fibrillationandheartfailure心房纤颤和心力衰竭课件

Psirropoulos Z. Dimitrios, MD, PhD Head Director Cardiology Department & CCU “G. Gennimatas” General Hospital Thessaloniki, Greece,Atrial Fibrillation and Heart Failure,New Trends in Cardiology April 9-11, 2009 Hyatt Regency Hotel Thessaloniki Greece,Atrial Fibrillation in Heart Failure,Background Pathophysiology Influence on disease state and progression Clinical approach Management,Heart Failure in the USA,Prevalence: 5 million patients Annual new diagnoses: 550,000 per year Mortality: 54,000 per year Consumption of medical resources: 12 to 15 million office visits / year 6.5 million hospital days / year Predicted steady increase,ACC / AHA Guidelines 2006,Correlation Between AF and HF Severity,% Patients with Atrial Fibrillation,Atrial fibrillation: prevalence increases with severity of heart failure,Class I II Class III - IV,Wang, T. J. et al. Circulation 2003;107:2920-2925,Development of AF was associated with increased mortality: hazard ratio of 1.6 (95% CI, 1.2 to 2.1) in men and 2.7 (95% CI, 2.0 to 3.6) in women.,Unadjusted cumulative incidence of first AF after Heart Failure - Framingham Study,20% of Patients with Heart Failure Develop AF within 4 Years,Wattigney, W. A. et al. Circulation 2003;108:711-716,Age-specific prevalence (per 10.000 population) of hospitalizations for atrial fib- among adults aged 35 yrs or older by year, 1985 to 1999,Concomitant Heart Failure: 13 % age 35 64 yrs 21 % age 65 yrs,Atrial Fibrillation is Increasing,Development of AF is Associated with Clinical Deterioration in Heart Failure,prospective follow-up of 344 patients with CHF and sinus rhythm for 19 12 months. 28 patients developed AF which became chronic in 18 pts When AF occurred NYHA class worsened (from 2.4 0.5 to 2.9 0.6, p = 0.0001), peak exercise O2 consumption declined (from 16 5 to 11 5 ml/kg per min, p = 0.002), cardiac index decreased (from 2.2 0.4 to 1.8 0.4, p = 0.0008), mitral and tricuspid regurgitation increased thromboembolism occurred in 3 of the 18 patients with AF. 9 of 18 patients died after AF occurrence of AF was a predictor of major cardiac events.,Pozolli et al, JACC 1999,Atrial Fibrillation is Associated with Increased Mortality in Heart Failure,RR 1.34 (1.11 - 1.61) adjusted for severity, medication,Atrial Fib-,Sinus,p,n,419,6098,Mortality,34%,23%,0.0001,Heart Failure Death,17%,9%,0.0001,Arrhythmic Death,7%,6%,NS,Dries et al, SOLVD, JACC 1998,Atrial Fibrillation in Heart Failure,Background Pathophysiology Influence on disease state and progression Clinical approach Management,Triggers,Asirvatham and Friedman. From: Shivkumar, Weiss, Fonarow, and Narula; eds. Braunwalds Atlas of EP in HF. 2005.,Paroxysmal AF,Persistent AF,Permanent AF,Triggers ectopic foci,Electrophysiologic Remodeling Chronic Substrate fibrosis,Stambler et al. JCE 2003;14:499 Li, Nattel et al. Circulation 1999;100:87-95,Types of AF,Atrial fibrillation In Dogs with Rapid Ventricular Pacing-Induced Heart Failure,CHF induced by 3 wks of rapid ventricular pacing Inducible focal atrial tachycardias consistent with triggerred automaticity associated with Ca+2 overload Atrial fibrosis Prolongation of atrial action potential duration,Stambler et al JCE 2003;14:499,Dynamic Nature of Atrial Fibrillation Substrate During Development and Reversal of Heart Failure in Dogs Shinagawa, K. et al. Circulation 2002;105:2672-2678,Masson trichrome-stained transverse LA sections from 1 representative dog per group (original magnification x400),Baseline Heart failure induced by rapid ventricular pacing Recovery from heart failure (5 weeks),Heart Failure,Atrial Fibrosis,Atrial Fibrillation,LA volume & pressure overload Angiotensin II & Aldosterone,Atrial Hypertrophy Altered Atrial Refractoriness,Sympathetic Tone Atrial Stretch,Triggered Ectopic Activity - Heterogeneous Conduction,-Stretch activated channels -Anionic currents,Neurohumoral changes,Modulation by autonomic influences,Half Cycle,Pathophysiology of Atrial Fibrillation in Heart Failure,Changes in coupling/geometry of the atrial muscle bundle at the pulmonary vein-atrial junction,Atrial Fibrillation in Heart Failure: Pathophysiology,Structural changes such as fibrosis are prominent in remodeled atria in the setting of heart failure,Myocardial Fibrosis: Structural Remodeling in Atrial Fibrillation,Li D et al. Circulation. Jul 1999;100:87-95.,Stretch-Related Changes in Conduction of Electrical Impulses from the Pulmonary Veins into the Atria in an Animal Model of Atrial Fibrillation,Kalifa et al. Circulation. 