Download First use of cardiac contractility modulation (CCM) in a patient failing

European Journal of Heart Failure 9 (2007) 955 – 958
www.elsevier.com/locate/ejheart
Case report
First use of cardiac contractility modulation (CCM) in a patient failing
CRT therapy: Clinical and technical aspects of combined therapies
Christian Butter ⁎, Jürgen Meyhöfer, Martin Seifert, Michael Neuss, Hans-Heinrich Minden
Heart Center Brandenburg in Bernau/Berlin, Department of Cardiology, Ladeburger Str. 17, 16321 Bernau b. Berlin, Germany
Received 5 March 2007; received in revised form 18 April 2007; accepted 17 May 2007
Available online 27 June 2007
Cardiac contractility modulating (CCM) signals delivered by the OPTIMIZER System are being investigated as a treatment for medically
refractory heart failure. Previous chronic studies of CCM have excluded patients with prolonged QRS and a cardiac resynchronization
therapy (CRT) device. However, symptoms persist in more than 25% of these CRT patients. CCM may offer a therapeutic option for these
non-responders. Here we report the first use of CCM signals in a patient who did not respond to treatment with a CRT-D device. We show
that the implantation is technically feasible, that the OPTIMIZER and CRT-D devices can coexist without interference and that acute
haemodynamic and clinical improvements can be observed. The results suggest that systematic investigation of CCM treatment in CRT nonresponders is warranted.
© 2007 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.
Keywords: Heart failure; Cardiac contractility modulation; Cardiac resynchronization therapy; Internal cardiac defibrillator
1. Background
Cardiac contractility modulating (CCM) signals are
electrical impulses delivered during the absolute cardiac
refractory period that enhance myocardial strength [1,2]. In
isolated cardiac muscle, acute CCM signal application
increases the action potential plateau voltage and enhances
calcium entry [3]. When applied to a region of intact heart in
normal animals and in animals with experimentally induced
heart failure, CCM signals also appear to acutely enhance
global ventricular strength through local increases in muscle
contractility and change in load in remote regions [4,5].
Studies in experimental heart failure, however, have revealed
that when applied chronically, CCM signals normalize
expression of many abnormally expressed genes [6,7] and
also normalize phosphorylation of several abnormally
phosphorylated proteins characteristic of the heart failure
state [6]. The mechanism of these molecular effects, which
⁎ Corresponding author. Tel.: +49 3338 694610/11; fax: +49 3338 694644.
E-mail address: [email protected] (C. Butter).
are now believed to underlie the chronic clinical effects of
CCM, remain to be elucidated.
When delivered chronically to patients with medically
refractory heart failure, CCM signals improve quality of life
and exercise tolerance [8]. Previous chronic studies of CCM
have excluded patients with prolonged QRS and a cardiac
resynchronization therapy (CRT) device. However, more
than 25% of CRT patients do not respond to therapy. These
patients have few therapeutic options [9]. It has been
suggested that CCM signals may offer a possible treatment
option in these patients. This report summarizes the clinical
and technical aspects of the first reported case of adding
CCM treatment in a patient who did not respond to CRT.
2. Methods and results
A 69 year old man with ischaemic cardiomyopathy
underwent pacemaker implantation (VVI, Biotronik) in 2001
at another hospital. He was first evaluated at our institution in
February 2006, when he presented with symptomatic heart
failure and atrial fibrillation. He was loaded with amiodarone
1388-9842/$ - see front matter © 2007 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.ejheart.2007.05.012
Downloaded from eurjhf.oxfordjournals.org by guest on January 9, 2011
Abstract
956
C. Butter et al. / European Journal of Heart Failure 9 (2007) 955–958
Fig. 1. Post-procedure chest X-ray showing the final positioning of the CRT-D device, the OPTIMIZER System, the atrial and two ventricular leads of the
OPTIMIZER System (▴), the atrial, LV lead and RV lead of the CRT-D device (⁎) and an abandoned RV lead from the original pacemaker (♦).
Fig. 2. Recording of beat-by-beat dP / dtmax CCM signals initiated (arrow).
dP / dtmax increased by ∼ 12% within 10 min of CCM initiation.
