Suvremena Terapija Atrijalne Fibrilacije

Kantonalna Bolnica Zenica

Enes Abdović

• …has assumed increasing importance in the 21st century, in which the global demographic tide has resulted in a rapidly expanding elderly population”.

• “AF is considered to be one of the three growing CV epidemics in the 21st century in conjunction with congestive heart failure (CHF), and type II diabetes mellitus, and/or metabolic syndrome. Moreover, AF and CHF frequently co-exist and each may exert an adverse prognostic impact upon the other”.

“Atrial fibrillation (AF), an ‘old’ arrhythmia first described in 1909,

…

Background

• Atrial fibrillation (AF) is the most prevalent sustained cardiac arrhythmia in developed countries. 

• It is a disease of the elderly and it is

common in patients (pts) with organic heart disease.

• Hypertension, DM, heart failure and valvular heart disease are predisposing factors to AF.

Sex and Age Distribution of pts with AF

0

50

100

150

200

250

16-20 21-25 26-30 31-35 36-40 41-45 46-50 51-55 56-60 61-65 66-70 71-75 76-80 81-85 86-90 91-95 96-100

Males

Females

Abdovic et al. Europace 2005

Etiological distribution of pts with AF

5%14%18%

23%

37%

3%

0%

5%

10%

15%

20%

25%

30%

35%

40%

HHD DCM CHD VHD Lone Other

Abdovic E. et al. Europace, 2005

Results

Median age 71 years (16-100)

Male gender 51% (881)

Chronic AF 71% (1239)

Hypertension 67% (1167)

Diabetes mellitus 14.3% (249)

IV block 24% (421)

Thyroid gland diseases 5% (90)

Abdovic et al. Europace 2005

Transitory vs. Chronic AF

Transitory AF

Chronic AF

FemalesOR=1.28 95% CI=1.00-

1.64Sex

Males

Younger ptsOR=1.04 95% CI=1.02-

1.05Age

Older pts

LoneAFOR=3.85 95% CI=1.64-

9.04

Concomitant/

Underlying Disease

DCMOR=2.19 95% CI=1.20-4.01

HypertensionOR=1.47 95% CI=1.07-

2.04

VHDOR=4.27 95% CI=2.24-8.15

Prevalence of AF in several major CHF trials

The interrelations between AF and CHF could constitute a vicious cycle. However, both conditions may be markers of a common pathophysiological substrate. According to data from the Framingham Heart Study, AF preceded CHF about as often as CHF preceded AF, and in one-fifth ofsubjects, AF and CHF were diagnosed for the first time on the same day.

The future of atrial fibrillation therapy: the 2nd AFNET/EHRA consensus

conference:

• Three main areas in need of research were identified:

• Understanding the mechanisms of AF • Improving rhythm control monitoring and management • Validation and implementation of comprehensive

cardiovascular risk management in AF patients

• The expectation was that, in the future, adequate therapy for AF will need to simultaneously address:

1. management of underlying and concomitant diseases, 2. early and comprehensive rhythm control therapy, 3. adequate control of ventricular rate and cardiac

function, 4. continuous therapy to prevent AF-associated

complications

General schema representing AF

mechanisms and the role of remodeling

"trigger" factor

• In the presence of an opportunely modulated substrate, a prerequisite for the triggering of a multiple atrial reentry is the presence of an adequate "trigger" factor

• This is represented, in most cases, by ectopic atrial beats, commonly originating in the pulmonary veins...

Autonomic modulation preceding the onset of atrial fibrillation

Maisel et al. JACC

• Among patients with structurally normal hearts, some have observed an increase in vagal predominance in the minutes preceding AF onset, while others have noted a marked shift towards sympathetic predominance

• A number of other studies have also demonstrated that fluctuations in autonomic tone, as measured by HRV, precede the onset of AF

• Acetylcholine shortens the atrial refractory period and increases the heterogeneity of atrial refractoriness, effects that predispose to reentry

vns - af

• This survey shows that an autonomic trigger pattern for AF may be found in over 20% of patients. These patients are highly symptomatic explaining the more frequent application of rhythm control...

