Download Enhanced Inotropic State of the Failing Left Ventricle by Cardiac

Journal of Cardiac Failure Vol. 13 No. 2 2007
Basic Science and Experimental Studies
Enhanced Inotropic State of the Failing Left Ventricle by Cardiac
Contractility Modulation Electrical Signals Is Not Associated
With Increased Myocardial Oxygen Consumption
CHRISTIAN BUTTER, MD,1 ERNST WELLNHOFER, MD,1 MICHAEL SCHLEGL, MD,1 GEORGIA WINBECK, MD,1
ECKART FLECK, MD,1 AND HANI N. SABBAH, PhD2
Berlin, Germany; Detroit, Michigan
ABSTRACT
Background: Previous studies in patients and in dogs with experimentally induced heart failure (HF)
showed that electrical signals applied to the failing myocardium during the absolute refractory period
improved left ventricular (LV) function. We examined the effects these same cardiac contractility modulating (CCM) electrical signals on myocardial oxygen consumption (MVO2) in both patients and dogs
with chronic HF.
Methods and Results: Six dogs with microembolizations-induced HF and 9 HF patients underwent CCM
leads and generator (OPTIMIZER II) implantation. After baseline measurements, CCM signals were delivered continuously for 2 hours in dogs and for 30 minutes in patients. MVO2 was measured before and
after CCM therapy. In dogs, CCM therapy increased LV ejection fraction at 2 hours (26 6 1 versus 31 6 2
%, P 5 .001) without increasing MVO2 (257 6 41 versus 180 6 34 mmol/min). In patients, CCM therapy
increased LV peak þdP/dt by 10.1 6 1.5 %. As with dogs, the increase in LV function after 30 minutes of
CCM therapy was not associated with increased MVO2 (13.6 6 9.7 versus 12.5 6 7.2 mL O2/min).
Conclusions: The study results suggest that unlike cAMP-dependent positive inotropic drugs, the
increase in LV function during CCM therapy is elicited without increasing MVO2. (J Cardiac Fail
2007;13:137e142)
Key Words: Ventricular function, Positive inotropic agents, Congestive heart failure, Device therapy for
heart failure.
Despite marked improvements in pharmacologic treatments that reduce mortality and morbidity in patients
with chronic heart failure (HF),1e3 a large number of patients with advanced HF are refractory to optimal standard
medical therapy. This patient population mostly New York
Heart Association (NYHA) class III and IV require
additional therapy to limit progression of their disease
and improve their quality of life. The need for further therapeutic interventions in this patient population has given
rise to a host of device-based therapies such cardiac resynchronization therapy among others. Biventricular pacing
or resynchronization therapy has been shown to improve
LV systolic function and quality of life in a subset of these
patients who a manifest wide QRS complex.4e7 Cardiac
contractility modulation (CCM) electrical signals delivered
to the failing myocardium during the absolute refractory
period is another device-based therapy targeting this HF
population. CCM electrical signals applied to the myocardium during the absolute refractory period can increase
have been shown to increase systolic function of the failing
LV.8e17 Preliminary clinical studies of CCM signals delivered to the myocardium of patients with chronic HF suggest
that CCM therapy is safe and can also improve exercise
tolerance and quality of life.18,19 Classic positive inotropic
From the 1German Heart Institute Berlin, Berlin, Germany and
Division of Cardiovascular Medicine, Henry Ford Health System, Detroit,
Michigan.
Manuscript received January 13, 2006; revised manuscript received
November 2, 2006; revised manuscript accepted November 3, 2006.
Reprint requests: Christian Butter, MD, Heart Center Brandenburg
Bernau/Berlin, Ladeburger Str. 17, 16321 Bernau, Germany.
Supported, in part, by research grants from Impulse Dynamics USA and
by National Heart, Lung, and Blood Institute PO1 HL074237-03.