74 mm, 2+ mitral and tricuspid regurgitation and an estimated
PAP pressure of 60 mm Hg. Medication at this time included
furosemide (100 mg/day iv), spironolactone (50 mg/day),
digoxin (0.07 mg/day), amiodarone (200 mg/day) and ramipril
(2.5 mg/day).
In view of these persistent symptoms, it was decided to
implant an OPTIMIZER System (IMPULSE Dynamics,
Orangeburg NY) to deliver CCM signals, in addition to the
CRT-D device. One atrial and two right ventricular septal
pacing leads were inserted. A micromanometer pressure
sensor (Millar Instruments, Huston) was advanced via the
femoral artery into the LV to record responses to acute CCM
signal application. The post-procedure chest X-ray shows the
relative lead positions (Fig. 1). Following lead positioning, a
relatively stable baseline haemodynamic state was established, followed by initiation of CCM signal delivery. dP /
dtmax increased from a baseline value of 560 mm Hg/s (a
normal reading being N 1000 mm Hg/s) to 625 mm Hg/s
within 10 min, representing an almost 12% increase (Fig. 2).
Simultaneous tracings from the CRT-D and OPTIMIZER
Systems are shown in Fig. 3 on two beats just prior to and
just after initiating CCM signal delivery. The CCM signals
are delivered within the QRS complex, and thus occur during
the implantable cardioverter defibrillator (ICD) blanking
period and are therefore not sensed by the ICD. After
haemodynamic testing, additional testing of cross talk
between the OPTIMIZER and the ICD was performed by
varying the OPTIMIZER parameters over a broad range of
settings, this demonstrated a lack of CCM signal sensing by
the ICD and appropriate VF detection. The patient was
discharged home the next day.
Six weeks after CCM implantation the patient had
improved from NYHA class IV to II, LV end-diastolic
dimensions decreased from 74 to 67 mm and ejection fraction
increased from 15% to 20%. However, given the variability of
echocardiographic assessment of ejection fraction, this change
may not be clinically significant. Blood pressure had increased
Downloaded from eurjhf.oxfordjournals.org by guest on January 9, 2011
and successfully cardioverted approximately two weeks later.
From that point onwards he remained in sinus rhythm with
intrinsic A–V conduction without the need for RV pacing. Due
to persistent NYHA Class IV symptoms, ejection fraction (EF)
of 10%, intrinsic QRS duration of 150 ms and echocardiographic evaluation revealing an interventricular delay (PAAO: 40 ms) as well as an intraventricular delay (TSI triplanar
SD 91 ms), the device was upgraded to a CRT-D device
(Medtronic Insync Maximo with Medtronic ATTAIN 4193
unipolar LV lead) in April 2006. Coronary angiography
performed prior to CRT-D implantation, showed the previously documented chronic occlusion of the right coronary
artery with no progression of disease in other arteries. During
CRT-D treatment, QRS duration remained prolonged at
180 ms. Despite 8 months of CRT-D treatment, the patient
remained in NYHA class IV, required nasal oxygen and had
persistent peripheral oedema. Blood pressure was 81/57 mm
Hg and the patient did not tolerate β-blockade. Blood tests
revealed an elevated NT-proBNP level of 8063 pg/ml. EF
remained at 15%, with an LV internal diastolic dimension of
C. Butter et al. / European Journal of Heart Failure 9 (2007) 955–958
957
to 110/70 mm Hg and pulmonary systolic pressure had
decreased from 60 to 46 mm Hg. NT-proBNP level decreased
from 8063 to 4187 pg/ml.
3. Discussion
In a previous clinical study, it was shown that the acute
haemodynamic effects of CRT and CCM signals are additive,
when administered to patients with prolonged QRS duration
and mechanical dyssynchrony [10]. This is because the
mechanisms of these two types of therapy are different and
unrelated [1]. However, prior studies of chronic CCM signal
delivery have excluded patients already having a CRT device
[10]. Since a relatively large proportion of patients receiving
CRT have persistent symptoms and are considered nonresponders [9], and because these patients have very few
therapeutic options, it has been suggested that CCM signals
might be a treatment option for such patients [10].
We report here the first use of the OPTIMIZER System in
a CRT-D non-responder. From a technical standpoint, the
OPTIMIZER System implantation procedure and device
programming is not different to when the device is implanted
in conjunction with a standard ICD. Formal testing at the
time of implantation shows that the two devices can coexist
without interfering with the proper functioning of the other.
