Upstream Therapy for Atrial Fibrillation in Heart Failure

Upstream Therapy for Atrial F i b r i l l a t i o n i n H e a r t F a i l u re Andreas Goette, MD KEYWORDS  Atrial fibrillation  Heart failure  Upstream therapy  Statins  Prevention

KEY POINTS

PATHOPHYSIOLOGY OF ATRIAL FIBRILLATION IN HEART FAILURE Atrial fibrillation (AF) is the most common sustained arrhythmia in humans, causing an increasing number of complications and deaths.1–3 Reports suggest that approximately 1% of the total population is affected.4 The number of patients with AF is likely to double or triple within the next 2 to 3 decades.5 The prevalence of AF is clearly age dependent. Patients with AF usually seek medical attention because of AF-related symptoms, and the treatment of these symptoms has been the main motivation for AF therapy in the past. However, even the presence of asymptomatic AF markedly decreases quality of life.2,6 AF also doubles mortality independently of other known disease-causing factors and is one of the most common causes for stroke. Left ventricular function, the best-validated clinical parameter for cardiac prognosis, can be markedly impaired in

patients with AF and improves when sinus rhythm is maintained for a longer period of time.2,7 Heart failure with dyspnea on exertion (New York Heart Association [NYHA] classes II–IV) is found in 30% of patients with AF,8 and AF is found in 30% to 40% of patients with heart failure.2,9 Heart failure and AF seem to promote each other, with AF compromising left ventricular function and left ventricular dysfunction causing atrial dilation and pressure overload. Treatment of heart failure is able to prevent AF,2,10 adding to the evidence that AF is promoted by these conditions. In order to investigate how congestive heart failure (CHF) promotes AF, experimental models of CHF have been described.11 When CHF was induced by pacing with a ventricular pacemaker at a high rate (>200 beats per minute) for 5 weeks, atrial fibrosis was dramatically increased in dogs with CHF,11 with large areas of connective tissue. These structural abnormalities were accompanied

Disclosures: The author has nothing to disclose. Department of Cardiology and Intensive Care Medicine, St. Vincenz Hospital Paderborn GmbH, EUTRAF Working Group, University Hospital Magdeburg, Am Busdorf 2, Paderborn 33098, Germany E-mail address: [email protected] Heart Failure Clin 9 (2013) 417–425 http://dx.doi.org/10.1016/j.hfc.2013.07.010 1551-7136/13/$ – see front matter Ó 2013 Elsevier Inc. All rights reserved.

heartfailure.theclinics.com

 Heart failure is a major factor that increases the likelihood for atrial fibrillation (AF).  Several aspects of the morphologic and electrophysiologic alterations promoting AF in heart failure (congestive heart failure [CHF]) have been studied in animal models and in patients with CHF; under these conditions, ectopic activity originating from the pulmonary veins or other sites is more likely to occur and to trigger longer episodes of AF.  Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and spironolactone may help to reduce the occurrence of AF.  Statins are indicated if patients have an indication for their use, such as increased low-density lipoprotein levels or established coronary artery disease.  Results for secondary prevention are very heterogeneous, and the effect of upstream therapy is less well established in this clinical setting.

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Goette by regional conduction heterogeneity. Studies have supported the role of atrial fibrosis in the promotion of AF in CHF.2,12,13 Atrial damage in the CHF model occurs rapidly, with a peak in inflammation, apoptosis, and necrosis within 24 hours after activation of the ventricular pacemaker.2,14 The renin-angiotensin system is an important mediator in the development of an AF substrate in CHF. Inhibition of angiotensin II (AT II) production by the angiotensin-converting enzyme (ACE) blocker enalapril not only attenuated CHFinduced atrial fibrosis but also reduced conduction heterogeneity and AF stability.2,15,16 Atrial fibrosis and increased AF stability in the canine CHF model can also be inhibited by simvastatin,17 pirfenidone,18 polyunsaturated u-3 fatty acids,19 and sprionolactone.20 The peroxisome proliferatoractivated receptor a (PPARa) activator fenofibrate was not effective in this model17; but in rabbits with tachycardiomyopathy-induced CHF, the PPARg activator pioglitazone did reduce atrial structural remodeling and AF stability.2,21

