Genotype To Phenotype Correlations

In 1930, Wolff, Parkinson, and White[1] described patients with electrocardiograms showing a short PR interval, a delta wave, and a wide QRS complex. It was postulated an accessory atrial ventricular pathway would explain the particular ECG and the recurrent tachycardias. Electro-physiological investigations, cardiac electrical mapping, surgical findings, anatomic studies, and results of ablation treatment have confirmed the presence of accessory conduction pathways (Fig. 1). The normal cardiac conduction is from the atrium to the ventricles through the AV node. In WPW syndrome, there is an accessory pathway between the atrium and the ventricle which bypasses the AV node and this prematurely depolarizes a portion of the ventricle to give you the short PR interval and the slurred upstroke of the QRS. However, the overall activation of the ventricle is slightly later due to the normal electrical impulse which passes through the AV node. A property of the AV node is to decrease the rate of transmission to the ventricle. Under certain conditions, conduction through the AV node to the ventricle can give rise to retrograde conduction from the ventricle to the atrium through the accessory pathway. Upon arrival in the atrium, the AV nodal conduction system has recovered resulting in reentry of the impulse into the AV node. Arrival of this impulse in the ventricle can now again be transmitted retrograde back through the accessory pathway generating a circus movement leading to reentry tachycardia. Wolff-Parkinson-White syndrome has long been regarded as intriguing to cardiologist and particularly to the electrophysiologist as it is the sine quo non of reentry tachycardia. The most common form of supra-

ventricular tachycardia observed with WPW is that of antegrade conduction through the AV node with retrograde conduction through the accessory pathway. The usual result is a regular supraventricular tachycardia with a rate of about 120 to 160 beats per minute. The overall configuration is a narrow QRS. The vectors of the QRS, however, may vary depending on the anatomical location of the accessory bundle. The most common anatomical bundle is that which goes from the left atrium to the left ventricle and occurs in about 50%; a posteroseptal, right ventricular, or anteroseptal insertion of the AV pathway is found in approximately 30%, 13%, and 7% of patients, respectively. It is claimed that about 80% of the supraventricular arrhythmias associated with WPW have a regular supraventricular tachycardia with a narrow QRS. In the remaining 20% the arrhythmia is generally atrial fibrillation. The incidence of tachyarrhythmias in WPW syndrome is unknown. Reports from a variety of studies indicate 10-80%. Atrial fibrillation is very dangerous because it predisposes to failure and sudden death. This is because the rapid rate is transferred to the ventricle due to lack of the damping effect of the AV node. This rapid rate of the ventricle prevents proper relaxation during diastolic for adequate blood to return to the heart resulting in

Atrium Proper

Fig. 1 Cardiac electrical conduction is normally from the SA node through the atrium and subsequently transmitted to the ventricles by the AV node and right and left bundles. In WPW, there is an accessory pathway as indicated in the figure connecting the atrium to the ventricle without going through the AV node. Thus, an impulse arising in the atrium may get conducted to a portion of the ventricle through the accessory pathway and subsequently be retrograde conducted through the normal conduction system including the AV node. Arrival of this retrograde conduction impulse is delayed in the AV node permitting adequate recovery time for the accessory pathway so that it may be conducted again through the accessory pathway giving you reentry tachycardia. Other times conduction through the accessory pathway will simply give preexcitation of only a portion of the ventricle indicated by the short PR interval and the slurred upstroke of the QRS. The remainder of the QRS is generated by conduction through the AV node and bundle branch system.

decreased cardiac output, cardiac failure, and may deteriorate into ventricular tachycardia or fibrillation and sudden death. Atrial fibrillation is particularly dangerous if there is a short antegrade refractory period as ventricular fibrillation is more likely to occur.

The genetic defect is in the PRKAG2 gene which encodes for the gamma subunit of the kinase AMPK. AMP-activated protein kinase is a sensor of the body's ATP level. AMP-activated protein kinase is activated by an increase in the ratio of AMP to ATP. AMP-activated protein kinase increases the availability of ATP by increasing glucose absorption, inhibiting glycogen synthesis, increasing fatty acid oxidation, and decreasing fatty acid synthesis. The phenotype consistently observed in addition to WPW syndrome is excess glycogen in the myocytes of the heart.[10] Hypertrophy of the heart is also observed in a percentage of the patients. Several genetic animal models expressing either the R302Q mutation[8] or the mutation N488I[9] as a transgene have been generated. All of them have the preexcitation syndrome and excessive myocardial glycogen phenotype. The model expressing the R302Q mutation has the preexcitation syndrome, increased cardiac glycogen, and inducible supraventricular reentry tachycardia as observed in the human phenotype. In this model,[8] we have shown there is loss of function of AMPK leading to loss of inhibition of glycogen synthase resulting in increased formation of glycogen in the heart. The hypertrophy is probably a compensatory feature due to less ATP available for contractility inducing formation of more sarcomeres. The mechanism whereby AMPK leads to accessory pathways or alters conduction remains to be determined. AMP-activated protein kinase with the R302Q mutation has been shown to inhibit the cardiac sodium inward current in in vitro studies.[11] This is an exciting area of research as AMPK is also one of the pivotal enzymes in obesity, insulin resistance, and the metabolic syndrome.

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