Disease Basis

The causes of arrhythmias can be considered at various levels of pathology:

1. At the underlying level of nonelectrophysiological causes such as cardiac pathologies that include: myocardial regional ischemia, myocardial scarring, excessive tension on myocardial chamber walls, inflammation, and/or excessive autonomic nervous system activity. These cause disturbances in ion channel function giving rise to arrhythmias, and/or to changes in conduction pathways.

2. At the level of release of arrhythmogens,3 there are endogenous chemical substances that alter activity of ion channels and thereby precipitate arrhythmias. Arrhythmogens may act directly on myocytes, or indirectly, via nerves or blood vessels. Recognized arrhythmogens include catecholamines, H +, K+, eicosanoids, and other fatty acid products.

3. At the genetic level, where mutations are responsible for arrhythmias as a result of pathological changes in channel structure.4 This is particularly so for torsades caused by a long QT syndrome due to mutations in potassium or sodium channels.

4. At the level of abnormal activation of channels that are usually closed. The classic example of this is the IKATP channel, normally closed but opened to provide outward potassium current when intracellular concentrations of ATP fall below critical levels. Cardiac tissue also contains ion channels that are sensitive to stretch and thus pathological stretch of cardiac tissue gives rise to arrhythmias (stretch-induced arrhythmias) via activation of this channel.

5. Iatrogenic causes such as inappropriate use of drugs, particularly antiarrhythmic drugs, other drugs that prolong the QT interval, or drugs and procedures that cause arrhythmogenic changes in ionic imbalances, e.g., hypo- or hyperkalemia.

All of the above have direct consequences on the electrophysiological behavior of cardiac muscle, and these changes are the fundamental cause of arrhythmias. Changes in cellular electrophysiological behavior change one or more of the basic cardiac electrophysiological functions of:

• Excitability - a measure of the ability of cardiac cells to be excited by invading electrical currents, so that they generate action potentials. Excitability is directly related to the number of sodium ion channels available for opening in atrial and ventricular tissue, and to calcium channels in nodal tissue.

• Pacemaking or automaticity - the ability, normally found in SA and AV nodes, and in ventricular Purkinje tissue, to spontaneously generate action potentials. While automaticity is normally restricted to the above tissues, damaged atrial and ventricular tissue may exhibit pacing.

• Conduction velocity - the speed of conduction of action potentials through cardiac tissue. Conduction velocity is sodium current dependent in ventricles as well as atria, and calcium current dependent in SA and AV nodal tissue.

• Refractoriness - the temporal resistance of cardiac tissue to excitation such that a second action potential cannot be initiated on a first action potential. Refractoriness is governed by the duration of the action potential which regulates sodium channel dependent excitability as they revert from an inactivated to a resting state (see later).

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