Corresponding Author:  Saina Attaran 46, Queen of Denmark Court, Finland Street London, SE16 7TB UK.

Abstract

Background

Post cardiac surgery atrial fibrillation is common after cardiac surgery. Despite the advances in medical and surgical treatment, its incidence remains high and unchanged for decades. The aim of this review was to summarize studies published in 2011 on identifying factors, prevention strategies, treatment and effect of post operative atrial fibrillation (POAF) on the outcome after cardiac surgery.

Methods

A review was performed on Medline, Embase and Chocrane on all of the English-language, peer-reviewed published clinical studies on POAF; studies investigating the mechanism of developing POAF, prevention, treatment and outcome were all included and analyzed. Case reports, studies on persistent/preoperative atrial fibrillation (AF), POAF after cardiac transplant, congenital cases and nonclinical studies were all excluded. We have also valuated these studies based on the type of the study, their originality, impact factor of the journal and their limitations.

Results

Overall 62 studies were reviewed and analyzed; 26 on POAF predictive factors, 31 on preventative strategies and 6 on the outcome of POAF. Of these studies only two were original and the remaining were either performed in AF in general population (n=10) or had been studied and reported several times before in cardiac surgery (n=50). The average impact factor of the journals that POAF was published in was only 2.8 ranging between 0.5 and 14.5.

Conclusion

Post cardiac surgery atrial fibrillation is a multi-factorial and complex condition. Cardiac surgery may be a risk factor for developing POAF in patients already susceptible to this condition and may not be a complication of cardiac surgery. Future studies should mainly focus on histological changes in the conductive tissue of atrium and related treatment strategies rather than predictive factors of POAF and more funding should be made available to study this condition from new and entirely different perspectives.

Introduction

Post Operative Atrial fibrillation (POAF) is common after cardiac surgery. POAF predisposing factors are unclear and its incidence is reported to be between 15-50%.^1,2 POAF is considered a favorite research topic and hundreds of original articles and reviews investigate POAF every year. These studies focus on predictive and risk factorsof developing POAF, strategies to prevent POAF, treatment options and effect of POAF in short and long-term, on the outcome and survival of the patients post cardiac surgery. Majority of these studies have adopted a similar trend that repeat previously published data describing certain predictive factors that increase POAF rate. These studies still find their way into the literature without any additional value to what we already know about POAF.

In this review, we have assessed all the published studies in 2011 investigating POAF; we aimed to create a summary of all the recent studies published in one year and also we have evaluated them and their contribution to the current literature. We also discussed possible future studies that may add benefit to this morbid condition post cardiac surgery.

Methods

A review was performed on Medline, Embase and Chocrane on all the English-language, peerreviewed published clinical studies on POAF as primary or secondary endpoint. Animal models, studies on chronic/persistent AF, case reports and AF after congenital cardiac surgery, thoracic surgery and transplant cases were all excluded. Overall 61 studies that met our criteria were reviewed.

They were divided into three main categories (Figure 1); A) Predictive/identifying factors, B) Preventative measures and C) Outcomes and Consequences.

We also developed a scoring system to assess these studies based on their originalities; The studies were scored.^{1,2 or 3} based on their originality, 3) Original topic that has never been studied previously in cardiology or cardiac surgery, (2) Studies that have been reviewed in cardiac patients and in general but it is the first time that the hypothesis is being investigated in cardiac surgery, (1) Studies that have been assessed in cardiac surgery before and data has been published several times with similar or different conclusion (Table 1).

Figure 1: Publications on POAF in 2011

Results

Summary of the publications are listed in Table 1. There were only two original articles (scoring 3), 10 scored 2 (studies preformed on cardiac patients and general population but not on POAF), and the rest or 50 papers were studies and reports that were not original and were performed several times before by different authors and in various institutions reporting similar results as the previous ones with only minor differences. The average impact factor of the journals that these articles were published was only 2.83 ranging between. ^0.5-14.5 Of all the 62 studies, 26 were on POAF predictive factors (A), 30 on prevention (B), and 6 on the outcome (C). In all of these studies POAF rate has been reported to be between 3 to 50%.

