Chu‐Pak Lau

Electrophysiological effects of a single intravenous administration of ivabradine (S 16257) in adult patients with normal baseline electrophysiology.

AbstractIntroduction: Ivabradine is a heart rate-lowering agent that selectively inhibits the pacemaker current, If, in the sinoatrial node. The objective of this study was to evaluate the effects of a single intravenous administration of ivabradine on cardiac electrophysiological parameters in patients with normal baseline electrophysiology. The safety profile of ivabradine was also investigated. Study design: This was an open-label, single-dose, non-controlled study conducted at one centre. Patients received a single dose of ivabradine (0.2 mg/kg) intravenously as a slow bolus over 15 seconds. Electrophysiological investigations, after catheter ablation for cardiac dysrhythmia, were performed at baseline and 30 minutes and 1 hour after drug administration. Electrode catheters were introduced and advanced to the right atrium, the bundle of His and the right ventricular apex of the heart. Electrophysiological parameters assessed included heart rate, QT interval, corrected QT interval (QTc), PR interval, sinoatrial conduction time, sinus node recovery time, and right atrial and ventricle refractory periods. Changes in electrophysiological parameters over time were assessed using one-way analysis of variance. In the case of a significant time effect, the Newman-Keuls procedure was used for comparison. Patients: A total of 14 patients, 12 male and 2 female, aged 18–75 years were included in the study. The arrhythmia requiring catheter ablation was atrioventricular (AV) excitation in seven patients, paroxysmal supraventricular tachycardia in five patients, atrial fibrillation and flutter in one patient, and cardiac dysrhythmia in one patient. All patients had normal electrophysiology at baseline. Results: Mean heart rate decreased significantly with ivabradine by 12.9 beats/min at 30 minutes and 14.1 beats/min at 1 hour. The mean QT interval increased but QTc showed no significant change from baseline. The PR and QRS intervals were unchanged. The right atrial and right ventricle refractory periods showed no significant change from baseline. The measured QT interval and the sinus node recovery time were increased. There were no clinically relevant changes in any other major electrophysiological parameters. Ivabradine was well tolerated and no serious adverse events occurred. Conclusion: A single intravenous dose of ivabradine had a significant heart ratelowering effect, observed at 30 minutes and 1 hour after administration. Ivabradine did not prolong QTc or modify conductivity and refractoriness of the atrium, AV node, His-Purkinje system and ventricles, or repolarisation duration. These results confirm the action of ivabradine as a specific heart rate-lowering agent.

Comparison of exercise performance of six rate-adaptive right ventricular cardiac pacemakers

Single chamber cardiac pacemakers capable of automatically adjusting the rate according to body requirements have become an important means of physiologic pacing in patients with bradycardias. Such pacemakers are dependent on a nonatrial sensor of physiologic needs to optimize the rate response. Fifty rate-adaptive right ventricular pacemakers were implanted in 46 patients with a mean age of 60 +/- 4 years (mean +/- standard error of the mean). There were 2 types of activity-sensing pacemakers (Activitrax and Sensolog 702), the QT-sensing pacemakers (TX2 and Quintech), 2 types of respiratory-sensing pacemakers (Biorate [RDP3 and MB1] and Meta) and a rate-adaptive pacemaker that senses right ventricular dP/dt (Deltatrax). The rate responses of a group of 9 volunteers of similar age (62 +/- 2 years) were also included for comparison. Improvement in exercise duration in the rate-adaptive mode compared to the constant-rate ventricular pacing (VVI) mode was achieved during randomized symptom-limited treadmill exercise (from 26 to 49%). Compared with the sinus responses, the activity-sensing pacemakers responded most appropriately in speed. However, their rate responses were not related to workload and had lower correlations with estimated oxygen consumption (r = 0.7 and 0.47 for Activitrax and Sensolog, respectively). Respiratory-sensing pacemakers responded more appropriately in magnitude (r greater than 0.8) although their rate responses were slower. All pacemakers studied either showed no response or a reverse-rate response to the Valsalva maneuver. It is concluded that the currently available rate-adaptive ventricular pacemakers improve exercise performance compared with VVI pacemakers in patients with bradycardias.(ABSTRACT TRUNCATED AT 250 WORDS)

