Temporal decline in defibrillation thresholds with an active pectoral lead system.

OBJECTIVES: The objective of this study was to characterize temporal changes in defibrillation thresholds (DFTs) after implantation with an active pectoral, dual-coil transvenous lead system. BACKGROUND: Ventricular DFTs rise over time when monophasic waveforms are used with non-thoracotomy lead systems. This effect is attenuated when biphasic waveforms are used with transvenous lead systems; however, significant increases in DFT still occur in a minority of patients. The long-term stability of DFTs with contemporary active pectoral lead systems is unknown. METHODS: This study was a prospective assessment of temporal changes in DFT using a uniform testing algorithm, shock polarity and dual-coil active pectoral lead system. Thresholds were measured at implantation, before discharge and at long-term follow-up (70 +/- 40 weeks) in 50 patients. RESULTS: The DFTs were 9.2 +/- 5.4 J at implantation, 8.3 +/- 5.8 J before discharge and 6.9 +/- 3.6 J at long-term follow-up (p < 0.01 by analysis of variance; p < 0.05 for long-term follow-up vs. at implantation or before discharge). The effect was most marked in a prespecified subgroup with high implant DFTs (> or =15 J). No patient developed an inadequate safety margin (< 9 J) during follow-up. CONCLUSIONS: The DFTs declined significantly after implantation with an active pectoral, dual-coil transvenous lead system, and no clinically significant increases in DFT were observed. Therefore, routine defibrillation testing may not be required during the first two years after implantation with this lead system, in the absence of a change in the cardiac substrate or treatment with antiarrhythmic drugs.

I(Ca(TTX)) channels are distinct from those generating the classical cardiac Na(+) current.

The Na(+) current component I(Ca(TTX)) is functionally distinct from the main body of Na(+) current, I(Na). It was proposed that I(Ca(TTX)) channels are I(Na) channels that were altered by bathing media containing Ca(2+), but no, or very little, Na(+). It is known that Na(+)-free conditions are not required to demonstrate I(Ca(TTX).) We show here that Ca(2+) is also not required. Whole-cell, tetrodotoxin-blockable currents from fresh adult rat ventricular cells in 65 mm Cs(+) and no Ca(2+) were compared to those in 3 mM Ca(2+) and no Cs(+) (i.e., I(Ca(TTX))). I(Ca(TTX)) parameters were shifted to more positive voltages than those for Cs(+). The Cs(+) conductance-voltage curve slope factor (mean, -4.68 mV; range, -3.63 to -5.72 mV, eight cells) is indistinguishable from that reported for I(Ca(TTX)) (mean, -4.49 mV; range, -3.95 to -5.49 mV). Cs(+) current and I(Ca(TTX)) time courses were superimposable after accounting for the voltage shift. Inactivation time constants as functions of potential for the Cs(+) current and I(Ca(TTX)) also superimposed after voltage shifting, as did the inactivation curves. Neither of the proposed conditions for conversion of I(Na) into I(Ca(TTX)) channels is required to demonstrate I(Ca(TTX)). Moreover, we find that cardiac Na(+) (H1) channels expressed heterologously in HEK 293 cells are not converted to I(Ca(TTX)) channels by Na(+)-free, Ca(2+)-containing bathing media. The gating properties of the Na(+) current through H1 and those of Ca(2+) current through H1 are identical. All observations are consistent with two non-interconvertable Na(+) channel populations: a larger that expresses little Ca(2+) permeability and a smaller that is appreciably Ca(2+)-permeable.

Calcium currents and arrhythmias: insights from molecular biology.

Calcium channels are critical to normal cardiac function. They are involved in the generation and conduction of the action potential and in contraction. Three surface membrane channels have been identified. The L-type Ca channel is most abundant and is responsible for Ca entry into the cell that triggers contraction. T-type Ca channels are most prevalent in the conduction system and are probably involved in automaticity. A newly described TTX-sensitive calcium current may be important in "boosting" or enhancing conduction and contraction. The main intracellular Ca channel resides in the sarcoplasmic reticulum and is responsible for the release of the Ca that activates contraction. Oscillatory behavior of this channel influences the sarcolemmal membrane, causing delayed aftercontractions and arrhythmias such as those seen in digoxin toxicity. The on-going molecular characterization of these channels will enhance our knowledge of their normal function and dysfunction in disease states, leading to the development of new therapeutic agents to treat arrhythmias and contractile dysfunction.

