抗心律失常药物的离子流机制 和临床应用进展,Gan-Xin Yan, MD, PhD, F.A.C.C Main Line Health Heart Center Jefferson Medical College,Case 1 (病例1),A 45 year-old female is referred to your office because of symptomatic paroxysmal atrial fibrillation. She also has a history of asthma. She tried Ca+ blockers and dofetilide before, but none of them suppressed atrial fibrillation. She has not been on any medications for a couple of weeks. Her recent echocardiogram and stress test were normal. In your office, 12 lead ECG shows atrial fibrillation with ventricular responses at 80 beats per minute. She states that she always knows the onset of atrial fibrillation that occurs when she takes a nap or is hungry.,Question for Case 1 (病例1),Which of the following antiarrhythmic drugs is the best choice for the patient?,Amiodarone; Propafenone (心律平); Sotalol; Disopyramide.,Question,Lidocaine (利多卡因) and mexiletine are Class Ib antiarrhythmic drugs. Which of the following arrhythmias is most likely suppressed by the Class Ib antiarrhythmic drugs? Why?,AV nodal or AV reentry tachycardia Ventricular arrhythmias in the setting of myocardial ischemia Ventricular fibrillation in people with structurally normal hearts Atrial arrhythmias,Basic Electrophysiology,基础电生理,Electrical driving force; Chemical Gradient; Ion Channel Permeability (voltage and time dependent),Genesis of Cardiac Resting and Action Potentials,I,II,III,IV,Extracellular,INa Sodium Channel (SCN5A),Domains,COOH,NH2,*,R1623Q,R1644H,T1645M,* * *,S1710L,1786,*,T1620M,R1512W,A1924T,R1232W,R1432G,1397,*,T1304M,E1784K,D1790G,1795insD,N1325S,IVS22+2TC,L567Q,T632M,IVS7+4insAA,DKPQ 1505-1507,G1406R,Y1795H,R1192Q,A735V,R367H,G298S,G514C,A1924T,D1595N,DK1500,Brugada syndrome,Long QT syndrome 3,Conduction Disease,Brugada /Conduction Disease,Brugada / LQT3 / Conduction Disease,Atrial standstill,Major Ionic Currents in Ventricular Action Potential,0,1,2,2,3,4,The States of Voltage-Dependent Ionic Channel,Na channel is deactivated at potential positive than -60 mV!,Relationship between Volatge-dependent Ion Channel Statuses and Action Potential,INa-mediated action potentials (钠通道介导的动作电位, resting membrane potential -60 mV ): slow phase 0 upstroke and conduction velocity that is suppressed by ICa,L blockers.Sinus and AV nodes.,Two Types of Action Potentials: Determined by Resting Potentials,Heart Electrical System and Action Potential Features,-50 mV,-60 mV,-85 mV,-85 mV,-80 mV,Ionic Currents and Diseases,Genesis of Cardiac Arrhythmias,Abnormal Impulse FormationAutomaticity: enhanced pacemaker;Triggered Activity: early afterdepolarization (EAD) and delayed afterdepolarization (DAD) Reentry (Circus Movement )Electrical Obstacle (such as scar tissue due to MI)Functional Block (relative larger dispersion of repolarization),Reentry Mechanism,Spatial Excitable Gap,The wavelength = conduction velocity x refractory period,For example: if conduction velocity is 1.0 m/s, and refractory period is 0.4 s (400 ms), the wavelength is equal to 0.4 m (400 mm).,For example: if conduction velocity is 0.1 m/s, and refractory period is 0.4 s (400 ms), the wavelength is equal to 0.04 m (40 mm).,Therefore, conduction slowing is a major contributor to reentrant tachycardia!,Tricuspid or mitral valves are also the electrical obstacles. Can a reentry (circus movement) arrhythmia occur along the tricuspid or mitral valves?,Courtesy of Mayo Clinic,Antiarrhythmic Effects on Reentry Arrhythmias can be potentially Archived via the Following Mechanisms,To suppress the trigger that is able to penetrate into the reentry circuitbeta blockers, calcium channel blockersTo increase the wavelength by prolonging effective refractory period (ERP)APD prolongation by inhibiting outward currents: dofetilide, sotalol, azimilide etcInward current inhibition (no change or decrease in APD but an increase in ERP): lidocaine, flecainide etc for sodium mediated action potential and calcium channel blockers calcium-mediated action potentialTo increase conduction velocity Drug on development to increase gap junction coupling; RF ablation to get rid of slow and unidirectional conduction To decrease reentrant circuitReducing dispersion of repolarization for functional reentryMaze procedure ?,Case 2 (病例2),A 65 year-old male with a past medical history of myocardial infarction, by-pass surgery 5 years ago and status post ICD implant who was admitted with multiple ICD shocks. ICD interrogation showed ventricular tachycardia with cycle lengths of about 340 ms and adequate ICD therapy. In hospital, cardiac enzymes were negative and cardiac catheterization showed patent grafts. During his hospital stay, he had multiple episodes more monomorphic VT with same morphology. This patient then underwent VT ablation. In one spot, electrical signal was fragmented and the onset of this signal was 60 ms earlier than the beginning of QRS during VT. RF ablation was delivered at this spot. After ablation, no VT was inducible.,