1071-9164/$ - see front matter
Ó 2007 Elsevier Inc. All rights reserved.
doi:10.1016/j.cardfail.2006.11.004
2
137
138 Journal of Cardiac Failure Vol. 13 No. 2 March 2007
agents such as dobutamine and milrinone improve LV
systolic function in patients with HF. The cost for this
improvement, however, is increased myocardial oxygen
consumption (MVO2), a payment that the failing LV myocardium can ill afford.20 The purpose of this study was to
determine whether the increase of LV systolic function
observed during CCM therapy is also associated with
increased MVO2.
Methods
Animal Protocol
The canine model of chronic HF used in the present study was
previously described in detail.13e15 In this experimental preparation, chronic LV dysfunction and failure is produced by multiple
sequential intracoronary embolizations with polystyrene Latex microspheres (70e102 mm in diameter) that result in loss of viable
myocardium, LV enlargement, and a decrease in LV ejection
fraction. In the present study, 11 healthy mongrel dogs weighing
between 20 and 26 kg underwent serial coronary microembolizations to produce HF. Embolizations were performed 1 week apart
and were discontinued when LV ejection fraction, determined angiographically, was !30%. Microembolizations were performed
during cardiac catheterization under general anesthesia and sterile
conditions. Animals were sedated with intravenous oxymorphone
hydrochloride (0.22 mg/kg) and diazepam (0.17 mg/kg) and
a plane of anesthesia was maintained with 1% to 2% isoflurane.
The study was approved by Henry Ford Health System Institutional Animal Care and Use Committee and conformed to the National Institute of Health ‘‘Guide and Care for Use of Laboratory
Animals’’ and the ‘‘Position of the American Heart Association on
Research Animal Use.’’
Two weeks after the target LV ejection fraction was reached,
dogs were anesthetized as described previously, intubated, and
ventilated with room air. In 6 dogs, the right external jugular
vein was surgically exposed and used to position the CCM leads.
Two standard active fixation leads were positioned on the anterior
and posterior septal grooves and were used sense ventricular activity and to deliver CCM electrical signals. A third active fixation
lead was positioned in the right atrium for sensing. The leads
were connected to a CCM signal generator (OPTIMIZER II, Impulse Dynamics USA, Inc, Orangeburg, NY). The generator was
implanted in a subcutaneous pocket created on the right side of
the neck. The animals were allowed to recover. Studies were performed 2 weeks after CCM system implantation. This period of
time also allowed the tip of the leads to mature into place. The
remaining 5 of 11 dogs were not treated and served as controls.
Two weeks after CCM system implantation, dogs were anesthetized and underwent a baseline left and right heart catheterization
that included measurement of MVO2. The Optimizer II system
was then activated to deliver 7.73 volts CCM electrical signals
continuously for 2 hours. At the end of 2 hours of CCM delivery,
all hemodynamic measures were repeated including MVO2. Left
ventricular pressure was measured using a catheter-tip micromanometer (Millar Instruments, Houston, TX) and LV end-diastolic
pressure was measured from the phasic LV pressure waveform.
Stroke volume was calculated as the ratio of cardiac output to
heart rate. MVO2 and LV external power (watts) were measured
as previously described in detail.21 The same hemodynamic measurements were made at the same study time points in control
dogs.
Table 1. Hemodynamic and Ventriculographic Findings
in Untreated Heart Failure Control Dogs Obtained
at Baseline and After 2 hours of Follow-up (n 5 5)
Baseline
HR (beats/min)
Peak LVP (mm Hg)
LV EDP (mm Hg)
Stroke Volume (mL)
LV EDV (mL)
LV ESV (mL)
LV EF (%)
LV CBF (mL/min)
LV Power (watts)
MVO2 (mmol/min)
90
98
12
18
67
49
27
20
0.35
191
6
6
6
6
6
6
6
6
6
6
5
9
1
1
2
1
1
2
0.03
19
2 Hours
P value
6
6
6
6
6
6
6
6
6
6
.39
.39
.10
.18
.53
.78
.37
.13
.82
.54
95
108
12
18
67
49
27
22
0.38
201
5
6
1
1
1
1
1
2
0.03
31
HR, heart rate; LVP, left ventricular systolic pressure; EDP, end-diastolic
pressure; EDV, end-diastolic volume; ESV, end-systolic volume; EF,
ejection fraction; CBF, coronary blood flow; MVO2, myocardial oxygen
consumption; P value 5 probability value of baseline versus 2 hours.
