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(Circulation. 1995;92:2540-2549.)
© 1995 American Heart Association, Inc.
Articles |
Reduced Contraction and Altered Frequency Response of Isolated Ventricular Myocytes From Patients With Heart Failure
From the Departments of Cardiac Medicine (C.H.D., K.D., P.A.P.-W., S.E.H.) and Surgery (J.G.B., J.R.P.), National Heart and Lung Institute, London, UK.
Correspondence to Dr C.H. Davies, Department of Cardiac Medicine, National Heart and Lung Institute, Dovehouse St, London, UK SW3 6LY.
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Abstract |
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 Top Abstract IntroductionMethods Results Discussion References |
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Background Previous work has failed to demonstrate reduced maximal contraction of isolated ventricular myocytes from failing human hearts compared with nonfailing control hearts. The effect of alterations in stimulation frequency and temperature on the contraction of isolated ventricular myocytes has been investigated. Left ventricular myocytes were isolated from the hearts of patients with severe heart failure undergoing heart transplantation and compared with myocytes isolated from myocardial biopsies from patients with coronary disease but preserved left ventricular systolic function or from myocytes from rejected donor hearts.
Methods and Results Myocytes were exposed to either a maximally activating level of extracellular calcium at 37°C or to 2 mmol/L calcium at 32°C. There was no significant difference in the contraction amplitude between myocytes from failing and nonfailing hearts at 0.2 Hz. With increasing stimulation frequency, there was a reduction in contraction amplitude in cells from failing hearts relative to control hearts in both maximal calcium from 0.33 Hz (4.5% versus 6.6%) to 1.4 Hz (3.9% versus 8.8%) (ANCOVA, P<.001) and at 2 mmol/L calcium from 0.50 Hz (2.3% versus 3.5%) to 1.4 Hz (1.8% versus 3.9%) (ANCOVA, P<.001). The time to peak contraction and the times to 50% and 90% relaxation were prolonged in myocytes from failing hearts at stimulation rate of 0.2 Hz (P<.01), but only the time to 50% relaxation was prolonged at 1.0 Hz (P<.05).
Conclusions Reduced contraction, slowed relaxation, and impaired frequency response occurring at the level of the individual ventricular myocyte can be demonstrated in human heart failure. This demonstrates that disruption of myocyte function can contribute to both the systolic and the diastolic abnormalities that occur in the failing human heart.
Key Words: myocytes • heart failure • contractility
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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There remains uncertainty as to the contractile function of the individual ventricular myocytes in the failing human heart. Our previous studies have demonstrated ß-adrenoceptor desensitization1 as well as prolongation of TTP and R50 in myocytes isolated from patients with left ventricular failure.2 However, the maximum contraction amplitude has not been reduced in myocytes obtained from failing hearts compared with nonfailing control hearts.1
This surprising finding might be a reflection of either the true state of the remaining viable myocytes in human heart failure or merely inappropriate experimental conditions. As we recently reviewed,3 studies with papillary muscle and trabecular preparations have shown conflicting results, with some demonstrating reduced force of contraction in preparations from failing hearts4 5 and others unable to demonstrate a difference.6 7 As the studies that demonstrated a reduction in the force of contraction were in general those that used higher temperatures and stimulation frequencies, we examined the effects of these variables on the contraction amplitude of ventricular myocytes isolated from patients with normal and impaired systolic left ventricular function.
In addition, we have been concerned about the suitability of the hearts of brain-dead organ donors for use as normal control subjects in these experiments. We therefore investigated the use of small biopsy samples obtained from patients with normal systolic function undergoing coronary surgery to serve as control subjects.
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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Myocyte Preparation From Explanted Hearts
Human ventricular myocardium was obtained from 18 patients with severe cardiac failure secondary to ischemic heart disease (n=12), dilated cardiomyopathy (n=5), or end-stage valvular disease (n=1) at the time of transplantation (Tables 1
and 2). Informed consent was obtained
before the operation. Myocytes were also isolated from the hearts of 2
patients without heart failure whose hearts were technically unsuitable
for use as organ donors (Table 3). Tissue
was transported in ice-cold cardioplegia solution (131 mmol/L
Na+, 5 mmol/L K+, 111 mmol/L
Cl-, 2 mmol/L Ca2+,
29 mmol/L lactate, and 20 mmol/L procaine). Average transit time to the
laboratory was 90 minutes, although in 4 patients (indicated by an
asterisk in Tables 1 and 2) the average transit
time was <5 minutes.