Limitations of Rate Response of an Activity-Sensing Rate-Responsive Pacemaker to Different Forms of Activity

The responses of an activity‐sensing rate‐responsive system (Activitrax) to various forms of physiological activity were assessed in 15 individuals who had this pacemaker. Nine were patients with complete heart block and atrial arrhythmias; their mean age was 60 years (range, 41–85 years). Six were age‐matched healthy volunteers who were exercised with an external Activitrax system attached firmly to the chest wall. The pacemaker was programmed to achieve a pacing rate of about 100 bpm at the end of the first stage of the Bruce protocol (pacemaker settings; rate = 70–150 bpm; threshold = low to medium; response = 6–9). In the activity‐sensing ventricular pacing mode, oil patients achieved a significant increase in treadmill time compared to constant‐rate ventricular pacing (mean ± SD, 8.0 ± 3.3 vs 5.4 ± 2.3 minutes; p < 0.01), with a mean maximum pacing rate of 123 ± 18 bpm. Jogging in place produced a prompt increase in pacing rate, with the maximum achieved at the end of the exercise. However, physiological activities such as hand‐grip, the Valsalva maneuver and standing resulted in only minimal rate response. Pacing rate after ascending 4 flights of stairs was the same as that achieved after descending the same stairs (100 ± 8 vs 105 ± 4 bpm; p < 0.1). All 15 subjects were exercised from resting heart rate for 3 minutes on a treadmill at 1.2 mph and 2.5 mph with four gradients at each speed. Although the pacing rate increased with a faster treadmill speed (p < 0.005), it did not respond appropriately to a change in gradient compared to the sinus rate. We conclude that although activity‐sensing rate‐responsive pacing gives a prompt increase in pacing rate and improves maximum exercise tolerance, further refinement is necessary because: (1) physiological activities not associated with significant movement are not detected by this pacing system; (2) detection of vibrations as an indicator of activities does not correlate well with the level of exertion.

Selective Vibration Sensing: A New Concept for Activity-Sensing Rate-Responsive Pacing

A clinically available model of an activity‐sensing, rate‐responsive pacemaker (Activitrax, Medtronic) utilizes body vibration during exercise as an indicator of the need for a rate increase. Although having the advantage of rapid onset of rate response, this system lacks specificity and the rate response does not closely correlate with the level for exertion. In addition, this pacemaker is susceptible to the effects of extraneous vibration. In this study involving 20 normal subjects fitted with an external Activitrax pacemaker, the rate responses to a variety of exercises were studied and were compared with the corresponding sinus rates. The vibration generated at the level of the pacemaker was also measured by accelerometers in three axes. Only a fair correlation (r = 0.51) was achieved between the pacemaker rate and the sinus rate. The total root mean square value of acceleration in either the anteroposterior or the vertical axes was found to have a better correlation (r = 0.8). As the main accelerations during physical activities were in the lower frequency range (0.1–4 Hz), a low‐pass filter was used to reduce the influence of extraneous vibration. Selective sensing of the acceleration level may be usefully implemented in an algorithm for activity pacing.

Initial Clinical Experience with a Minute Ventilation Sensing Rate Modulated Pacemaker: Improvements in Exercise Capacity and Symptomatology

A minute ventilation sensing rate modulated pacemaker was implanted in nine patients with bradycardia. Minute ventilation is sensed in this pacemaker by means of a standard bipolar pacing electrode. Compared with exercise in the constant rate ventricular pacing (WI) mode at 1 month after pacemaker implantation, rate responsive pacing resulted in an improvement of exercise capacity of 33 ± 5% (from 437 ± 42 s in the WI mode to 593 ±57 s in the rate modulated mode, P < 0.01, Bruce protocol). This improvement was maintained in the seven patients in whom an exercise test was repeated at 3 months after implantation. The pacing rate was significantly correlated with oxygen consumption (r = 0.8A ± 0.04) and measured minute ventilation (r = 0.76 ± 0.06), Symptomatology in these patients was assessed by means of self‐assessment questionnaires in a double blind, randomized cross‐over study in which the pacemaker was alternatively programmed into the WI and rate modulated modes. Significant improvements in “shortness of breath” and “energy during daily activities” were documented during rate modulated pacing and “palpitations” and “chest pain” were not worsened. Most patients preferred the rate modulated mode during the study. In conclusion, rate modulated pacing by sensing minute ventilation resulted in better exercise capacity and symptomatology. The pacing rate also showed good correlation with the individuals oxygen requirement.

