title: First human chronic experience with cardiac contractility modulation by nonexcitatory electrical currents for treating systolic heart failure: mid-term safety and efficacy results from a multicenter study.
abstract: BACKGROUND
  Conventional electrical therapies for heart failure (HF) encompass defibrillation and ventricular resynchronization for patients at high risk for lethal arrhythmias and/or with inhomogeneous ventricular contraction. Cardiac contractility modulation (CCM) by means of nonexcitatory electrical currents delivered during the action potential plateau has been shown to acutely enhance systolic function in humans with HF. The aim of this multicenter study was to assess the chronic safety and preliminary efficacy of an implantable device delivering this novel form of electrical therapy.
  
  
  RESULTS
  Thirteen patients with drug-resistant HF (New York Heart Association [NYHA] class III) were consecutively implanted with a device (OPTIMIZER II) delivering CCM biphasic square-wave pulses (20 ms, 5.8-7.7 V, 30 ms after detection of local activation) through two right ventricular leads screwed into the right aspect of the interventricular septum. CCM signals were delivered 3 hours daily over 8 weeks (3-hour phase) and 7 hours daily over the next 24 weeks (7-hour phase). Safety and feasibility of this novel therapy were regarded as primary endpoints. Preliminary clinical efficacy, -as expressed by changes in ejection fraction (EF), NYHA class, 6-minute walking test (6-MWT), peak O(2) uptake (peak VO(2)), and Minnesota Living with HF Questionnaire (MLWHFQ), was assessed at baseline and at the end of each phase. At the end of follow-up (8.8 +/- 0.2 months), all patients were alive, without heart transplantation or need for left ventricular assist device. Serial 24-hour Holter analysis revealed no proarrhythmic effect. No devices malfunctioned or failed for any reason other than end-of-battery life. Throughout the two study phases, EF improved from 22.7 +/- 7% to 28.7 +/- 7% and 37 +/- 13% (P = 0.004), 6-MWT from 418 +/- 99 m to 477 +/- 96 m and 510 +/- 107 m (P = 0.002), MLWHFQ from 36 +/- 21 to 18 +/- 12 and 7 +/- 6 (P = 0.002), peak VO(2) from 13.7 +/- 1.1 to 14.9 +/- 1.9 to 16.2 +/- 2.4 (P = 0.037), and NYHA class from 3 to 1.8 +/- 0.4 to 1.5 +/- 0.7 (P < 0.001).
  
  
  CONCLUSIONS
  CCM therapy appears to be safe and feasible. Proarrhythmic effects of this novel therapy seem unlikely. Preliminary data indicate that CCM gradually and significantly improves systolic performance, symptoms, and functional status. CCM therapy for 7 hours per day is associated with greater dispersion near the mean, emphasizing the need to individually tailor CCM delivery duration. The technique appears to be attractive as an additive treatment for severe HF. Controlled randomized studies are needed to validate this novel concept.
authors.affiliation: Department of Cardiology, Electrophysiology and Cardiac Pacing Unit, San Raffaele University Hospital, Via Olgettina 60, 20132 Milan, Italy. pappone.carlo@hsr.it
authors.forename: Carlo
authors.initials: C
authors.lastname: Pappone
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Augello
authors.forename: Salvatore
authors.initials: S
authors.lastname: Rosanio
authors.forename: Gabriele
authors.initials: G
authors.lastname: Vicedomini
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Santinelli
authors.forename: Massimo
authors.initials: M
authors.lastname: Romano
authors.forename: Eustachio
authors.initials: E
authors.lastname: Agricola
authors.forename: Francesco
authors.initials: F
authors.lastname: Maggi
authors.forename: Gerhard
authors.initials: G
authors.lastname: Buchmayr
authors.forename: Giovanni
authors.initials: G
authors.lastname: Moretti
authors.forename: Yuval
authors.initials: Y
authors.lastname: Mika
authors.forename: Shlomo A
authors.initials: SA
authors.lastname: Ben-Haim
authors.forename: Michael
authors.initials: M
authors.lastname: Wolzt
authors.forename: Guenter
authors.initials: G
authors.lastname: Stix
authors.forename: Herwig
authors.initials: H
authors.lastname: Schmidinger
mesh_terms: D002908:Chronic Disease / Q000628:therapy; D017147:Defibrillators, Implantable; D004351:Drug Resistance; D004599:Electric Stimulation Therapy / Q000009:adverse effects / Q000379:methods*; D006333:Heart Failure / Q000628:therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009200:Myocardial Contraction / Q000502:physiology*; D011446:Prospective Studies; D012307:Risk Factors; D012449:Safety; D011795:Surveys and Questionnaires; D013599:Systole / Q000502:physiology*; D016896:Treatment Outcome