Patient and Protocol
The clinical characteristics of all 9 patients included in this single center sub-study are shown in Table 1. The cohort of 9 patients
was participating in a randomized, double blind multicenter study
to test the safety and efficacy of CCM therapy in patients with HF
(the FIX-HF-4 Study, IMPULSE Dynamics USA, Inc). All 9 patients had NYHA class III symptoms despite of treatment with
b-blockers, angiotensin-converting enzyme inhibitors, or angiotensin receptor blockers and, with 1 exception, the aldosterone receptor antagonist spironolactone. Patients were excluded from the
study if they had been hospitalized within 1 month for acute exacerbation of HF or had undergone revascularization within 1 month
with either percutaneous coronary intervention of coronary artery
bypass surgery or they experience an acute myocardial infarction
within 3 months of entry into the study. The study was approved
by the local institutional review committee. Written informed consent was obtained from all patients before entry into the study.
Right heart and left heart catheterizations were performed according to standard clinical practice using the transfemoral approach. The OPTIMIZER II system employs 2 leads placed on
the right ventricular septum and one lead in the right atrium
(Fig. 1). Septal lead placement is optimized to achieve the greatest
possible increase in peak LV þdP/dt. The latter was measured in
Fig. 1. Example of instrumentation in anteroposterior view (A)
and final lead placement in left anterior oblique projection (B)
in patients. The Millar catheter (pigtail) is placed in the left ventricle. The 2 right ventricular septal leads apply cardiac contractility modulating signals. The venous catheter is in the coronary
sinus and the defibrillator lead points to the right ventricular apex.
Oxygen Consumption With CCM Therapy
all patients. The OPTIMIZER II system was implanted in all patients in whom peak LV þdP/dt increased more than 5% during
CCM signal delivery. A 0.014-inch Doppler guide wire (Jometrics,
FloWire XT, Jomed, Rancho Cordova)22 was positioned in the left
main coronary artery to measure average peak flow velocity
(APV). The diameter (D) in mm of the coronary arterial segment
used for flow sampling was estimated by quantitative angiography.
Assuming a parabolic flow profile and a circular lumen coronary
blood flow (CBF) was calculated as: CBF 5 60*APV/
2*0.01*(p/4)*D2 mL/min.23 A coronary sinus catheter was
placed for coronary venous blood sampling. Coronary sinus and
coronary arterial blood samples were analyzed for hemoglobin
concentration and oxygen saturation, which were converted to
blood oxygen content (volume %, mL O2/100 mL blood). The
product of CBF and arteriovenous oxygen content difference
(AVDO2) was used as a measure of MVO2.21 CBF and AVDO2
were measured in triplicate and the average of all 3 measurements
reported. After baseline hemodynamic measurements and
acquisition of blood samples, CCM signals were delivered for
30 minutes. Measurements were then repeated. Stability of the
Doppler flow wire tip position was confirmed with fluoroscopy.
Data Analysis
Comparison between baseline measurements and measurements
obtained at 2 hours (dogs) and 30 minutes (patients) after initiating
CCM signal delivery were made using a Students paired t-test
with significance set at P value ! .05. All data are reported as
the mean 6 SEM.
Results
Butter et al
139
rate and peak LV pressure did not change with CCM
therapy. Compared with baseline, CCM therapy significantly decreased LV end-diastolic pressure and significantly
increased stroke volume. Left ventricular end-diastolic
volume and end-systolic volume both decrease significantly
with CCM therapy and LV ejection fraction and LV external
power increased significantly. Compared with baseline,
CBF decreased with CCM therapy and MVO2 tended to
decrease but the reduction did not reach statistical significance (Table 2).