Clinical experience with Sensolog 703: a new activity sensing rate responsive pacemaker.

Sensolog 703 is a new activity sensing rate responsive pacemaker which detects body vibration during physical exercise and uses the vibration as an indicator of the physiological need for a rate increase. This pacemaker was implanted in 11 patients with complete heart block and atrial arrhythmias. Their mean age was 58 (range 39–72) years. With appropriate rate response, exercise capacity, as assessed by the duration of graded treadmill exercise using the Bruce protocol, was significantly improved over the WI pacing mode (mean ± SEM, 462 ± 52 s in the rate responsive mode and 368 ± 34 s in the VVI mode, P < 0.02). Cardiac output at peak exercise, as assessed by continuous wave Doppler sampling of aortic root blood flow, was also significantly increased compared to the resting value in both piecing modes. However, the increase was more marked when exercise was performed in the rate response mode (93 ± 22% increase over resting cardiac output in the rate responsive mode and 57 ± 13% increase in the WI mode, P < 0.05). The rate responses of this pacemaker were compared with those of a Medtronic Activitrax pacemaker. Although both pacemakers responded to an increase in walking speed, neither responded appropriately to walking up different gradients. In both cases, ascending and descending four flights of stairs resulted in similar pacing rates. There was no response to physiological activities with minimal body movements such as isometric exercise and the Valsalva maneuver. Technical problems were encountered in two implanted Sensoiog pacemakers: one had spontaneous rate acceleration at rest immediately following implantation and one showed intermittent rate acceleration while the patient was at rest. Both units were programmed to the WI mode. In conclusion, satisfactory rate response, improvement in exercise duration and increase in cardiac output were achieved with the Sensolog 703 pacemaker. However, as body vibration is not closely related to physiological needs, it has similar limitations in rate response as the Activitrax pacemaker.

Comparative Evaluation of Chronotropic Responses of QT Sensing and Activity Sensing Rate Responsive Pacemakers

The rate responses of activity sensing (ATS) and QT sensing (QTS) rate responsive pacemakers to different forms and durations of exercises were compared. Nine patients with ATS and five with QTS were studied. All had complete heart block and atrial arrhythmias. At (he onset, (he pacemakers were programmed to achieve a pacing rate of 100–110 bpm by the end of stage 1 of the Bruce protocol, and to a pacing rate range of 70–150 bpm. With progressive exercise, using a treodmill (Bruce protocol), the maximum pacing rates in the two groups were not significantly different (mean ± SD; 123 ± 18 vs 129 ± 23 bpm, ATS vs QTS). The time taken to return to the baseline pacing rate during recovery was significantly longer with QTS (178 ± 70 vs 264 ± 68 s, p < 0.05). Brief exercise tests on a treadmill were performed for 3 min each with different combinations of treadmill speeds (1.2 and 2.5 mph) and gradients (0, 5, 10 and 15%). In both groups of patients, faster walking speed was associated with a faster pacing rate at each gradient. However, with increasing gradients, at each speed, there was a rise in the maximum pacing rate only in patients with QTS. During brief exercise tests, the maximum rate was achieved by the end of exercise in patients with ATS, but was delayed by 33 ± 20 s after exercise in patients with QTS. With very brief exercises lasting less than 1 minute (jogging on the spot), which require immediate rate response, patients with ATS had a rapid rate response and the maximum pacing rates were achieved by the end of the activities. The response of QTS was delayed and maximum pacing rate occurred during recovery. Ascending and descending four flights of stairs resulted in similar pacing rates in patients with ATS (100 ± 8 vs 105 ± 4 bpm, NS). Higher pacing rates were achieved on ascending stairs in patients with QTS (115 ± 24 vs 93 ± 28 bpm, p < 0.01). We conclude that with comparable pacemaker settings, ATS results in a more prompt rate response while the peak pacing rate of QTS is delayed. Rate responses are similar with gradually progressive exercise. However, the magnitude of rate response with QTS is more proportional to the level of exertion.