Table 1: Comparison of Apixaban with Dabigatran and Rivaroxaban

Predictive factors

In 2011, over 40% of studies on POAF were analyzing predictive factors of developing POAF and are divided in three categories:

A1. Patient factors

The main patient related predictive factor studied in 2011 was the effect of race on POAF; studies were performed on over 30,000 North American patients who underwent cardiac surgery. They have emphasized the findings of many other studies published previously and showed a link between genetic specifications /race and atrial fibrillation in the normal population as well as POAF.^3-5 All of these reports have concluded that despite higher incidences of preoperative co-morbidities in black people and African/Americans, the risk of developing POAF is 30-40% less compared to the European/Americans (p<0.05).⁶ Besides genetic association, another explanation was linked to the smaller size of left atrium in black people compared to the white patients which resulted in lower risk of developing POAF.⁴

Other preoperative patient factors such as history of high blood pressure, heart failure, and age, as well as, operative and postoperative features such as mitral valve surgery, prolonged cross-clamp and cardio-pulmonary bypass time, use of cardioplegia, inotropic use and intra-aortic balloon pump have all have been reported again and shown to be associated with higher incidence of POAF.^7-9 79 Most of these studies were retrospective, single institutional reports and on a small number of patients undergoing cardiac surgery. They have also shown that the use of opium preoperatively and postoperative complications such as pneumonia, renal impairment and transfusion rate can all increase POAF. ^{8, 9}

Another important patient related factor is body mass index (BMI) and reports in over 20,000 patients showed higher incidence of POAF with high BMI. ^{10, 11} The mechanism of this association have been reported to be increased plasma volume and left ventricular mass, ventricular diastolic dysfunction, increased basal sympathetic tone, and a hypercoagulable state in obese patients that promotes systemic inflammation that are known to be responsible for POAF in obese patients.¹²

Despite these frequently published studies on POAF, one paper has focused on POAF post discharge; the authors have concluded a significant decrease in the AF rate on a small number of patients with higher physical activity during the year before cardiac surgery. Although an interesting concept, the validity of the study is questionable as preoperative arrhythmias and medications on discharge have not been taken into consideration when analysing the results¹³ Incidence of post discharge AF was also shown to be associated with the presence of postoperative arrhythmias as well as early onset POAF.¹⁴

A2. Cardiac factors

Studies in this category investigated cardiac related predisposing factors. The association between POAF with preoperative ECG specifications, echocardiographic and angiographic features, as well as some histological changes were investigated: Kinoshita et al investigated standard deviation of all normal-to-normal QRS complexes (SDNN) and square root of mean of sum of squares of differences between adjacent normal-to-normal QRS complexes (RMSSD) of the patients admitted days before their cardiac operations and concluded that reduced heart rate variability decreases the rate of POAF significantly. ¹⁵ In over 13,000 patients undergoing cardiac surgery P-wave amplitude in leads aVR and V(1) and a less negative P-wave amplitude in aVR were strong predictors of POAF.¹⁶ The differences in the ECG patterns seen in these patients can be a demonstration of the morphological changes in the diameter of the cardiac chambers and some studies have focused on identifying the predictors of POAF based on the echocardiographic features; left ventricular diastolic dysfunction, decreased ventricular compliance, left ventricular segmental kinetic disturbances, decreased left atrial emptying capacity all have been identified to be associated with increased risk of POAF. ^17-19 These changes in the morphology and compliance of cardiac muscles can result in stretch of the pulmonary veins and increase in their arrhythmogenic activity.^{20, 21} It has also been shown that proximal lesion in the right coronary artery, increases the risk of developing POAF. ²²

Another study has compared left ventricular electro-mechanical delay (LVEMD) by echocardiogram and Doppler imaging postoperatively and concluded that despite comparable LVEMD preoperatively, LVEMD is prolonged postoperatively in patients who develop POAF. ²³ Conclusions from these findings can be rather confusing as some studies suggest preoperative differences in cardiac morphology that can result in POAF and the other group showed change in postoperative characteristics that can predict developing POAF. Latter was done on only 16 patients.²³ and will require further studies prior to a concrete conclusion and preoperative characteristics have been found to be more important than postoperative parameters in developing POAF.

