New Insights into the Mechanistic Links between Inflammation, Oxidative Stress and AF, and Prevention of AF: A Basic Scientist’s Perspective

David Van Wagoner, PhD

David Van Wagoner, PhD

The problem of AF is a challenging one. With an open mind and a focus on the mechanisms, there are exciting opportunities ahead.

“We often conclude that, as atrial fibrillation (AF) occurs with increasing frequency with advancing age in both men and women, the occurrence of AF is inevitable,” David Van Wagoner, PhD (Cleveland Clinic Foundation, Cleveland, OH) told AF Symposium News ahead of his presentation.

“I have had the good fortune as a basic scientist to work with clinical colleagues who treat patients with AF since 1993. In the past we years, much progress has been made in understanding the mechanisms and improving he treatment of AF. However, it remains clear that even the latest ablation therapies are frequently ineffective in suppressing AF and/or its rapid recurrence.”

He continued: “As someone trained as a basic and translational electrophysiologist, I am very interested in the fundamental mechanisms of AF. One of the first questions that I addressed in the 1990s was whether AF was primarily a problem due to faulty ion channel activity that could best be treated by blocking those ion channels. With a few exceptions due to sporadic and rare genetic mutations, the answer has been a pretty clear ‘no.’ The ion channel distribution and activity in patients with no history of AF. We and others have found consistent changes in ion channel activity in persistent/longstanding persistent AF (particularly down regulation of the L-type calcium channel (CACNA1C) current (I Ca’L ) and the transient outward potassium current (I TO ). As the loss of these currents contributes to reduced contractility, further blocking these channels was clearly not a logical approach. There have been many efforts to identify and block ‘atrial selective ion channels’; the progress with these has been frustrating or negative.”

“In the early 2000s, we did some for the first studies that implication oxidative stress as a potential mediator of atrial dysfunction; oxidants interact nonspecifically with cellular lipids and protein, and can cause previously functional proteins to become dysfunctional,” explained Dr. Van Wagoner. “Recent studies have showed that, as in aging-related neurologic conductions such Alzheimer’s and Parkinson’s diseases, processing of the dysfunctional proteins (proteostasis) is impaired in hearts stressed by either excessive stimulation rate of by hemodynamic changes in the atria (Figure 1). 1 Many oxidized proteins can forma aggregates that begin as pre-amyloid oligomers that are cytotoxic; in the atria, these oligomers are often formed by atrial natriuretic peptides that cannot be properly processed. Over time, this becomes evident in atrial tissues as amyloid aggregates, much like the tau proteins that accumulate in the Alzheimer’s brain.”

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Hemodynamic stress also promotes activation of the renin-angiotensin-endothelin-1-aldosterone system. This system promotes myofibroblast activation and accumulation of interstitial fibrosis that surround the stressed and/or injured atrial myocytes. Altered and slowed conduction is common following experimental infusion of angiotensin-II as well as in hypertensive patients, obese patients, or those with sleep apnea (Figure 2). 2 Increased sympathetic nerve activity coupled with oxidation of RyR2 receptors my promote ectopy that triggers the onset of AF. Further, it is likely that the association of sleep apnea and obesity (which is both a sleep apnea and AF risk factor) is due to their impact on arrhythmia substrate changes (atrial hypertrophy and fibrosis).

“From these mechanist studies, it is clear that there are novel pathways that have not yet been clinically evaluated, where targeted interventions may have a positive impact on AF risk—if we can intervene early enough,” he remarked. “With the knowledge that atrial ectopy is a powerful predictor of future AF, and improving wearable and implantable technology to monitor atrial ectopy, it seems plausible that steps toward AF prevention may be realized. During a meeting organized by the Heart Rhythm Society, a group of basic and translational scientists met to address the challenge of AF prevention—in both the primary and secondary sense. 3 Several of these are summarized in Table 1. Also important but not listed in Table 1 are the exciting approaches being pioneered by Dr. Sanders, Kalman, and colleagues in Australia 4 ; there seems to be great potential for reducing the burden of AF by implementing a greater focus on lifestyle changes that increase fitness and reduce body fat mass in a sustainable manner.

Dr. Wagoner concluded: “The problem of AF is a challenging one. With an open mind and a focus on the mechanisms, there are exciting opportunities ahead."


  1. Gutierrez A, Van Wagoner DR, Mehra R. Oxidant and Infalmmatory Mechanisms and Targeted Therapy in Atrial Fibrillation: An Update. J Cardiovasc Pharmacol. 2015;66(6):523-529.
  2. May AM, Van Wagoner DR, Mehra R. Obstructive Sleep Apnea and Cardiac Arrhythmogenesis: Mechanistic Insights. Chest. 2016 16 Sep 29 [Epub ahead of print]
  3. Van Wagoner DR, Piccini JP, Albert CM, et al. Progress toward the prevention and treatment of atrial fibrillation: A summary of the Heart Rhythm Society Research Forum on the Treatment and Prevention of Atrial Fibrillation, Washington, DC, December 9-10, 2013. Heart Rhythm. 2015; 12(1):e5-e29.
  4. Naliah CJ, Sanders P, Kottkamp H, Kalman JM. The role of obesity in atrial fibrillation. Eur Heart J. 2016;37(20):1565-1572. PMID:
Tammy Griffin-Kumpey