ADELAIDE, AUSTRALIA. Twenty-five years ago Dr. Philippe Coumel of the Lariboisiere Hospital in Paris postulated that lone atrial fibrillation only occurs when the following three conditions are met:
- The heart tissue (myocardium) is abnormally sensitive and capable of being triggered into and sustaining an afib episode.
- The autonomic nervous system is out of balance (overly vagal or overly adrenergic).
- A trigger or precipitating cause capable of initiating an afib episode is present.
While a fair bit of research has been done in regard to conditions 2 and 3, so far little attention has been devoted to determine why the myocardium is "abnormally sensitive".
Dr. Prash Sanders and colleagues at the Royal Adelaide Hospital have now stepped in to fill this very important gap in our knowledge regarding the mechanism underlying lone atrial fibrillation. Before getting into details of their study it is, however, necessary to ensure that the reader has a basic understanding of the parameters governing normal as well as abnormal heart rhythms (arrhythmias). 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 atrioventricular (AV) node is a specialized conglomeration of myocytes that acts as the speed controller for ventricular contractions (depolarization) just as the SA node does for atrial contractions. Normally, the AV node receives its "instructions" directly from the SA node through a well-defined "wiring circuit"; however, during atrial fibrillation the AV node is bombarded by impulses from rogue atrial cells which, if they are not filtered out by the AV node will cause the rapid, irregular ventricular contractions characteristic of atrial fibrillation. 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.
The Adelaide team performed an exhaustive electrophysiological study on 25 paroxysmal lone afibbers (average age 53 years, 80% male, average duration of afib 5 years, longest episode 3 days) who had been in sinus rhythm for the previous 7 days and compared the results to those obtained in a group (reference group) of afib-free patients who were undergoing ablation for atrioventricular tachycardia (left-sided accessory pathway). Using two 10-pole and two 20-pole catheters to carry out measurement in both atria, the team observed the following major differences between the afib group and the reference group:
- Members of the afib group had a significantly larger left atrium (average parasternal diameter of 41 mm) than did those of the reference group (34 mm). The average right atrium volume was 94 mL in the afib group (69 mL in reference group) and the left atrial volume was 99 mL versus 77 mL in the reference group.
- The ERP was measured at 10 different sites at pacing rates of 100 bpm (600 ms/cycle) and 135 bpm (450 ms/cycle). The researchers found that the ERPs at all sites were longer in duration when paced at 100 bpm than when paced at 135 bpm. Generally, ERPs were also longer in the afib group than in the reference group, which is somewhat surprising since remodeling in AF patients is known to shorten ERP.
- P wave duration was significantly longer in the afib group than in the reference group (128 ms vs. 95 ms).
- Patients with afib had a significantly greater number of points with double potentials or fractionated signals than did reference patients (27% vs. 8%)
- AF patients had impaired sinus node function as indicated by a substantially longer corrected sinus node recovery time (at 100 bpm pacing) than found in the reference group (average 265 ms vs. 185 ms).
- The mean voltage measured between poles in the catheters was significantly less in the afib group than in the reference group. In the right atrium 1.7 mV vs. 2.9 mV and in the left atrium 1.7 mV vs. 3.3 mV - a decrease of 41% and 48% respectively.
- Afibbers had a significantly slower mean conduction velocity during sinus rhythm than did the reference group. In the right atrium the conduction velocity was 1.3 mm/ms in the afib group versus 2.1 mm/ms in the reference group. Corresponding numbers for the left atrium were 1.2 mm/ms vs. 2.2 mm/ms.
The Australian researchers conclude that lone, paroxysmal afibbers have an abnormal atrial substrate and that this abnormality is what promotes progression of AF. They also reach the somewhat discouraging conclusion that "sinus rhythm does not beget sinus rhythm". Other observations made by the team include:
- Patients with recent AF have been shown to have shorter ERP than control groups, as well as sinus dysfunction and conduction delay.
- The predominant contributors to the abnormal substrate underlying AF are the structural and associated conduction abnormalities rather than changes in refractoriness. Future strategies to treat AF should focus on atrial myocardial structure and conduction.
- Pulmonary vein isolation is highly successful in eliminating afib; however, data on long-term outcome is very limited. The findings of the study raises the possibility of continuing modification of the atrial substrate perhaps eventually leading to renewed afib despite early procedural success.
In an accompanying editorial Dr. Maurits Allessie from the University of Maastricht suggests that the results of an electrophysiological study such as carried out by the Australian group, with particular emphasis on atrial enlargement and conduction abnormalities, may be useful in predicting the risk of paroxysmal afib progressing to the persistent or permanent variety. Stiles, MK, et al. Paroxysmal lone atrial fibrillation is associated with abnormal atrial substrate. Journal of the American College of Cardiology, Vol. 53, April 7, 2009, pp. 1182-91
Allessie, M. The "second factor": a first step toward diagnosing the substrate of atrial fibrillation? Journal of the American College of Cardiology, Vol. 53, April 7, 2009, pp. 1192-93 Editor's comment:
The study by Prash Sanders and colleagues will, no doubt, be cited as a landmark study in future years. While it has long been assumed that lone afibbers have an abnormal atrial substrate, this is the first time that the abnormalities have been clearly defined. We now know that the following features are characteristic of the atria in lone, paroxysmal afibbers:
- Distinct signs of inflammation and fibrosis;
- Larger than normal volume of both atria and a longer left atrial parasternal diameter;
- Longer than normal effective refractory period (ERP). NOTE: This finding is likely to be controversial;
- Longer P wave duration;
- Greater number of complex fractionated electrograms (points of abnormal electrical activity and slowed conduction);
- Slower conduction velocity;
- Impaired sinus node function;
- Lower voltages in both atria.
While the approach of the Adelaide team and the majority of researchers in the field will, no doubt, be to develop pharmaceutical drugs that target one or more of these abnormalities, there is an alternative – to determine what causes or caused the abnormalities in the first place and then devise strategies to deal with these causes directly. It is likely that magnesium and, to some extent, potassium deficiencies will rank high as causal factors in lone atrial fibrillation, especially in view of the recent finding by Sachin Shah and his team at Hartford Hospital that 90% of lone afibbers are deficient in intracellular magnesium although their serum levels are in the normal range.
For a detailed discussion of the importance of magnesium and potassium in lone AF please see Dr. Patrick Chambers' excellent article Magnesium and Potassium in LAF
 Frustaci, A, et al. Histological substrate of atrial biopsies in patients with lone atrial fibrillation. Circulation, Vol. 96, August 19, 1997, pp. 1180-84
 Shah, SA, et al. The impact of magnesium sulfate on serum magnesium concentrations and intracellular electrolyte concentrations among patients undergoing radio frequency catheter ablation. Connecticut Medicine, Vol. 72, May 2008, pp. 261-65