Rate modulation by arm movements of the respiratory dependent rate responsive pacemaker.

The rate response to arm movements of the respiratory dependent rate responsive pacemaker (RDP3, Biotec) was assessed in four patients implanted with this pacemaker. The pacemaker was implanted in the left prepectoral region and the auxiliary impedance measuring electrode positioned subcutaneously over the right second intercostal space with its tip lateral to the mid‐clavicular line. The lower rate of the pacemaker was programmed to 75 bpm. While holding the breath, swinging arm movements (30 times) resulted in rate acceleration. The peak rate was faster when the arm on the side of the auxiliary electrode was swung (mean ± SEM, 117 ±8 compared to 130 ± 5 bpm, P < 0.5). The mean rate response of the subjects to brie/ treadmill exercise (Bruce stage 1) performed with both hands holding the support rails, swinging the right arm only, swinging left arm only and swinging both arms were 108, 140, 135 and 128 bpm respectively. Impedance measurement confirmed the significant influence of arm movements on thoracic “impedance” changes, which was mainly caused by electrode motion artifacts affecting the two electrode measuring system. This effect was dependent on the relative positions of the impedance measuring electrodes (i.e., between the pacemaker casing the auxiliary lead). Subsequently the auxiliary lead of the respiratory pacemaker (MB‐1, and Biorate) was implanted in the lower part of the chest on the right sternal edge in another patient. Rate acceleration was only observed when the arm on the side of the pacemaker was swung. As arm movements often accompany physical activities, pacing rate can be affected and should be considered when programming this pacemaker.

Myopotential Interference in Unipolar Rate Responsive Pacemakers

The effects of myopotential interference on unipolar rate responsive pacemakers were assessed in 22 patients. Six types of pacemakers (from four manufacturers) were studied: five TX2 (QT sensing), seven Biorate (five RDP3 and two MB‐1, respiratory rate sensing), seven Adivitrax (activity sensing), two Medtronic 2503 (dP/dt sensing), and one Sensolog P703 (activity sensing). Provocative tests using arm exercises were performed in both VVI and rate responsive modes. At nominal sensitivity settings (1.8–2.5 mV), 55% of these patients were myopotential positive for at least 1 provocative test. Pressing the palms together was found to be the most sensitive provocative test Rate response was achieved with treadmill exercise (all patients), hyperventilation (RDP3 and MB‐1) and tapping (Activitrax) or wobbling the pacemaker in its pocket (Sensolog). During continued rate acceleration, myopotential interference was induced by arm exercises. The duration of inhibition was shorter when the provocative tests were performed during rate response compared to that occurred at rest. Short periods of myopotential interference resulted in temporary inhibition of pacing but rate response continued immediately on removal of the interference. In one patient with a RDP3 pacemaker, a prolonged episode of myopotential interference during treadmill exercise resulted in reversion of the pacemaker to the interference mode. Appropriate adjustment of the sensitivity setting effectively controlled the symptoms in most patients. However, one patient with a QT sensing pacemaker and symptomatic myopotential interference required programming to the VVT pacing mode. Two out of five patients with RDP3 required pacemaker replacement because of uncontrolled myopotential interference. In conclusion, myopotential interference is a significant problem in unipolar rate responsive pacemakers. The use of provocative tests may assist in the diagnosis of this problem.

A severe case of myopotential interference in a patient with a respiratory-dependent rate modulated pacemaker

Symptomatic myopotential interference was observed in a patient with a respiratory-dependent rate modulated pacemaker (RDP3). During treadmill exercise, prolonged interference suspended the rate responsive function and resulted in reversion to the interference mode with the pacing rate falling back to the basic frequency during the interference. This loss of rate response resulted in severe impairment of exercise tolerance and reduction in cardiac output during exercise. The unit was replaced with a bipolar activity sensing rate modulated pacemaker.