Based on these findings, some investigators have analyzed atrial samples for any identifiable differences between the patients who develop POAF and who remain in sinus rhythm. Samples were tested for the accumulation of autophagic vesicles and lipofucin, and have shown that impaired cardiac autophagy and ultrastructural remodeling were predictive factors for developing POAF. ²⁴ Similarly, left atrial samples have shown changes in 19 special proteins, proinflammatory state and apoptosis to be different between patients who develop POAF and patients with no AF. ²⁵ These studies further stress the theory of the presence of an organic factor preoperatively which can result in POAF. Even genetic studies have indicated variants in 4q25 to be associated with higher incidence of POAF. ²⁶

A3. Biochemical markers

Presence of higher level of certain circulatory biochemical markers preoperatively in patients with POAF compared to those in SR also has attracted investigators' interest for years. In 2011 alone, several studies were published on this topic and results showed, not for the first time, that high circulatory Brain Natriuretic Peptide (BNP), tropnin I, C-reactive protein (pre and postoperatively) and Docosahexaenoic acid (DHA) was associated with increased POAF rare. ^27-32 Conversely, circulatoryArachidoinc acid levels are shown to be lower pre and postoperatively in patients with POAF.³¹ This was a novel finding. However prostaglandin series derived from AA have been shown to have arrhythmic effects, which is contrary to the effect of free AA in the circulation described in this study.

In addition, lower Hemoglobin A1C (HbA1C) preoperatively was shown to increase POAF. This was in accordance with another study from 2008 on a large number of patients undergoing cardiac surgery; Halkos et al revealed that high levels of HbA1C results in more postoperative morbidities, but less POAF. ³⁴ These findings, surprisingly contradicts with studies showing higher incidence of POAF in diabetic patients and studies on the general population that supports a positive and independent relationship between HbA1C levels and incidence of AF. ³⁵

B. Prevention

Despite no clear etiological factor for POAF, in 2011, more studies (n=29) were conducted investigating prevention from POAF. They mainly focused on medical therapy (B1) and some on surgical techniques (B2) to reduce POAF .

B1. Medical therapy

Several reports focused on long-chain, omega 3 fatty acids; prevciously there were some initial promising results with preoperative use of Omega-3 in reducing POAF, however further analyzes and studies on larger population showed no statistically proven benefit of this group of fatty acids in reducing POAF. In 2011, one report on a small group showed positive results³⁶ , however another study 37 and two meta- analysis published in 2011 showed no real place for Omega-3 in decreasing the risk of POAF. ^{38, 39}

Other groups investigated the effect of medications that reduces inflammation; Postoperative Colchicine has been tried which showed POAF reduction but adverse effects are seen with its use that prevented further studies. ⁴⁰ Naproxen, despite being an anti-inflammatory medication, has shown to have no effect in the reduction of POAF but its preoperative use has decreased POAF duration. ⁴¹

The inflammation theory has encouraged the investigators to use corticosteroids but no reduction in POAF in patients who underwent OPCAB. was observed, however its use postoperatively showed reduction in POAF after a study in all cardiac procedures. ⁴⁴ The authors believed that in OPCAB due to a less inflammatory response, no major effect of these anti-inflammatory steroids can be observed. ^{42, 43}

Another group of medications with anti-inflammatory properties that have been used for several years is Statins. In 2011, of five studies and one meta-analysis on the role of pre and postoperative Statins in POAF, except in one retrospective study. ⁴⁵ , all have concluded that Statin reduces POAF. ^{32, 46-49} In the study that showed no benefit with the use of Statin patients with preoperative AF were also included which may have influenced the results. Overall, Statins have been shown to have a great role in prevention from POAF, however treatment with Statins failed to eradicated POAF completely.

Angiotensin-converting enzyme inhibitors (ACEI) and alpha-receptor blockers (ARB) are another group of medications that have been assessed for the prevention of POAF. Their anti-inflammatory properties alongside several other characteristics such as lowering blood pressure and reducing volume overload were expected to reduce POAF, however results from several studies were conflicting; a RCT with Irbesartan showed significant decrease in POAF. ⁵⁰ On the other hand, a retrospective study on over 3000 CABG patients showed in fact, ACEI was a risk factor for developing POAF. However, in their study patients with preoperative AF were not excluded and higher number of AF patients were on ACEI, which could have affected the results. ⁵¹ These two studies published in 2011 were contradictory to the previous reviews that showed a statistically significant decrease in POAF recurrence but no benefits with the use of ARBs. ⁵²

Benefits of antioxidants such as vitamins C and E have been studied extensively; a meta-analysis on five randomized controlled trials (RCT) and a RCT have shown reduction in POAF [53, 54]. These findings were in accordance with previously published data, however data on cost effectiveness and the duration required for the use of these vitamins are yet to be determined.

