Download Long-term effects of non-excitatory cardiac contractility modulation

The European Journal of Heart Failure 6 2004 145–150
Long-term effects of non-excitatory cardiac contractility modulation
electric signals on the progression of heart failure in dogs
Hideaki Moritaa, George Suzukia, Walid Haddadb, Yuval Mikab, Elaine J. Tanhehcoa,
Sidney Goldsteina , Shlomo Ben-Haimb , Hani N. Sabbahaô*
a
Ü»°¿®¬³»²¬- ±º Ó»¼·½·²»ô Ü·ª·-·±² ±º Ý¿®¼·±ª¿-½«´¿® Ó»¼·½·²»ô Ý¿®¼·±ª¿-½«´¿® λ-»¿®½¸ô Ø»²®§ Ú±®¼ Ø»¿®¬ ¿²¼ Ê¿-½«´¿® ײ-¬·¬«¬»ô
Ø»²®§ Ú±®¼ Ø»¿´¬¸ ͧ-¬»³ô Ø»²®§ Ú±®¼ ر-°·¬¿´ô îéçç É»-¬ Ù®¿²¼ Þ±«´»ª¿®¼ô Ü»¬®±·¬ô Ó× ìèîðîô ËÍß
b
׳°«´-» ܧ²¿³·½-ô Ó±«²¬ Ô¿«®»´ô ÒÖô ËÍß
Received 23 December 2002; received in revised form 30 October 2003; accepted 13 November 2003
ß¾-¬®¿½¬
Ѿ¶»½¬·ª»: We previously showed that acute delivery of non-excitatory cardiac contractility modulation CCM electric signal
during the absolute refractory period improved LV function in dogs with chronic heart failure HF . In the present study we
examined the long-term effects of CCM signal delivery on the progression of LV dysfunction and remodeling in dogs with
chronic HF. Ó»¬¸±¼-: Chronic HF was produced in 12 dogs by multiple sequential intracoronary microembolizations. The CCM
signal was delivered using a lead implanted in the distal anterior coronary vein. A right ventricular and a right atrial lead were
implanted and used for timing of CCM signal delivery. In six dogs, CCM signals were delivered continuously for 6 h daily with
an average amplitude of 3.3 V for 3 months. Six HF dogs did not have leads implanted and served as controls. λ-«´¬-: In control
dogs, LV end-diastolic volume EDV and LV end-systolic volume ESV increased 64 5 ml vs. 75 6 ml, Ð 0.003; 46 4
ml vs. 57 4 ml, Ð 0.003; respectively , and ejection fraction EF decreased 28 1% vs. 23 1%, Ð 0.001 over the course
of 3 months of follow-up. In contrast, CCM-treated dogs showed a smaller increase in EDV 66 4 vs. 73 5 ml, Ð 0.01 , no
change in ESV, and an increase in EF from 31 1 to 34 2% Ð 0.04 after 3 months of therapy. ݱ²½´«-·±²-: In dogs with
HF, long-term CCM therapy prevents progressive LV dysfunction and attenuates global LV remodeling. These findings provide
compelling rationale for exploring the use of CCM for the treatment of patients with chronic HF.
2003 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.
Õ»§©±®¼-æ Contractile function; Heart failure; Hemodynamics; Remodeling; Ventricular function
ïò ײ¬®±¼«½¬·±²
Despite recent progress in pharmacological therapy,
heart failure HF remains one of the leading causes of
morbidity and mortality in Western countries. Many
patients with HF sustain a markedly limited quality of
life and continue to succumb to the disease. Pharmacologic positive inotropic agents have been shown to
improve cardiac contractility and improve quality of life.
Their chronic use, however, is often associated with
increased mortality 1–3 . Left ventricular assist devices
have also been used as a bridge to cardiac transplantation
Supported, in part, by grants from Impulse Dynamics and the
National Heart, Lung, and Blood Institute, HL 49090-08.
*Corresponding author. Tel.: 1-313-916-7360; fax: 1-313-9163001.
Û󳿷´ ¿¼¼®»--æ [email protected] H.N. Sabbah .
in this patient population. However, they carry several
drawbacks, including infection, thromboembolic events,
prolonged intensive care, and high economic burden.