2003;108:668.,Stretch-Related Changes in Frequency of Excitation of the Pulmonary Veins and Atria in an Animal Model of Atrial Fibrillation,Kalifa et al. Circulation. 2003;108:668.,Kleber AG. et al. Physiol. Rev. 2004; 84:431-488 van Capelle and Durrer. Circ Res 1980; 47:,Initiation of spiral wave reentry,Atrial Fibrillation in HF: Functional Changes,ICaL and window,Ito,Ik1 If,Transmembrane Potential (Millivolts),Threshold,INa,Ikr, Ikur, Iksus,Atrial Fibrillation in HF: Pathophysiology,Reductions in L-type Ca2+ current, apparently caused by transcriptional downregulation of the 1c pore-forming Ca2+-channel subunit, Cav1.2, are important in mediating electrophysiological changes caused by atrial tachycardia remodeling,Heart Failure,Atrial Fibrosis,Atrial Fibrillation,LA volume & pressure overload Angiotensin II & Aldosterone,Atrial Hypertrophy Altered Atrial Refractoriness,Sympathetic Tone Atrial Stretch,Triggered Ectopic Activity - Heterogeneous Conduction,-Stretch activated channels -Anionic currents,Neurohumoral changes,Modulation by autonomic influences,Loss of atrial contraction,Rapid ventricular rate -Energy Depletion -Remodeling -Ischemia -Adnl Ca2+ Handling,Irregular R-R Intervals - Variability,Complete Cycle,*p 0.01,NSR AF VVI VVI VVT 60 AVG,VVI -AVG VVT,Cardiac Output (L/Min),Cardiac Output (L/Min),Clark DM. JACC 1997; 30:1039-45,Adverse Hemodynamic Effects of AF Irregular RR Intervals Impair Cardiac Performance,N=16,Integration of Clinical and Experimental Data,AF (short duration),AF (variable duration),DISEASED ATRIUM + Trigger (?Accentuation of preexisting heterogeneity),NORMAL ATRIUM + Trigger (preexisting heterogeneity),REMODELING,PERMANENT Atrial Fibrillation,Shivkumar K and Weiss JN. Atrial fibrillation from cells to computers. Cardiovasc Res. 2001.,Atrial Fibrillation in Heart Failure,Background Pathophysiology Influence on disease state and progression Clinical approach Management,Pozolli et al. 1998;31(1):197-204.,The DIG Investigators. Chest. 2000;118:914-922. From: Shivkumar, Weiss, Fonarow, and Narula; eds. Braunwalds Atlas of EP in HF.,SOLVD Investigators: J Am Coll Cardiol. 1998;32:695-703. From: Shivkumar, Weiss, Fonarow, and Narula; eds. Braunwalds Atlas of EP in HF.,Hospitalization with Atrial Fibrillation and Heart Failure: similar prognosis for patients with depressed compared to preserved LV function,EF 0.50 n = 218 mean age 72 yrs,EF 0.50 n = 260 mean age 76 yrs,Years,Survival,Parkash et al AHJ 2005,Atrial Fibrillation in Heart Failure,Background Pathophysiology Influence on disease state and progression Clinical approach Management,Impact of Treatment of Heart Failure on Atrial Fibrillation,Treatment for the CHF patient with concomitant AF that has no reversible cause poses a number of challenges. An appreciation of the interrelationships between the substrate and the arrhythmia allows a choice of therapies, including non-pharmacologic (eg, dual-site pacing) and pharmacologic, which comprises a spectrum of cardioactive drugs. The question facing the physician is which to treat first - the AF or the heart failure.,Atrial Fibrillation in Heart Failure: Clinical Approach,Assure guideline-based medical management Assess structural issues (dilatation due to valve regurgitation, diastolic dysfunction, etc) Anticoagulation Rhythm management,Pharmacological A) Heart Failure therapy B) Antiarrhythmic drugs Non Pharmacological A) Catheter ablation (atria) B) AV nodal ablation and bi-V pacing C) Atrial defibrillators,Atrial Fibrillation in Heart Failure: Clinical Approach,A) Impact of Treatment of Heart Failure on Atrial Fibrillation,In the case of patients in whom AF develops in the setting of heart failure, the therapeutic approach needs to be viewed in the context of a disorder with a complex pathophysiologic substrate that may need to be modulated by a variety of pharmacologic interventions. These interventions may exert a fundamental influence on the outcome of heart failure and this may, in turn, augment the difficulty in defining the impact on the major end points of antiarrhythmic therapy keyed to maintaining sinus rhythm.,A) Impact of Treatment of Heart Failure on Atrial