Amongst all the medications that have been tried in prevention of POAF, the value of antiarrhythmic medications in the prevention and treatment of POAF remains invincible and the evidence has been considered (I) and (IIa) for beta-blockers and Amiodarone respectively.⁵⁵ Studies continue to explore new and old antiarrhythmic agents and different regimes; Bisoprolol in a recent RCT has been shown superior to Carvedilol in POAF reduction in patients with impaired ventricular function. ⁵⁶ This is possible that its greater beta selectivity increases its anti-arrhythmogenic effects. Landilol, an ultra short acting beta-blocker, with very high beta1 selectivity has been infused intra-operatively and which showed a significant POAF reduction compared to saline. ⁵⁷ but did not compare Landilol with other beta-blockers. Landilol was introduced in 2002 however data regarding its clinical usage is yet to be investigated Another treatment against POAF that has been tried recently is Ranolazine, an antianginal agent that inhibits abnormal late sodium channel current in atrial and ventricular tissue. In comparison with preoperative administration of Amiodarine, Ranolazine was shown to be more effective in decreasing POAF. ⁵⁸ However, in that study patients in the Amiodarone group had lower ejection fraction compared to the patients on Ranolazine, which could have affected the results. It is well known that Amiodarone is one of the best antiarrhythmic agents for POAF and still some centers continue to publish their data on Amiodarone. ⁵⁹

Besides the studies on medical agents, a metaanalysis on the infusion of glucose/insulin/potassium (GIK) pre- intra- and postoperatively, has shown that POAF decreased in patients with diabetes but the incidence of POAF in the rest of the patients was unchanged. ⁶⁰ With the results of this report and the study on hemoglobin A1C described earlier. ³³ , no conclusion can be drawn from these contradictory results, one showing worse diabetic control preoperatively decreases POAF. ³³ and the other one confirms better diabetic control peri-operatively to decrease POAF. 60 Finally, in this category a small study investigated the role of holistic therapy preoperatively on a small group of patients and found no effect on POAF. ⁶¹

B2. Surgical strategies

Despite the importance of different surgical strategies, only a few papers were published last year on this topic; posterior pericardiotomy is one of the well-known techniques to decrease POAF, and another RCT in 2011 has shown POAF to be as low as 3% . ⁶² Despite, its usefulness the technique is not widely adopted by the cardiac surgeons and care must be taken to make a small incision to prevent cardiac herniation. Significant POAF reduction has also been reported with minimized perfusion circuits. ⁶³ and extracorporeal vacuum assisted devices. ⁶⁴ on small group of patients. The authors have concluded less hemodilution, transfusion requirement and less inflammatory marker release with short circuit and better organ perfusion with vacuum device that result in better outcome and less POAF. Changes on cardioplegia have been tried and despite the myocardioprotective effects of magnesium a study by Caputo has shown no reduction in POAF with high dose magnesium in warm blood cardioplegia.⁶⁵ Interestingly, same authors found a two-fold decrease in POAF with high Magnesium in warm blood cardioplegia in a study published in 2002. ⁶⁶

C. Outcomes and consequences

Despite POAF being a short-lived and self-limiting complication, it has been shown to affect the outcome after cardiac surgery in short- and long-term and result in devastating complications. Postoperative delirium has been shown to be associated with several factors one of them POAF. Delirium was previously related to preoperative AF. ⁶⁷ , however a direct link between POAF and developing delirium postoperatively that was reported in this study is questionable as POAF commonly occurred on the third postoperative day whereas signs of delirium in the study by Andrejaitiene et al was observed prior to that and during their stay at intensive care unit .⁶⁸ Other studies, showed statistically significant association between POAF and stroke. ^69-72 A study on over 17000 all cardiac patients by the author of this manuscript showed significantly lower survival rate in patients who develop POAF at five and ten years. However, after propensity matching for the preoperative characteristics only in the CABG patients POAF increased the postoperativ e complications, stroke rate and sur viv al.⁷³ This has been reported before and it w as speculated that unlike in CABG cases, patients undergoing v alv e or other cardiac operations are subjected to better and more frequent follow ups and in cases of mechanical v alv es regular anti coagulation reduces stroke in this group of pa tients who may dev elop AF ev en after discharge. ⁷⁴

