4% AFL 9% SSS 8% Conduction Disease 3% SCD 10% VT Arrhythmia as principal diagnosis Mortality Framigham Study Benjamin EJ et al, Framigham Heart Study, Circulation 98; 98: 946-952 55 - 74 years 75 94 y 心房颤动的病理生理和电生理机制心房颤动的病理生理和电生理机制 房颤常发生于三种

4、不同的临床情况房颤常发生于三种不同的临床情况 无心脏病证据患者，无心脏病证据患者，称原发性房颤称原发性房颤 虽无心脏病证据，但有诱发房颤发生的非心脏虽无心脏病证据，但有诱发房颤发生的非心脏 性疾病性疾病( (甲亢等甲亢等) )，为继发性房颤，为继发性房颤 发生于器质性心脏病者的发生于器质性心脏病者的继发性房颤继发性房颤 心房颤动的病理生理和电生理机制心房颤动的病理生理和电生理机制 心房颤动的病理组织学心房颤动的病理组织学 心房扩张和不均匀分布的纤维化心房扩张和不均匀分布的纤维化( (窦房结窦房结) ) 见于器质性心脏病见于器质性心脏病 非特异的散在纤维化非特异的散在纤维化 继发于全身性疾病继发

5、于全身性疾病 心房肌细胞离子通道的功能异常或未识心房肌细胞离子通道的功能异常或未识 别的非病理性结构异常别的非病理性结构异常 发生于健康人的阵发性房颤发生于健康人的阵发性房颤( (孤立性房颤孤立性房颤) ) 心房颤动的病理生理和电生理机制心房颤动的病理生理和电生理机制 心房颤动的电生理机制心房颤动的电生理机制 异位局灶自律性增强学说异位局灶自律性增强学说(Scherf 等，等，1953) 多个子波折返激动学说多个子波折返激动学说(Moe等，等，1959) 触发因素：触发因素：房早、房扑、房速、房早、房扑、房速、AVNRT、 AVRT、交感或迷走神经活性改变等、交感或迷走神经活性改变等 心房颤动

6、的病理生理和电生理机制心房颤动的病理生理和电生理机制 局灶性房颤的起源部位局灶性房颤的起源部位 肺静脉肺静脉( (90%以上以上尤其为左、右上肺静脉尤其为左、右上肺静脉) ) 其他部位包括：其他部位包括：界嵴、上、下腔静脉、冠状静脉界嵴、上、下腔静脉、冠状静脉 窦、房室交界区、房间隔、窦、房室交界区、房间隔、 Marshall 韧带、心房韧带、心房 游离壁游离壁 起源于肺静脉、腔静脉、冠状静脉窦的房颤可起源于肺静脉、腔静脉、冠状静脉窦的房颤可 能与肌袖能与肌袖(muscular sleeve)有关有关? ? 心房颤动的分类心房颤动的分类 阵发性房颤：阵发性房颤： 发作持续发作持续7d，大多可自

7、行转复，并可反复发作，大多可自行转复，并可反复发作 持续性房颤：持续性房颤： 发作发作48小时以上未能自行转复而需要药物或非药物干预小时以上未能自行转复而需要药物或非药物干预 永久性房颤永久性房颤： 发作持续几天（发作持续几天（7d）或几年）或几年 心房颤动的治疗原则心房颤动的治疗原则 控制心室率控制心室率 预防栓塞性事件预防栓塞性事件 转复心房颤动为窦性心律转复心房颤动为窦性心律 直流电转复心律直流电转复心律 药物复律及维持窦性心律药物复律及维持窦性心律 非药物预防房颤复发非药物预防房颤复发 心脏起搏预防心房颤动心脏起搏预防心房颤动( (?) ) Treatment strategies f

8、or AF Atrial fibrillation Antiarrhythmic drugs Preventive Pacing Alate and bpace Hybrid therapyAtrial Defibrillator MAZE-surgery Catheter ablation ACE-I、ARB、 Statin、Diuretic Effectiveness of rhythm control in AF with OAP and AAD after linear RACA Hybrid therapy utilizing cathter RA maze procedures w

9、ith OAP and AAD can be performed safely and can reestablish rhythm control in selected patients with refractory persistent or permanent AF OAP: overdrive atrial pacing AAD: antiarrhythmic durg 具有抗心律失常作用具有抗心律失常作用的的 非抗心律失常药物非抗心律失常药物 Angiotensin converting enzyme inhibitors (ACE-I) Angiotensin receptor