Effect of second-phase duration on the strength-duration relation for human transvenous defibrillation.

BACKGROUND: The mechanism by which biphasic waveforms improve defibrillation efficacy is unclear. In addition, the optimal shape of the biphasic waveforms remains controversial. Animal experiments suggest that prolonging the duration of the second phase longer than the first worsens defibrillation thresholds (DFT). The purpose of this study was to determine the strength-duration relation for the second phase of a biphasic defibrillation waveform in humans. METHODS AND RESULTS: This was a prospective, randomized study of biphasic DFT in 36 patients; a uniform dual-coil transvenous lead system was used. In each patient, 3 DFTs were determined with the pulse duration for the second phase of the defibrillation waveform varying between 1 and 18 ms. The duration of the first phase was fixed at 6 ms and the capacitance was 150 microF. There was a significant increase in the leading edge voltage at DFT only when the second-phase pulse duration was decreased to 1 ms. There was no increase in DFT voltage even when the second-phase pulse duration was increased from 2 to 18 ms. Similar relations were observed for stored energy, leading edge current, or phase 2 energy. The normalized average current delivered during phase 2 decreased monotonically with increasing phase 2 duration. CONCLUSIONS: In humans, the biphasic DFT voltage or energy is increased only when the second phase of the waveform is <2 ms. The DFT voltage is insensitive to increasing the second phase of the defibrillator waveform to as long as 18 ms, or 3 times the duration of the first phase of the waveform.

Acute hemodynamic effects of right ventricular pacing site and pacing mode in patients with congestive heart failure secondary to either ischemic or idiopathic dilated cardiomyopathy.

The hemodynamic effects of pacing in patients with congestive heart failure (CHF) remain controversial. Early studies reported that pacing from the right ventricular (RV) apex improved acute hemodynamic parameters in patients with left ventricular systolic dysfunction, but these findings were not confirmed in subsequent controlled studies. More recently, it has been proposed that pacing from the RV side of the ventricular septum improves hemodynamic function compared with intrinsic conduction or apical pacing. Either dual-chamber or ventricular pacing have been evaluated, again with inconsistent findings. To assess the effects of pacing site and mode on acute hemodynamic function, we evaluated 21 subjects with CHF and intrinsic conduction disease. Hemodynamics were compared in AAI, VVI, and DDD modes with pacing from the RV apex or high septum. The pacing rate was constant in each patient and the order of testing was randomized. In the absence of ventricular pacing (AAI mode), the mean systemic arterial pressure was 85 +/- 11 mm Hg, the right atrial pressure was 11 +/- 4 mm Hg, the pulmonary capillary wedge pressure was 18 +/- 8 mm Hg and the cardiac index was 2.4 +/- 0.7 L/min/m(2). Compared with AAI pacing, there were no improvements in any hemodynamic parameter with DDD pacing from either RV site. Hemodynamic function worsened with VVI pacing from both RV sites. Subgroup analyses of patients with dilated cardiomyopathy, with prolonged PR interval, or with significant mitral regurgitation also failed to demonstrate an improvement with pacing. We conclude that pacing mode but not RV pacing site affects acute hemodynamic function. Pacing in the DDD mode prevents the deleterious effects of VVI pacing in this patient population.

Sensing lead failure in implantable defibrillators: a comparison of two commonly used leads.

INTRODUCTION: Despite major technological advances, structural problems in implantable cardioverter defibrillator (ICD) endocardial sensing leads remain a significant problem. There are two types of ICD sensing leads: (1) dedicated bipolar leads and (2) integrated lead systems that include defibrillation coils. The long-term performance of these two lead systems has not been directly compared. METHODS AND RESULTS: We prospectively examined the incidence of lead failure manifested by inappropriate arrhythmia detection in 247 consecutive patients undergoing abdominal ICD implant at a single center between 1991 and 1995. A total of 107 patients received BT-10 (dedicated bipolar) leads and 140 patients received Endotak (integrated bipolar) leads. Over a mean follow-up of 860 +/- 442 days, there were 19 (17.8%) lead failures with the BT-10 lead (261 to 1,505 days postimplant) compared with only 6 (4.3%; P < 0.01) with the Endotak lead (410 to 1,211 days postimplant). Lead failure was due to an insulation defect in all cases, with the problem occurring in the proximal lead (within the pulse generator pocket) in all but one case. Lead survival was significantly better with the Endotak lead (P = 0.015, risk ratio = 3.0, 95% confidence intervals 1.2 to 7.6). CONCLUSION: Late lead failure due to insulation defects in BT-10 sensing leads (causing inappropriate ICD activation) is a relatively common and progressive phenomenon, with difficulties becoming apparent as long as 4 years after implant. This problem is a likely cause of inappropriate shocks in patients with BT-10 leads. Implantation of a new sensing lead should be considered at the time of elective pulse generator replacement, even in the absence of demonstrable oversensing.