Myocytes were isolated as previously described.1 A sample
of the left ventricle (average weight, 1 g) was cut into chunks of
approximately 1 mm3 with the use of a razor array and was
incubated at 35°C in 25 mL of an LC medium containing NTA as a
calcium buffer. The composition of the LC medium was (in mmol/L): NaCl
120, KCl 5.4, MgSO4 5, pyruvate 5, glucose 20, taurine 20,
HEPES 10, and NTA 5, bubbled with 100% O2. pH was adjusted
to 6.95, and the measured free [Ca2+] was 1 to 3
µmol/L. The medium was changed three times at 3-minute intervals (12
minutes total). The chunks were then drained and transferred to LC
without NTA and with 50 µmol/L calcium added with 4 U/mL Sigma type
XXIV protease (Pronase) at the same temperature for 45 minutes. The
solution was shaken under an atmosphere of 100% oxygen throughout the
procedure. Two additional digests were undertaken using 1 mg/mL Sigma
type V collagenase with or without 0.5 mg/mL Sigma
hyaluronidase. The cell suspension was then filtered through 300-µm
gauze to remove undigested tissue, and the myocytes were pelleted by
gentle centrifugation. The pellet was resuspended in
preoxygenated LC without NTA.
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Myocyte Preparation From Biopsies
We used a modification of
our method for explanted hearts,
incorporating some of the suggestions of Peeters et al.8
Fifteen patients were selected with stable angina who required
coronary artery surgery but who had unimpaired systolic
ventricular function (ejection fraction >60% as defined
by left ventricular angiography) (Tables 4 and
5). Patients were excluded if they had a
history of myocardial infarction. After the institution of
cardiopulmonary bypass, the heart was electrically
fibrillated, and before the instillation of cardioplegia, a small
biopsy sample of the left ventricular free wall was taken
with a No. 11 blade. The average biopsy weight was 125 mg. There were
no adverse effects from this procedure.
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The sample was placed into an ice-cold LC medium for 30 minutes. The sample was then placed in a vibratome (Micro Cut 1200, Energy Beam Sciences) and cut into 400-µm sections before being placed in an ice-cold solution of protease (0.5 mg/mL) and collagenase (1.5 mg/mL) in LC solution but with the addition of 50 µmol/L calcium and without NTA. This was then warmed to 35°C for 30 minutes while being gently shaken in an atmosphere of 100% oxygen. This solution was then exchanged for one containing collagenase (1.0 mg/mL) and hyaluronidase (0.5 mg/mL) and incubated for an additional 90 minutes. The supernatant was removed, and the myocytes were pelleted by gentle centrifugation before resuspension in LC without NTA but with the addition of 0.5 g/L BSA and a final calcium concentration of 300 µmol/L (patients 1 through 10). These solutions were supplemented by the addition of BDM 30 mmol/L for biopsy patients 1 through 5 and the addition of insulin 0.1 U/L for biopsy patients 1 through 6. All patients gave informed consent, and the procedure was approved by the Ethical Committee of the Royal Brompton National Heart and Lung Hospital.
Myocyte Contraction Experiments
Myocytes were placed in a
bath on an inverted microscope stage
as previously described9 in Krebs-Henseleit solution with
a composition of (in mmol/L): NaCl 120, KCl 4.7, MgSO4
0.97, KH2PO4 1.2, NaHCO3 25,
glucose 11, and calcium 1.0 and equilibrated with 95%
O2/5% CO2. Myocytes were chosen for
study on the basis of a number of criteria: (1) morphological
appearance (rod shaped, no large blebs or areas of hypercontracture),
(2) sarcomere length >1.72 µm, (3) no spontaneous contractions when
unstimulated at 1 mmol/L Ca2+, and (4) steady
contraction amplitude and diastolic length at a stimulation
rate of 0.2 Hz (using a biphasic pulse).
Experiments were performed in two groups; with the exception of transplant group A patients 8 and 9 and nonfailing group A patient 7, whose cells were examined in both groups, the two groups were mutually exclusive. Myocytes of group A patients were studied at 37°C in maximally stimulating Ca2+ (defined as the point at which no further increment in contraction occurred after an increase in the level of extracellular Ca2+). Myocytes from group B and those from the nonfailing donor hearts were studied at 32°C in 2 mmol/L Ca2+. The effect of a range of frequencies on contraction amplitude was then examined (0.1 to 1.42 Hz), following which the cell was again stimulated at 0.2 Hz to ensure internal consistency. Contraction was monitored using a video edge-detection system.9 Contraction was described either in terms of the systolic and diastolic sarcomere lengths (µm) or in terms of percent systolic shortening (systolic change in cell length/diastolic cell length). The TTP and R50 and R90 were measured from three consecutive contractions in myocytes in maximal Ca2+. The lower contraction amplitudes of myocytes in 2 mmol/L Ca2+ precluded the accurate measurement of these data in group B patients.
