a Department of Cardiology, University of Vienna, AKH Wien, Waehringer Guertel 18-20, 1090 Vienna, Austria
b I Medizinische Klinik, University Hospital, Mannheim, Germany
c Department of Cardiology, University of Leipzig, Germany
d Department of Cardiology and Angiology, Westfälische Wilhelms-Universität, Münster, Germany
e Department of Physiology and Biophysics, Technion-Israel Institute of Technology, Haifa, Israel
f The Heart Failure Center, Columbia University, New York, USA
Received December 18, 2003;
revised February 13, 2004;
accepted February 26, 2004
* Corresponding author. Tel.: +43-1-40400-4614; fax: +43-1-4081148
E-mail address: guenter.stix{at}univie.ac.at
See page 626 for the editorial comment on this article1
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Abstract |
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Methods and results Twenty-five patients, 23 males, with a mean age of 62±9 years and drug-refractory NYHA class III heart failure were assigned to CCM-generator implantation. The underlying heart disease was idiopathic dilated cardiomyopathy in 12 patients and coronary heart disease in 13 patients. Acute efficacy of CCM with 7.73-V stimuli delivered via two right ventricular leads was evaluated by measuring the time derivative of left ventricular pressure (dP/dt). After implantation, the CCM generator was activated for 3 h daily over 8 weeks.
In 23/25 patients the CCM system was implanted successfully. Heart failure significantly improved from NYHA class III to class II in 15 patients and to class I in 4 patients , left ventricular ejection fraction improved from 22±7% to 28±8%
, and the Minnesota Living with Heart Failure Score improved from 43±22 to 25±18
. The 6-min walk test increased from 411±86 to 465±81 m
. Nine patients (39%) had intermittent sensations associated with CCM delivery. There were two (8%) non-device-related deaths during follow-up.
Conclusions These preliminary data indicate that CCM by delivery of intermittent nonexcitatory electrical stimuli is a promising technique for improving ventricular systolic function and symptoms in patients with drug-refractory NYHA class III heart failure.
Key Words: Heart failure Electrical stimulation Absolute refractory period Systolic function
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Introduction |
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The aim of this study was to evaluate the feasibility, safety, and efficacy of chronically implanted CCM generators in patients with severe chronic heart failure who are already on optimised medical therapy.
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Methods |
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In the CCM device used for chronic therapy in this study, built-in safety-designed algorithms inhibit the generation of CCM signals when any irregular electrical activity is detected, such as premature atrial or ventricular complexes, atrial fibrillation, or sensing defects. Therefore, this system includes an atrial lead in addition to two right ventricular leads. To achieve a substantial number of QRS complexes suitable for stimulation during the absolute refractory period, a maximum of 8900 ventricular ectopic beats per 24 h, monitored over a period of 4 days, was allowed. Subjects with documented sustained ventricular tachycardia and patients scheduled for, or who had undergone, revascularisation within three months of enrolment were excluded.
Written, informed consent was obtained from all patients. The study was approved by the respective Ethics Committees of the participating hospitals and carried out in compliance with the Declaration of Helsinki.
The CCM signal generator (OptimizerTM II, Impulse Dynamics, New Jersey, USA) used in this study is an implantable system that delivers two biphasic, square-wave signals of up to 7.73 V during the absolute refractory period (Fig. 1). The implanted system does not produce any kind of conventional single or dual-chamber pacing. Two commercially available pacemaker leads were used for sensing right ventricular activity and delivery of CCM signals (Tendril DX1388T-58, St. Jude Medical, St. Paul, USA). Another commercially available right atrial lead was used to record electrical signals from the right atrium (4068-52, Medtronic Inc, Minneapolis, USA) (Fig. 2).
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On signal delivery during the absolute effective refractory period via both right ventricular leads, left ventricular pressure measurements were made simultaneously and dP/dt was derived. A minimum increase in dP/dt of 5% was required for device implantation. In case of an insufficient increase in dP/dt with the initial lead configuration, one or both right ventricular leads were positioned differently and stimulation was tested again. Every stimulation test via both right ventricular leads was counted as one right ventricular lead position. If, despite testing different lead positions, CCM stimulation failed to sufficiently increase dP/dt and/or maximum output testing resulted in phrenic nerve stimulation, device implantation was abandoned.
The patients were discharged with the devices programmed to deliver CCM signals for 3 h a day between 7 and 10 p.m. The time and duration of daily signal delivery were chosen arbitrarily, since there was no prior human experience available other than acute catheterisation laboratory tests. The patients did not know how their devices were programmed.
