New insights into the mechanism of lone AF

ATHENS, GREECE. Researchers at the University of Athens have just published an article regarding the association between lone atrial fibrillation (LAF) and inflammation and oxidative stress. The paper is highly technical, but could contain some important clues in relation to the development and recurrence of persistent LAF. In order to summarize the article it is necessary to become familiar with some technical terms.

Markers of Inflammation

  • Cytokine – A chemical messenger protein released by white blood cells to facilitate communication by immune system cells.
  • CRP (C-reactive protein) – A general indicator of systemic inflammation and infection.
  • TNF (tumour necrosis factor alpha) – A cytokine that promotes the inflammatory response which in turn causes many of the problems associated with autoimmune disorders such as rheumatoid arthritis, Crohn’s disease, asthma, psoriasis, etc.
  • IL-6 (interleukin-6) – A cytokine secreted by macrophages (large white blood cells that destroy or ingest foreign substances) to stimulate immune response to trauma.
  • IL-10 (interleukin-10) – An anti-inflammatory cytokine that can inhibit the production of inflammatory cytokines such as TNF.
  • sICAM-1 (soluble intercellular adhesion molecule-1) – An important biomarker of inflammatory processes, especially in atherosclerosis and cancer.
  • sVCAM-1 (soluble vascular cell adhesion molecule-1) – An important biomarker of inflammatory processes, particularly those involving endothelial cells (cells lining the heart and blood vessels). There is evidence that fish oil can decrease SVCAM levels in men over the age of 55 years.

Markers of Oxidative Stress

  • Malondialdehyde (MDA) – A prominent marker of oxidative stress formed by the oxidation of polyunsaturated fatty acids.
  • Nitrotyrosine (NT) – A marker for cell damage and inflammation caused by reactive nitrogen species (nitrogen oxide and peroxynitrite).

The Greek study involved 41 afibbers with persistent LAF (average age of 47 years, 27 males, 14 females). All participants were carefully screened to rule out hypertension, heart failure, coronary artery disease, valvular heart disease, myocarditis, and any other cardiomyopathy. Patients with diabetes, thyroid dysfunction, active inflammation, cancer, infection, renal failure, obstructive pulmonary disease, or alcohol or drug abuse were also excluded from the study. Thus, the study group truly consisted of otherwise healthy lone afibbers. A group of 41 equally healthy volunteers (matched for age, gender, and body mass) served as control (group C).

All study participants had blood samples drawn at baseline (24 hours before pharmaceutical conversion, or 1 hour before electrocardioversion) and at 1 hour, 24 hours, 1, 2, 4 and 6 weeks after cardioversion. All samples were analyzed for the above-mentioned biomarkers for inflammation and oxidative stress. Pharmaceutical conversion was attempted with amiodarone and all participants (except the control group) remained on amiodarone during the study period. During the 12-month follow-up after cardioversion, 25 of the participants remained in sinus rhythm except for 7 who experienced short episodes of afib (group A). Among the remaining participants, 8 had recurrence of persistent afib, 4 experienced episodes lasting longer than 30% of total ECG recording time, and 4 had paroxysmal episodes lasting longer than 6 hours (group B). In other words, cardioversion was largely successful in group A, but unsuccessful in group B. The results of the blood analyses were as follows:

Baseline Values

  • CRP levels were higher in group B than in groups A and C (no difference between A and C).
  • TNF levels were higher in group B than in group A and both were elevated compared to group C.
  • IL-6 was undetectable in controls, but 3 times higher in group B than in group A.
  • IL-10 was lower in group B than in group A, but both were significantly higher than in the control group.
  • sICAM-1 was highest in group B, followed by group A and controls.
  • sVCAM-1 was about the same in groups A and C, but substantially lower in group B.
  • MDA levels were significantly higher than controls in groups A and B with group B levels being twice as high as those in group A.
  • NT levels were significantly higher than controls in groups A and B with group B levels being about 50% higher than in group A.

From the above data it is clear that recurrence of afib was associated with a higher level of inflammation and oxidative stress.

Comparing the changes in the biomarkers evaluated post-cardioversion, the researchers conclude that the following markers could reliably (80% certainty) distinguish between afibbers who would largely remain in sinus rhythm (group A) and those who would not (group B). Thus, maintenance of sinus rhythm was associated with a low baseline level of MDA, a low level of IL-6 one week after cardioversion, and low levels of sICAM-1 and NT two weeks after cardioversion. The most reliable and potent markers of success were a greater than 36.1% decrease in IL-6 one week after cardioversion, a decrease in sICAM-1 of more than 5.2% two weeks following cardioversion, and a decrease in NT of more than 22.2% two weeks after cardioversion.

The researchers conclude that there is an association between persistent lone atrial fibrillation and the presence of oxidative stress and inflammation. They also point out that CRP is not a useful marker when it comes to LAF. Unfortunately, they also state, “It is still unclear whether the elevated levels of inflammatory and oxidative markers have a causative relation to AF or they are epiphenomena of the arrhythmia”. In other words, it is not clear which is the “chicken” and which is the “egg”.

Leftheriotis, DI, et al. The predictive value of inflammatory and oxidative markers following the successful cardioversion of persistent lone atrial fibrillation. International Journal of Cardiology, July 18, 2008 [Epub ahead of print]

Editor’s comment: Inflammation and oxidative stress have long been associated with atrial fibrillation. However, this is the first study to prove that the association is present in true lone afib and thus is not due to comorbid heart disease. The uncertainty as to whether the inflammation and oxidative stress causes afib or whether the continued presence of afib causes oxidative stress and inflammation, of course, makes it difficult to translate the findings of the study to practical advice for afibbers. It seems intuitively possible that inflammation could be either the cause or effect of afib, but it is a little harder to visualize how the presence of afib could result in oxidative stress. Perhaps the most likely explanation is that we are dealing with a vicious cycle in which inflammation and oxidative stress begets afib and afib begets inflammation and perhaps, oxidative stress. In this case, it should be possible to break the cycle either by cardioversion, or by dampening inflammation and oxidative stress. Since both systemic inflammation and oxidative stress have been implicated in a wide range of diseases and disorders, it would seem prudent for all afibbers to supplement with antioxidants (vitamin C, vitamin E, selenium, coenzyme Q-10, alpha-lipoic acid, etc) and anti-inflammatories (fish oils, Zyflamend, beta-sitosterol, bromelain, curcumin, boswellia, quercetin, Moducare).