Word Count: 1,390
The ancient Egyptians wrote in the Book of the Dead, that all deeds in
life, whether good or bad, remain in our hearts. As such, when a person
died their spirit traveled to the underworld to be judged by the weight
of their heart by Osiris, the Lord of the Underworld. A heavy heart
reflected a life of poor choices and deeds and as a consequence the
heart was thrown into the jaws of Amenti, a God with the face of a
crocodile, and their soul would cease to exist. If their heart was
light, a reflection of good deeds and choices, they then lived in the
eternal paradise of the Field of Reeds.(1)
Atrial fibrillation (AF) is the most common sustained clinical
arrhythmia and is increasingly across the world in both developed and
developing countries.(2) The increase in AF has been attributed to aging
of the population, higher rates of traditional risk factors for AF, and
also, as of now, additional unknown risk factors. Obesity is commonplace
in electrophysiology practices and as illustrated by the median body
mass index (BMI) of 30 kg/m2 reported in the CABANA
trial, the level at which obesity is defined, a common comorbid
condition in patients with AF.(3)
In an analysis of 626,603 people, incident AF risk was increased by 19%
(OR: 1.19, 95% CI: 1.13 to 1.26) for every 5-unit BMI increase in
case-control studies.(4) The mechanisms underlying the AF-obesity
association are not fully understood and on the surface are
multifactorial and often synergistic. Amongst these mechanisms is the
contribution to AF risk related to the presence and extent of
pericardial and epicardial adipose tissue (EAT).
EAT is a marker of obesity, in particular central or visceral obesity,
more so than BMI alone.(5) In a meta-analysis of 38 studies, the EAT was
7.5 ± 0.1 mm in thickness in the patients with metabolic syndrome
compared to 4.0 ± 0.1 mm in controls. EAT also correlates with a higher
systolic blood pressure, fasting blood glucose, and triglycerides.(5)
Recently it has been discovered the EAT is metabolically active and
directly influences the adjacent myocardium through inflammatory,
paracrine, and vasocrine signaling that results in lower myocardial
bipolar voltage and electrogram fractionation; substrate associated with
AF genesis and maintenance.(6) In a supportive ovine model, obese sheep
had increased voltage heterogeneity, more frequent and durable episodes
of AF, more atrial fibrosis, and reduced endocardial voltage in regions
with epicardial fat infiltration.(7)
Despite these recent observations regarding the negative influence of
EAT on myocardial substrate that becomes vulnerable to arrhythmia,
questions such as how AF is triggered and how the arrhythmia is
maintained as a consequence to the presence and severity of EAT remain
unknown. In order to answer these questions, Otsuka and colleagues from
the University of Nihon created a novel canine model with groups exposed
to obesity, obesity with rapid triggered atrial activity from pacing,
and a combination of both.(8) The model consisted of 3 year old health
beagle dogs and obesity was stimulated through feeding them with a
high-fat diet (standard diet plus 235 g/day of white rice and 400 g/day
of high-calorie dog food [2210 kcal/day]) for at least 20 weeks. In
a subset of animals, right atrial pacing was performed to stimulate AF
induction and triggering during the last 6 weeks of the dietary period,
whether in the standard diet group or in the high-fat diet group. Pacing
was performed from two sites within the right atrium and to prevent
tachy-mediated heart failure, an AV node ablation was performed with
subsequent dependent VVI pacing. All animals underwent a baseline and
terminal electrophysiology study and bipolar voltage mapping.
There were several interesting findings that implicate both obesity and
right atrial pacing as mediators of AF vulnerability through similar
pathways. For example, gene expression mediators of inflammation and
fibrosis, fibronectin, collagen I, collagen III, and TGF-β1 mRNA
expression levels were significantly increased in the obese, obese with
right atrial pacing, and right atrial pacing groups compared to controls
with the largest relative differences in the two groups with right
atrial pacing.