This was anticipated and is largely due to the fact that the
CCM spike is delivered during the ICD blanking period.
The initial clinical response in this patient is encouraging.
Increased EF, reduced end-diastolic dimension, decreased
pulmonary pressures and decreased NT-proBNP levels are
all consistent with the improvement in symptoms reported by
the patient. Of course, prospective randomised trials are
needed to evaluate the degree to which such effects can be
reproduced in the challenging group of patients referred to as
CRT non-responders.
Acknowledgements
The authors would like to thank Jana Hoffmann and Dr.
Daniel Burkhoff for their continuous clinical and scientific
support.
References
[1] Burkhoff D, Ben Haim SA. Nonexcitatory electrical signals for
enhancing ventricular contractility: rationale and initial investigations
of an experimental treatment for heart failure. Am J Physiol Heart Circ
Physiol Jun 2005;288(6):H2550–6.
[2] Lawo T, Borggrefe M, Butter C, et al. Electrical signals applied during
the absolute refractory period: an investigational treatment for
advanced heart failure in patients with normal QRS duration. J Am
Coll Cardiol Dec 20 2005;46(12):2229–36.
[3] Brunckhorst CB, Shemer I, Mika Y, Ben Haim SA, Burkhoff D.
Cardiac contractility modulation by non-excitatory currents: studies in
isolated cardiac muscle. Eur J Heart Fail Jan 2006;8(1):7–15.
[4] Mohri S, He KL, Dickstein M, et al. Cardiac contractility modulation
by electric currents applied during the refractory period. Am J Physiol
Heart Circ Physiol May 2002;282(5):H1642–7.
[5] Morita H, Suzuki G, Haddad W, et al. Cardiac contractility modulation
with nonexcitatory electric signals improves left ventricular function in
dogs with chronic heart failure. J Card Fail Feb 2003;9(1):69–75.
Downloaded from eurjhf.oxfordjournals.org by guest on January 9, 2011
Fig. 3. Recordings from the CRT-D and OPTIMIZER Systems on two beats just before and just after initiating CCM signal application. (A) The CRT-D channels show
atrial sense followed by delivery of the biventricular pacing spike after the preset AV delay. When CCM is activated, a large signal artefact is seen within the QRS complex
on both the surface and intracardiac electrocardiograms. Note that the presence of the CCM artefact does not result in a sensed event by the CRT-D device, since it occurs
within the blanking period. (B) The OPTIMIZER System marker channel reveals sensing of atrial depolarization followed by sensing of right ventricular depolarization at
each of the two RV leads. Also note the timing of CCM signal delivery on the marker channel and the artefact on the surface ECG once CCM is activated.
958
C. Butter et al. / European Journal of Heart Failure 9 (2007) 955–958
[6] Imai M, Rastogi S, Gupta RC, Mishra S, Sharov VG, Stanley WC, et
al. Therapy with cardiac contractility modulation electric signals
improves left ventricular function and remodeling in dogs with chronic
heart failure. J Am Coll Cardiol 2007;49(21):2120–8.
[7] Butter C, Rastogi S, Sabbah HN. Chronic therapy with non-excitatory
cardiac contractility modulation electrical signals normalizes cardiac
mRNA expression of the maladaptive fetal gene program and upregulates sarcoplasmic reticulum calcium cycling genes in patients
with chronic heart failure. Heart Rhythm 2006;3(Suppl 1):S209.
[8] Pappone C, Augello G, Rosanio S, et al. 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. J Cardiovasc Electrophysiol Apr 2004;15
(4):418–27.
[9] Adamson PB, Abraham WT. Cardiac resynchronization therapy for
advanced heart failure. Curr Treat Options Cardiovasc Med Aug
2003;5(4):301–9.
[10] Pappone C, Rosanio S, Burkhoff D, et al. Cardiac contractility
modulation by electric currents applied during the refractory period in
patients with heart failure secondary to ischemic or idiopathic dilated
cardiomyopathy. Am J Cardiol Dec 15 2002;90(12):1307–13.
Downloaded from eurjhf.oxfordjournals.org by guest on January 9, 2011