MOLECULAR DRUG TARGETS FOR UPSTREAM THERAPY Chronic atrial stretch seems to be one of the most prominent trigger mechanisms for signaling changes involved in the pathogenesis of AF. Atria seem to react much faster and more strongly to increased wall stress caused by atrial dilatation than ventricular myocardium.14 The induction of heart failure by rapid ventricular pacing induces the development of apoptosis and increased collagen synthesis in the atria within a couple of days, whereas the degree of such changes is substantially smaller and the time course much slower in the ventricles.2,11 At the molecular level, the development of atrial fibrosis caused by pressure and/or volume overload is mediated by both angiotensin II-dependent and independent mechanisms.2,15,17 Left ventricular failure increases atrial synthesis of angiotensin II, and thereby atrial fibrosis is induced via activation of mitogenactivated protein (MAP) kinases.2,22 Signaling pathways mediated by angiotensin II type 1 receptors (AT-1 receptors) are linked to G proteins. Studies have shown a linear correlation between angiotensin II, MAP kinase activation, and the degree of atrial fibrosis.15 Another tyrosine kinase that is activated by angiotensin II is Janus kinase 2 (JAK2).22 JAK2 initiates the activation of transcription factors signal transducer and activator of transcription (STAT)-1 and STAT-3. A recent study demonstrated that the angiotensin II/Rac1/ STAT3 pathway is an important signaling pathway involved in atrial structural remodeling.23

In addition to angiotensin II, pacing-induced ventricular failure also increases atrial transforming growth factor (TGF)-b and platelet-derived growth factor (PDGF) levels. TGF-b operates predominantly by autocrine and paracrine mechanisms. Binding of a TGF-b homodimer to 2 TGF-b type II receptors causes phosphorylation of signaling molecules belonging to the family known as SMADs. When phosphorylated, SMADs aggregate and enter the nucleus to induce myocardial fibrosis.24 In addition, TGF-b1 can redirect protein synthesis to favor expression of fetal genes as described in fibrillating atria.25 Atrial fibroblasts are activated significantly faster than ventricular fibroblasts in the CHF models, explaining the rapid and more severe degree of interstitial fibrosis in the atria.26 Another important contributor to atrial remodeling in CHF is oxidative stress.27 The PPARg activator pioglitazone antagonizes angiotensin II actions and possesses antiinflammatory and antioxidant properties. Pioglitazone attenuated CHF-induced atrial structural remodeling and AF vulnerability.2 In the same study, both pioglitazone and candesartan reduced TGF-b, tumor necrosis factor a, and MAP kinase, but neither affected p38 kinase or c-Jun N-terminal kinase activation. In contrast, u-3 polyunsaturated fatty acids attenuate CHF-related phosphorylation of the MAP kinases ERK and p38.2,19 In failing human myocardium, NADPH oxidase-related reactive oxygen species (ROS) production increases, with enhanced expression and activity of Rac1. The application of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) like simvastatin inhibits myocardial Rac1-GTPase activity.17 The small GTPase Rac1 regulates NADPH oxidase activity. Statins downregulate Rac1-GTPase activity by reducing isoprenylation and translocation of Rac1 to the cell membrane.28 The inhibition of Rac1 by statins decreases NADPH oxidaserelated reactive oxygen species production in cardiac myocytes and reduces myocardial hypertrophy. Furthermore, simvastatin reduces human atrial myofibroblast proliferation via a RhoA pathway.29 In addition, simvastatin, but not fenofibrate (PPARa agonist), inhibits canine atrial fibroblast proliferation, which paralleled collagensynthetic fibroblast function.2 Thus, statins and PPARa agonists have very different efficacy in preventing CHF-related atrial structural remodeling. In addition to cellular effects, atrial stretch is also associated with an altered expression of matrix metalloproteinases (MMP). In patients with AF with congestive heart failure, an increased collagen I fraction seems to be associated with upregulation of MMP-2 and downregulation of tissue inhibitor of metalloprotease-1.2,30,31 In addition to MMPs,