Fibrillation,Angiotensin-converting enzyme (ACE) inhibitors, digitalis, and spironolactone decrease the risk of hospitalization in heart failure patients. The SOLVD Investigators. N Engl J Med. 1991; 325: 293302 The effect of digoxin on mortality and morbidity in patients with heart failure. The Digitalis Investigation Group. N Engl J Med. 1997; 336: 525533 Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med. 1999; 341: 709717.,A) Impact of Treatment of Heart Failure on Atrial Fibrillation - RAAS,Targeting atrial-specific ion channels and developing antiarrhythmic drugs with selected channel-blocking profiles are very attractive approaches. Success in preventing components of AF pathophysiology, including the prevention of AF-promoting structural remodelling by suppressing reninangiotensin activation, has been achieved in animal experiments. Clinical trials indicate the value of inhibiting angiotensin-converting enzyme or blocking angiotensin type-1 receptors in preventing AF recurrence (RAAS). Antiarrhythmic drugs for atrial fibrillation: Do we need better use, better drugs or a randomized trial of ablation as primary therapy? Stanley Nattel, Montreal Heart Institute Research Center, CMAJ 2004 ; 171 (7).,Impact of Treatment of Heart Failure on Atrial Fibrillation (blocking angiotensin type-1 receptors CHARM Study),Atrial fibrillation is associated with an increased risk of CV outcomes in patients with CHF and either reduced EF or PEF. Candesartan was associated with similar treatment effects regardless of baseline rhythm. Candesartan improved outcomes similarly regardless of baseline rhythm. Lars G. O, et al. Atrial Fibrillation and Risk of Clinical Events in Chronic Heart Failure With and Without Left Ventricular Systolic Dysfunction. Results From the Candesartan in Heart failure-Assessment of Reduction in Mortality and Morbidity (CHARM) Program.,ACE inhibition reduces atrial fibrosis in a heart failure model,Control,5 Weeks,5 Weeks +Enalapril,Li, Nattel, et al, Circulation 2001;104: 2608 - 2614,Prevention of Atrial Fib With Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers: A Meta-Analysis,11 studies with 56,308 patients Overall, ACEIs and ARBs reduced the relative risk of AF by 28% (95% C 15% to 40% Benefit is similar for ACE-inhibitors and AII blockers Reduction in AF was greatest in patients with heart failure (relative risk reduction 44%, p = 0.007).,Healey, et al JACC 2005;45:1832,A) Impact of Treatment of Heart Failure on Atrial Fibrillation - RAAS,A potentially important component of the reninangiotensin system that has not been fully investigated in AF management with CHF is the mineralocorticoid aldosterone. Aldosterone production is increased by activation of the reninangiotensin system, via the action of angiotensin-II on aldosterone-producing cells. Although the primary source of aldosterone production is the renal cortex, there is also evidence for intracardiac aldosterone generation. Stanley Nattel . Aldosterone antagonism and atrial fibrillation: time for clinical assessment? European Heart Journal 2005 26(20):2079-2080 Milliez P, DeAngelis N, Rucker-Martin C, Leenhardt A, Vicaut E, Robidel E, Beaufils P, Delcayre C, Hatem SN, Spironolactone reduces fibrosis of dilated atria during heart failure in rats with myocardial infarction. Eur Heart J 2005;26:21932199. First published on September 1, 2005,A) Impact of Treatment of Heart Failure on Atrial Fibrillation - RAAS,Aldosterone has a wide range of both genomic and non-genomic actions and is a potent stimulus for cardiac fibrosis. In addition, aldosterone may produce direct electrophysiological changes. AF increases serum aldosterone concentrations, whereas restoration of sinus rhythm returns aldosterone concentrations to normal. Aldosterone production is enhanced by the reninangiotensin activation occurring in CHF, and it would not be surprising if the resulting mineralocorticoid receptor stimulation contributed to the atrial fibrosis that is an important component of the AF substrate associated with CHF. Stanley Nattel . Aldosterone antagonism and atrial fibrillation: time for clinical assessment? European Heart Journal 2005 26(20):2079-2080 Milliez P, DeAngelis N, Rucker-Martin C, Leenhardt A, Vicaut E, Robidel E, Beaufils P, Delcayre C, Hatem SN, Spironolactone reduces fibrosis of dilated atria during heart failure in rats with myocardial infarction. Eur Heart J 2005;26:21932199. First published on September 1, 2005,Anne W, Willems R, Van der Merwe N, et al. AF after RF ablation of atrial flutter: preventive effect of ACEI, ARB and diuretics. Heart. 