Descriptive statistics were calculated for all variables (means±SD). Datasets were tested for normal distribution. For comparisons of outcome parameters between baseline and follow-up, the two-sided Friedman ANOVA test was used for NYHA classification, left ventricular ejection fraction, Minnesota Living with Heart Failure Score, and ventricular ectopic activity; no corrections were made for multiple testing in this feasibility study. The Wilcoxon matched-pairs test was used to compare the results of the 6-min walk test, which were log-normally distributed. A p value <0.05 was considered statistically significant.
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Results |
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Overall, the clinical condition of the patients improved significantly (Fig. 4). Left ventricular ejection fraction and quality of life significantly improved from 22±7% to 28±8% and from 43±22 to 25±18 (p=0.001), respectively (Table 2). The 6-min walk test, performed in 7 patients at one of the participating centres, increased from 411±86 to 465±81 m
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Discussion |
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In good accordance with experimental studies3,7 and studies in humans in the electrophysiologic laboratory,8 intraoperative testing showed an immediate increase in dP/dt upon CCM initiation, which was maintained during signal delivery. As stipulated by the protocol to allow device implantation, a minimum increase in dP/dt of 5% was seen in almost all patients (96%) irrespective of the underlying heart disease. This response of dP/dt during acute testing was transformed into a sustained increase in left ventricular ejection fraction that was paralleled by an improvement in clinical parameters during follow-up. A placebo effect due to device implantation appears unlikely since device therapy was only allowed in patients that showed substantial haemodynamic improvement during acute intraoperative testing. Nevertheless, in order to evaluate the contribution of a device-placebo effect to the clinical effects observed during a more extensive follow-up, a prospective double blind study is required.
Although CCM stimulation was carried out only 3 h a day, the increase in systolic function was sustained for at least several hours upon CCM termination, since a significant increase in the ejection fraction was demonstrated when the device had been inactive for at least 12 h. How long the beneficial effect of intermittent CCM stimulation is sustained cannot be answered by our data. However, as seen in one of the patients, whose device was inhibited by atrial undersensing, the inotropic effect may gradually disappear, resulting in concomitant clinical deterioration.
The precise mechanism by which CCM stimulation exerts its beneficial effects remains unknown. In particular, the phenomenon whereby right ventricular septal stimulation results in significant improvement of left ventricular systolic function cannot be fully explained at this point in time and requires further investigation. One of the hypotheses of nonexcitatory stimulation postulates that the high-energy electrical current applied during the absolute myocardial refractory period results in prolongation of the duration of the action potential with a concurrent increase in calcium delivery to myofilaments.2,3
The high current necessary for sufficient prolongation of the action potential may cause intermittent sensations: in 1/25 patients, phrenic nerve stimulation precluded device implantation and in 8/23 chronically implanted patients, intermittent mild sensations associated with CCM stimulation occurred during follow-up. This phenomenon occurred although intraoperative high-output testing had been negative in these patients, even necessitating surgical lead repositioning in one patient. This may best be explained as a posture-related phenomenon. Intraoperatively, acute testing is performed in the supine position whereas in the clinical setting CCM stimulation occurred mainly in the standing or sitting position, which changed the anatomic distance between the phrenic nerve and site of stimulation.
Apart from these minor sensations, which did not have a significant impact on quality of life in the vast majority of the patients, no device-related complications were observed. In particular, no proarrhythmic effects associated with this therapy were observed during Holter monitoring.
However, two patients with ischaemic cardiomyopathy died suddenly during follow-up. Both deaths were witnessed and occurred at a time when the implanted devices were inactive. Thus, a causal relationship between CCM and the sudden deaths appears unlikely. Patients with ischaemic cardiomyopathy are at high risk for sudden cardiac death9 and concomitant implantable cardioverter-defibrillator use is highly recommended. However, in patients with nonischaemic cardiomyopathy the role of prophylactic ICD therapy has not yet been defined. As to whether the positive inotropic effect of CCM therapy may increase the risk of sudden cardiac death in patients with severely depressed left ventricular function needs further investigation.
The application of CCM stimulation for 3 h a day was chosen arbitrarily in this study because no experience of chronic CCM application in humans was available prior to this study. The energy requirements of biphasic impulses of 7.7 V/5.4 ms are high, which will result in an expected longevity of CCM devices of approximately one year with current battery systems. Therefore, dose-finding studies, including application of CCM on demand upon clinical grounds and/or different stimulation modes, are mandatory.
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Conclusion |
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Acknowledgments |
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Footnotes |
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References |
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