Upstream Treatments for Atrial Fibrillation

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Atrial fibrillation (AF) is the most frequently observed sustained cardiac arrhythmia encountered in clinical practice. Its incidence is increasing in the US.1 Numerous risk factors have been implicated in the development of AF, including non-modifiable risk factors such as age and gender, modifiable risk factors such as obesity—itself a risk factor for obstructive sleep apnea (OSA)—and smoking, and disease-specific risk factors such as hypertension (HTN), diabetes, heart failure (HF), coronary and valvular heart disease (particularly mitral regurgitation), and thyroid disease.2–5 The aim of this paper is to discuss the impact of the ‘upstream’ modulation of some these risk factors on the subsequent development of AF.

Obesity and Obstructive Sleep Apnea

The prevalence of obesity continues to rise at an alarming rate and represents a major public health concern in the US.6 Cardiovascular disease represents one of the major sequelae of this condition.7 Previous research has suggested that adiposity may adversely influence cardiac remodeling, thus raising the likelihood of AF as a possible consequence of obesity.8
The Framingham Heart Study examined the association between body mass index (BMI) and the risk of developing AF in a cohort of 5,282 patients.9 After 13.7 years of follow-up, 292 men and 234 women developed AF. After adjustment for age, a one-unit increase in BMI was associated with a 5% increase in the risk of AF for men and 4% for women. Of note, the relative risk of developing AF was 45 and 49% in obese (BMI ≥25) men and women, respectively. The higher risk of developing AF may be related to the left atrial (LA) enlargement seen in these patients. For example, the mean LA diameter was significantly greater in obese men (4.4cm) and women (4cm) compared with normal (BMI ≤25) men (3.8cm) and women (3.5cm).
Obesity is also the main patient risk factor for OSA, a condition that causes hypoxemia and nocturnal carbon dioxide retention and leads to sympathetic activation and surges in arterial pressure.10 Prospective data examining the effect of treatment of OSA on arrhythmias are currently limited. Kangala et al. evaluated the risk of recurrent AF following electrical cardioversion in patients with OSA.11 They identified 39 patients with OSA who underwent electrical cardioversion and then had at least 12 months of post-cardioversion follow-up.

Within this cohort, 27 patients were identified as being non-compliant with continuous positive airway pressure (CPAP), whereas the other 12 patients were compliant. A recurrence of AF was observed in 22/27 (82%) non-compliant patients compared with 5/12 (42%) compliant patients (p=0.013). Of note, the non-compliant patients had a worse outcome despite having a lower BMI and a lower likelihood of being hypertensive compared with compliant patients. There also appeared to be an association between lower nocturnal oxygen saturation and risk of recurrent AF. The effect of treatment of OSA with CPAP on the risk of developing AF merits further investigation.

Smoking

Cigarette smoking is frequently implicated in the development of cardiovascular disease, including cardiac arrhythmias. Nicotine, the active agent in tobacco, elevates plasma catecholamines, which increase myocardial work, which in turn has been implicated in the generation of supraventricular, junctional, and ventricular arrhythmias.12 Specifically, nicotine appears to induce AF—in a concentration-dependent manner—via inhibition of various ion channels including the cardiac Ito channels.13 A recent case-control study examined this phenomenon in atrial tissue by comparing 46 smokers with 49 non-smokers undergoing coronary artery bypass grafting (CABG).14 The right atrial appendage was examined for atrial fibrosis and collagen expression and the findings were correlated with the risk of developing post-operative AF. Nicotine use was associated with right atrial fibrosis, which was associated with a higher risk of post-operative AF. More data are needed to determine the relationship between smoking cessation and potential reduced risk of developing AF.

Hypertension and Heart Failure

Hypertension is associated with adverse electrophysiological and structural cardiac remodeling. This includes shortening of the atrial refractory period and prolongation of intra-atrial conduction, as well as LA dilation and left ventricular hypertrophy (LVH).5 In addition, AF can be associated with rapid ventricular response, which can contribute to left ventricular (LV) dysfunction and development of HF. The resulting elevation in LA filling pressures and LA dilation further contribute to the development of AF.15

The renin-angiotensin-aldosterone system (RAAS) is implicated in both HTN and HF through its affect on sodium and water retention, kaliuresis, collagen turnover, and organ remodeling. In turn, manipulation of the RAAS using either angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin-II receptor blockers (ARBs) is clinically beneficial.16,17 One particularly important benefit may be a reduction in the risk of developing de novo AF, particularly with ARBs.18