Biventricular pacing or resynchronization therapy has
also been shown to improve systolic function and quality
of life in patients with HF 4,5 . At present, however,
this form of therapy is limited to HF patients with
intraventricular conduction disturbances. Recent studies
have shown that delivery of non-excitatory electrical
signals during the absolute refractory period acutely
improves global LV function in normal dogs and dogs
with HF 6–8 . This therapy can modulate contractile
function on demand and may be mediated, in part, by
modulation of Ca2 cycling within sarcoplasmic reticulum. The purpose of the present study is to examine
the long-term efficacy of non-excitatory cardiac contractility modulation CCM signals on the progression of
1388-9842/04/$30.00 2003 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.ejheart.2003.11.001
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146
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left ventricular LV dysfunction and remodeling in
dogs with chronic HF.
îò Ó»¬¸±¼îòïò ß²·³¿´ ³±¼»´
The canine model of chronic HF used in the present
study was previously described in detail 9 . In this
experimental preparation, chronic LV dysfunction and
failure is produced by multiple sequential intracoronary
embolizations with polystyrene Latex microspheres
70–102 m in diameter , which result in loss of viable
myocardium, LV enlargement and a decrease in LV
ejection fraction. In the present study, 12 healthy mongrel dogs weighing between 19 and 30 kg underwent
serial coronary microembolizations to produce HF.
Embolizations were performed 1–3 weeks apart and
were discontinued when LV ejection fraction, determined
angiographically, was 35%. Microembolizations were
performed during cardiac catheterization under general
anesthesia and sterile conditions. The anesthesia regimen
used consisted of a combination of intravenous injection
of oxymorphone 0.22 mg kg , diazepam 0.17 mg
kg , and sodium pentobarbital 150–250 mg to effect
and was previously shown to have no effect on global
LV function 10 . 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’.
formed in the neck. The animals were allowed to recover
for a period of 2 weeks before initiating the study. This
period of time also allowed the tip of the leads to
mature into place. The remaining six dogs did not
undergo implantation of the CCM signal generator and
leads and thus served as controls.
îòíò ͬ«¼§ °®±¬±½±´
Two weeks after CCM signal generator implantation,
dogs, from both groups, underwent a pre-treatment left
and right heart catheterization. One day after the pretreatment cardiac catheterization, six dogs were assigned
to 3 months of CCM treatment and six dogs to the
control arm. The CCM signal was set at a biphasic
square wave with duration of 14.50 ms for each phase,
and an amplitude of 5.05 V. The duration and amplitude
of CCM signals were selected based on earlier studies
6 that showed efficacy at these levels. The signal was
delivered with a delay of 30 ms from detection of local
electrical activation by local sensing electrodes to ensure
delivery during the absolute refractory period. If the
CCM signal caused diaphragmatic stimulation, the
amplitude was reduced until diaphragmatic stimulation
stopped. The CCM signal was delivered for 6 h each
day for 3 months. No other drugs were used during the
3 months of follow-up. Hemodynamic, angiographic and
echocardiographic measurements were made prior to
initiation of therapy pre-treatment and after 3 month
of therapy post-treatment . In the CCM group, the
CCM signal was turned off 1 day prior to post-treatment
measurement in order to eliminate any device-mediated
acute positive inotropic effects.
îòîò ׳°´¿²¬¿¬·±² ±º ÝÝÓ ´»¿¼- ¿²¼ -·¹²¿´ ¹»²»®¿¬±®
Two weeks after the target ejection fraction was
reached, six dogs were anesthetized as described above,
intubated and ventilated with room air. The left carotid
external jugular vein was surgically exposed. A preformed 7F guiding catheter was advanced through the
jugular vein, positioned in the ostium of the coronary
sinus and the tip advanced into the great cardiac vein.
The lead used for delivery of CCM signals was introduced through the guiding catheter and advanced into
the distal portion of the anterior coronary vein. The lead
contains a pair of electrodes that are used for sensing
the local activity of the LV and a pair of coils for
delivery of the CCM signal. The same jugular vein was
used to position two standard active fixation bipolar
leads Medtronics, Minneapolis, MN , one positioned at
the high right atrial wall and one at the right ventricular
apex. The right atrial and right ventricular leads were
used to time the delivery of the CCM signal. All three
leads were connected to the CCM signal generator
OPTIMIZER, Impulse Dynamics, Mount Laurel, NJ .
