Nonexcitatory stimulation as a novel treatment for heart failure: cause for excitement?

Rik Willemsa and Karin R Sipidob,*

a Division of Cardiology, University Hospital Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium
b Laboratory of Experimental Cardiology, University of Leuven, Leuven, Belgium

* Correspondence to: Tel.: +32-16-347-153; fax: +32-16-345-844
E-mail address: karin.sipido{at}med.kuleuven.ac.be

This editorial refers to "Chronic electrical stimulation during the absolute refractory period of the myocardium improves severe heart failure"1 by G. Stix et al. on page 650.

The prevalence of heart failure is increasing and the "heart failure epidemic" is a growing socioeconomic burden to the public health sector.1 Although recent improvements in heart failure therapy have resulted in increased survival, the need for better treatment remains.2 In this issue, Stix et al.3 present their early experience with a new implantable device for the treatment of severe heart failure. The OptimizerTM II (Impulse Dynamics, NJ, USA) delivers electrical stimuli via 2 leads in the right ventricle. A 30-ms biphasic pulse is applied immediately after local activation, i.e., within the refractory period, a technique that has been coined "cardiac contractility modulation," or CCM. The term is based on the observation that such pulses could enhance contraction in acute animal experiments, which were carried out by coauthors of the current study (references in3). This device was implanted successfully in 23/25 patients with New York Heart Association (NYHA) class III heart failure on maximal tolerated medical treatment. The device was set to pace in the refractory period during 3 h a day for 8 weeks. The authors report an improvement in NYHA functional class, quality of life, echocardiographically defined ejection fraction, and the 6-min walk test with this new treatment. Although these results are exciting, major questions remain.

Mechanisms that could explain CCM effects: favourable in the long-term?

It is proposed that the CCM stimulus prolongs the action potential, thereby raising intracellular Ca2+.2 Although prolonging the depolarisation can indeed increase the cellular Ca2+ load,4,5 evidence that the action potential becomes more prolonged with CCM is scant. An action-potential recording with the CCM stimulus signal removed showed a modest prolongation,6 but there are no further experimental data available. Measurements of global QTc did not show any effect of CCM in an earlier experimental study7 and no data are available for the current study. Since the CCM pulse is biphasic and the actual current differs near the anode and cathode, both depolarisation and repolarisation could occur. Experiments whereby current was injected early in the action potential in single cardiac myocytes have shown a pronounced effect on early repolarisation, but much less on the duration of the action potential.8,9 Effects on Ca2+ handling are profound: the application of depolarising current early in the action potential decreases Ca2+ release from the sarcoplasmic reticulum, whereas early repolarisation enhances Ca2+ release.8,9 This is particularly true for the failing heart, which has a reduced early repolarisation due to loss of the transient outward current.8 Ideally, experimental studies should be designed to measure action potentials and monophasic action potential (MAP) recordings, while in patients in vivo local electrograms (MAPs) should be obtained in addition to QTc. Until such evidence is available, the exact effects on the action potential remain speculative. This is not without consequence, since prolongation of the action potential in heart failure is recognised to be a major factor in the enhanced risk for arrhythmias and sudden death.10,11 Any intervention which would further prolong the action potential therefore is not without potential risk.

Similarly, until now any chronic inotropic therapy which produces an increase of cellular Ca2+ has resulted in increased mortality.12 Experimentally, an increase in Ca2+ transients has been documented during CCM,13 but it is unclear whether this is present throughout the heart or only in the region close to the stimulation sites. Indeed, the increase in contraction may be a local effect, with the global effects related to altered loading,14 consistent with the view that a local current injection during the refractory period is unlikely to be transmitted electrotonically throughout the ventricle. If there is indeed only a local increase in Ca2+, and if CCM needs to be applied only intermittently, then this would be an advantage over traditional inotropic therapy. Again, this aspect needs to be further investigated.

The most intriguing unexplained finding is actually the long-term effect on function of intermittent CCM, which has not been studied experimentally. Is there indeed an increase in the intrinsic contractility of the failing heart? Typically, true measurements of contractility, such as relations, remain in the realm of experimental studies. The and ejection fraction presented in the current study are load-dependent parameters and one would have liked to see data on preload, end-diastolic pressure and volume, and/or afterload. Although this may seem esoteric for clinical applications, it is important to know if CCM, perhaps by improving loading, indeed leads to reverse remodelling of the failing heart, as has been documented for left ventricular assist devices.15,16 If it does, this may outweigh the disadvantages associated with typical inotropic therapy.

Clinical relevance

The clinical improvements reported with this highly experimental device are encouraging, but the results clearly need further confirmation in a controlled prospective study with a larger number of patients. Although the authors refer to the clinical deterioration of one patient to demonstrate the reversibility of the effect, a crossover design with periods with and without nonexcitatory stimulation is needed to substantiate this. Similarly, one would like to see different endpoints. The main endpoints used in the study (quality of life and NYHA functional class) are subjective and thus prone to a possible placebo effect. Experience with cardiac resynchronisation therapy for heart failure17 and with pacing for neuromediated syncope18 has demonstrated that device implantation itself can have a strong placebo effect. Functional improvement was objectively assessed in only seven patients, using a 6-min walk test. Although frequently used, the prognostic value and correlation with cardiac function of the 6-min walk test is still contested19 and outcome is highly dependent on the encouragement given by the person supervising the test.20

The experience with the OptimizerTM II illustrates the limitations of device therapy in heart failure. Experience with cardiac resynchronisation therapy has taught us that implant failure, procedural complications, and the identification of responders are still concerns. In this study the device could not be implanted in 8% of patients and the complications of successful implants were substantial: one patient (4%) had an implant-related pocket haematoma and nine patients (39%) had symptoms of nonexcitatory stimulation, which were intolerable in 1 (4%).3 This has to be considered in the light of a response rate of 2/3 patients.

Perhaps the most alarming finding is the observation that 2 out of 23 patients died suddenly during a follow-up of only 2 months. Although sudden-death rates are expected to be high in this population, 9% in 2 months exceeds clearly the 8-week all-cause mortality rates in the COPERNICUS trial in NYHA III and IV patients.21 A possible increase in sudden-death rates with nonexcitatory stimulation might be linked to the mechanisms of action discussed above and, if so, is a major concern.

Several technical problems also need to be addressed, namely the limited lifetime of the device and the feasibility of multiple implants. With the growing importance of device therapy in patients with poor left ventricular function, either to prevent sudden death with defibrillators or to treat heart failure with cardiac resynchronisation devices, it is doubtful that nonexcitatory stimulation in a separate device has a future. This technology would necessarily have to be incorporated in defibrillators or pacemakers. The prime reason to do so should, however, be the medical indication, and economic pressure from the device industry should be resisted. Considering the industry involvement and financial investment in the design and trials of these devices, this is not easy.

Conclusion

The report by Stix et al.3 on nonexcitatory stimulation introduces a conceptually novel treatment of heart failure. Clearly, the positive results of this small trial need to be confirmed in a blind, randomised way before broad clinical application of this treatment can be considered. More insight is needed into the underlying mechanisms and their consequences for long-term application of the CCM device. If the promising results are corroborated, incorporation of this technology in pacemakers and/or defibrillators will be appealing.

Footnotes

1 doi:10.1016/j.ehj.2004.02.027. Back

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Related articles in EHJ:

Chronic electrical stimulation during the absolute refractory period of the myocardium improves severe heart failure
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EHJ 2004 25: 650-655. [Abstract] [Full Text]  




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