• adrenergic (exercise, emotion, daytime only)

• vagal (postprandial, sleep, night time only)

Fibrosis is a hallmark of arrhythmogenic structural

remodeling• The fundamental mechanisms underlying AF have long

been debated, but electrical, contractile, and structural remodeling are each important synergistic contributors to the AF substrate.

• In the dog model, atrial fibrosis causes localized regions of conduction slowing, increasing conduction heterogeneity and providing an AF substrate

• Fibrosis is a hallmark of arrhythmogenic structural remodeling. Tissue fibrosis results from an accumulation of fibrillar collagen deposits, occurring most commonly as a reparative process to replace degenerating myocardial parenchyma with concomitant reactive fibrosis, which causes interstitial expansion.

Moe’s theory the multiple reentry wavelet

hypothesisMoe GK. On the multiple wavelet hypothesis of atrial fibrillation.

Arch Int Pharmacodyn Ther 1962;140:183–8.

• ... has served for nearly 50 years as a dominant conceptual model for explanation of the activation patterns and the maintenance of AF.

• The hypothesis, initially demonstrated via computer modeling, found experimental and clinical support in humans with the therapeutic efficacy of the Maze procedure

A Proposed Model for the Pathogenesis of AF

Experimental and clinical studies have shown that AF is maintained by multiple reentrant wavelets within the atrial muscle.

It has been estimated that a critical number of wavelets (from 3 to 6) is necessary for perpetuation of AF...

“Single/Multi Level Disease” of

the Cardiac Conduction System

Sick sinus syndromeSinus node

(Intra, inter) atrial level

Atrio-ventricular level

Intra-ventricular level

Intra- and inter-atrial blocks

Atrio-ventricular blocks

Intra-ventricular blocks

Cardiac Conduction System

P-wave duration is generally accepted as the most reliable non-invasive marker of atrial conduction and its prolongation has been

associated with history of AFPlatonov PG, Cardiol J. 2008, 15;402-408

• Despite the advancements in pharmacological and non-pharmacological management of atrial fibrillation (AF) observed during last decades, available treatment modalities and predictors of their success are still far from optimal.

• Understanding of pathophysiological mechanisms underlying AF and assessment of atrial electrophysiological properties using easily available non-invasive diagnostic tools such as surface ECG are essential for further improvement of patient-tailored treatment strategies.

Efficacy of amiodarone compared with control for the (A) prevention of sudden cardiac death, (B) cardiovascular death, and (C) all-cause mortality in patients with cardiomyopathy

(Piccini JP et al, 2009 E Heart J)

… the future of antiarrhythmic therapy.

• …classified the perspectives into 3 groups: • Atrial selective agents including vernakalant, amiodarone

congeners and particularly dronedarone and others. • The latter group represents gap junction blockers, serotonin

receptor antagonists and muscarinic receptor blockers.

• Does dronedarone represent a progress in terms of efficacy and safety? Yes referring to the recent results of the ATHENA trial, which showed that dronedarone decreased cardiovascular hospitalisation by 26 per cent, the first AF related hospitalisation by 46 per cent, all AF related hospitalisation by 23per cent and reduction of the number of days of hospitalisation. This multichannel blocker without iodine is the first antiarrhythmic agent which reduced cardiovascular events and cardiovascular mortality.

Advantages and disadvantages of “rate control” and “rhythm control”

Angiotensin II Antagonist Prevents Electrical Remodeling in Atrial

Fibrillation Nakashima H et al. Circulation 2000;101:2612.

• The inhibition of endogenous Ang II prevented AERP shortening during rapid atrial pacing.

• These results indicate for the first time that Ang II may be involved in the mechanism of atrial electrical remodeling and that the blockade of Ang II may lead to the better therapeutic management of human atrial fibrillation.

Mechanism of Cardioembolic Ischemic Stroke Caused by Atrial

Fibrillation

Stroke risk in patients with AFaccording to the CHADS2 risk index.

The colour coded bar graphs indicate the appropriate antithrombotic treatment

strategy.