Statistical Analysis
Significance was assessed on grouped
data with the
ANCOVA (or the general linear model where appropriate) and Student's
t test (for paired and unpaired samples as appropriate).
Data from one to three cells for each patient were pooled before
analysis. Values are expressed as mean±SEM.
Materials
Salts were obtained from Merck and were AnalaR
grade except for
KCl, taurine, and glucose, which were AristaR grade. AnalaR water was
used for the low Ca2+ solutions and double distilled
deionized water (MilliQ system) was used for the remainder. BDM was
obtained from Sigma Chemical Co, and human insulin was obtained from
Eli Lilly.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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Basal Sarcomere Lengths
There was a nonsignificant trend toward longer sarcomere lengths under basal conditions (1 mmol/L Ca2+ and a stimulation rate of 0.2 Hz) of group A patients in myocytes from control subjects with nonfailing hearts (1.90±0.03 µm) than from patients with heart failure (1.82±0.03 µm, P=NS). This difference in diastolic sarcomere length became statistically significant in maximally activating Ca2+ (at 0.2 Hz: nonfailing, 1.88±0.03 µm; failing, 1.79±0.03 µm; P<.05) (Fig 1
,
top). In group B patients, sarcomere lengths under basal conditions
were not significantly different between nonfailing and failing hearts
(nonfailing, 1.84±0.03 µm; failing, 1.84±0.02 µm) (Fig
1, bottom). Because BDM was present for six of
eight in the series A control subjects (37°C) but not for series B
(32°C), we also examined the sarcomere lengths obtained during a
parallel series of experiments performed at 32°C in which cells were
prepared in the presence of BDM. In these experiments, there was no
difference in the sarcomere lengths between cells from nonfailing
(1.89±0.06 µm, n=13) and failing (1.90±0.04 µm,
n=20 cells,
P=NS) groups. Further experiments comparing the effects of
vibratome versus razor sectioning in human atrial myocytes failed to
detect any differences in sarcomere length between the two methods.
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Contraction at 0.2 Hz
There was no significant difference in
the contraction amplitude
expressed in terms of percentage shortening of cells from failing and
nonfailing hearts at 0.2 Hz in either maximal or 2 mmol/L
Ca2+, and this finding is in accordance with
our previous data obtained at 32°C in maximal
Ca2+10 (Fig 2). The reduced
magnitude of the
maximally stimulated contraction at 37°C compared with experiments
performed at lower temperatures is also consistent with other
studies.11 Maximal contraction in response to increasing
calcium was obtained in myocytes from group A patients at 8.71±0.78
mmol/L Ca2+ in cells from control patients and
7.75±0.62 mmol/L in cells from patients with heart failure
(P=NS).
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Contraction in Maximal Calcium With Increasing Stimulation
Frequency at 37°C (Group A Patients)
With increasing stimulation
frequency, there was a progressive
increase in the amplitude of contraction in myocytes from nonfailing
hearts, whereas in those from failing hearts there was a decline. These
markedly different responses to increases in stimulation rate were
statistically significant overall (ANCOVA, P<.001) and at
the individual frequencies of 0.33 (P<.05); 0.5
(P<.01); and 0.66, 0.80, 1.0, and 1.42 Hz
(P<.001) (t tests) (Tables 6 and
7 and Fig 3). The results
obtained without the use of BDM in patients 6 and 7 (Table 4
)
were similar in terms of the increased amplitude
obtained with increasing stimulation frequency and in terms of the
increased contraction compared with cells from patients with heart
failure at higher frequencies. Systolic and
diastolic sarcomere lengths decreased in parallel in
response to increases in simulation rate for both failing and
nonfailing hearts, but the changes in both were greater for cells from
nonfailing hearts (Tables 6 and 7; ANCOVA,
failing versus nonfailing
P<.01 for both systolic and diastolic
sarcomere lengths).
