Presentation on theme: "Atrial Fibrillation: Clinical Significance, Mechanisms, and Treatments"— Presentation transcript:
1Atrial Fibrillation: Clinical Significance, Mechanisms, and Treatments Alexander Burashnikov PhD, FHRSCardiac Research InstituteMasonic Medical Research LaboratoryUtica NYCardiac Research Institute logoCampaign for QualityOctober 17-18, 2013
2Heart and ECG Normal electrical activation Left atrium Sinus node RightatriumAV nodeventricleLeft atriumConductionpathwaysLeftFigure 1The impulse then travels to the ventricles through conduction pathways made of specialized muscle fibers. The pathways divide into a network of smaller fibers which distribute the impulse throughout both ventricles. The impulse stimulates the ventricles, causing them to contract and pump blood. At rest, the sinus node normally initiates 60 to 80 beats a minute. With activity or excitement, the body requires greater blood circulation. A healthy sinus node responds to these changes in the body by increasing the heart rate accordingly.
5Atrial fibrillation (AF or AFib) Sinus nodeAV node
6AF Prevalence by Age and Sex Atrial Fibrillation: PrevalenceCurrently: millions people have AF in the USAIn 2050: 7 – 15 millions people will have AF in the USAAF Prevalence by Age and SexAge, yPrevalence of AF in a population of 1.89 million members of a large health maintenance organization in California. The error bars represent 95% confidence intervals. The numbers represent the number of men and women with AF in each age category.Go AS, et al. JAMA. 2001;285:
10Atrial Fibrillation vs. Ventricular Fibrillation Ventricular fibrillation lasts for seconds or minutes in vivo.Kills within minutes.Atrial fibrillation can last for years Generally mild immediate consequencesAtrial fibrillation can cause serious complications in a long ran:stroketachycardia-mediated cardiomyopathy
11Stroke15-20% of all stroke in the United State is due to atrial fibrillation.
13Atrial fibrillation: Risk factors Older than 60 years of ageDiabetesHigh blood pressureCoronary artery diseasePrior heart attacksCongestive heart failureStructural heart disease (valve problems or congenital defects)Prior open-heart surgeryUntreated atrial flutter (another type of abnormal heart rhythm)Thyroid diseaseChronic lung diseaseSleep apneaExcessive alcohol or stimulant use
14Risk of atrial fibrillation. The population-attributable risk of atrial fibrillation in men and women determined from a community-based longitudinal study.36 For both men and women, a substantial portion of atrial fibrillation risk remains unexplained. MI indicates myocardial infarction; HTN, hypertension; HF, heart failure; VHD, valvular heart disease; DM, diabetes mellitus; and LVH, ECG left ventricular hypertrophy.MI indicates myocardial infarction; HTN, hypertension; HF, heart failure; VHD, valvular heart disease; DM, diabetes mellitus; and LVH, ECG left ventricular hypertrophy.Benjamin et al . JAMA 1994
15Symptoms and Documentation of atrial fibrillation Shortness of breathPalpitationsChest painFatigueReduced exercise capacityDizziness, lightheadedness15-30% of patients with AF are asymptomatic.Stroke is often the initial presenting sign of AF
18Mechanisms of cardiac arrhythmias Impulse formation:
19Mechanisms of cardiac arrhythmias Conduction disturbances:reentry
20Initiation and maintenance Atrial fibrillation:Initiation and maintenanceTrigger(or extra-beat)Substrate(remodeling)ECGAction potential
21Mechanisms of maintenance of atrial fibrillation Nattel J Cardiovascular Research 54 (2002)
22Masonic Medical Research Laboratory, Utica, NY Gordon Moe, 1958, 1962, 1964Masonic Medical Research Laboratory, Utica, NYThe multiple Wavelet Hypothesis has been the dominating theory of cardiac fibrillation for several decades
23Atrial fibrillation: Spatial and temporal electrical heterogeneity
24AF begets AF: Atrial electrical and structural remodeling Wijffels et al Circulation 1995
25Constitutively Active (CA) Atrial electrical remodeling(commonly due to AF)NormalAtriaRemodeledAtriaIto1ICaIto1IKurIKurItoIKurICaICaIK1IKrIKrIK-ACh (CA)IKsIKsIK1IK1INaINaIK-ACh, IK-ATPIK-ACh, IK-ATPConstitutively Active (CA)
26Atrial structural remodeling Can be due to:Rapid activation rate (AF)HypertensionCoronary artery diseaseHeart failureAge
28Atrial fibrillation classification: Paroxysmal AF – self-terminating (< 7 days)Persistent AF – (> 7 days). Can be terminated(drugs, ablation or electrical cardioversion)Permanent AF – completely refractory to revision to sinus rhythmAF often progresses from short, rare episodes, to longer and more frequent attacks.
29Treatment of Atrial fibrillation Rhythm or Rate control?Rhythm control:maintenance of sinus rhythmRate control:control ventricular rate without making any specific attempts to suppress or prevent AFAnticoagulation (to prevent stroke):Commonly in both
30Rhythm control: Restoration and maintenance of sinus rhythm. PharmacologicalCatheter ablationSurgeryElectrical cardioversion
31Rhythm control: pharmacological Sodium channel blockers (propafenone, flecainide, etc):Potassium channel blockers (sotalol, dofetilide, ibutilide, etc):Multiple channel blockers (amiodarone, ranolazine, etc)Drugs prolong repolarization and depress excitability.AFTermination of AF
32“Pill-in-the-Pocket” approach for termination of paroxysmal AF
33Antiarrhythmic Drug Proarrhythmia: an Extension of Pharmacologic Effects Class IC toxicity: Atrial flutter with 1:1 AV conductionClass IA/III toxicity: Torsades de pointes
39Anticoagulation Risk of stroke in patients with atrial fibrillation Score ≥ 2. Long term anti-coagulation is recommended
40Anticoagulation reduces stroke occurrence in patients with atrial fibrillation Hart et al Ann Intern Med, 1999
41Old and new anticoagulants Aspirin (often used with clopidogrel)WarfarinNew:DabigatranRivaroxabanApixaban
42Several large clinical trials (i. e Several large clinical trials (i.e., AFFIRM, RACE, PIAF, HOT CAFÉ, STAF, AF-CHF) have demonstrated that the rhythm control with anti-arrhythmic drugs is not superior to the rate control in terms of morbidity and mortalityAdverse effects of drugs may balance or even exceed the beneficial effects.Several post-hoc or sub-study analyses of the large clinical trials (such as the DIAMOND, AFFIRM, CHF-STAF trials), directly comparing “sinus rhythm” vs. “AF” regardless of the initial rate or rhythm control assignment, indicate that AF patients maintained in sinus rhythm (with or without drugs) have better survival rate and better quality of life than those in whom AF persists
47Current investigational pharmacological strategies for AF treatment Atrial specific or selective therapytargets:IKurIK-AChCA IK-AChINa (+IKr ?)“Upstream” therapy Targets:Structural remodelingInflammationOxidative stressHypertrophy,Stretch,etc.Gap junction therapy targets:Cx40Cx43Normalization of intracellular calcium homeostasisImprovement of “old” agents:Amiodarone derivatives:DronedaroneCelivaroneATI-2042Thank you
48Treatment of Atrial fibrillation Fuster et al Circ 2011About 40% patients in whom AF first time detectedwill not develop AF within next 5 years.
49Pro-arrhythmias in ventricles! At slow heart rates and pauses, specific IKr blockers predominantly prolong ventricular vs. atrial APD/ERP and induce EAD and TdP in ventricles not in atria.