Atrial Fibrillation and Non-cardiovascular Diseases: A Systematic Review

Atrial fibrillation (AF) is the most common cardiac arrhythmia and is associated with an unfavorable prognosis, increasing the risk of stroke and death. Although traditionally associated with cardiovascular diseases, there is increasing evidence of high incidence of AF in patients with highly prevalent noncardiovascular diseases, such as cancer, sepsis, chronic obstructive pulmonary disease, obstructive sleep apnea and chronic kidney disease. Therefore, considerable number of patients has been affected by these comorbidities, leading to an increased risk of adverse outcomes. The authors performed a systematic review of the literature aiming to better elucidate the interaction between these conditions. Several mechanisms seem to contribute to the concomitant presence of AF and noncardiovascular diseases. Comorbidities, advanced age, autonomic dysfunction, electrolyte disturbance and inflammation are common to these conditions and may predispose to AF. The treatment of AF in these patients represents a clinical challenge, especially in terms of antithrombotic therapy, since the scores for stratification of thromboembolic risk, such as the CHADS2 and CHA2DS2VASc scores, and the scores for hemorrhagic risk, like the HAS-BLED score have limitations when applied in these conditions. The evidence in this area is still scarce and further investigations to elucidate aspects like epidemiology, pathogenesis, prevention and treatment of AF in noncardiovascular diseases are still needed.


Prophylaxis
Administration of 300 mg of amiodarone intravenously over 20 minutes immediately after surgery for lung cancer and an oral dose of 600mg twice daily during the first five postoperative days reduced the risk of AF by 23% 10 . Nojiri et al 11 reported that patients with elevated BNP levels (> 30 pg/mL) who received low-dose human atrial natriuretic peptide had lower incidence of postoperative AF than patients who received placebo.

Treatment
Landiolol, an ultra-short-acting beta-blocker, when administered to a small group of patients who developed AF after lung resection, experienced a significant reduction in heart rate and early restoration of sinus rhythm as compared to verapamil and digoxin 12 .

Prophylaxis
A recent study investigated the effect of esmolol in patients with septic shock 13 . Although reduction in heart rate may lead to improvement of cardiovascular function, treatment of sinus tachycardia, and consequently potentially prevent AF, the use of esmolol in sepsis is still controversial. Further studies to establish the recommendations regarding prophylaxis are needed 14 .

Treatment
According to current recommendations, reversal of hypoxemia and acidosis should be the first therapeutic approaches in new-onset AF. However, in patients who become hemodynamically unstable, synchronized cardioversion should be considered, although the strategy for rhythm control may be ineffective until the respiratory decompensation is corrected.
For ventricular rate control, diltiazem or verapamil are the recommended drugs for COPD patients. The use of β-adrenergic agonists and theophylline is discouraged, since they may precipitate atrial fibrillation and make ventricular rate control difficult. Non-selective beta-blockers, sotalol, propafenone and adenosine are contraindicated in patients with bronchospasm 15 .

Prognosis
Few studies have investigated the effect of AF on OSA. OSA is associated with increased risk of stroke, but it is not clear whether AF increases the risk of stroke in OSA. The Sleep Heart Health study 16 , a prospective study which followed up 5,422 individuals with no history of stroke for a mean of 8.7 years, reported that OSA increases the risk of stroke, particularly in men in the highest severity quartile (obstructive apnea-hypopnea index > 19: adjusted HR 2.86, 95% CI 1.1-7.4). After secondary analyses that excluded individuals with AF, lower OR for stroke was observed in OSA patients, with no change in overall results, suggesting that AF does not fully explain the association between OSA and AF. However, the proportion of patients with AF in this study was small (2%), and the authors suggested that underdiagnosed paroxysmal AF was a mediating factor.
More recently, a case -control study involving 108 individuals reported a significant association between AF and stroke, even after adjusting for other risk factors (corrected OR 5.34, 95% CI 1.79-17.29) 17 . Further studies to confirm whether AF increases the risk of stroke in patients with OSA are necessary.

Pathophysiology
In addition to cardiovascular diseases, other comorbidities are commonly encountered in AF and CKD. Curiously, the combination of CKD and anemia increases substantially the risk of stroke (HR 5.43, 95% CI 2.04-14.41) 18 , which may be related to an increased risk for AF. In fact, anemia, a common complication of CKD, and CKD are independent risk factors of AF, and a recent study demonstrated a synergic association between CKD and anemia for AF onset 19 .

Treatment
Several international anticoagulation therapy guidelines in CKD are currently available. In 2011, the Kidney Disease Outcomes Quality Initiative recommended that anticoagulation therapy should only be prescribed for patients with CKD as a secondary prevention of stroke and careful monitoring of patients, and not as primary prevention, since these patients were not included in controlled, randomized studies 20 . However, the 2014 AHA/ACC/HRS guidelines support the prescription of warfarin (INR 2.0-3.0) for oral anticoagulation for patients with nonvalvular AF, CHA 2 DS 2 VAS C ≥ 2, and who have ESRD or are on hemodialysis, recognizing that anticoagulation increases the hemorrhagic risk in this population. With respect to AF in moderate to severe CKD with CHA2DS2-VASc ≥ 2, treatment with lower doses of direct thrombin or factor Xa inhibitors may be considered, although safety and efficacy have not been established 15 .  43 , 2007 Retrospective unicentric 3,542 The magnitude of nocturnal oxygen desaturation is an independent risk factor for AF in patients aged less than 65 years.
Gami et al 44  -CKD, particularly 3-5 stage CKD, is associated with increased risk of AF.
-After AF development, the mortality rate is higher in patients with advanced CKD than in patients without CKD