Upstream Therapy ADAMs (a disintegrin and metalloproteinase) also influence interstitial matrix composition and cellcell and cell-matrix interactions. ADAMs form a large family of membrane-bound glycoproteins that function in proteolysis, signaling, cell adhesion, and cleavage-secretion of membranebound proteins.2 Arndt and colleagues32 described the effect of AF in patients with concomitant heart diseases on the regulation of ADAMs. Atrial tissue of patients with permanent AF shows increased levels of ADAM10 and ADAM15. Membrane expression of ADAM15 is significantly upregulated during AF, whereas most ADAM15 is retarded in the cytoplasm during sinus rhythm. The ADAM15/integrin b1 ratio is significantly increased in fibrillating tissue and correlates with the left atrial diameter and the duration of fibrillation. Thus, the regulation of MMPs and ADAMs influences the composition of interstitial matrix and contributes to geometric changes and dilatation of the atria and ventricles.2,33 Although atrial fibrosis is proarrhythmic in some animal models,2,34,35 the quantitative association between atrial fibrosis and AF is not very strong. Some but not all human studies have found that atrial fibrosis is more pronounced in patients with chronic AF than in patients in sinus rhythm.2,36 The degree of atrial fibrosis and fibrogenic activity correlates with the persistence of AF.2,37 However, from these studies, it is unclear whether increased fibrosis is caused by underlying structural disease or by AF itself.2

UPSTREAM THERAPY FOR AF As described, the treatment of CHF has been shown to reduce the incidence of AF in experimental models and clinical studies. Animal studies showed that the antiarrhythmic effects of ACE inhibitors and angiotensin receptor blockers (ARB) are related to their effect on atrial morphology.38,39 The results are supported by analyses of several clinical trials: Valsartan Heart Failure Trial (ValHeFT), Studies of Left Ventricular Dysfunction (SOLVD), and Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM).40 Furthermore, the Randomized Aldactone Evaluation Study (RALES) trial showed that spironolactone (an aldosterone antagonist) reduces circulating procollagen I and III levels in patients with CHF, which was associated with an improved survival.41 Other targets and drugs for upstream therapy like statins, polyunsaturated fatty acids are less well studied in clinical trials so far. Of note, the results for primary prevention are significantly better than data for secondary prevention of AF in patients with CHF.

RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM INHIBITION IN CHF In patients, several post hoc analyses of clinical trials suggest that therapy with ACE inhibitors, AT-1receptor blocker, statins, and polyunsaturated fatty acids (PUFAs) are useful to prevent AF (Table 1). CHF is one of the most important risk factors for AF and, as evidenced by multivariate analysis from the Framingham Study, increases the risk of AF by 4.5-fold in men and 5.9-fold in women.42,43 Diastolic left ventricular dysfunction is associated with a 5.26-fold increased risk of AF.43,44 The occurrence of CHF in middle age confers an 8% risk of developing AF over a 10-year period if the patient’s age at the time of CHF diagnosis was 55 to 64 years, which increases to 30% if CHF was diagnosed at 45 to 54 years of age.43,45 Furthermore, the presence of CHF not only increases the likelihood of developing AF but is also the leading independent predictor of progression to permanent AF, with an odds ratio of 2.2.46 New-onset AF in CHF is associated with clinical deterioration and poor prognosis.43,47 There are reports that the absence of AF is associated with fewer symptoms and better functional status and left ventricular function in patients with CHF.43,48,49 The true benefit of preserving sinus rhythm in patients with CHF in the AF-CHF and other secondary prevention studies might have been offset by the relatively low efficacy and adverse effects of antiarrhythmic drugs. Thus, upstream therapies (eg, reninangiotensin-aldosterone system [RAAS] inhibitors) that target both the underlying condition and the substrate formation for AF may offer a greater benefit than specific antiarrhythmic drugs.43,50 The first large study to report the beneficial effect of RAAS inhibition on the occurrence of new-onset AF was the Trandolapril Cardiac Evaluation (TRACE) study in patients with recent myocardial infarction and an ejection fraction of 35% or less.10 Patients who received trandolapril were less likely to develop new-onset AF during 2 to 4 years of follow-up compared with the placebo group (2.8% vs 5.3%). The report from the TRACE study was followed by similar retrospective analysis of the single-center results from the SOLVD trial, which also demonstrated less AF occurrence in patients with CHF and an ejection fraction of 35% or less with enalapril as opposed to placebo after 2.9 years of follow-up (5.4% vs 24.0%).43 Later studies with ARBs yielded similar results. In the Val-HeFT study, in 4395 patients with symptomatic CHF, therapy with valsartan was associated with a 37% reduction in relative risk of newly detected AF compared with placebo