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Contraction in 2 mmol/L Ca2+ With Increasing
Stimulation Frequency at 32°C (Group B Patients)
Myocytes from 5
patients (2 with nonfailing and 3 with failing
hearts) did not follow the driving frequency at 1.4 Hz. As with the
experiments conducted in maximal calcium, there was a progressive
increase in contraction amplitude in myocytes from nonfailing hearts
with increasing stimulation rate (Tables 8 and 9
and Fig 4). In contrast,
there was an initial increase in shortening of myocytes from failing
hearts with increasing stimulation frequency up to 0.5 Hz, although
this was smaller than that seen with myocytes from nonfailing hearts
(Fig 4). However, at stimulation rates in excess of 0.5
Hz, there was a progressive decline in contraction amplitude. This
divergence in the response to increasing stimulation frequency resulted
in a significant depression of contraction amplitude in myocytes from
patients with heart failure at higher stimulation rates (ANCOVA,
failing versus nonfailing hearts, P<.001). Similar results
were obtained in myocytes obtained from the nonfailing donor hearts
(Table 3). There was a progressive decrease in
systolic sarcomere lengths in response to increasing
stimulation rate in myocytes from nonfailing hearts in contrast to the
flatter response in myocytes from patients with heart failure (failing
versus nonfailing hearts, ANCOVA, P<.05) (Tables 8
and 9
and Fig 5). There were small reductions (of the order of
1%) in diastolic sarcomere length with increasing
stimulation rate in myocytes from both failing and nonfailing hearts,
and these were significant by paired t test
(P<.02). There was, however, no difference in
diastolic shortening between the two groups (failing versus
nonfailing ANCOVA, P=NS) (Figs 1 and
5).
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and 
, Cardiac
failure; 
and 
, nonfailing hearts; open symbols indicate
diastolic, and closed symbols indicate systolic.
ANCOVA, failing vs nonfailing hearts, P<.05 for
systolic sarcomere lengths and P=NS for
diastolic sarcomere lengths.
Characteristics of Contraction and Relaxation
TTP and
R50 and R90 were significantly
prolonged in cells from failing hearts at a stimulation frequency of
0.2 Hz (P<.01) (Fig 6, top). This is
consistent with our previous observations at
32°C.2 At a stimulation rate of 1.0 Hz, only
R50 achieved statistical significance (Fig 6,
bottom). This was due to a significant reduction in
R50 and R90 in myocytes from failing hearts at
1.0 Hz compared with 0.2 Hz (P<.05) and to an increase in
TTP in myocytes from nonfailing hearts (P<.05).
R50 and R90 in myocytes from nonfailing hearts
appeared to be independent of stimulation rate. The expanded tracings
(Fig 7) demonstrate that this effect is
not due to fusion of beats.
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Effect of Transit Times on Myocyte Contraction
Transplants
were performed at two centers—one distant from
the laboratory (where transit times were averaged 90 minutes) and one
on the same site as the laboratory (where transit times were <5
minutes; indicated with an asterisk in Tables 1 and
2). All biopsies
were performed at the center adjacent to the laboratory. We examined
the effect of transit times on contraction amplitude and found a small
increase in contraction amplitude in myocytes performed at the nearer
center compared with those obtained from the remote center in group A
patients (Fig 8); this difference was
significant (ANCOVA, P<.05). The magnitude of this
difference was small compared with the differences observed between
failing and nonfailing groups. A comparison between the short transit
time transplants and the nonfailing biopsies reveals significant
depression of contraction amplitude (ANCOVA, P<.001).
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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The results of the present study demonstrate that at physiological stimulation frequencies, abnormalities of both contraction and relaxation can be detected at the level of the individual cardiac myocyte in the failing human heart.
Systolic Shortening
The finding of similar degrees of
shortening in myocytes from
failing and nonfailing hearts at 0.2 Hz and 37°C is in agreement with
our previous work,1 demonstrating that the lower
temperature (32°C) was not responsible for our failure to detect a
difference. The finding of reduced shortening at higher frequencies in
isolated cardiac myocytes from failing human hearts demonstrates that
myocyte loss12 and abnormalities of the extracellular
matrix13 are not solely responsible for the depression of
ventricular function in heart failure. The fact that the
depressed shortening becomes apparent at higher stimulation rates is in
agreement with clinical studies in which the depression of cardiac
output in the failing heart occurs at higher heart
rates.14 15 Although the majority of the patients in
this
series had ischemic heart disease as a primary diagnosis, the
results obtained in patients with dilated
cardiomyopathy were similar, suggesting that it is
the presence of long-standing heart failure itself that produces
these abnormalities regardless of its underlying cause.