Unlike the prior ovine study(7), in this model, there were no observed
regional differences in bipolar voltages after comparing findings from 5
discrete left atrial sites and 3 venoatrial junctions amongst the
different groups, although the obese paced group had significantly lower
sampled voltages throughout followed by the right atrial pacing nonobese
group. These findings suggest more of a generalized myopathic process
related to pacing that may be accelerated or further mediated by the
presence of obesity. This myopathic process may have been driven in part
by higher left atrial pressures that were more common in obese animals
compared to nonobese animals.
Animals exposed to right atrial pacing, both obese and not obese,
demonstrated shorter effective refractory periods in the pulmonary
veins. However, the obese animals at the terminal study were 3-4 times
more likely to sustain AF, a finding that suggests obesity within this
model was contributing to the substrate and maintenance of properties of
AF.
The finding most interesting to me was uncovered in histologic analysis.
The extent of EAT differed significantly between the 4 groups: control
93 (41–179) μm; right atrial pacing not obese 249 (178–355) μm; obese
233 (136–329) μm; right atrial pacing obese; 334 (243–550) μm,
p=0.006. In addition, the percent of fatty infiltration in the
myocardium differed significantly: control 7.3 (0.7–17.1)%; right
atrial pacing not obese 29.3 (21.4–47.6)%; obese 27.9 (12.5–31.7)%;
right atrial pacing obese; 43.1 (38.6–48.6)%, P<0.001. It
was not surprising based upon prior studies that obesity influenced EAT
and EAT infiltration into the myocardium. However, pacing alone resulted
in greater EAT accumulation and infiltration than diet alone and this
maladaptive response to the adverse electrical stimulus was
significantly augmented by the presence of obesity. The pathways that
leads to EAT and myocardial infiltration of fat, that results in a
higher risk of AF, may serve as therapeutic opportunities to lower risk
in people with AF triggers with and without obesity. The development and
infiltration of EAT may also explain why outcomes with rhythm control
are much better when used early in the course of AF, before atrial
structural changes become nonreversible.(9)
There are some limitations to consider with this study. Importantly, it
was unclear if the obesity model truly created a metabolic syndrome that
would impact myocardial function and health. Leptin is synthesized and
secreted into the circulation largely by adipocytes and was similar in
all groups, despite higher insulin levels in the obese groups. Higher
levels of leptin are associated with worse outcomes in patients with
coronary artery disease, left ventricular hypertrophy, and heart
failure.(10) It is possible that a more chronic model of obesity beyond
20 weeks in previously healthy animals may have elicited a greater
adverse influence of obesity alone. Next, there were relatively few
animals, 20 total, with multiple comparisons of 4 discrete treatment
groups (5 in each), which increases the likelihood of a type 2
statistical error. As a consequence, additional studies are needed to
reproduce these findings and expand on their insights. Despite these
limitations, the authors are to be congratulated on developing this
model and providing a comprehensive analysis to improve our mechanistic
understanding underlying the contribution of obesity and AF incidence
and progression.
Circling back to the beginning, do our deeds impact the “weight” of
our hearts. Or in other words, how much of obesity is related to
lifestyle choices versus genetic and as a consequence how much of EAT is
modifiable? In a study of 1608 white people studied over 25 years,
polygenetic risk scores predicted the BMI at 25 years in 13.6% of the
population.(11) Within this study, fitness improved model prediction and
predicted BMI at 25 years in 18.1% of the population. The BMI at
enrollment in early adulthood was the strongest predictor of BMI 25
years later. With this study in mind, our choices to maintain fitness
influence risk of obesity similar to, or perhaps slightly more, than our
genetics. Second, these choices to pursue a fit life need to be
considered early as the adopted lifestyles that convey risk tend to
remain over decades of life. Perhaps electrophysiologists have learned
what the Egyptians knew centuries before, that our hearts convey a
lifetime of experiences and if we are not careful, some future misery
along the way.
References
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Encyclopedia AH, editor.
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