Psirropoulos Z. Dimitrios, MD, PhD Head Director Cardiology Department CCU G. Gennimatas General Hospital Thessalonik

2. New Trends in Cardiology April 9-11, 2009 Hyatt Regency Hotel Thessaloniki Greece

3. Atrial Fibrillation in Heart Failure Background Pathophysiology Influence on disease state and progression Clinical approach – Management

4. 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

9. 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.

11. Atrial Fibrillation in Heart Failure Background Pathophysiology Influence on disease state and progression Clinical approach Management

15. 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

18. Pathophysiology of AtrialFibrillation in Heart Failure Changes in coupling/geometry of the atrial muscle bundle at the pulmonary vein-atrial junction

19. Atrial Fibrillation in Heart Failure: Pathophysiology Structural changes such as fibrosis are prominent in remodeled atria in the setting of heart failure

24. Atrial Fibrillation in HF:Functional Changes The stimulation process can be described in “phases:” The output voltage produces an electrical field at the electrode-tissue interface. The electrical field permeates cardiac cells via ionic movement and changes voltage on the cell membrane, which brings the cell membrane “above threshold” and alters its permeability. Phase 0 is the result of this part of the process. During Phase 0, sodium rushes in, which results in depolarization followed by cellular repolarization via sodium/potassium infusion. NOTE: The electrical field generated by the stimulation pulse must last long enough to excite the tissue. To effectively raise the membrane potential, the intensity of the stimulation must be balanced with the length of time it is applied.The stimulation process can be described in “phases:” The output voltage produces an electrical field at the electrode-tissue interface. The electrical field permeates cardiac cells via ionic movement and changes voltage on the cell membrane, which brings the cell membrane “above threshold” and alters its permeability. Phase 0 is the result of this part of the process. During Phase 0, sodium rushes in, which results in depolarization followed by cellular repolarization via sodium/potassium infusion. NOTE: The electrical field generated by the stimulation pulse must last long enough to excite the tissue. To effectively raise the membrane potential, the intensity of the stimulation must be balanced with the length of time it is applied.

25. 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

29. Atrial Fibrillation in Heart Failure Background Pathophysiology Influence on disease state and progression Clinical approach Management

33. Hospitalization with Atrial Fibrillation and Heart Failure: similar prognosis for patients with depressed compared to preserved LV function

34. Atrial Fibrillation in Heart Failure Background Pathophysiology Influence on disease state and progression Clinical approach Management

35. 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.

36. 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

37. 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

38. 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.

39. 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: 293–302 The effect of digoxin on mortality and morbidity in patients with heart failure. The Digitalis Investigation Group. N Engl J Med. 1997; 336: 525–533 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: 709–717.

40. 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 renin–angiotensin 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).

41. 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.

43. 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).

44. A) Impact of Treatment of Heart Failure on Atrial Fibrillation - RAAS A potentially important component of the renin–angiotensin system that has not been fully investigated in AF management with CHF is the mineralocorticoid aldosterone. Aldosterone production is increased by activation of the renin–angiotensin 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;26:2193–2199. First published on September 1, 2005

45. 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 renin–angiotensin 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;26:2193–2199. First published on September 1, 2005

49. 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.

50. Large-Scale Clinical Trials Reporting ß-Blocker Effects on Heart Failure Morbidity

51. 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.

52. 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. Kühlkamp 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.

53. Treatment of symptomatic AF: issues of anticoagulation The goal of atrial stabilizing therapy, as correctly stated by Kühlkamp 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.

54. Treatment of symptomatic AF: issues of anticoagulation Maintenance of anticoagulation provides protection from thromboembolic complications of recurrent AF and allows prompt conversion of sinus mechanism when recurrent AF is recognized If anticoagulation is ever discontinued, that two steps need to be considered prior to the drug change. First, a Holter monitor should be placed to evaluate for asymptomatic AF; Second, one should consider discontinuing treatment with any agents likely to reduce symptoms (such as AV nodal blocking drugs). This may seem paradoxical, but allowing a higher rate, when AF does recur, allows the best possible "warning system" for recurrent AF. Finally, although the data are not strong for its use in AF, in the absence of warfarin, aspirin, 325 mg daily, should be prescribed

55. Cardiomyopathy can be caused by any tachycardia (>110 bpm) that occurs as little as 10-15% of day Severity related to rate and duration of ? HR Maximal improvement after rate control may require up to 8 months After improvement susceptibility to rapid deterioration remains if tachycardia recurs

56. Some Conclusions

58. Atrial Fibrillation in HF Heart failure and atrial fibrillation are ‘emerging epidemics’ Tachycardia mediated cardiomyopathyin 10% patients Prevalence of atrial fibrillation increases with worsening ventricular dysfunction Atrial fibrillation increases mortality

59. Atrial Fibrillation and Heart Failure Prevention – the best medicine Neurohormonal antagonists Aggressive therapy of initial AF episodes? Anticoagulation Statins? Targeting heart failure