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OTTAWA, CANADA. The observation that lone atrial fibrillation (LAF) may be inherited has spawned considerable research aimed at identifying the genes predisposing to LAF.
Researchers at the Ottawa Heart Institute have determined six sub-classifications of LAF each associated with a specific mutation in a gene.
Genes 101
Genes are the �blueprint� that governs our initial �construction� and �repair and maintenance� for the rest of our lives. Humans have about 100,000 different genes
made up by stringing together about 3 billion molecules of the four nucleic acids � adenine, thymine, cytosine, and guanine. The genes make up strands of DNA
which in turn are bundled into chromosomes. The genes contain messages that tell each individual cell in our body what protein to produce and when to produce it.
The DNA strands containing the genes duplicate themselves when our cells divide so that each cell contains a complete set of genes. Every time a DNA strand
duplicates itself, there is a risk that an error (mutation) may occur, the sequence may be wrong, or there may be too many or too few nucleic acids in a gene sequence.
The cells have special enzymes which repair errors in DNA duplication; however, even they sometimes fail and the error goes uncorrected. If the mutant DNA strand is
able to replicate itself a number of times it can become established and one is left with a permanent faulty gene.
The six sub-classifications are:
Heart Rhythm 101
The membrane (sarcolemma) of a resting heart cell (myocyte) is polarized � that is, the inside (intracellular space) of the cell (cytoplasm) is negatively charged in respect
to the outside environment (extracellular space). Responding to an impulse from the sinoatrial (SA) node (the heart�s natural pacemaker controlled by the autonomic nervous
system) the myocytes depolarize resulting in contraction of the heart muscle. The depolarization is caused by a rapid influx of positive sodium (Na+) ions followed by a slower
influx of calcium ions (Ca++). During depolarization the outward leakage of potassium ions (K+) is restricted. Atrial depolarization shows up as a P wave on an
electrocardiogram (ECG) while ventricular depolarization is identified as the QRS complex � that is, the time period on the ECG during which the ventricles depolarize
(contract). The P wave is absent during atrial fibrillation. The time interval between the start of the P wave and the beginning of the QRS complex is a vulnerable period
for afib initiation.
Depolarization is followed by repolarization (recovery). During this phase, an outflow of K+ ions is followed by a period during which the intracellular concentrations
of K+ and Na+ in the myocytes are restored to their resting potential through the action of Na+/K+ ATPase pumps �powered� by magnesium. Magnesium ions (Mg++)
also play an important role during this phase by slowing down the outward (from intracellular space to extracellular space) flow of potassium ions. At the risk of
oversimplification, one could say that while Na+ and Ca++ are �excitatory� ions K+ and Mg++ ions are �calming�. Thus it is not surprising that a deficiency of
K+ and Mg++ facilitate atrial fibrillation. Repolarization is identified on the ECG as the time period from the end of ventricular depolarization to the peak of the
T wave (ST segment).
The period from the start of the QRS complex to the peak of the T wave is of particular interest when it comes to atrial fibrillation. During this period
(the effective refractory period or ERP) myocyte depolarization cannot be triggered by stimulus originating from rogue atrial cells thus preventing afib
from being initiated. However, atrial fibrillation can be triggered during the last half of the T wave (relative refractory period or RRP) making it highly
desirable that the ERP is as long as possible and the RRP as short as possible. Several medications aim to exploit this fact by acting to extend the ERP
so that the RRP (the vulnerable period) becomes as short as possible. This is particularly important in the case of the AV node as during the ERP the
node cannot be stimulated and thus in essence filters out the erratic atrial impulses.
The speed with which an electrical impulse moves across the atrium (normally directly from the SA node to the AV node) is called the conduction velocity
and is a measure of the effectiveness of cell-to-cell depolarization. It is measured in millimeter/millisecond (mm/ms) or in meter/second (m/s).
Sympathetic (adrenergic) stimulation increases conduction velocity while parasympathetic (vagal) stimulation reduces it. Slow conduction is associated
with the presence of complex fractionated atrial electrograms (CFAEs) defined as electrograms (direct measurements of electrical activity inside the atrium)
with a cycle length less than or equal to 120 ms or shorter than in the coronary sinus or that are fractionated or display continuous electrical activity. CFAEs
are believed to be associated with fibrosis and serve as targets in some ablation procedures for atrial fibrillation.
Enhanced atrial action potential repolarization
Delayed atrial action potential repolarization
Conduction velocity heterogeneity
Cellular hyperexcitability
Hormonal modulation of atrial electrophysiology
Enhanced cholinergic (vagal) sensitivity
The Canadian researchers conclude that the heterogeneous nature of AF triggers and factors responsible for arrhythmia maintenance make it very
difficult to find therapeutic approaches that will apply to all afibbers. However, if genetic testing could identify specific abnormalities in an individual,
then it may be possible to eliminate, or at least ameliorate, that individual�s AF burden by the use of a targeted pharmaceutical drug.
Roberts, JD and Gollob, MH. Impact of genetic discoveries on the classification of lone atrial fibrillation. Journal of the American College of Cardiology,
Vol. 55, No. 8, February 23, 2010, pp. 705-12
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