Department of Cardiovascular Medicine, Cleveland Clinic Foundation,Cleveland, OH, USA
* Correspondence to: David R. Van Wagonering, Department of Cardiovascular Medicine, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA. Tel.: +1-216-444-0820; fax: +1-216-444-9155
E-mail address: vanwagd{at}ccf.org
This editorial refers to "Relationship between C-reactive protein concentrations during glucocorticoid therapy and recurrent atrial fibrillation"1 by J. Dernellis et al. on page 1100
Elevated C-reactive protein (CRP) levels are associated with numerous cardiovascular diseases, and have been shown to predict future cardiac events.1 Bruins and colleagues were the first to report an association between CRP elevation and the occurrence of atrial fibrillation (AF), in their case in the context of AF following cardiac surgery.2 They demonstrated that CRP levels peaked on the second post-operative day, and that increased levels of complement-CRP complexes peaked on the second or third post-operative day. The incidence of post-operative atrial arrhythmias similarly peaks at these times. AF following cardiac surgery affects 2050% of all patients (depending on age and type of surgery), and CRP levels in this setting can increase more than 100-fold.
In 2001, we reported that, apart from the surgical setting, low level CRP elevation was present in patients with paroxysmal atrial fibrillation and that these levels were even more elevated in patients with persistent AF. We concluded that CRP elevation may reflect the inflammatory processes that lead to structural remodelling of the atria, thus increasing the persistence of AF.3 At the same time, Dernellis and Panaretou4 reported similar results, demonstrating that CRP elevation was present in patients with paroxysmal atrial fibrillation and that CRP levels were greater in patients that failed cardioversion than in those in whom cardioversion was successful.
These studies thus suggested the intriguing possibility that CRP-lowering therapy might reduce the recurrence of atrial fibrillation. While anti-inflammatory therapies such as steroids have shown some efficacy in preventing atrial fibrillation following cardiac surgery5, no studies have prospectively evaluated the efficacy of anti-inflammatory therapies to reduce the occurrence or recurrence of atrial fibrillation in the general population of non-surgical AF patients. The scientific rationale for such a study is obvious, and the clinical potential for such a treatment approach may be great.
In this issue of the European Heart Journal, Dernellis and Panaretou6 report the results of a randomised study designed to test the hypothesis that anti-inflammatory therapy would decrease the recurrence of AF in patients treated early in the course of their disease. They report that patients receiving methylprednisone after their first episode of symptomatic persistent AF were less likely to develop recurrent AF, and that this correlated with a significant decrease in plasma CRP levels. Average CRP during follow up for the whole cohort (with and without methylprednisone therapy) correlated with the risk of AF recurrence, and a CRP cut-off point for detecting AF recurrence was reported. Importantly, patients in either treatment group with similar CRP values had the same relative risk for AF recurrence, thus supporting the concept that it is the anti-inflammatory effects of the steroids that decreases AF recurrence. This conclusion is plausible and consistent with previous studies suggesting a correlation between inflammation and non-post-operative AF. What should be the reaction to this study, and how do these results apply to the current practice?
The population in this study consisted of patients with newly diagnosed symptomatic AF who presented to their physicians soon after their first episode of symptomatic, persistent AF. The atria of patients with persistent AF undergo a process of electrical and structural remodelling that further promotes the persistence of AF.7 A role of inflammation in these processes has been suggested.3,8 In the present study, electrical and structural remodelling has probably been minimal, therefore the use of glucocorticoids may help to prevent these changes from developing.
The whole cohort in this study was kept on propafenone for the entire follow-up time. While this supports the authors' conclusion that methyl-prednisone was responsible for decreasing AF recurrence, it is still important to determine whether steroids, or other agents that decrease CRP, would have the same benefit when used without anti-arrhythmic agents. This is especially important for patients with structural and coronary heart disease in whom the use of agents like propafenone would be contra-indicated.
In this study methyl-prednisone was given daily for four months and, while no major side effects of steroid treatment were reported, potential serious complications from this relatively lengthy use of steroids must be considered. It also remains to be determined whether the reported success in using glucocorticoids is applicable to patients with more prolonged histories of AF. However, this important proof-of-concept study opens the door for additional studies that further investigate the use of steroids and other agents that have the potential to reduce CRP.
Statins have emerged as one of the most effective therapies to reduce cardiovascular risk. Furthermore, multiple recent studies have shown that statins can significantly decrease CRP levels. In the AFCAPS/TexCAPS trial, lovastatin therapy reduced the level of CRP independently of its effect on cholesterol levels and its benefit extended for patients with total cholesterol to HDL cholesterol ratio below the median if they had elevated CRP.9 This suggests a role for the pleiotropic effect of statins in decreasing cardiovascular risk. Nissen and colleagues have recently shown a greater decrease in CRP with 80 mg atorvastatin compared to 40 mg of pravastatin (36.4% vs. 5.2%, ).10 While the effects of atorvastatin on AF in the general population have not yet been evaluated, it is intriguing to note that, in the canine sterile pericarditis model, atorvastatin treatment both attenuated the elevation of CRP induced by the pericarditis, and prevented the induction of atrial fibrillation in this setting.11
Effective treatments for the prevention of recurrent AF have thus far been elusive. Thus, it is with hope that we note the positive results in the present study by Dernellis and Panaretou.6 Their results, in combination with other recent advances demonstrating a mechanistic link between inflammatory processes and the development of persistent AF, suggests that more effective and tolerable treatment and prevention strategies for this most common and vexing arrhythmia may soon be on the horizon.
Footnotes
References
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