The increased force and amplitude of contraction that occur with increasing stimulation frequency in cardiac muscle fibers was first described by Bowditch11 and has been attributed to increases in the L-type Ca2+ current16 and intracellular [Na+]17 accompanied by reduced sensitivity of the Na+/Ca2+ exchanger.18 Although this effect has been demonstrated to occur both isotonically19 and isometrically20 in isolated guinea pig myocytes, it has not been previously described in isolated human cells. The attenuation or reversal of this effect both in papillary muscle preparations21 22 and clinically14 15 in patients with heart failure has also been described. Although in the majority of reports this negative frequency response occurs in heart failure due to a wide range of causes, some authors have suggested that it is dependent on the underlying cause of heart failure.23 24 The negative force-frequency relation in papillary preparations from failing hearts is potentiated by increased extracellular calcium concentrations23 and reversed by magnesium,25 ouabain,26 isoprenaline,26 and forskolin.27 The underlying mechanisms responsible for these observations remain unclear with experiments from isometric papillary muscles demonstrating both reduced availability of28 and insensitivity to29 intracellular calcium with increasing stimulation frequency in heart failure. In isotonically contracting isolated cardiac myocytes, Beuckelmann et al30 demonstrated a reduction in the calcium transient peak in myocytes from failing hearts at a stimulation rate of 0.5 Hz, whereas in isotonically contracting trabecular preparations Vahl et al31 demonstrated an increased Ca2+ transient in heart failure relative to hearts from control subjects at 1.0 Hz.
Diastolic Shortening in Maximal Ca2+
and 37°C (Group A Patients)
There was no significant difference in
the sarcomere lengths
of myocytes under basal conditions (0.2 Hz and 1 mmol/L
Ca2+), and this is in agreement with previous
observations.1 31 In contrast to our previous
observations
at 32°C,1 the presence of maximally stimulating
Ca2+ produced significant shortening of
diastolic sarcomere lengths in myocytes from patients with
heart failure (Fig 1). Although this observation is
consistent with the proposed impairment of
diastolic Ca2+ handling in the failing
hearts,30 it is possible that impairment of myofilament
Ca2+ sensitivity occurring at shorter sarcomere
lengths32 contributed to the observed depression of
contractility in myocytes from patients with heart
failure. The levels of sarcomere shortening that occurred are in excess
of those producing sarcomere overlap and contracture. The fact that a
comparable depression of shortening in myocytes from failing hearts
occurred in group B (with 2 mmol/L Ca2+) suggests
that the mechanism of depressed contractility in high
Ca2+ is unrelated to small changes in sarcomere
length under these experimental conditions.
Diastolic Shortening at 2 mmol/L
Ca2+ and 32°C (Group B Patients)
There was no
difference in the diastolic sarcomere
length with increasing stimulation frequency between myocytes from
failing and nonfailing hearts (Tables 7 and 8
and Fig 5). This demonstrates that the failure of the myocytes
from impaired ventricles to increase their systolic shortening
was not simply due to excessive diastolic contracture.
Characteristics of Contraction and Relaxation
The
prolongation of TTP and R50 and R90 in
cells from failing hearts at 0.2 Hz is consistent with our
previous findings at 32°C.2 In addition, this finding is
compatible with descriptions of prolongation of the calcium transient
decay occurring in isolated cells from failing hearts30
and in trabecular preparations.31 33 In
contrast to this, previous trabecular experiments have
failed to demonstrate prolongation of the time to 50% mechanical
relaxation at 0.5 Hz,26 1.0 Hz,26 34 or
2.0
Hz26 and in one study, there was a trend toward faster
relaxation in muscles from failing hearts.26 That the
prolongation of R90 at 0.2 Hz in myocytes from failing
hearts becomes less prominent at 1.0 Hz and that this occurs in the
absence of diastolic fusion have not been previously
described. These findings suggest that some of the well-recognized
abnormalities of diastolic function that occur in heart
failure35 may originate at the level of the individual
cardiac myocyte and that the use of isometric preparations can
partially obscure these abnormalities.
