AF Symposium 2017
Links Between Inflammation, Oxidative Stress and A-Fib
Predicting and Preventing A-Fib
One of the most important frontiers of A-Fib research is trying to determine why and how Atrial Fibrillation develops. Dr. David Van Wagoner of the Cleveland Clinic, Cleveland, OH talked about the mechanistic links between inflammation, oxidative stress, and A-Fib.
Oxidative stress can cause oxidants to interact with lipids and proteins and cause previously functional proteins to become dysfunctional. Proteostasis, the process of processing dysfunctional proteins, is impaired as in diseases like Alzheimer’s.
Stressors like sleep apnea and obesity impact arrhythmia substrate changes.
A-Fib hemodynamic stress or ‘stress activated’ changes (for example, by stressors like hypertension or obesity) produce reactive oxygen species (ROS) generation which can cause oxidized proteins to form amyloid aggregates like the tau proteins that accumulate in the Alzheimer’s brain. Stressors like sleep apnea and obesity impact arrhythmia substrate changes such as atrial hypertrophy and fibrosis.
These stress activated changes also promotes myofibroblast activation (fibrosis), inflammatory cytotine production, and heat shock endoplasmic reticulum (ER) stress.
Atrial Ectopy (extra beats)
Hemodynamic stress increases sympathetic nerve activity which promotes ectopy (extra beats) that trigger the onset of A-Fib.
Recommended Further Study
Dr. Van Wagoner recommends targeting and researching certain pathways in order to treat and even prevent A-Fib:
• Atrial Ectopy
• Atrial Fibrosis
• Proteostasis Modulation
He suggests that further study of these mechanistic pathways may help us both predict and prevent A-Fib. For example, monitoring for atrial ectopy can be a powerful predictor of future A-Fib.
Second Dr. Van Wagoner Presentation: Prevention of A-Fib
In a second talk, Dr. Van Wagoner built on his earlier presentation and laid out a game plan for research priorities to prevent Atrial Fibrillation:
1. Find the mechanisms underlying ectopy (extra beats). Why does ectopy predominately result in A-Fib in older people?
2. Identify the genes. signaling pathways, and mechanisms that impact the risk of A-Fib. How are they modifiable?
3. Determine the stages in A-Fib progression where reducing risk factors (obesity, sleep apnea, etc.) can reverse remodeling or prevent A-Fib progression.
4. Develop preventive strategies based on A-Fib mechanisms (atrial ectopy, oxidant stress, proteostasis, fibrosis, etc.)
What A-Fib Patients Need to Know
Being able to predict who will develop A-Fib would be a major advance for patients. (See how research shows that, as Dr. Van Wagoner discusses, ectopic beats do predict the development of A-Fib: FAQ: Coping with A-Fib PVCs & PACs.)
But an even more important step in A-Fib research would be to develop ways to prevent A-Fib. Further study of Dr. Van Wagoner’s mechanistic pathways of A-Fib may bring us closer to actually preventing A-Fib.
Obesity Strong Predictor of A-Fib Risk and Recurrence
Report by Steve S. Ryan, PhD
Dr. David Wilber of Loyola University Medical Center in Chicago, IL gave a presentation entitled “Obesity, Inflammation and Atrial Fibrillation.”
Dr. Wilber described the findings of several studies on obesity and A-Fib:
1. Obese Patients Are at Greater Risk of Developing A-Fib.
In the Framingham Heart Study of 5,282 patients followed for 13.7 years, obese patients had a 1.5 greater risk of developing A-Fib. (Wang et al. JAMA 2004; 2022:2474)
In studies involving 68,000 people, obese patients had a 49% increased risk of new onset A-Fib (Wanahita et al. AHJ 2008; 155:310-315)
Increase In BMI (Body Mass Index) Is associated with a risk of developing A-Fib
♦ 16% for a BMI increase of 5-15%
♦ 46% for a BMI increase of 16-35%
♦ 90% for a BMI increase of over 35%
2. Obesity Produces Left Atrium Volume Changes and Overload
In the MONICA study of 1212 patients followed for ten years, 36% had hypertension, 34% were obese. Only obesity predicted Left Atrium volume changes and produced volume overload. (Hypertension produced pressure overload.) (Stritzke et al. JACC 2009; 54:1982-9)
3. Predictably Progress to Permanent A-Fib
In the Olmstead County study of 3,248 patients with Paroxysmal A-Fib (1980-2000), BMI greater than 35 (obese) predicted progression to permanent A-Fib independent of age, gender and clinical variables.
Obesity Factors Influencing or Responsible for A-Fib
Dr. Wilber then examined what factors or elements of obesity were responsible for affecting A-Fib.
1. Epicardial fat had more local chemokines, cytokines, and cellular infiltrates (fibrosis) than subcutaneous fat. He described an experimental study where epicardial and subcutaneous fat were added to atrial rat tissue. (Epicardial fat had higher levels of activin A and other biomarkers of fibrosis.)
2. In the Framingham Offspring study, only pericardial fat volume was significantly associated with A-Fib risk. 13% increased risk of A-Fib per 10 ml volume of pericardial fat.
3. In sheep experiments, obesity was profibrotic (increase in interstitial and cytoplasmic TGF-B1, PDGF-BB, and CTGF levels). Increasing weight produced significant increase in A-Fib burden (more and longer A-Fib episodes)
4. Risk of recurrence increases with obesity (Guijian et al, PACE 2013; 36:748-756). Left Atrium fat volume was the only significant predictor of recurrence (Tsao et al 2011)
5. A 19% decrease in weight significantly decreases A-Fib burden.
Dr. Wilber’s Conclusions
• Obesity is a strong independent predictor of A-Fib risk
• Obesity produces cardiac structural remodeling, notably LA volume and diastolic dysfunction
• Local direct effects which promote Left Atrium fibrosis through inflammatory and profibrotic cytokines
• Epicardial fat volume may be a useful way to measure or be a marker for local direct effects like fibrosis. Epicardial fat is independently associated with A-Fib risk relative to BMI, Left Atrial Volume, and other risk factors
• Obesity significantly impacts A-Fib recurrence after ablation
• Weight lost reduces the risk of new onset A-Fib, and subsequent progression/recurrence after A-Fib onset
Obesity is a major problem particularly in the US, so we can expect to see an increased number of the obese developing A-Fib (along with a host of other problems like hypertension, diabetes, coronary disease and sleep apnea).
The most startling statistic Dr. Wilber cited was that a BMI increase of 35% in men from age 25 to 50 increased the risk of developing A-Fib by 90%. Practically speaking, almost everyone who becomes obese in their lifetime will develop A-Fib. That’s a really scary statistic with enormous public health consequences.
And paroxysmal A-Fib patients who are obese will predictably progress to persistent (chronic) A-Fib.
“Is it a waste of time to perform a catheter ablation on someone who is obese? Aren’t they more at risk of recurrence?” They certainly are more at risk of recurrence. But a successful catheter ablation will change their lives and improve their quality of life. However, EPs should insist that obese patients who have a successful ablation must lose weight. But that should be easier to do if the obese person is in normal sinus rhythm and isn’t plagued by A-Fib symptoms like being unable to exercise because of a racing heart.
As Dr. Wilber suggests, measurement of epicardial fat volume should become a routine part of a yearly physical. For example, if a patient has a certain amount of epicardial fat volume, they should be told they are at a greater risk of developing A-Fib (and other health problems).
The good news is that weight loss both reduces the risk of developing A-Fib and reduces A-Fib burden (how badly A-Fib affects us). And it lowers the risk of recurrence after a successful catheter ablation.
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Last updated: Tuesday, February 9, 2016