The Losartan Intervention for End Point Reduction in Hypertension (LIFE) Study evaluated 9,193 patients aged 55–80 years with treated or untreated HTN. All patients had LVH as defined by the Cornell voltage–duration product criteria on electrocardiogram (ECG). In these patients, the effect of an ARB (losartan) was compared with a beta-blocker (atenolol) on an endpoint of cardiovascular morbidity (myocardial infarction and stroke) and mortality.19 Both groups showed a similar reduction in blood pressure. New-onset AF was identified from annual in-study ECGs coded at a single ECG core center. Of the 8,851 patients without AF at baseline, after at least four years of follow-up new-onset AF occurred in 150 losartan patients versus 221 atenolol-treated patients, representing a 33% reduction in risk of developing AF in patients treated with losartan.
The Valsartan Antihypertensive Long-term Use Evaluation (VALUE) Trial compared the effect of the ARB valsartan with that of the calcium channel blocker (CCB) amlodipine on cardiac mortality.20 In this study, 15,245 patients from 31 nations were followed for 4.2 years until a pre-specified number of patients (1,450) had a primary cardiac event. New-onset AF (as assessed by an annual ECG) was a pre-specified secondary outcome of the study.21 The incidence of new AF (paroxysmal and persistent) was 16% lower in the valsartan arm (3.67% versus 4.34% in the amlodipine arm, p=0.044).
Similar data exist for an HF population. The Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) Program examined 7,601 patients with symptomatic HF.22 Patients were randomized to receive either the ARB candesartan or placebo. The primary end-point was all-cause mortality. In a pre-specified secondary outcomes analysis, patients without AF were surveyed by a case report form at their exit interview. Of 6,379 patients without AF at baseline, 392 patients subsequently developed AF. Risk factors for developing AF included advanced age, male gender, diabetes, and worsening HF. After adjustment for covariates, treatment with candesartan was associated with a 20% reduction (5.55% versus 6.74%, p=0.039) in risk of developing AF.

Lipid-lowering Therapy

In AF, atrial tissue is characterized by the presence of inflammatory cells.23 In addition, markers of inflammation such as C-reactive protein are elevated in patients with AF, which may contribute to hypertrophy and fibrosis.24 Lipid-lowering drugs such as the 3-hydroxy-3-methylglutaryl coenzyme A inhibitors (statins) may attenuate these adverse effects; thus, the role of statin therapy in the prevention of AF is under active investigation. The effect of lipid-lowering therapy on risk of developing AF was recently examined through a multicenter observational registry.25 Of 25,268 patients with an LV ejection fraction ≤40%, 7,027 patients were classified as having had AF. In these patients, lipid-lowering therapy (mainly statins) was associated with a 31% reduction in risk of developing AF, an effect that was independent of the lipid profile.

Fish Oil

Dietary interventions have also been proposed as a means to decrease the risk of developing AF. Specifically, n-3 polyunsaturated fatty acids (PUFAs) such as those found in soya, canola, and walnut oils have been shown to reduce coronary artery disease and have antiarrhythmic benefits.26 The latter may occur because PUFAs may stabilize the phospholipid membranes of cardiac myocytes and PUFAs may cause direct ion channel stabilization.27 In a recent study, the effects of PUFAs on stretch-induced vulnerability to AF was investigated in a rabbit model.28 After 12 weeks of dietary intervention with PUFAs, AF was significantly more difficult to induce.
To date, there are no randomized prospective trials that have evaluated the use of PUFAs for the primary prevention of AF. However, PUFAs have been studied in a post-CABG population, since these patients are at particularly high risk for developing AF.29 A cohort of 160 patients was given PUFAs beginning at least five days prior to CABG; PUFAs were then continued until hospital discharge. The primary end-point of the study was the risk of developing AF post-operatively, and a secondary end-point was length of hospital stay. Atrial fibrillation was observed in 39 patients (24%); patients treated with PUFAs were 54% less likely to have AF (12 versus 27 patients, p=0.013). Of note, treatment with PUFAs did not reduce the time to first episode of AF; however, the duration of AF was much shorter in the PUFAs group. Finally, the mean length of stay for the PUFAs group was shorter (7.3±2.1 days) compared with the control group (8.2±2.6 days).

Ongoing Studies

Several ongoing trials will further define the role of ARBs in patients with AF. The Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events (ACTIVE) Trial is enrolling 14,000 patients with AF.30 It will assess the effect of combination therapy with clopidogrel and irbesartan on the reduction of vascular events. Additionally, the Gruppo Italiano per lo Studio della Streptochinasi nell’Infarto Miocardico (GISSI) Atrial Fibrillation Trial will enroll 1,400 patients with recently symptomatic or cardioverted AF and compare the effect of valsartan versus placebo on recurrence of AF as well as the LA dimension and neurohormonal milieu.31

Conclusions

The ‘upstream’ management of certain risk factors may result in an important ‘downstream’ effect, namely a reduced likelihood of developing de novo AF. Towards this end, treatment of HTN and HF with an ARB and institution of lipid-lowering therapy appear to be the most promising approaches. Furthermore, recent studies also suggest promise for strategies designed to treat OSA or promote cessation of smoking, as well as dietary supplementation with n-3 PUFAs. 

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