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Table 1 Clinical trials of renin-angiotensin systems inhibition to prevent new-onset AF in patients with CHF or AMI (primary prevention) References

Study Design

Patients

Intervention

Primary Outcome

Pedersen et al, 1999

TRACE study (post hoc analysis)

1577 with AMI and reduced LVEF

Reduced incidence of new-onset AF

Pizetti et al

GISSI-3 study (post 17,749 with AMI hoc analysis)

Vermes et al

SOLVD study (post hoc analysis) SOLVD study (post hoc analysis)

347 with LV dysfunction 6797 with LV dysfunction

Trandolapril vs placebo Follow-up: 2–4 y Lisinopril vs no lisinopril Follow-up: 4 y Enalapril vs placebo Follow-up: 2.9 y Enalapril vs placebo Follow-up: 34 mo

Val-HeFT study (post hoc analysis) CHARM study (prespecified secondary end point) CAPPP study (randomized, open label [analysis on adverse event reports]) STOP-2 study (randomized, open label)

4395 with chronic symptomatic HF

Retrospective longitudinal cohort study LIFE study (randomized, double blind)

10,926 with hypertension

10

Alsheikh-Ali et al Maggioni et al

Ducharme et al,52 2006

Hansson et al

Hansson et al

Lh’Allier et al

Wachtell et al,64 2005

6379 with symptomatic CHF

Valsartan vs placebo Follow-up: 23 mo Candesartan vs placebo Follow-up: 37.7 mo

No difference in new-onset AF Reduced incidence of new-onset AF Reduced incidence of hospitalization with AF Reduced incidence of new-onset AF Reduced incidence of new-onset AF

10,985 with hypertension

Captopril vs diuretics  betablocker Follow-up: 6.1 y

6628 with hypertension

Enalapril/lisinopril No difference in vs CCB vs diuretics new-onset AF  beta-blocker Study duration: 4 y Reduced incidence ACEI vs CCB of new-onset AF Average follow-up: 4.5 y Losartan vs atenolol Reduced incidence Follow-up: 4.8 y of new-onset AF

8851 with hypertension 1 ECG LVH

No difference in new-onset AF

Abbreviations: ACEI, ACE inhibitor; AMI, acute myocardial infarction; CCB, calcium channel blockers; ECG, electrocardiogram; GISSI, Gruppo Italiano per lo Studio della Sopravvivenza nell’Insufficienza cardiaca; HF, heart failure; LIFE, Losartan Intervention For End Point Reduction in Hypertension; LV, left ventricular; LVEF, left ventricular ejection fraction; LVH, left ventricular hypertrophy. Adapted from Savelieva I, Kakouros N, Kourliouros A, et al. Upstream therapies for management of atrial fibrillation. Part I: primary prevention. Europace 2011;13:308–28; with permission.

(5.12% vs 7.95%) during 1.9 years.43,51 This benefit from an ARB was present despite a high (93%) rate of concomitant use of ACE inhibitors (ACEIs). This study has also demonstrated that the occurrence of AF was independently associated with adverse major outcomes, such as allcause death and combined mortality and morbidity, which increased by 40% and 38%, respectively, in the presence of AF. However, whether valsartan therapy improved the outcome within the new-onset AF group compared with placebo has not been reported.43