The generator was implanted in a subcutaneous pocket
îòìò Ø»³±¼§²¿³·½ô ¿²¹·±¹®¿°¸·½ ¿²¼ »½¸±½¿®¼·±¹®¿°¸ó
·½ ³»¿-«®»³»²¬Hemodynamic, angiographic and echocardiographic
measurements were made before initiation of CCM
signal and after 3 months of CCM signal treatment.
Aortic and LV pressures were measured with cathetertip micromanometers Millar Instruments, Houston,
TX . Peak rates of changes of LV pressure during
isovolumic contraction peak LV dÐ d¬ and relaxation peak LV dÐ d¬ and LV end-diastolic pressures
were measured from the phasic LV pressure waveform.
Cardiac output was measured in duplicate using the
thermodilution method. Stroke volume was calculated
as the ratio of cardiac output to heart rate. The Q–T
interval was measured from the beginning of the QRS
complex of the electrocardiogram to the end of the Twave. The Q–Tc interval was calculated as the ratio of
the Q–T interval to the square root of the R–R interval.
Left ventriculograms were obtained after completion
of the hemodynamic measurements with the dog placed
on its right side. Ventriculograms were recorded on 35
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Table 1
Hemodynamic, angiographic and echocardiographic measurements in
control dogs
Control group
Pre
HR beats min
Mean AoP mmHg
LV EDP mmHg
Peak dÐ d¬ mmHg s
Peak dÐ d¬ mmHg s
CO l min
SV ml
FAS %
LV sphericity index
LV EDV ml
LV ESV ml
LV EF %
Q–Tc ms
82
89
15
1687
1445
1.5
18
30
1.37
64
46
28
318
Ð-value
Post
5
4
1
56
93
0.2
1
1
0.04
5
4
1
6
93
90
15
1460
1248
1.6
18
24
1.30
75
57
23
320
4
4
0
136
102
0.2
2
1
0.05
6
4
1
17
0.155
0.877
0.704
0.070
0.110
0.279
0.530
0.004
0.008
0.003
0.003
0.001
0.397
HR heart rate; AoP aortic pressure; EDP end-diastolic pressure; dÐ d¬ rate of change of LV pressure during isovolumic conand relaxation
; CO cardiac output; LV left
traction
ventricular; FAS fractional area of shortening; EDV end-diastolic
volume; ESV end-systolic volume; EF ejection fraction.
mm cinefilm at 30 frames per second during the injection of 20 ml of contrast material Reno-M-60, Squibb,
Princeton, NJ . Correction for image magnification was
made with a radiopaque calibrated grid placed at the
level of the left ventricle. LV end-diastolic volume
EDV and end-systolic volume ESV were calculated
from ventricular silhouettes using the area-length method. Left ventricular ejection fraction was calculated as
the ratio of the difference of EDV and ESV to EDV
times 100. The LV end-diastolic sphericity index was
calculated from ventriculogram as the ratio of the majorto-minor axis at end-diastole 11 . As this ratio
approaches unity, the LV shape approaches that of a
sphere. Extrasystolic and post-extrasystolic beats were
excluded from all analyses involving ventriculograms.
Two-dimensional echocardiographic studies were performed as previously described 12 using a HewlettPackard model 77020A ultrasound system with a 3.5
MHz transducer. Measurements were made with the dog
placed in the right lateral decubitous position. Echocardiograms were recorded on a Panasonic 6300 VHS
recorder for off-line analysis. A LV short-axis view at
the midpapillary muscle level was recorded and used to
calculate the LV fractional area shortening, defined as
the difference between the end-diastolic and end-systolic
area divided end-diastolic area times 100. The LV
endocardial tracings used for this analysis were drawn
to include the papillary muscle within the outlines.
îòëò ͬ¿¬·-¬·½¿´ ¿²¿´§-·Within group comparison between pre-treatment and
post-treatment measures were made using Student’s
147
paired ¬-test with Ð 0.05 considered significant. To
assess treatment effect, the change
in each measure
from pre-treatment to post-treatment was calculated for
each of the two study arms. To determine whether
significant differences in
were present between the
two groups, a ¬-statistic for two means was used with
Ð 0.05 considered significant. All data are reported as
the mean S.E.M.
íò λ-«´¬In three of six CCM dogs, the CCM signal amplitude
was reduced to avoid diaphragmatic stimulation. The
other three dogs did not have any diaphragmatic stimulation at 5.05 V. The average CCM signal voltage for
all six dogs over the course of 3 months was 3.3 V.
