The mechanism and significance of the slow changes of ventricular action potential duration following a change of heart rate

Abstract

This article reviews the effects of changes of heart rate on the ventricular action potential duration. These can be divided into short term (fractions of a second), resulting from the kinetics of recovery of membrane currents, through to long term (up to days), resulting from changes of protein expression. We concentrate on the medium-term changes (time course of the order of 100 s). These medium-term changes occur in isolated tissues and in the intact human heart. They may protect against cardiac arrhythmias. Finally, we discuss the cellular mechanisms responsible for these changes. The action potential duration (APD)It is essential that the cardiac action potential duration (APD) is regulated precisely. The APD determines the refractory period of the heart and if it becomes too short premature re-excitation can occur, leading to such arrhythmogenic phenomena as re-entry. Much evidence has shown that conditions, such as heart failure and ischaemia, where APD varies between different regions of the ventricle, are particularly dangerous in terms of inducing arrhythmias. In contrast, excessive prolongation of the APD is also dangerous. This can result in early after-depolarizations and arrhythmias seen on the ECG as 'torsades de pointes' . Indeed, prolongation of the APD (or QT interval) and perceived pro-arrhythmic risk has led to the withdrawal of many, otherwise potentially useful, drugs (Fenichel et al. 2004). The APD is not uniform throughout the ventricle; differences of APD either across the ventricular wall or between base and apex are thought to be responsible for the fact that in many leads the T wave of the ECG has the same polarity as the QRS complex. Effects of heart rate on APDThe APD varies with heart rate. Indeed, in order to increase the heart rate, it is essential that the APD and therefore the refractory period decrease. The relationship between heart rate and APD is well appreciated in clinical work, and the QT interval is often corrected for heart rate (QT c ; Luo et al. 2004). The effects on APD of a sudden change of heart rate develop over a variety of time courses. For the purpose of this review we will focus on three phases, as follows: (1) an early phase (milliseconds to hundreds of milliseconds), due to changes of voltage-and timedependent currents; (2) a slower phase, occurring over a minute or so; and (3) a very slow phase that develops over hours to days, the so-called cardiac memory. The first two phases recorded from a human heart are shown in Fig. 1 (Franz et al. 1988).The effects of rate on APD or QT interval result from a number of different mechanisms. While the main focus of this article is the slower phase, it is important to begin by briefly reviewing the early phase. Short-term effects due to incomplete recovery of ionic currentsChanges in several ionic currents contribute to the early phase of action potential shortening on increasing stimulation frequency. The short-term effects are best seen by interpolating an extra stimulus as shown in Fig. 2 (Bass, 1975). Here acti...

A βIV-spectrin/CaMKII signaling complex is essential for membrane excitability in mice

“…For example, although both large and small animals show APD adaptation in response to changes in pacing frequency (Supplemental Figure 9 and ref. 67), I Na,p is an important determinant of this behavior in mice, but the potential role of I Na,p is less clear in larger animals, where APD adaptation is primarily attributed to K + and/or Ca 2+ channel activity (reviewed in ref. 67).…”

“…67), I Na,p is an important determinant of this behavior in mice, but the potential role of I Na,p is less clear in larger animals, where APD adaptation is primarily attributed to K + and/or Ca 2+ channel activity (reviewed in ref. 67). Thus, we anticipate that studies in different animal models will be useful for studying all aspects of the β IV -spectrin/ CaMKII signaling complex.…”

KATPChannels in the Cardiovascular System

“…Kir6.2 Ϫ/Ϫ mice also develop arrhythmias and sudden death with sympathetic challenge (likely due to cellular Ca 2ϩ overload since it is preventable by Ca 2ϩ channel blockers), which points to a vital protective function of K ATP channels under physiological conditions (940). A recent finding points to a more subtle and important physiological function: when the heart rate is elevated, the action potential duration adapts (decreases) over the time course of a few minutes (202), which is responsible for a decreased refractoriness and prevention of arrhythmias. Both glibenclamide and loss of K ATP channel function (achieved by cardiac-specific overexpression of dominant-negative Kir6 subunits) largely eliminates frequency adaptation, which points to a key physiological action of K ATP channels in action potential adaptation at elevated heart rates (941).…”

Bradycardia alters Ca2+dynamics enhancing dispersion of repolarization and arrhythmia risk

“…On the other hand, most episodes of TdP in humans are not preceded by profound bradycardia, and more than one factor is often identified (29,32 (21) and the late Na ϩ current (I Na,L ) (24). Mathematical simulations of slow HR (SHR) indicated that the long diastolic intervals result in a complete deactivation of the slow component of the delayed rectifying K ϩ current (I Ks ) and complete recovery from inactivation of I Ca,L , which could theoretically explain APD adaptation in bradycardia (5, 27, 61).…”