Use of Biopsy Samples From Nonfailing Myocardium as
Control Samples
There are several potential disadvantages with the use
of donor
myocardium that has been found to be unsuitable for
transplantation as control tissue. First, significant abnormalities of
myocardial function can be observed in brain-dead
patients,36 and these commonly require inotropic and other
support before harvest. Second, the limited availability of such
patients is often reflected in the small numbers of control patients in
many series. In addition, documentation of the donors' preharvest
cardiovascular status is often poor, and the age range
is significantly younger than the population of patients with heart
failure. In preliminary experiments using human atrial appendage, we
have demonstrated that a threefold improvement in yield can be achieved
using vibratome sectioning in place of the traditional razor array with
no discernible alteration in myocyte function (unpublished
observations). In addition, the results presented here
demonstrate similar contractile characteristics at 0.2 Hz to previous
experiments using rejected donor hearts.1 Using the
technique described here, we have been successful in isolating viable
cardiac myocytes from 70% of biopsies and from samples as small as 40
mg. The development of this technique provides a plentiful supply of
control tissue and may permit the study of milder forms of
ventricular dysfunction in the future.
Study Limitations
The use of unloaded preparations clearly
does not fully reflect
the situation in the intact heart but may represent a useful
alternative perspective to traditional isometric preparations,
particularly as the heart spends only a small portion of each cycle
performing pure isometric work. In addition, recent work describing the
attenuation of the Frank-Starling mechanism in papillary preparations
from failing hearts37 implies that the lack of an external
load would cause us to underestimate the contractile deficit in
myocytes from failing hearts compared with myocytes from control
subjects with nonfailing hearts.
The second limitation is the use of BDM in the preparation of cells from 5 of the control patients but from none of the cells from failing hearts in group A. However, we do not believe that this significantly affected our results for several reasons. First, we have subsequently isolated cells from two patients from group A (patients 6 and 7) without the use of BDM and all of the patients in group B and from the rejected donor hearts with identical results. Second, the effects of BDM have been shown to be rapidly reversible on washout.38 BDM has been shown not to alter the force-frequency relation in papillary muscle preparations from failing and nonfailing hearts.22 As similar results were obtained with myocytes from nonfailing hearts regardless of whether they were prepared from explanted hearts or from biopsy samples, the differences observed in myocytes from failing hearts cannot be attributed to differences in the preparation techniques. All single myocyte studies have the inherent limitation of the potential for cell selection bias. It should be noted that the myocytes were selected for study at a stimulation rate of 0.2 Hz, where no differences in systolic contractility were apparent. By selecting for study only cells that met our stability criteria, we may have underestimated the true impairment of function among the myocyte population as a whole. Nevertheless, results of the present study demonstrate the profound abnormalities of contraction and relaxation present at higher stimulation rates in myocytes that are apparently morphologically intact. In addition, it should be noted that the depression of contractility is comparable to that seen in papillary and trabecular muscle studies.5 26
Conclusions
This study demonstrates that impaired shortening
occurs at the
level of the individual ventricular myocyte in human
cardiac failure and that myocyte abnormalities can contribute to both
systolic and diastolic dysfunction. The
production of working myocytes from biopsies of adult human
left ventricle has been described.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported by the British Heart Foundation. We are grateful to the Royal Brompton Charitable Trust for the purchase of the Vibratome. Sian Harding is a Wellcome Senior Lecturer. We thank the surgeons and immunologists of Harefield Hospital for their generous help with the samples of explanted hearts, and we express our gratitude to the patients who kindly donated myocardial biopsies.
Received January 10, 1995; revision received May 29, 1995; accepted June 3, 1995.
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References |
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TopAbstractIntroductionMethods Results Discussion References |
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1. Harding SE, Jones SM, del Monte F, Vescovo G, Poole-Wilson PA. Isolated ventricular myocytes from failing and nonfailing human heart: the relation of age and clinical status to isoproterenol response. J Mol Cell Cardiol. 1992;24:549-564. [Medline] [Order article via Infotrieve]
2. del Monte F, Harding SE, Rosano GMC, Poole-Wilson PA. Contractile properties of hypertrophic and nonhypertrophic human ventricular myocytes. J Am Coll Cardiol. 1993;21:778-773.
3. Harding SE, Macleod KT, Davies CH, Wynne DG, Poole-Wilson PA. Abnormalities of the myocytes in ischaemic cardiomyopathy. Eur Heart J. 1995;16(suppl I), 74-81.
4. Schwinger RHG, Böhm M, Erdmann E. Inotropic and lusitropic dysfunction in myocardium from patients with dilated cardiomyopathy. Am Heart J. 1992;123:116-128. [Medline] [Order article via Infotrieve]
5.
Hasenfuss G, Mulieri LA, Leavitt BJ, Allen PD,
Haeberle JR, Alpert NR. Alteration of contractile function and
excitation-contraction coupling in dilated
cardiomyopathy. Circ
Res. 1992;70:1225-1232.