There were no significant differences in any of the study
variables measured before initiating treatment pre-treatment between the two study groups Tables 1 and 2 .
íòïò Ú·²¼·²¹- ·² ½±²¬®±´ ¼±¹The hemodynamic, angiographic and echocardiographic data obtained at pre-treatment and post-treatment
in control dogs are shown in Table 1. Heart rate, mean
aortic pressure, LV end-diastolic pressure, cardiac output,
stroke volume, and Q–Tc interval did not change significantly at the end of the 3-month follow-up compared
to pre-treatment. Peak dÐ d¬ and peak dÐ d¬ tended
to decrease, however, but the changes did not reach
statistical significance. LV ejection fraction decreased
significantly from 28 1 to 23 1% Ð 0.001 during
the 3 month follow up period. This was accompanied
by a significant increase in EDV 64 5 ml vs. 75 6
ml, Ð 0.003 and ESV 46 4 ml vs. 57 4 ml, Ð
0.003 . The sphericity index decreased significantly,
indicating that the shape of the LV was becoming more
Table 2
Hemodynamic, angiographic and echocardiographic measurements in
CCM-treated dogs
CCM-treated group
Pre
HR beats min
Mean AoP mmHg
LV EDP mmHg
Peak dÐ d¬ mmHg s
Peak dÐ d¬ mmHg s
CO l min
SV ml
FAS %
LV sphericity index
LV EDV ml
LV ESV ml
LV EF %
Q–Tc ms
87
84
14
1545
1457
1.8
20
29
1.50
66
46
31
303
Abbreviations are the same as in Table 1.
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Ð-value
Post
4
2
1
93
35
0.2
2
2
0.07
4
3
1
5
80
89
8
1740
1667
1.9
24
35
1.50
71
47
34
305
6
4
0
216
173
0.2
2
3
0.05
5
4
2
10
0.143
0.174
0.010
0.288
0.230
0.271
0.026
0.056
0.957
0.014
0.080
0.056
0.439
148
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Table 3
Change
from pre-treatment to post-treatment in hemodynamic,
angiographic and echocardiographic variables for the two study
groups treatment effect
Control
HR beats min
Mean AoP mmHg
LV EDP mmHg
Peak dÐ d¬ mmHg s
Peak dÐ d¬ mmHg s
CO l min
SV ml
FAS %
LV sphericity index
LV EDV ml
LV ESV ml
LV EF %
Q–Tc ms
11
1
0
228
198
0.1
0
5
0.08
11
12
6
5
Ð-value
CCM
6
7
1
82
88
0.1
0
1
0.02
2
2
1
22
8
5
6
196
210
0.1
4
6
0.00
5
2
3
5
4
3
1
152
140
0.1
1
3
0.03
1
1
1
18
0.040
0.635
0.005
0.050
0.048
0.896
0.010
0.002
0.047
0.041
0.001
0.0001
0.240
Abbreviations are the same as in Table 1.
spherical. Fractional area shortening decreased significantly Table 1 .
íòîò Ú·²¼·²¹- ÝÝÓ󬮻¿¬»¼ ¼±¹The hemodynamic, angiographic and echocardiographic data obtained at pre-treatment and post-treatment
in CCM-treated dogs are shown in Table 2. Heart rate,
mean aortic pressure, cardiac output and the Q –Tc
interval did not change. Peak LV dÐ d¬ and peak LV
dÐ d¬ tended to increase after 3 months of CCM
therapy, but the increase did not reach statistical significance. Left ventricular ejection fraction increased from
31 1 to 34 2% Ð 0.056 and LV fractional area of
shortening also increased from 29 2% to 35 3% Ð
0.056 , but both reached only borderline significance.
Stroke volume increased significantly from 20 2 to
24 2 ml Ð 0.026 . This was accompanied by a
significant decrease in LV end-diastolic pressure. LV
EDV increased to a lesser degree compared to control
dogs 66 4 ml vs. 71 5 ml, Ð 0.014 ; whereas LV
ESV did not change during the 3 months of follow-up
46 3 ml vs. 47 4 ml, Ð 0.080 . The LV sphericity
index was not altered, indicating that heart maintained
its shape.
dogs compared to controls. Left ventricular EDV, ESV
Fig. 1 , and LV end-diastolic pressure were significantly lower in CCM-treated dogs compared to controls.