10、 Blocker (ARB) Statin Diuretics 非抗心律失常药物非抗心律失常药物 抗心律失常作用抗心律失常作用的可能机理的可能机理 ACE-I和和ARB 抗心律失常作用的可能机理包括：抗心律失常作用的可能机理包括： Decrease of wall stress and lowering of blood pressure Modulation of refractoriness Interference with ion currents Modification of sympathetic tone and stabilization of electrolyte con

11、centration Interaction between ARB and potassium channel blocker on transmembrane action potentials and currents ARB modified the cardiac delayed retifier hKv1.5. HEKG and Ks currents Angiotensinogen Angiotensin I Angiotensin II AT1AT2 Renin ACENon-ACE AT1 Blockers Vasoconstriction Neurohumoral rete

12、ntion Hydro-saline retention Cell growth Vasodilation Growth Inhibition Apoptosis Effects of AT1 receptor blockers on angiotensin II and bradikinin synthesis and inactivation Genetic Factors and Modifiers and Enrivironmental Stress Determinant Long-term Catecholamines Structural Free Radicals Modula

13、tors And acute Triggers ACE Angiotensin II Aldosterone Cytokines Nitric Oxide Structural and Electrical Remodeling Gene Structure Fibrosis Ion channerls Extracellular Matrix Aotonomics Fiber orientation Gap junctions Calcium handling Rate Activation sequence Enhancement of Arrhythmia Heterogencity F

14、acilitators Arrhythmia Arrhythmia Triggers Substrate Phenotypic Expression New approaches to antiarrhythmic therapy. Eur Heart J, 2001 Enalapril decrease the incidence of atrial fibrillation in patients with left ventricular dysfunction Insight From the Studies Of Left Ventricular Dysfunction (SOLVD

15、) Trial Background AF occurring in the course of experimental HF induced by rapid ventricular pacing is accompanied by atrial electrical and structural remodeling, including atrial dilation, contractile dysfunction, and fibrosis. ACEI have been demanstrated a role for ACEI in the prevention of this

16、atrial structure remodeling SOLVD Trial Methods and Results 391 Pts 374 Pts17 Pts 186 Pts/ACEI 55 Pts10 Pts45 Pts P0001 188 Pts/plac. Insight From the Studies Of Left Ventricular Dysfunction (SOLVD) Trial Conclusion Treatment with the ACE-I enalapril markedly reduces the risk of development of AF in

17、 patients with left ven- tricular dysfunction Circulation,2003; 107:2926-2931 Enalapril decrease the incidence of atrial fibrillation in patients with left ventricular dysfunction Trandolapril reduces the incidence of AF after AMI in pts with left ventricular dysfunction TRACE STUDY Background: ACE-

18、I have an antiarrhythmic effect on ventricular arrhythmias Have ACE-I an effect on AF ? Metholds and results: Trandoapril on the incidence of AF Pts with AMI and reduced left ventricular function A randomized double-blind placebo-controlled study Pedersen et al. Circulation,1999;100:376-380 Trandola

19、pril reduces the incidence of AF after AMI in pts with left ventricular dysfunction TRACE STUDY 1577/1749 pts in sinus rhythm 790 pts -ACEI787 pts-placebo N=22(2.8%)N=42(5.3%) AF AF F/u 2-4 years P0.05 Trandolapril reduces the incidence of AF after AMI in pts with left ventricular dysfunction TRACE

20、STUDY Conclusion The results from the present study demonstrate that trandolapril treatment reduces the incidence of atrial fibrillation in patients with left ventricular dysfunction after acute myocardial infarction Pedersen et al. Circulation,1999;100:376-380 ARB在房颤节律控制中的作用在房颤节律控制中的作用 ARB as adjun

21、ctive therapy for rhythm control in atrial fibrillation: Results of the Irbesartan- Amiodarone trial Madrid AH, et al. Cardiac Electrophysiology Review 2003 , 7 Group I Amio Group II Amio+ARB 154/186 pts after CV 84.7963.16 55.9179.52 recurrent AF free of AF 2 mon. of FU 254 d of FU (p = 0.007) ARB

22、therapy for rhythm control in AF The results of this prospective and randomized show that ARB irbesartan, combined with Amio. is more effective than Amio. alone in the maintenance of sinus rhythm in pts with persistent AF after cadioversion Most of the benefit of irbesartan occurrred during the firs