6.
Bristow MR, Anderson FL, Port DJ, Skerl L, Hershberger
RE, Larabee P, O'Connell JB, Renlund DG, Volkmann K, Murray J, Feldman
AM. Differences in ß-adrenergic neuroeffector mechanisms
in ischemic versus idiopathic dilated
cardiomyopathy.
Circulation. 1991;84:1024-1039.
7. von der Leyen H, Mende U, Meyer W, Neumann J, Nose M, Schmitz W, Scholz H, Starbatty J, Stein B, Wenzlaff H, Döring V, Kalamár P, Haverich A. Mechanism underlying the reduced positive inotropic effects of the phosphodiesterase III inhibitors pimobendan, adibendan and saterinone in failing as compared to nonfailing human cardiac muscle preparations. Naunyn Schmeidebergs Arch Pharmacol. 1991;344:90-100. [Medline] [Order article via Infotrieve]
8.
Peeters GA, Sanguinetta MC, Eki Y, Konarzewski H,
Renlund DG, Karwande SV, Barry WH. Method for isolation of human
ventricular myocytes from single endocardial and epicardial
biopsies. Am J Physiol. 1995;268:H1757-H1764.
9. Harding SE, Vescovo G, Kirby M, Jones SM, Gurden J, Poole-Wilson PA. Contractile responses of isolated adult rat and rabbit cardiac myocytes to isoprenaline and calcium. J Mol Cell Cardiol. 1988;20:635-647. [Medline] [Order article via Infotrieve]
10. Harding SE, Macleod KT, Jones SM, Poole-Wilson PA. Contractile responses of myocytes isolated from patients with cardiomyopathy. Eur Heart J. 1991;12(suppl D):44-48.
11. Bowditch HP. On the peculiarities of excitability which the fibres of cardiac muscle show. Berichte Königlich-Sächisten Gellenshaaft Wissenchaften. 1870;23:652-689.
12.
Beltrami CA, Finato N, Rocco M, Feruglio GA, Puricelli
C, Cigola E, Quani F, Sonnenblick EH, Olivetti G, Anversa P.
Structural basis of end stage ischaemic
cardiomyopathy.
Circulation. 1994;89:151-163.
13.
Weber KT, Brilla CG, Janicki JS. Myocardial
fibrosis: functional significance and regulatory factors.
Cardiovasc Res. 1993;27:341-348.
14.
Hasenfuss G, Holubarsch C, Hermann H-P, Astheimer K,
Pieske B, Just H. Influence of the force-frequency
relationship on haemodynamics and left ventricular function
in patients with non-failing hearts and in patients with dilated
cardiomyopathy. Eur Heart J. 1994;15:164-170.
15. Feldman MD, Alderman JD, Aroesty JM, Ferguson JJ, Owen RM, Grossman W, Mckay RG. Depression of systolic and diastolic myocardial reserve during atrial pacing tachycardia in patients with dilated cardiomyopathy. J Clin Invest. 1988;82:1661-1669.
16.
Lakatta EG, Spurgeon HA. Force staircase
kinetics in mammalian cardiac muscle: modulation by muscle
length. J Physiol. 1980;299:337-352.
17.
Cohen CJ, Fozzard HA. Increase in intracellular
sodium ion activity during stimulation in mammalian cardiac
muscle. Circ Res. 1982;50:651-662.
18. Boyett MR, Frampton JE, Harrison SM, Kirby MS, Levi PJ, McCall E, Milner DR, Orchard CH. The role of intracellular calcium, sodium and pH in rate-dependent changes of cardiac contractile force. In: Noble MIM, Seed WA, eds. The Interval-Force Relationship of the Heart: Bowditch Revisited. Cambridge, UK: Cambridge University Press; 1992:111-172.
19.
Sheppeard N, Vornanen M, Isenberg G. Force
measurements from voltage-clamped guinea pig
ventricular myocytes. Am J Physiol. 1990;258:H452-H459.
20.
Capogrossi MC, Kort AA, Spurgeon HA, Lakatta EG.
Single adult rabbit and rat cardiac myocytes retain the
Ca2+ and species dependent systolic
contractile properties of intact muscle. J Gen
Physiol. 1986;88:589-613.