One of the limitations of these retrospective analyses was that AF was not a prespecified end point, and a significant proportion of asymptomatic or mildly symptomatic episodes might not have been reported. The CHARM program designated AF as one of the secondary end points.43 The AF substudy from the CHARM trials has shown that adding candesartan to conventional CHF therapy in 6379 patients with symptomatic CHF and without a history of AF at enrollment led to a lower incidence of new-onset AF compared with placebo, albeit this reduction was not as

Upstream Therapy significant as in the previous reports (5.55% vs 6.74%).43,52 Of note, the magnitude of the preventative effect of RAAS inhibition varies in patients according to the degree of impairment of left ventricular function. Thus, although statistically there was no heterogeneity of the effect of candesartan on AF between the 3 component trials in the CHARM program, the greatest benefit was seen in patients with impaired systolic function and without the concurrent use of ACEIs enrolled in the CHARM-alternative study and the least in patients with CHF and preserved systolic function.51 Similarly, irbesartan did not influence the incidence of AF reported as an adverse event in the Irbesartan in Patients with Heart Failure and Preserved Ejection Fraction trial.53 Four metaanalyses have shown that the risk of new-onset AF in patients with CHF was reduced by 30% to 48%, suggesting that ACEIs and ARBs may be effective in the primary prevention of AF in this clinical setting.38,54–56 This finding is consistent with experimental evidence of atrial fibrosis as the leading mechanism of AF in CHF models and evidence of antifibrotic effects of RAAS inhibition. It is unclear whether therapy with ACEIs and ARBs can prevent or delay the occurrence of AF in patients with CHF and preserved systolic function. There is no direct evidence that upstream therapies with RAAS inhibitors can reduce morbidity and mortality in patients with CHF by deterring AF.43

STATINS IN CHF Retrospective analyses from randomized controlled trials (RCTs) and registries in patients with CHF have suggested a modest reduction in the incidence of AF, mainly newly detected AF, although the differentiation between truly newonset AF and recurrent AF has not always been possible.43,57–59 In the AdvancentSM registry of 25,268 patients with an ejection fraction of 40% or less and left ventricular dysfunction of an ischemic cause in 72%, lipid-lowering therapy

(mostly statins or combination therapy) was associated with a 31% reduction in relative risk of developing AF compared with no therapy.57 This effect was greater than that of beta-blockers and RAAS inhibitors. The Sudden Cardiac Death in Heart Failure Trial investigators reported a similar 28% reduction in relative risk of AF, which was comparable with that of amiodarone.43,58 The GISSI-HF (Gruppo Italiano per lo Studio della Sopravvivenza nell’Insufficienza cardiaca Heart Failure) study enrolled 3690 patients with sinus rhythm. Therapy with rosuvastatin reduced the risk of any AF during the study by only 13%. The difference with the placebo arm became statistically significant only after adjustment for clinical variables, laboratory findings, and concomitant therapy.59 In the prespecified subgroup of patients with no history of paroxysmal AF, the incidence of new-onset AF was 9.8% in the rosuvastatin arm and 11.6% in the placebo arm. Patients in whom AF was present on the baseline electrocardiogram (19.3%) were excluded, but it could not be ascertained whether all patients who developed AF in the course of the study had new-onset AF.43 There was a nonsignificant difference between the rosuvastatin and placebo arms in the proportion of patients with AF at study entry who were excluded from analysis (18.8% vs 19.8%). During the study, AF occurred in 15% patients: 13.9% in the rosuvastatin group and 16.0% in the placebo group (absolute difference 2.1%). It is possible that more patients in the rosuvastatin arm may have had unrecognized AF at baseline and, hence, a greater likelihood of recurrent AF.43 Because of the retrospective nature of these reports, much important information is not available. One brief report from a large cohort of patients with CHF who were prescribed statins has suggested that the intensity of treatment might play a role; thus, in this study, AF was less common in those who received high doses (atorvastatin 80 mg, simvastatin 80 mg, and lovastatin 40 mg) as opposed to lower doses of the same agent.43,60

Table 2 Clinical trials of statins to prevent new-onset and progression of AF (primary and secondary prevention) References

Study Design

Patients

Intervention

Primary Outcome

Hanna et al

Retrospective

25,268 with CHF

Adabag et al

Retrospective

13,783 with CHD

Lipid-lowering drug use vs no use Statins vs no statins Average follow-up: 4.8 y

Reduced incidence of new-onset AF No difference in new-onset AF

Abbreviation: CHD, coronary heart diseases. Adapted from Savelieva I, Kakouros N, Kourliouros A, et al. Upstream therapies for management of atrial fibrillation. Part I: primary prevention. Europace 2011;13:308–28; with permission.