2004;90:1025-1030.,A) Pharmacological Management: Effect of Heart Failure Drugs,A) Pharmacological Management: Effect of Heart Failure Drugs,Anne W, Willems R, Van der Merwe N, et al. AF after RF ablation of atrial flutter: preventive effect of ACEI, ARB and diuretics. Heart. 2004;90:1025-1030.,Shiroshita-Takeshita, Schram, Lavoie, and Nattel. Effect of simvastatin and antioxidant vitamins on atrial fibrillation promotion by atrial-tachycardia remodeling in dogs. Circulation. 2004;110:2313-2319.,Effect of Simvastatin and Antioxidant Vitamins on Atrial Fibrillation Due to Remodeling: L-type Ca Channel Alpha Subunit Protein,A) Impact of Treatment of Heart Failure on Atrial Fibrillation Beta Blockade,Beta-blockade in the context of severe heart failure, as well as in the broader context of cardiovascular therapy, is of profound therapeutic importance. However, when heart failure occurs in conjunction with AF, it remains to be determined whether beta-blockade will induce such a consistent effect on mortality. If it does, it will presumably be because a favorable change in the substrate per se reduces the incidence of AF in this setting. It will also be important to determine whether other non-beta-blocking drugs (eg, amiodarone or dofetilide) have synergistic antifibrillatory effects in the setting of patients with AF and concomitant CHF.,Packer M, Castaigne A, Coats A. COPERNICUS: a multicenter, randomized, double-blind, placebo-controlled study to determine the effect of carvedilol on mortality in patients with severe chronic heart failure. Presentation: Session 414: Late Breaking Clinical Trials II. Program and abstracts of the American College of Cardiology 50th Annual Scientific Session; March 18-21, 2000; Orlando, Florida,Large-Scale Clinical Trials Reporting -Blocker Effects on Heart Failure Morbidity,Beta-blocker therapy in treatment of atrial fibrillation,Randomized studies have confirmed the superiority of beta-blockers in controlling the ventricular response, especially with exercise. First, a small population of patients experience recurrent AF in association with stress or anxiety; these patients with adrenergically mediated AF may respond well to beta-blockade Second, and more common, is the use of beta-blockers for prevention of AF in patients following cardiothoracic surgery, in which AF occurs in approx. 30% of patients. The efficacy of beta-blockers in this circumstance likely relates to the elevated sympathetic tone present postoperatively.,Beta-blocker therapy in treatment of atrial fibrillation,It is widely believed that shortening of atrial refractoriness facilitates AF and prolonging refractoriness suppresses AF. In animals, rapid pacing shortens atrial refractoriness and allows sustained AF where it was previously nonsustained. Class IA and class III agents are thought to protect against AF by prolonging atrial refractoriness. Although beta-blockers are not generally regarded as membrane stabilizing agents, they may protect against AF by delaying atrial repolarization. Khlkamp et al. speculate that beta-blockers protect against adrenergically mediated shortening of the action potential duration (APD) that is thought to help precipitate and maintain AF. Another potential mechanism for preventing AF could result from suppression of pulmonary vein ectopy that triggers AF.,Treatment of symptomatic AF: issues of anticoagulation,The goal of atrial stabilizing therapy, as correctly stated by Khlkamp et al., is to prolong the time to recurrence of symptomatic AF. How important is asymptomatic AF? The answer depends on whether one is considering changes in anticoagulant therapy based on the apparent reduction in AF. Warfarin & aceno-coumarol, and perhaps to a much lesser degree, aspirin & triflusal, are the only therapies demonstrated to reduce the risk of embolic complications of AF. Based on the data regarding asymptomatic AF, it should be assumed that patients with AF are having more events than anyone recognizes, a situation exacerbated perhaps by drugs that block the AV node.,Treatment of symptomatic AF: issues of anticoagulation,Maintenance