21. Phillips PJ, Gwathmey JK, Feldman MD, Schoen FJ, Grossman W, Morgan JP. Post-extrasystolic potentiation and the force-frequency relationship: differential augmentation of myocardial contractility in working myocardium from patients with end-stage heart failure. J Mol Cell Cardiol. 1990;22:99-110. [Medline] [Order article via Infotrieve]
22. Schwinger RHG, Böhm M, Koch A, Uhlmann R, Überfuhr P, Kreuzer E, Reichart B, Erdmann E. Force-frequency-relation in human atrial and ventricular myocardium. Mol Cell Biochem. 1993;119:73-78. [Medline] [Order article via Infotrieve]
23. Pieske B, Hasenfuss G, Holubarsch C, Schwinger RHG, Böhm M, Just H. Alterations of the force-frequency relationship in the failing human heart depend on the underlying cardiac disease. Basic Res Cardiol. 1992;87(suppl 1):213-221.
24. Miserz M, Wei L, Mubagawa K, Flameng W. Force-frequency relationship and extracellular calcium sensitivity in failing human heart: relation to the etiology and/or degree of heart failure. J Mol Cell Cardiol. 1993;25(suppl I):S7.
25. Schwinger RHG, Böhm M, Uhlmann R, Schmidt R, Überfuhr P, Kreuzer E, Reichart B, Erdmann E. Magnesium restores the force-frequency relationship in failing human myocardium. Am Heart J. 1993;126:1018-1021. [Medline] [Order article via Infotrieve]
26. Schwinger RHG, Böhm M, Muller-Ehmsen J, Uhlmann R, Schmidt U, Stäblein A, Überfuhr P, Kreuzer E, Rieichart B, Eissner H-J, Erdmann E. Effect of inotropic stimulation on the negative force-frequency relationship in the failing human heart. Circulation. 1993;88(pt 1):2267-2276.
27.
Mulieri LA, Leavitt BJ, Martin BJ, Haeberle JR, Alpert
NR. Myocardial force-frequency defect in mitral
regurgitation heart failure is reversed by
forskolin. Circulation. 1993;88:2700-2704.
28. Hasenfuss G, Pieske B, Holubarsch C, Alpert NR, Just H. Excitation-contraction coupling and contractile protein function in failing and non-failing human myocardium. In: Sideman S, Beyar R, eds. Interactive Phenomena in the Cardiovascular System. New York, NY: Plenum Press; 1994:91-100.
29. Gwathmey JK, Slawsky MT, Hajjar RJ, Briggs GM, Morgan JP. Role of intracellular calcium handling in force-frequency relationships of human ventricular myocardium. J Clin Invest. 1990;85:1599-1613.
30.
Beuckelmann DJ, Nabauer M, Erdmann E.
Intracellular calcium handling in isolated ventricular
myocytes from patients with terminal heart failure.
Circulation. 1993;85:1046-1055.
31.
Vahl CF, Bonz A, Timek T, Hagl S. Intracellular
calcium transient of working human myocardium of seven
patients transplanted for congestive heart failure.
Circ Res. 1994;74:952-958.
32.
Hibberd MG, Jewell BR. Calcium- and
length-dependent force production in rat
ventricular muscle. J Physiol. 1982;329:527-540.
33.
Gwathmey JK, Copelas L, Mackinon R, Schoen FJ, Feldman
MD, Grossman W, Morgan JP. Abnormal intracellular calcium
handling in myocardium from patients with end stage heart
failure. Circ Res. 1987;61:70-76.
34.
Mulieri LA, Hasenfuss G, Leavitt BJ, Allen PD, Alpert
NR. Altered myocardial force-frequency relation in human
heart failure. Circulation. 1992;85:1743-1750.
35. Spirito P, Maron BJ, Bonow RO. Noninvasive assessment of left ventricular diastolic function: comparative analysis of Doppler echocardiographic and radionucleotide angiographic techniques. J Am Coll Cardiol. 1986;7:518-526. [Abstract]
36. Nishimura N, Miyata Y. Cardiovascular changes in the terminal stage of disease. Resuscitation. 1984;12:175-180.[Medline] [Order article via Infotrieve]
37.
Schwinger RHG, Böhm M, Koch A, Schmidt U, Morano
I, Eissner H-J, Überfuhr P, Reichart B, Erdmann E. The
failing human heart is unable to use the Frank-Starling
mechanism. Circ Res. 1994;74:959-969.
38.
Liu Y, Cabo C, Delmar RS, Davidenko J, Jalife J.
Effects of diacetyl monoxime on the electrical properties of sheep and
guinea pig ventricular muscle. Cardiovasc
Res. 1993;27:1991-1997.
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|
|
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|
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|
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|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
 |
|
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