It's easy to say two conditions are associated. Lots of things go together. It's much harder to claim one condition causes another.
In the US and other Western countries, obesity and atrial fibrillation are increasing in tandem. Ample evidence exists to associate the two diseases.
The question is: Does obesity cause AF? Or is it the other diseases that go with obesity, such as sleep apnea, hypertension, and diabetes? It's an important question because treatment (of any disease) is most successful when it targets the cause.
An elegant experiment [1] led by Dr Rajiv Mahajan (University of Adelaide, Australia) gets us very close to saying, yes, obesity does indeed cause AF.
As I tell you about this experiment, keep in mind what causes reentrant arrhythmia in the first place—multiple pathways, slowed conduction, and unidirectional block. In healthy cardiac muscle, conduction proceeds rapidly and smoothly through the cells; there is little chance of electrical reentry. In diseased muscle, inhomogeneity of conduction produces the milieu for reentry.
The Study
The Australian research team compared electrical and structural cardiac properties of two groups of animals—obese (n=10) and lean (n=10) sheep. They created obese sheep by overfeeding. After 36 weeks of persistent obesity, researchers performed blood testing, echocardiography, electrophysiology testing, electroanatomic studies, and histology in both groups. They found significant differences:
Basic Measures
Overfeeding easily produced obesity. On average, obese sheep weighed nearly twofold more than lean sheep.
Obese sheep had a larger atrium and higher right atrial, left atrial, and pulmonary artery pressures, but no differences in LV function.
Electrical Measures
Obese sheep had slower and more heterogeneous conduction velocity across atrial segments.
More than half (53%) of the LA signals of obese sheep were fractionated or split. Only 10.8% of LA signals from lean sheep were abnormal.
Obese sheep had greater regional heterogeneity of signal size (voltage) and lower amplitude signals on the posterior LA wall.
During programmed stimulation, obese sheep sustained more frequent and longer AF episodes.
Epicardial fat was more prominent in obese sheep.
In obese sheep, fatty infiltration was noted in atrial muscle, predominantly involving the posterior LA wall adjacent to the pulmonary veins. In contrast, lean sheep remained free of significant fatty infiltration.
Obese sheep had increased measures of interstitial fibrosis and fivefold greater levels of atrial TGF-ẞ1—an important cytokine mediator for fibrosis.
In the discussion section, the authors make the causation link between obesity and AF.
They start by citing evidence that common conditions, such as heart failure, atrial ischemia, and rheumatic mitral stenosis, create electrical (conduction slowing) and structural (fibrosis) abnormalities in the atria. Disruptions in physiology and anatomy form the "unifying feature" connecting these diseases to AF. No one disputes that CHF, ischemia, and valvular heart disease cause AF.
But what about obesity? Does being obese do the same things to the atria as CHF, ischemia, and mitral stenosis? One problem in sorting this out is the association of obesity and sleep apnea. The sheep model is useful because these animals do not experience sleep apnea.
The authors start with the finding of marked atrial fibrosis in the obese sheep. They note fibrosis is also seen in both heart-failure and hypertension models. In their obese-sheep model, fibrosis could easily explain the observation of heterogeneous voltage and conduction.
Where does the fibrosis come from? Here, the authors connect the finding of LA posterior-wall abnormalities, TGF-ẞ1 overexpression, and epicardial fat.
Epicardial fat is special. Previous work has shown fat cells adjacent to the heart are not inert. Epicardial fat produces many biologically active cytokines, which, by virtue of a lack of fascial barrier between the atrial myocytes and the epicardium, can exert a local (paracrine) action.[2] One group of these cytokines includes the TGF-ẞ1 superfamily, a group of chemicals that occupy a central position in the signal transduction pathway for fibrosis.
Now the picture becomes clear: Obesity induces structural changes in the heart—larger atrial volumes and higher pressures. Obesity also produces epicardial fat, which localizes adjacent to the posterior wall. The excess fat then infiltrates the atrial muscle and releases chemicals that promote fibrosis. Combined, these anatomic and electrical effects create the substrate for AF.
Comments
This may be research in an animal model, but it has direct relevance to patient care. Here is how: the main impediment to better AF treatment is a knowledge deficit. Namely, we don't know the cause of AF.
I go back to comparing AF with infectious disease. We are good at treating infections because everyone—patient and doctor—understands the target. We prescribe an antibiotic; the drug kills the bacteria; and the bacteria caused the disease. It doesn't work like that in AF, especially in overweight or obese patients. Rhythm-control AF drugs and ablation produce woeful results in these patients because both techniques target the result rather than cause of AF.
Studies like this one, taken together with previous work, teach us that the target in overweight patients with AF is the excess of fat cells. If not for excess fat, there would be no excess atrial stretch due to pressure overload, less muscle invasion of fat cells, no fibrosis-inducing cytokines, and smoother electrical conduction. Without these unifying features of obesity, the ubiquitous premature atrial complex (PAC) would have a much harder time inducing AF. Lean people, like lean sheep, would be less vulnerable to AF.
But let's go further. We are now close to the target, but not quite there.
Look at the first part of the methods section of this paper. How did the researchers create obese sheep? It was easy; they overfed them.
There's your target.
JMM
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Cite this: Sheep Study Lifts the Wool on Obesity as Cause of AF - Medscape - Jul 06, 2015.
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