Optimization of transvenous coil position for active can defibrillation thresholds.

INTRODUCTION: Lead systems that include an active pectoral pulse generator are now standard for initial defibrillator implantations. However, the optimal transvenous lead system and coil location for such active can configurations are unknown. The purpose of this study was to evaluate the benefit and optimal position of a superior vena cava (SVC) coil on defibrillation thresholds with an active left pectoral pulse generator and right ventricular coil. METHODS AND RESULTS: This prospective, randomized study was performed on 27 patients. Each subject was evaluated with three lead configurations, with the order of testing randomized. Biphasic shocks were delivered between the right ventricular coil and an active can alone (unipolar), or an active can in common with the proximal coil positioned either at the right atrial/SVC junction (low SVC) or in the left subclavian vein (high SVC). Stored energies at defibrillation threshold were higher for the single-coil, unipolar configuration (11.2 +/- 6.6 J) than for the high (8.9 +/- 4.2 J) or low (8.5 +/- 4.2 J) SVC configurations (P < 0.01). Moreover, 96% of subjects had low (< or = 15 J) thresholds with the SVC coil in either position compared with 81% for the single-coil configuration. Shock impedance (P < 0.001) was increased with the unipolar configuration, whereas peak current was reduced (P < 0.001). CONCLUSION: The addition of a proximal transvenous coil to an active can unipolar lead configuration reduces defibrillation energy requirements. The position of this coil has no significant effect on defibrillation thresholds.

Short term escape rhythm characteristics after radiofrequency ablation of the atrioventricular junction.

Radiofrequency ablation of the atrioventricular (AV) node has become an established method of treating drug-resistant supraventricular arrhythmias, especially atrial fibrillation. Although it is routine to implant a permanent pacemaker following ablation, one of the potential adverse effects of the procedure is that many patients become pacemaker-dependent and are at risk of an adverse outcome in the event of pacemaker malfunction. Obtaining information about the characteristics of the escape rhythm would be helpful in risk-stratifying these patients and might facilitate modifications of the procedure that would reduce the incidence of this problem. We prospectively studied the clinical parameters and escape rhythm characteristics in 24 patients undergoing radiofrequency ablation of the AV node. Initially, 2 patients had no detectable escape beats and 4 had escape rates <30 beats/min. At 12 hours, 3 of these 4 had adequate (>30 beats/min) escape rates (there were no 12-hour data in 2). The escape rhythm was stable in 17 of the other 18 while 1 had no escape beats at 12 hours. Patients developing right bundle branch block had a greater chance of having an inadequate escape rhythm at 12 hours but this difference was not seen at 24 hours. We conclude that an adequate escape rhythm is usually present immediately after radiofrequency ablation of the AV node and tends to remain stable up to 24 hours. The absence of an escape rhythm immediately after ablation is of limited prognostic value since reliable escape rhythms may emerge subsequently.

Atrial defibrillation with a transvenous lead: a randomized comparison of active can shocking pathways.

OBJECTIVES: The purpose of this study was to compare transvenous atrial defibrillation thresholds with lead configurations consisting of an active left pectoral electrode and either single or dual transvenous coils. BACKGROUND: Low atrial defibrillation thresholds are achieved using complex lead systems including coils in the coronary sinus. However, the efficacy of more simple ventricular defibrillation leads with active pectoral pulse generators to defibrillate atrial fibrillation (AF) is unknown. METHODS: This study was a prospective, randomized assessment of shock configuration on atrial defibrillation thresholds in 32 patients. The lead system was a dual coil Endotak DSP lead with a left pectoral pulse generator emulator. Shocks were delivered either between the right ventricular coil and an active can in common with the proximal atrial coil (triad) or between the atrial coil and active can (transatrial). RESULTS: Delivered energy at defibrillation threshold was 7.1 +/- 6.0 J in the transatrial configuration and 4.0 +/- 4.2 J in the triad configuration (p < 0.005). Moreover, a low threshold (< or = 3 J) was observed in 69% of subjects in the triad configuration but only 47% in the transatrial configuration. Peak voltage and shock impedance were also lowered significantly in the triad configuration. Left atrial size was the only clinical predictor of the defibrillation threshold (r = 0.57, p < 0.002). CONCLUSIONS: These results indicate that low atrial defibrillation thresholds can be achieved using a single-pass transvenous ventricular defibrillation lead with a conventional ventricular defibrillation pathway. These data support the development of the combined atrial and ventricular defibrillator system.

