Genetic variations in lone atrial fibrillation
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:
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
An enhanced repolarization results in a shortening of the overall action potential duration and a related reduction in the effective refractory period (ERP) thus favouring the initiation of atrial fibrillation. Four different gene mutations have now been identified (KCNQ1, KCNE2, KCNJ2 and KCNE5) all involved in the coding of the pores for various subtypes of potassium currents involved in repolarization.
Delayed atrial action potential repolarization
Somewhat paradoxically it is now also clear that delaying repolarization and thus extending the ERP can trigger atrial fibrillation. The presence of a mutated KCNA5 gene, which encodes the voltage-gated potassium channel responsible for the ultra-rapid component of the delayed rectifier potassium current, has been found to be associated with delayed atrial action potential repolarization as has the SCN5A gene encoding the voltage-gated sodium channel. It is estimated that mutations of the SCN5A gene can be found in as many as 20% of lone afibbers.
Conduction velocity heterogeneity
Although the initial genes implicated in familial AF encoded potassium channels, it is now clear that other gene mutations may be at play as well. Promising candidate genes include connexins, transmembrane spanning proteins that form gap junctions. Gap junctions serve as intercellular pores providing low-resistance pathways for the passage of current between adjacent cells. Research carried out at the Ottawa Heart Institute found mutations in the connexin 40 gene in 26% of paroxysmal afibbers. Mutant connexin 40 genes would cause exaggeration of regional differences in conduction velocity and thus predispose the atria to the initiation and maintenance of atrial fibrillation.
Cellular hyperexcitability
Rapid self-sustaining re-entry circuits have been identified as the culprit driving the ectopic foci in AF including those found in the pulmonary veins. Mutations in the SCN5A and K1493R genes have been associated with cellular hyperexcitability.
Hormonal modulation of atrial electrophysiology
Recent research has discovered that a mutation in the NPPA gene encoding for atrial natriuretic peptide (ANP) can shorten the ERP and thus make myocytes more vulnerable to initiation of an AF episode. The mutant gene contains 40 amino acid peptides as compared to only 28 in the normal gene and is far more prevalent than the normal gene in carriers of the mutation.
Enhanced cholinergic (vagal) sensitivity
The greatest density of vagal innervation within the left atrium occurs at the pulmonary veins which, perhaps not surprisingly, correspond to the location of rapidly firing ectopic foci capable of initiating and maintaining AF. Although no gene mutations associated with vagal dominance or indeed with autonomic nervous system balance have been found, it is very likely that such mutations exist and could be an important factor in elucidating the mechanism of vagally-mediated AF.
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
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:
- 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 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
An enhanced repolarization results in a shortening of the overall action potential duration and a related reduction in the effective refractory period (ERP) thus favouring the initiation of atrial fibrillation. Four different gene mutations have now been identified (KCNQ1, KCNE2, KCNJ2 and KCNE5) all involved in the coding of the pores for various subtypes of potassium currents involved in repolarization.
Delayed atrial action potential repolarization
Somewhat paradoxically it is now also clear that delaying repolarization and thus extending the ERP can trigger atrial fibrillation. The presence of a mutated KCNA5 gene, which encodes the voltage-gated potassium channel responsible for the ultra-rapid component of the delayed rectifier potassium current, has been found to be associated with delayed atrial action potential repolarization as has the SCN5A gene encoding the voltage-gated sodium channel. It is estimated that mutations of the SCN5A gene can be found in as many as 20% of lone afibbers.
Conduction velocity heterogeneity
Although the initial genes implicated in familial AF encoded potassium channels, it is now clear that other gene mutations may be at play as well. Promising candidate genes include connexins, transmembrane spanning proteins that form gap junctions. Gap junctions serve as intercellular pores providing low-resistance pathways for the passage of current between adjacent cells. Research carried out at the Ottawa Heart Institute found mutations in the connexin 40 gene in 26% of paroxysmal afibbers. Mutant connexin 40 genes would cause exaggeration of regional differences in conduction velocity and thus predispose the atria to the initiation and maintenance of atrial fibrillation.
Cellular hyperexcitability
Rapid self-sustaining re-entry circuits have been identified as the culprit driving the ectopic foci in AF including those found in the pulmonary veins. Mutations in the SCN5A and K1493R genes have been associated with cellular hyperexcitability.
Hormonal modulation of atrial electrophysiology
Recent research has discovered that a mutation in the NPPA gene encoding for atrial natriuretic peptide (ANP) can shorten the ERP and thus make myocytes more vulnerable to initiation of an AF episode. The mutant gene contains 40 amino acid peptides as compared to only 28 in the normal gene and is far more prevalent than the normal gene in carriers of the mutation.
Enhanced cholinergic (vagal) sensitivity
The greatest density of vagal innervation within the left atrium occurs at the pulmonary veins which, perhaps not surprisingly, correspond to the location of rapidly firing ectopic foci capable of initiating and maintaining AF. Although no gene mutations associated with vagal dominance or indeed with autonomic nervous system balance have been found, it is very likely that such mutations exist and could be an important factor in elucidating the mechanism of vagally-mediated AF.
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
The AFIB Report, Forum and Database do not provide medical advice. Do not attempt self-diagnosis or self-treatment based on our reports.
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A third donation method, beyond choosing either the Donate with PayPal or Donate with Credit/Debit card described elsewhere on this site, is for those who prefer to directly mail a check or money order to our business address at: The AFIB Report, A Non-Profit 501(c)(3) Corporation, C/O Shannon Dickson, P.O. Box 1016, Sedona, Arizona 86339. Any of the three donation options are fine with us based on each donor's preference, and with our sincere gratitude!
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