Findings in Patients With HF
Compared with baseline, 30 minutes of CCM therapy
significantly increased peak LV þdP/dt from 701 6 48 to
775 6 60 mm Hg/s (Table 3). APV between baseline (30 6
7 cm/s) and 30 minutes after initiating CCM delivery did
not change (29 6 8 cm/s). Differences in individual
patients were negligible (Fig. 2, top). Consistent with these
measurements, estimated average CBF was nearly identical
between baseline (100 6 20 mL/min) and 30 minutes after
initiating CCM signal delivery CCM (97 6 18 mL/min).
AVDO2 was not changed after CCM therapy compared
with baseline (13.2 6 1.0 versus 12.8 6 1.4 mL O2/100
mL). Thus, estimated MVO2 remained essentially unchanged (13.6 6 3.2 versus 12.5 6 2.4 mL O2/min)
(Fig. 2, bottom).
Discussion
Findings in Dogs with HF
The hemodynamic and ventriculographic results obtained in control dogs are shown in Table 1. Heart rate
and peak LV pressure did not change during the 2 hours
of follow-up. In this control group, 2 hours of follow-up
had no significant effects on LV end-diastolic pressure,
stroke volume, LV end-diastolic volume, LV end-systolic
volume, LV ejection fraction, CBF, LV external power, or
MVO2 when compared to baseline (Table 1).
The hemodynamic and ventriculographic results
obtained in CCM-treated dogs are shown in Table 2. Heart
Table 2. Hemodynamic and Ventriculographic Findings in
Dogs with Heart Failure Obtained at Baseline and 2 hours
After Initiating CCM Therapy (n 5 6)
Baseline
HR (beats/min)
Peak LVP (mm Hg)
LV EDP (mm Hg)
Stroke volume (mL)
LV EDV (mL)
LV ESV (mL)
LV EF (%)
LV CBF (mL/min)
LV Power (watts)
MVO2 (mmol/min)
79
101
14
18
71
53
26
35
0.32
257
6
6
6
6
6
6
6
6
6
6
3
5
1
1
8
7
1
4
0.02
41
2 Hours of CCM
P value
6
6
6
6
6
6
6
6
6
6
.26
.23
.005
.004
.001
.001
.001
.017
.040
.12
75
107
9
21
68
47
31
27
0.37
180
3
8
1
1
7
6
2
3
0.03
34
Abbreviations are same as in Table 1. CCM, cardiac contractility
modulation; P value 5 probability value of baseline versus CCM.
CCM-mediated enhancement of LV contractile performance is a new frontier of electrical therapy for HF in patients not eligible for resynchronization therapy. This is the
first study in both dogs with experimentally induced HF and
in patients with chronic HF that examined the effects of
CCM-mediated enhancement of contractile performance
on MVO2. The results suggest that acute CCM therapy significantly increased LV systolic function without increasing
MVO2. The extent acute increase in peak LV þ dP/dt in patients after acute CCM therapy seen in the present study is
consistent with changes of peak LV þ dP/dt reported in previous studies in patients with HF.16,18,19 The hemodynamic
and angiographic changes observed in this study in dogs
with HF that were treated with CCM could not be attributed
to changes in loading conditions that may have occurred
during the 2 hours of follow-up. A control group of HF
dogs also followed under anesthesia for 2 hours showed
no changes in indexes of LV function.