Discussion

Postoperativ e A trial Fibrillation is a common arrhythmia with no clear etiology. Studies ov er the decades hav e tried to analyze the role of intrinsic and extrinsic cardiac nervous system in dev elop ing AF; it is believ ed that stimulation of the v a gosympathetic trunks and autonomic innerv ation from the ganglionated plexui of the heart to heter ogeneously shorten refractoriness across the atria, results in a premature or series of atrial premature beats to induce and sustain atrial fibrillation^75-76 , especially the presence of this intrinsic cardiac au tonomic nervous system, in conjunction with the extrinsic projections of the v agosympathetic sys tem from the brain and spinal cord to the heart are thought to be involv ed in the dev elopment of the AF.^77-80

How ev er, the main reason for activ ation of these intrinsic and extrinsic nervous systems after car diac surgery is not fully understood. It has been shown that cardiac surgery may lead to decreased baroreflex sensitivity and result in heart rate v ari ability . How ev er, this concept has not been thor oughly inv estigated. In addition, it is not clear that why some patients and not all dev elop POAF. ⁸¹

In this review, w e hav e summarized all the studies that have been published on postoperative atrial fibrillation in a full year. This gives the reader an ov erview of what has been new on POAF and will encourage the inv estigators to focus on new ideas of identifying the causes, and prev ention from and treatment of POAF, rather than repeat ing and publishing the same results every year. Based on our analysis, only two articles out of w ere original with another ten being previous reports of AF in general population, which now examines the same theory on POAF for the first time. The low impact factor of the journals that these articles were published in also signifies that this important morbidity that occurs or manifest after cardiac surgery is not studied widely from new perspective and not many laboratories and research funds are dedicated to investigate POAF in the recent years.

Based on this review and several other publications from previous years, we know that POAF is a common complication that despite all the advances in cardiac surgery no etiology or treatment for it has yet been identified. The main reason is that POAF is a multi-factorial condition and unanswered questions are dominating our knowledge regarding all types of atrial fibrillation including POAF. Up to date and without any conflicting results, age is considered an independent predictor of all types of AF; at the age of 40 life-time risk of developing AF is one in four. ⁸² Other factors such as valvular heart disease, ischemic heart disease, heart failure, high blood pressure, and several other co-morbidities increase the risk even more. ^7-9 Some investigators believe the mechanism of the POAF is completely different from that of AF in the community. ⁸³ This theory and many other authors and investigators believe that POAF is a complication of cardiac surgery. However, by reviewing the published studies, we believe that atrial fibrillation is a complex disease that can manifest itself after certain conditions, one of them being cardiac surgery.

Several studies each year investigate POAF from different angles, some hope to offer new strategies to prevent POAF and some still report predictive factors of POAF. Of the studies investigating the topic this year, only the ones assessing the histological changes within atrial samples were original . ^{24, 25} This is an unexplored area, which can influence what we already know or hope to achieve regarding POAF. It is clear that atrial fibrillation is the manifestation of changes in automaticity levels of the conductive atrial cells. Age increases the degree of atrial fibrosis affecting the configuration of conductive cells. Similarly, factors such as size of the atrium in valvular heart disease or race related atrial appendage sizes described in this review. ^3-5 , decreased cardiac compliance stretching atria and pulmonary vasculature all affect cellular morphology. ^17-19 Presence of circulatory markers, on the other hand, has shown varying degree of association with POAF, therefore the effect of cardiac surgery, inflammation, inflammatory markers and the use of cardiopulmonary bypass can all be considered predisposing factors of POAF. Based on these findings, cell membrane stabilisers and medications decreasing sympathetic activities such as beta-blockers are considered best prevention for POAF. ^55-57

Furthermore, low survival rate in CABG patients who develop POAF was significantly affected by POAF. ⁷³ It is hard to accept that a condition that may have lasted only a few hours to a few days can increase the mortality rate even after 10 years. It is clear that POAF is the result of preoperative changes in the atrial tissue and maybe these patients without cardiac surgery would have developed AF at some point in the future but this is a theory that cannot easily be investigated.

In conclusion, we believe that studies should move away from just reporting AF rate and common predicting factors, as they do not offer a lot of benefit, and concentrate on changes at the histological level or the role of intrinsic and extrinsic autoimmune nervous system in developing postoperative AF, and hopefully treatment options that aim to improve, revert or slow down these changes. With POAF still being a common post cardiac surgery morbidity that can increase the cost of treatment postoperatively with devastating effects on the outcome in short and long-term, more funds and research laboratories should be dedicated to investigate POAF.

Disclosures

No disclosures relevant to this article were made by the authors.

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