In atrial fibrillation (AF) the individual muscle fibers of
the atria are either discharging independently or affected by irritable regions
in the atrial myocardium that spontaneously depolarizes independent of the SA
node (ectopic foci). The P waves
in an electrocardiogram (ECG) are visibly absent or aberrant (Figure 1).
Figure 1. The picture compares the chaos
inside the atria of AF patient and the normal electrical conduction of the heart.
Multiple regions of spontaneous depolarization interrupt the normal
electrophysiology of the heart, leading to ineffective atrial contractility and
blood passage into the ventricles.
The ECG demonstrates the absent and aberrant P waves in comparison with sinus rhythm.
The prevalence of AF is usually underestimated because of
its asymptomatic nature; it is the most common age-dependant cardiac
arrhythmia. AF affects 0.5% of 50-59 year old Americans, but gains momentum and
affects 9% 80-89 year olds Americans, inducing fainting, electrical
disturbances, and ischemic stroke from an increased risk of thromboembolisms,
resulting in pronounced morbidity and mortality (Ying et. al. 2011).
Recent physiological research has focused on an
investigation of microRNA (miRNA) in the electrical remodeling associated with AF.
These genes encode for double-stranded hairpin mRNA that are processed into
single stranded passenger RNA by the RNA-induced splicing complex (RISC) (Yale
University 2014). Passenger RNA serve as the seeing eye dogs of the RISC
complex, and their complementarity guides RISC to targeted endogenous mRNA for
cleavage and cellular degradation.
This regulation mechanism blocks translation of mRNA.
Recent epigenetic studies have shown that miRNA 328 was elevated
3.9 fold in atrial samples, which serve to target L-type Ca2+ receptors in AF
patients (Lu et. al. 2010). This
down-regulation of L-type Ca2+ receptors blunts the hearts ability to release
intracellular calcium for coordinated atrial contraction. miRNA 328’s reduction of these
voltage-gated channels diminishes the myocardial cell’s capacity for the
conformational changes that open mechanically-linked ryanodine recptors and
liberate Ca2+. This results in depressed rate of action potential and decreased
action potential duration.
In coordination with miRNA 328, AF patient samples also
demonstrated an 86% reduction in miRNA 1.
This miRNA serves to inhibit/limit the expression of hyperpolarizing K+
channels. The reduction in miRNA 1,
or the up-regulation of receptors that increase K+ efflux, substantially
enhance the breadth of the relative refractory period and support AF
maintenance (Girmatsion et. al. 2009).
It is thought that if we can counteract the concentration of these
age-induced miRNA, we can provide hope in the battle against AF. Epigenetic drug agents such as
anti-miRNA inhibitors of miRNA 328 hope to rectify the reduction of L-type Ca2+
channels (Ying et. al. 2011).
Additionally, miRNA mimics for miRNA 1 are being developed to mitigate
the up-regulation of K+ channels in myocardial cells exhibited in AF patients
(Ying et. al, 2011).
References:
Girmatsion Z, Biliczki P, Bonauer A, et al. Changes in
microRNA-1 expression and IK1 up-regulation in human atrial fibrillation. Heart
Rhythm. [Internet] (6)1802–1809
Yale University. 2014. microRNAs. Yale Online. [Internet].
Available from: http://www.yale.edu/giraldezlab/miRNA.html
.
Lu Y, Zhang Y, Wang N, Pan Z, Gao X, Zhang Y, Shan H, Lup X,
Bai Y, Sun L, Song W, Xu C, Wang Z, Yang B. 2010. MicroRNA-328 contribute to
adverse electrical remodeling in atrial fibrillation. The American Heart
Association Online. [Internet]. Available from: http://circ.ahajournals.org/content/122/23/2378.full.pdf+html
.
Ying L, DeLi D, BaoFeng Y. 2011. Atrial remodeling in atrial
fibrillation and association between microRNA network and atrial
fibrillation. Science China.
[Internet]. Available from: http://download.springer.com/static/pdf/3/art%253A10.1007%252Fs11427-011-4241-3.pdf?auth66=1417039989_016b0b63c3f229d12e6509524a43f388&ext=.pdf
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This is interesting, well written. I am curious to know if in your research if you found that while an increase in age correlates to an increase in A-Fib if there was a sex link to the increased prevalence of AF in patients or an ethnic link to an increase in A-Fib. That perhaps the miRNA 328 presence is higher in males or females or different ethnicities, putting someone at an even greater relative risk for eventual A-Fib onset as they get older.
ReplyDeleteI also had the same question that Will posed, i.e. if there was sex or ethnic differences.
ReplyDeleteAdditionally, are these drugs just putting the miRNA into the body or are they actually changing the epigenetics within the body? If it is just a drug that puts miRNA into the body I foresee that the half-life of this drug would be incredibly short, as your body would quickly recognize it as foreign DNA and it would mount an immune response against it. On the other hand if we are changing the epigenetics of the entire body to correct these changes what are some of the possible side effects? I can see multiple upsides of fixing the A-Fib but would that also change the repolarization of other areas of the body. It could possibly lower the intensity of hyperpolarization making the body more capable of producing action potentials. If this is the case this could be one of those drugs that almost has a better side effect than it does main effect. On top of possibly fixing the A-Fib would this make these individuals more active and feel more youthful? As we age our body begins to break down and doesn't function the same as it us to. We may not be able to reverse the issue at hand but is it possible to mask it and produce a better quality of life for our later years?
Also, what was the size of the sample pool and populations that they used?