Comparison of bipolar and integrated sensing for redetection of ventricular fibrillation.

BACKGROUND: Implantable cardioverter-defibrillator function is critically dependent on reliable sensing of intracardiac signals. Lead systems that use integrated sensing, in which the distal shocking coil is part of both the sensing and shocking pathways, may be prone to undersensing of ventricular fibrillation, especially during redetection after a failed first shock. To assess the effect of endocardial lead system on redetection, we compared a dedicated rate-sensing lead and 2 generations of integrated sensing defibrillator leads with a uniform testing algorithm and pulse generator. METHODS: The study group consisted of 72 patients after implantable cardioverter-defibrillator implantation. Three transvenous rate-sensing leads were evaluated: a standard pacing lead, incorporating true bipolar sensing without ventricular coils, or an integrated shocking and sensing lead (Endotak C) with either 6-mm (60 series) or 12-mm (70 series) spacing between the sensing tip and shocking coil. Redetection was assessed from a failed first shock just below defibrillation threshold. RESULTS: Compared with the dedicated bipolar lead, redetection was prolonged with the 60 series lead (8.3 +/- 3.6 vs 6.6 +/- 2.3 seconds, P =.04). Moreover, prolonged redetection (>8 seconds) was observed in 41% of patients with 60 series leads compared with only 11% with dedicated bipolar leads (P <.01). No significant effects on redetection were noted with an integrated lead with greater spacing between the tip and coil (70 series). CONCLUSIONS: Delayed redetection is frequently noted with an integrated lead with close spacing between the tip and coil. Detailed evaluation of detection and redetection of these leads should be performed at the time of pulse generator replacement.

The effect of procainamide on T wave alternans.

INTRODUCTION: The measurement of microvolt level T wave alternans (TWA) is a technique for detecting arrhythmia vulnerability. Previous studies demonstrated that the magnitude of TWA is dependent on heart rate. However, the effects of antiarrhythmic drugs on TWA are unknown. METHODS AND RESULTS: This was a prospective evaluation of intravenous procainamide on TWA in 24 subjects with inducible sustained ventricular tachycardia (VT). Measurements of TWA were performed at baseline in the drug-free state and after procainamide loading (1,204+/-278 mg). Recordings were made in normal sinus rhythm, and during atrial pacing at 100 beats/min and 120 beats/min. The magnitude of TWA in the vector magnitude lead was decreased by procainamide at all heart rates: 0.6+/-0.8 to 0.3+/-0.4 microV in sinus rhythm, 2.0+/-1.6 to 0.7+/-0.7 microV at 100 beats/min, and 3.0+/-2.0 to 1.7+/-1.8 microV at 120 beats/min (P<0.001 by analysis of variance). The sensitivity of TWA for the induction of VT at baseline was 5% in sinus, 60% at 100 beats/min, and 87% at 120 beats/min, while it decreased with procainamide to 5%, 19%, and 60%, respectively. Decreases in TWA in response to procainamide were independent of the antiarrhythmic effects on VT inducibility. CONCLUSIONS: These results indicate that the magnitude of TWA decreases with acute procainamide loading and this effect decreases the sensitivity of TWA for the induction of sustained VT.

Intravenous amiodarone suppression of electrical storm refractory to chronic oral amiodarone.

We report the case of an electrical storm in a cardiac arrest survivor with an ICD, in whom chronic oral amiodarone failed to suppress ventricular arrhythmias, and in whom intravenous amiodarone resulted in stability for 6 weeks prior to successful cardiac transplantation. Intravenous amiodarone can be successful in suppressing life-threatening ventricular arrhythmias, even when chronic oral amiodarone is unsuccessful.

Cellular mechanisms of altered contractility in the hypertrophied heart: big hearts, big sparks.