New anticoagulants with mechanisms of action that are

different from vitamin K antagonists…

• … the novel factor IIa and Xa antagonists like dabigatran and rivaroxaban, their mechanism of action and presently available results.

• In patients with atrial fibrillation, dabigatran 110 mg was associated with similar rates of stroke and systemic embolism to warfarin, and lower rates of major hemorrhage. Dabigatran 150 mg was associated with lower rates of stroke and systemic embolism than warfarin, and similar rates of major hemorrhage.

Cumulative Hazard Rates for the Primary Outcome of Stroke or Systemic

Embolism, According to Treatment Group.

The Watchman Left Atrial

Appendage Closure Device

The device is a self-expanding nitinol structure

that is delivered percutaneously with femoral

venous access and transseptal technique to the

LAA.

The device is positioned with the use of angiography and

TEE, and implantation is performed in either a cardiac

catheterization or electrophysiology laboratory

with the patient under general anesthesia or conscious sedation.

The Maze procedure Black lines delineate surgical incisions in both the right and

left atria, encircling the pulmonary veins (PV) and around the coronary artery sinus orifice. The atrial appendages are also

excluded.

Diagram of the Sites of 69 Foci Triggering Atrial Fibrillation in 45 Patients. Note the clustering in the pulmonary veins, particularly in both superior pulmonary

veins. Numbers indicate the distribution of foci in the pulmonary veins.

Overview of balloon based pulmonary vein isolation techniques

Radiofrequency catheter ablation of AF by pulmonary vein isolation

has emerged as an important treatment modality.

• However, despite initial success, there is a substantial recurrence rate.

• In a high percentage, the reason for recurrence is that pulmonary vein isolation is not complete due to local recovery of conduction out of the pulmonary veins. Re-ablation is then the method of choice.

• In other cases, it might be important to change the underlying atrial substrate by identifying regions with continuous fractionated atrial electrograms which stand for regional fibrosis.

… the outcome and complications of AF ablation.

• The difficulty of evaluating AF ablation comes from the number of techniques used in ablation procedures.

• All the series comparing ablation to pharmacological therapy have shown that the percentage of patients treated with ablation in sinus rhythm is superior (64 per cent) to medical therapy (26 per cent); in their series, 89 per cent versus 23 per cent.

• The complications have an incidence which depends on the center and the experience of the operators. These complications concern the vascular access, the trans-septal puncture and the injury to the cardiac chambers. The risk of death during the procedure is reported to be around 0.1 per cent.

Schematic depiction of different ablation techniques targeting the lateral pulmonary veins (PVs).

(A) Simultaneous isolation of the ipsilateral PVs by a long ‘‘pointby-

point’’ lesion encircling the antrum area of the lateral PVs. (B) ‘‘Single shot’’ PV isolation using aballoon shaped catheter

aiming at the LIPV.

… the statement of international societies concerning AF ablation and

ablation guidelines cannot include class A recommendation as prospective

comparative randomized trials are not available.

Registries such as the one conducted by Dr Cappato are useful but the long –term results are difficult to evaluate with a registry.

The CABANA trial will cover this gap and will randomize recent onset paroxysmal AF to antiarrhythmic medications or to ablation, which will include pulmonary vein isolation as a minimum procedure.

The primary endpoint will be mortality and secondary endpoints will include cardiovascular death, hospitalizations, heart failure, cost and quality of life.

Conclusion(1)• The classical risk factors for developing AF

include HA, diabetes mellitus, valvular disease, ischaemic cardiomyopathy, CHF and thyroid disease.

• HHD was by far the most prevalent associated medical condition.

• Chronic AF was predominant in groups with advanced cardiac remodeling such as DCM and VHD. On the contrary to transient AF, it is a disease of the elderly.

Conclusion(2)

1. In order to prevent or postpone the development of AF an optimal treatment of hypertension and diabetes mellitus is necessery

2. early and comprehensive rhythm control therapy,

3. adequate control of ventricular rate and cardiac function,

4. continuous therapy to prevent AF-associated complications