There was no statistically significant difference in the
Q–Tc interval between the two study groups.
ìò Ü·-½«--·±²
The results of this study indicate that long-term
therapy with non-excitatory CCM signals attenuates
progressive LV dysfunction and remodeling in dogs with
HF. These findings are supported by observations of
improved LV function evidenced by improvement in LV
ejection fraction, stroke volume, and LV fractional area
of shortening and by attenuation of LV remodeling as
evidenced by reduced LV volumes and preservation of
LV shape in CCM-treated dogs when compared to
control dogs.
Contractile dysfunction of the failing heart can be
attributed, in part, to defects in intracellular calcium
handling due to abnormalities of sarcoplasmic reticulum
proteins 13,14 . In isolated cardiomyocytes from dogs
with HF, application of CCM signals, in-vitro, elicited a
27% increase in the extent of myocytes shortening, a
19% increase in peak rate of shortening, a 32% increase
in peak rate of relengthening, and a 19% increase in
peak and integral of Ca2 transients 6 . Exposure of
isolated rabbit papillary muscle to ryanodine, which
inhibits release of Ca2 from the sarcoplasmic reticulum,
markedly attenuated the increase in contractility elicited
by CCM signal delivery, indicating that benefits of CCM
therapy may be mediated, in part, by modulation of
Ca2 cycling within sarcoplasmic reticulum 12 . It may
also be speculated that the inotropic effects of the CCM
signals may be mediated by norepinephrine release by
the nerve fibers of the myocardium. However, in a
separate study it was shown that -blockers did not
alter the increase in peak intracellular calcium levels
íòíò ݱ³°¿®·-±²- ±º ¬®»¿¬³»²¬ »ºº»½¬
Intragroup comparisons of the changes
between
pre-treatment and post-treatment hemodynamic, angiographic and echocardiographic measurements are shown
in Table 3. Compared to control dogs, CCM treated
dogs did not experience a change in mean aortic pressure, but did show a significant decrease in heart rate.
LV ejection fraction Fig. 1 , stroke volume, LV fractional area of shortening, peak LV dP dt, and peak
LV dP dt were significantly higher in CCM-treated
Fig. 1. The change
from pre-treatment to post-treatment for left
ventricular LV end-diastolic volume EDV , end-systolic volume
ESV and ejection fraction EF in control dogs gray bars and dogs
treated with non-excitatory cardiac contractility modulation CCM
signals.
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elicited by CCM signals and only had a minor effect on
contractility 15 . In the present study, CCM signals
elicited a significant reduction in heart rate that was
evident between the control group and the treated group.
It is possible that the reduction in heart rate seen with
CCM therapy may itself have contributed, in part, to
the observed improvement in global LV function.
In the present study, three out of six dogs experienced
diaphragmatic stimulation when the CCM signal was
delivered necessitating reduction of the CCM signal
amplitude. Diaphragmatic stimulation was most likely
caused by anatomical factors, such as the anterior
coronary vein being close to phrenic nerves. Another
possibility is that the heart position changed with the
dog’s posture. It should be noted that, on average, the
increase in EDV and ESV in dogs that received lower
voltage was greater than in dogs that received the
standard 5.05 V suggesting a voltage-dependent response. This issue, however, requires further investigation.
While it would appear that chronic therapy with CCM
signals improves LV function, the results merit cautious
interpretation. All data were obtained in anesthetized
dogs and, as such, anesthesia may have partly influenced
the outcome. This, however, is not very likely in that
both study groups received the same anesthesia regimen
at both baseline and after 3 months of active therapy or
follow-up. Thus, any effect of anesthesia on hemodynamics is likely to be constant and would not influence
the observed treatment effect at least from a directional
standpoint. In this study, CCM therapy was associated
with a reduction of heart rate. It is possible that the
reduction of heart rate may itself have resulted in
improved LV function. However, stroke volume which
takes into account heart rate, also increased significantly
following CCM therapy. Stroke volume is determined
by three main factors namely, afterload, preload and
contractility. In the present study, afterload, reflected by
mean aortic pressure, was unchanged and thus could not
have contributed to the increase in stroke volume.