To investigate the cellular mechanisms for altered Ca2+ homeostasis and contractility in cardiac hypertrophy, we measured whole-cell L-type Ca2+ currents (ICa,L), whole-cell Ca2+ transients ([Ca2+]i), and Ca2+ sparks in ventricular cells from 6-month-old spontaneously hypertensive rats (SHRs) and from age- and sex-matched Wistar-Kyoto and Sprague-Dawley control rats. By echocardiography, SHR hearts had cardiac hypertrophy and enhanced contractility (increased fractional shortening) and no signs of heart failure. SHR cells had a voltage-dependent increase in peak [Ca2+]i amplitude (at 0 mV, 1330+/-62 nmol/L [SHRs] versus 836+/-48 nmol/L [controls], P<0.05) that was not associated with changes in ICa,L density or kinetics, resting [Ca2+]i, or Ca2+ content of the sarcoplasmic reticulum (SR). SHR cells had increased time of relaxation. Ca2+ sparks from SHR cells had larger average amplitudes (173+/-192 nmol/L [SHRs] versus 109+/-64 nmol/L [control]; P<0.05), which was due to redistribution of Ca2+ sparks to a larger amplitude population. This change in Ca2+ spark amplitude distribution was not associated with any change in the density of ryanodine receptors, calsequestrin, junctin, triadin 1, Ca2+-ATPase, or phospholamban. Therefore, SHRs with cardiac hypertrophy have increased contractility, [Ca2+]i amplitude, time to relaxation, and average Ca2+ spark amplitude ("big sparks"). Importantly, big sparks occurred without alteration in the trigger for SR Ca2+ release (ICa,L), SR Ca2+ content, or the expression of several SR Ca2+-cycling proteins. Thus, cardiac hypertrophy in SHRs is linked with an alteration in the coupling of Ca2+ entry through L-type Ca2+ channels and the release of Ca2+ from the SR, leading to big sparks and enhanced contractility. Alterations in the microdomain between L-type Ca2+ channels and SR Ca2+ release channels may underlie the changes in Ca2+ homeostasis observed in cardiac hypertrophy. Modulation of SR Ca2+ release may provide a new therapeutic strategy for cardiac hypertrophy and for its progression to heart failure and sudden death.

The effect of shock configuration and delivered energy on defibrillation impedance.

Shock impedance is an important determinant of defibrillation efficacy. Lead configuration, shock polarity, and delivered energy can affect shock impedance, but these variables have not been studied in active can lead systems. The present study was a prospective evaluation of 25 patients undergoing initial transvenous defibrillator implantation. In all patients, a dual coil lead and pectoral emulator were placed and three lead configurations were tested in random order: Lead (distal to proximal coil), unipolar (distal coil to can), and triad (distal coil to can + proximal coil). Shock energies of 0.1- to 15-J shock were evaluated. Impedance increased a mean of 21% as delivered energy was decreased (P < 0.001), an effect independent of lead configuration. At all delivered energies, impedances in the unipolar configuration were about 40% higher than triad, while the lead configuration was about 20% higher than triad (ps < 0.001). Polarity did not affect impedance. These results indicate that transvenous lead configurations and delivered energy, but not polarity, significantly influence shock impedance. The magnitude of the increase of impedance at low energies is independent of the shocking pathway. This effect has important implications for low energy shocks used to terminate atrial fibrillation or ventricular tachycardia.

A new defibrillator discrimination algorithm utilizing electrogram morphology analysis.

Inappropriate therapies delivered by implantable cardioverter defibrillators (ICDs) for supraventricular arrhythmias remain a common problem, particularly in the event of rapidly conducted atrial fibrillation or marked sinus tachycardia. The ability to differentiate between ventricular tachycardia and supraventricular arrhythmias is the major goal of discrimination algorithms. Therefore, we developed a new algorithm, SimDis, utilizing morphological features of the shocking electrograms. This algorithm was developed from electrogram data obtained from 36 patients undergoing ICD implantation. An independent test set was evaluated in 25 patients. Recordings were made in sinus rhythm, sinus tachycardia, and following the induction of ventricular tachycardia and atrial fibrillation. The arrhythmia complex is defined as wide if the duration is at least 30% greater than the template in sinus rhythm. For narrow complexes, four maximum and minimum values were measured to form a 4-element feature vector, which was compared with a representative feature vector during normal sinus rhythm. For each rhythm, any wide complex was classified as ventricular tachycardia. For narrow complexes, the second step of the algorithm compared the electrogram with the template, computing similarity and dissimilarity values. These values were then mapped to determine if they fell within a previously established discrimination boundary. On the independent test set, the SimDis algorithm correctly classified 100% of ventricular tachycardias (27/27), 98% of sinus tachycardias (54/55), and 100% of episodes of atrial fibrillation (37/37). We conclude that the SimDis algorithm yields high sensitivity (100%) and specificity (99%) for arrhythmia discrimination, using the computational capabilities of an ICD system.