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Table 3 Clinical trials of u-3 (omega-3) polyunsaturated fatty acids to prevent AF in patients without CHF References

Study Design

Patients Intervention

Mozaffarian et al

Cardiovascular Health 4815 Study (population-based, prospective cohort) Frost et al Danish Diet, Cancer 47,949 and Health study (population-based, prospective cohort) Brouwer et al Rotterdam study: 5184 (population-based, prospective cohort)

Primary Outcome

Dietary intake assessment Reduced incidence Follow-up: 12 y of AF Dietary intake assessment No difference in Mean follow-up: 5.4 y incidence of AF

Dietary intake assessment No difference in Follow-up: 6.4 y incidence of AF

Adapted from Savelieva I, Kakouros N, Kourliouros A, et al. Upstream therapies for management of atrial fibrillation. Part I: primary prevention. Europace 2011;13:308–28; with permission.

META-ANALYSES OF STATIN TRIALS

SUMMARY

Other meta-analyses of the efficacy of statins for primary prevention of AF in different clinical settings have yielded controversial results (Table 2).43,60,61 The first meta-analysis by Fauchier and colleagues,60 which included 3 RCTs of primary prevention (one in ACS and 2 in postoperative AF) in 3101 patients, has shown a nonsignificant trend toward fewer AF events. In a meta-analysis by Liu and colleagues,61 statin treatment was associated with a reduction in new-onset AF both after cardiac surgery and in the nonsurgical setting but only in the observational studies. No effect on AF was seen when the results of RCTs were analyzed. The most recent meta-analysis, which has not yet been published in full, has confirmed the previous findings by showing a 30% reduction in relative risk of new-onset or recurrent AF with statins compared with control in 7 hypothesis-generating relatively small and short-term studies in mixed populations, including patients with acute coronary syndrome (ACS), cardiac surgery, and after electrical cardioversion (411 events in 3609 patients).62 However, in 15 (1514 events in 68,504 patients) hypothesis-testing long-term prospective RCTs in large patient populations with and without cardiovascular pathologic conditions, the use of statins had no effect on the occurrence of (mainly) newonset AF compared with control or placebo.43 Further analysis revealed no difference in the effects of statins in patients with coronary artery disease (CAD) versus other underlying cardiovascular pathology. Thus, the value of statins for the primary prevention of AF has not been sufficiently demonstrated, except perhaps for patients undergoing cardiac surgery. Nevertheless, several positive reports suggest some benefit of statins in patients with underlying heart disease, particularly CHF.43,63

CHF induces substantial molecular alteration in atrial tissue. These changes are proarrhythmic and increase the likelihood for AF. Thus, aggressive therapy for CHF has been shown to be useful for the primary prevention of AF in these patients; in particular, ACE inhibitors, ARBs, and spironolactone may help to reduce the occurrence of AF. Statins are indicated if patients have an indication for their use, such as increased low-density lipoprotein levels or established CAD. Results for secondary prevention are very heterogeneous, and the effect of upstream therapy is less well established in this clinical setting. This point may be explained by the fact that an established proarrhythmic atrial fibrosis is not reversible; therefore, the burden of AF cannot be decreased by such therapies. The impact of PUFA therapy is not established in patients with CHF (Table 3). Although there are experimental data showing antiarrhythmic effects, the true clinical benefit of longterm PUFA application is very vague in patients with CHF.2,43,47,64–70 There is a good deal of supporting evidence for the use of upstream therapies, mostly in favor of modification of the RAAS axis. It is, therefore, entirely appropriate that drugs acting beneficially on the RAAS are prescribed in the heart failure population using the additional benefit on the predisposition to AF to provide supporting arguments.

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