However, preload, reflected by LV end-diastolic pressure, decreased with CCM therapy and may have contributed to the increase in stroke volume. Also, when
one takes into account the observed treatment effect,
which is intended to correct for variations in pretreatment conditions, all global measures of LV function contractility including LV dÐ d¬, LV fractional
area of shortening and LV ejection fraction improved
significantly in the CCM treated group suggesting that
improved myocardial contractility may have also contributed to the observed improvement in stroke volume.
Finally, one could view the reduction of heart rate and
preload seen with chronic CCM therapy as a reflection
of the improvement in myocardial function. Additional
studies are needed to further explore these issues.
149
ëò ݱ²½´«-·±²In dogs with HF, long-term therapy with non-excitatory CCM signals improves LV function and attenuates
progressive global LV remodeling. Preclinical studies
with larger groups of animals, however, are needed to
further explore the usefulness of this therapeutic modality as adjunctive therapy for the treatment of patients
with advanced HF.
λº»®»²½»1 Packer M. Vasodilator and inotropic drugs for treatment of
chronic heart failure: distinguishing hope from hope. J Am
Coll Cardiol 1988;12:1299 –317.
2 Packer M, Carver JR, Rodeheffer RJ, et al. Effect of oral
milrinone on mortality in severe chronic heart failure. The
PROMISE Study Research Group. N Engl J Med
1991;325:1468 –75.
3 Packer M. The development of positive inotropic agents for
chronic heart failure: how have we gone astray? J Am Coll
Cardiol 1993;22:119A–126A.
4 Abraham WT, Fisher WG, Smith AL, et al. Cardiac resynchronization in chronic heart failure. N Engl J Med. 2002;346:1845 –
53.
5 Auricchio A, Stellbrink C, Sack S, et al. Long-term clinical
effect of hemodynamically optimized cardiac resynchronization
therapy in patients with heart failure and ventricular conduction
delay. J Am Coll Cardiol. 2002;39:2026 –33.
6 Sabbah HN, Haddad W, Mika Y, et al. Cardiac contractility
modulation with the impulse dynamics signal: studies in dogs
with chronic heart failure. Heart Fail Rev 2001;6:45 –53.
7 Morita H, Suzuki G, Haddad W, et al. Cardiac contractility
modulation with non-excitatory electric signals improves left
ventricular ejection fraction in dogs with chronic heart failure.
J Cardiac Fail 2003;9:69 –75.
8 Mohri S, He KL, Dickstein M, et al. Cardiac contractility
modulation by electric currents applied during the refractory
period. Am J Physiol 2002;282:H1642 –H1647.
9 Sabbah HN, Stein PD, Kono T, et al. A canine model of
chronic heart failure produce by multiple sequential coronary
microembolizations. Am J Physiol 1991;260:H1379 –H1384.
10 Sabbah HN, Shimoyama H, Kono T, et al. Effects of longterm monotherapy with enalapril, metoprolol, digoxin on the
progression of left ventricular dysfunction and dilatation in
dogs with reduced ejection fraction. Circulation 1994;89:2852 –
9.
11 Kono T, Sabbah HN, Stein PD, Brymer JF, Khaja F. Left
ventricular shape as a determinant of functional mitral regurgitation in patients with severe heart failure secondary to either
coronary artery disease or idiopathic dilated cardiomyopathy.
Am J Cardiol 1991;68:355 –9.
12 Kono T, Sabbah HN, Rosman H, Lesch M, Goldstein S,
Undrovinas AI. Mechanism of functional mitral regurgitation
during acute myocardial ischemia. J Am Coll Cardiol
1992;19:1101 –5.
13 Maltsev VA, Sabbah HN, Tanimura M, Lesch M, Goldstein S,
Undrovinas AI. Relationship between action potential, contraction-relaxation pattern, and intracellular Ca2 transient in
cardiomyocytes of dogs with chronic heart failure. Cell Mol
Life Sci 1998;54:597 –605.
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150
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14 Mishra S, Gupta RC, Tiwari N, Sharov VG, Sabbah HN.
Molecular mechanisms of reduced sarcoplasmic reticulum
Ca2 uptake in human failing left ventricular myocardium. J
Heart Lung Transplant 2002;21:366 –73.
15 Mohri S, Shimizu J, Mika Y, et al. Electric currents applied
during the refractory period increased peak intracelluler calcium and contractility in ferret hearts. Am J Physiol Heart Circ
Physiol 2003;284:H119 –H1123.
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