Overdrive atrial pacing for conversion of atrial flutter: comparison of postoperative with nonpostoperative patients.

BACKGROUND: Previous studies have reported varying success rates in overdrive pace termination of atrial flutter. We hypothesized that these discrepancies might be caused by differences in study populations. Accordingly, we prospectively compared the success rate of pacing in patients with atrial flutter that occurred after heart surgery with that of patients with atrial flutter from other causes. METHODS AND RESULTS: The study population consisted of 65 consecutive patients referred for pace termination of typical (type I) atrial flutter. Pacing was performed in 30-second bursts, starting at the flutter cycle length, and repeated in 5-ms decrements until normal sinus rhythm or atrial fibrillation occurred. Normal sinus rhythm was restored in 38 (65%) patients. Of 20 patients whose flutter was precipitated by heart surgery, 19 (95%) were successfully pace terminated. In contrast, pace termination was successful in only 47% of the remainder of the population (P <.001). No other clinical parameters were predictive of outcome. CONCLUSIONS: We conclude that overdrive pacing is an effective means of terminating atrial flutter that has occurred after heart surgery. Alternative methods should be considered as the initial therapeutic approach in patients with atrial flutter from other causes.

The effect of delivered energy on defibrillation shock impedance.

The impedance of internal defibrillator shocks is an important determinant of defibrillation efficacy. To assess the effect of delivered energy on impedance, we studied 97 patients with 4 different lead systems. The lead systems evaluated were two epicardial patches, a hybrid system of a patch and right atrial coil, a dual coil transvenous lead and a transvenous lead with a subcutaneous patch. Impedances were measured for 6 shock energies between 0.1 and 30 J. Shock impedance increased at low energies for all lead systems (p < 0.001), although the rate of increase varied markedly between systems. The energy factor (FE), which is the ratio of impedances for the 0.1 and 10 J shocks, was least for the platinum transvenous lead (1.2 +/- 0.02) and greatest for the titanium hybrid lead (4.2 +/- 0.2). Reversing the polarity of the hybrid lead markedly attenuated the impedance rise. These findings indicate that there is at least a modest rise (20%) of shock impedance at very low delivered energies. The largest increases noted with titanium lead systems are primarily due to polarization. Titanium transvenous leads should be avoided when low energy shocks are utilized such as for the cardioversion of ventricular tachycardia or atrial fibrillation.

Effect of heart rate on T wave alternans.

INTRODUCTION: T wave alternans (TWA) is a promising technique for detecting arrhythmia vulnerability. Previous studies in animals demonstrated that the magnitude of TWA is dependent on heart rate. However, the effects of heart rate on TWA in humans and the clinical relevance of this effect remain controversial. METHODS AND RESULTS: This was a prospective evaluation of pacing rate and monitoring lead configuration on TWA in subjects undergoing electrophysiologic study. Measurements of TWA were performed on 45 patients in the absence of antiarrhythmic drugs. Recordings were made in normal sinus rhythm and during atrial pacing at 100 and 120 beats/min. Sustained monomorphic ventricular tachycardia (VT) was induced in 29 patients with programmed stimulation. TWA in the vector magnitude lead increased with heart rate, independent of VT inducibility (0.4 +/- 0.7 microV, 1.6 +/- 1.9 microV, and 2.4 +/- 2.1 microV in sinus rhythm and at 100 and at 120 beats/min, respectively; P < 0.001). In addition, the diagnostic performance of TWA for inducible VT was dependent on heart rate (sensitivity 4%, 42%, and 65%, and specificity 100%, 93%, and 63% at 77, 100, and 120 beats/min, respectively). By analyzing orthogonal leads rather than the vector magnitude lead, the sensitivity is increased from 42% to 59% at 100 beats/min, but the specificity is reduced from 93% to 72%. CONCLUSION: These results indicate that TWA in humans is strongly dependent on heart rate with regard to both magnitude and diagnostic performance. The optimal heart rate for the measurement of TWA is between 100 and 120 beats/min and multiple leads should be monitored.