With the growing number of patients with advanced HF in
whom pharmacologic therapy has been optimized, but who
remain symptomatic with depressed LV systolic function,
efforts continue to identify safe therapies to improve LV
function and relieve symptoms. In the past, b-adrenoceptor
agonists and selective phosphodiesterase III inhibitors were
explored for this purpose but were associated with increased
mortality. The causes of adverse effects of these agents,
which act primarily via cAMP mechanisms are not fully
140 Journal of Cardiac Failure Vol. 13 No. 2 March 2007
Table 3. Patient Characteristics at Baseline and Peak Left Ventricular þdP/dt During CCM Application
Patient
Gender
Age
(years)
HF
Etiology
EF
(%)
VO2-max
(mL$min$kg)
Baseline Peak
LV þdP/dt (mm Hg/s)
CCM Peak
LV þdP/dt (mm Hg/s)
Peak
LVþ dP/dt (% change)
Male
Male
Male
Male
Male
Male
Male
Male
Male
65
63
50
50
66
48
66
40
62
DCM
DCM
DCM
DCM
CAD
DCM
CAD
CAD
CAD
25
25
22
19
28
23
25
30
29
13.4
12.3
12.9
17.2
13.6
11.7
17.3
12.4
17.3
733
580
770
900
550
460
860
750
710
847
613
834
988
601
485
1020
830
761
15.6
5.7
8.3
9.8
9.3
5.4
18.6
10.7
7.2
25
1
14.2
0.8
701
48
775
60
10.1
1.5
PR
GS
HP
GS
LS
SU
HO
NB
DL
Mean
SEM
57
3
EF, ejection fraction; HF, heart failure; VO2-max, peak oxygen consumption; LV, left ventricular; þdP/dt, peak positive rate of change of LV pressure
during isovolumic period, CCM, cardiac contractility modulation.
Average Peak Velocity (cm/s)
understood. It has been shown that MVO2 increases with dobutamine by as much as 42% when the dose of dobutamine
was sufficient to increase peak LV þ dP/dt by 37%.6 The effects of new HF treatments on MVO2 remain of primary interest. Furthermore, in contrast to systemic pharmacologic
inotropes with multiple actions on the heart and the vascular
system, an electrical treatment such as CCM acts locally and
appears to be devoid of positive chronotropic effects, proarrhythmic effects and systemic blood pressure lowering
effects. In addition, CCM therapy is designed to be intermittent and, therefore, the phenomenon of tachyphylaxis may
not be a factor in contrast to pharmacologic treatment.
Trend Average Peak Velocity
100.00
PR 04-12-01
GS 04-12-02
HP 04-12-04
GS 04-12-05
LS 04-12-06
SU 04-12-07
HO 04-12-08
NB 04-12-09
RM 04-12-10
RW 04-12-11
DL 04-12-12
Average
80.00
60.00
40.00
20.00
0.00
1
2
Oxygen consumption (ml/min)
1: Prä CCM - 2: Post CCM
Trend myocardial oxygen consumption
70.00
PR 04-12-01
GS 04-12-02
HP 04-12-04
GS 04-12-05
LS 04-12-06
SU 04-12-07
HO 04-12-08
NB 04-12-09
RM 04-12-10
RW 04-12-11
DL 04-12-12
Average
60.00
50.00
40.00
30.00
20.00
10.00
0.00
1
2
1: Prä CCM - 2: Post CCM
Fig. 2. Coronary blood flow velocity (top) and myocardial oxygen
consumption (bottom) at baseline (PRE) and after cardiac contractility modulating signal application (POST).
Acute increases in peak LV þ dP/dt in the range of 20%
have been reported with cardiac resynchronization therapy.
This increase in peak LV þ dP/dt were also associated with
no change in MVO2. Although the changes are somewhat
larger than observed in the present study with CCM therapy, preliminary findings indicate that LV ejection fraction
increases by about 5% with chronic CCM,18,19 which compares favorably with the reported effects of chronic treatment with resynchronization therapy.5 The results seen in
this study in dogs with HF also suggest that the effects of
CCM on LV systolic function is more robust as time of therapy is increased and, despite a marked increase in LV ejection fraction in the dogs, MVO2 remained unchanged. The
mechanism by which CCM signals are believed to acutely
enhance contractility have been attributed to normalization
of calcium handling,14,24,25 whereas mechanisms that underlie the benefits of resynchronization therapy are likely
related to coordination of myocardial contraction. Thus
synergistic effects of CRT and CCM may be expected.10,16
Early studies in isolated Langendorff-perfused ferret
hearts of the mechanisms of action of CCM therapy suggested that the positive inotropism of CCM therapy may be
due to increased peak [Ca2þ]i.12 Early studies also focused
on the potential impact of CCM signals on action potential
configuration which acts to enhance calcium loading of the
SR.8,11 In these early studies, the increase in calcium was assumed to be the sole cause of the increase in contractility.