23、t 2 months after cardioversion Irbesartan reduced the immediate recurrence of AF and the socalled subacute recurrences during the first weeks Madrid AH, et al. Cardiac Electrophysiology Review 2003 , 7 ARB therapy for rhythm control in AF ARB therapy for rhythm control in AF Conclusions Irbesartan m

24、ay have antifibrotic effects due not only to the ability to diminish the synthesis of collagen type I molecules but also to its capacity to stimulate the degradation of collagen type I fiber To reduce the structural changes that occur during AF may be more useful in preventing recurrences than effor

25、ts designed to minimize the electrical changes alone Madrid AH, et al. Cardiac Electrophysiology Review 2003 , 7 The preventive effect of ACEI、ARB and Diuretics to AF after RFCA of AFL Background: ACE expression is increased in atrial biopsies of Pts with AF and Ang II concentrations are increased i

26、n animal models of AF ACEI diminish the incidence of AF after MI and in the setting of heart failure ARB reduce the recurrence of AF after cardioversion for persist.AF Methods: 196 Pts received RFCA AF occurrence, echocardiographic, procedural factors periprocedural drug use was analysed retrospecti

27、vely by a Cox proportional hazard method Heart, 2004, 90: 1025-1030 Results: Follow up 2.2 y, 114 (58%) developed 1 episode of AF Associated factors: Presence of preprocedural AF History of cardioversion The number of antiarrhythmic drugs used before the procedure Use of ACEI, ARB, and diuretics was

28、 significantly associated by univariate and multivariate analyses with less development of AF Heart, 2004, 90: 1025-1030 The preventive effect of ACEI、ARB and Diuretics to AF after RFCA of AFL Conclusions: A high proportion of Pts develop AF after AFL ablation The incidence of AF is related to pre-a

29、blation AFL and its persistence ACEI, ARB and diuretics seem to protect against AF Heart, 2004, 90: 1025-1030 The preventive effect of ACEI、ARB and Diuretics to AF after RFCA of AFL Reduction in the occurrence of AF in hypertensive Pts with ACEI therapy Background: AFAng II Hypertension CCBACEI The

30、occurrence of AF ? Methods: Retrospective, longitudinal cohort study Time for investigation: 1995 Jan-1999 June prescription for either an ACEI or a CCB 8 million Pts Age 18 y Final cohorts: 2002 Survival analysis: Compare the incidence of AF between groups JACC 2004,44:159-164 Reduction in the occu

31、rrence of AF in hypertensive Pts with ACEI therapy Results: Subjects: 10926 pts Mean age: 65 y New-onset AF: ACEI vs CCB (0.85, 95% CI: 0.74-0.97) Hospitalization: ACEI vs CCB (0.74, 95% CI: 0.62-0.89) JACC 2004,44:159-164 Reduction in the occurrence of AF in hypertensive Pts with ACEI therapy Concl

32、usions: ACEI was associated with a reduced incidence of AF for pts with hypertension in a usual care setting These results need to be confirmed in a large-scale randomized clinical trial JACC 2004,44:159-164 Reduction in the occurrence of AF in hypertensive Pts with ACEI therapy 应用应用ACE-I和和ARB预防房颤预防

33、房颤 (a meta-analysis) Objective: To identify all randomized clinical trial data evalua- ting ACE-I or ARB for the prevention of AF Metholds: A systematic rewiew of the literature about all reports of the effect of ACEIs or ARBs on the development of AF J Am Coll Cardiol, 2005 Jun 7; 45(11): 1832-9 应用

34、应用ACE-I和和ARB预防房颤预防房颤 (a meta-analysis) RESULTS 11 studies N=56308 4 in HF3 in H-BP2 F/u CV2 F/u MI ACE-Is/ARBs reduced RRR of AF 28% : ACE-I: 28%, p=0.01; ARB: 29%, p=0.00002; HF: 44%, p=0.007; Hypertension only 12%, p=0.4 and in patients following CV 48% 应用应用ACE-I和和ARB预防房颤预防房颤 (a meta-analysis) Conclusion: Both ACE-Is and ARBs appear to be effective in the prevention of AF. This benefit appears to be limited to pts with systolic left ventricu-lar dysfunction or LV hypertrophy J Am Coll Cardiol, 2005 Jun 7; 45(11): 1832-9 Relation between ACE II gen