More recent studies, however, have suggested that in vivo delivery of CCM signals to the failing canine myocardium can,
within a short period of 2 to 4 hours, lead to increased phosphorylation of phospholamban.14 It has been suggested that
electromagnetic fields can modify enzyme reactions.26 Enhanced phosphorylation of phospholamban seen within as little as 2 hours of CCM signal application suggests that this
type of electrical therapy can modulate the phosphorylation
of proteins. In this case, the already existing phospholamban
protein is being phosphorylated rather than synthesis of new
protein. Phosphorylation of phospholamban enhances sarcoplasmic reticulum calcium sequestration by enhancing the
activity or affinity of SERCA-2a for calcium. In turn, this
Oxygen Consumption With CCM Therapy
enhances intracellular calcium cycling capacity and, hence,
contractility.
In the short-term (hours and days), CCM therapy is
thought to improve function in the LV region adjacent to
the site of CCM signal delivery.11 In the present studies,
the site of CCM signal delivery in both patients and dogs
was the interventricular septum. Acute delivery of CCM therapy appears to impact enough myocardium at the regional
level so as to enhance global LV function13,27 as also evident
from the present study. Thus measures of global LV contractile function such as ejection fraction and peak þ dP/dt, are
expected to correlate with global measures of MVO2 that
are partly based on measurements of oxygen content in blood
drawn from the coronary sinus. Limited studies have suggested that in dogs, not all venous affluent from the interventricular septum empties into the coronary sinus28 an anatomic
condition that may affect the correlation between LV
function and MVO2 in the present study.
In addition to these limitations, there are other limitations to the study that merit consideration. The study in patients and the one in dogs were conducted in different
laboratories with different protocols and were only combined after the fact to illustrate the same effects of CCM
therapy in both patients and dogs with HF. This led to the
use of different indexes of LV performance. Nonetheless,
the results from both patients and dogs were directionally
similar. Calculation of MVO2 from coronary blood flow
velocity measurements and arteriovenous oxygen content
difference is an established method,6 estimates of total
CBF were made in both studies in dogs with HF and in
HF patients.21 In patients and in dogs, measurements of velocity and oxygen content of blood samples and additional
quantitative coronary angiography were made in triplicate
or in duplicate to enhance the accuracy. In the present
study, the increase in peak LV þ dP/dt measured in patients
undergoing implantation of the CCM system was modest
(approximately 10%) and one may argue that this modest
increase may not be sufficient to elicit an increase MVO2.
Studies in dogs in which CCM therapy was delivered for
a longer time (2 hours) in the absence of the type of constraints that one faces in studies in human subjects, however, also showed that MVO2 was unchanged despite an
increase in LV ejection fraction of approximately 20%.
Conclusions
In a manner consistent with previous studies, the present
study suggests that acutely applied CCM signals increase
systolic LV function in patients with advanced HF despite
background therapy with angiotensin-converting enzyme
inhibitors, b-adrenergic receptor blockers, and, in some
cases, aldosterone receptor blockers. Importantly, the study
results suggest that the increase in LV function during CCM
therapy is elicited without increasing MVO2. At present,
CCM therapy remains investigational. Ongoing randomized
clinical trials are underway in Europe and the United States
and, when completed, will establish the efficacy or lack
Butter et al
141
thereof of this form of novel electrical therapy for chronic
advanced HF.
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