© 1997 American Heart Association, Inc.
Articles |
Changes in Cell-to-Cell Electrical Coupling Associated With Left Ventricular Hypertrophy
From the Institute of Urology and Nephrology (W.R.J.W., C.H.F.), University College London, and Academic Cardiology Unit (M.C., D.J.S.), St. Mary's Hospital Medical School, London, UK.
Correspondence to C.H. Fry, Institute of Urology and Nephrology, 67 Riding House St, London W1P 7PN, UK. E-mail chris.fry{at}ucl.ac.uk
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Abstract |
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Abstract The impedance to current flow in the intracellular compartment of guinea pig left ventricular myocardium was measured at 20°C and 37°C using tissue from hypertrophied hearts subjected to aortic constriction. Alternating current of varying frequency was passed longitudinally along myocardial preparations, which revealed two time constants: one attributed to the surface membrane at the ends of the preparation and a second lying in the intracellular pathway. The longitudinal impedance was quantitatively analyzed in terms of a parallel intracellular and extracellular pathway; the former had two series components, one attributable to the sarcoplasm and the other to the low-resistance junctions between adjacent cells. This interpretation was consistent (1) with control experiments using n-heptanol, which increased the component attributed to intercellular junctions but not sarcoplasmic resistivity, and (2) with suspensions of isolated myocytes, which yielded a similar value for the sarcoplasmic resistivity. Aortic constriction increased the heart weight–to–body weight ratio of experimental animals from a mean value of 3.10±0.28 to 5.05±0.83 g/kg after 50 days of constriction and 5.60±0.95 g/kg after 150 days of constriction. An increase of heart weight–to–body weight ratio at 150 days of constriction was associated with an increased intracellular resistivity, which could be attributed solely to an increase of the junctional resistance between adjacent cells by
44% at 20°C and 140% at 37°C; the
sarcoplasmic resistivity was unchanged. The results are discussed in
terms of altered conduction in hypertrophied myocardium as
a possible basis for arrhythmias in this tissue.
Key Words: hypertrophy • longitudinal impedance • intracellular resistance
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Left ventricular hypertrophy significantly increases the risk of sudden cardiac death1 and is associated with a greater prevalence of cardiac arrhythmias,2 which could arise from reentrant mechanisms, afterdepolarizations, or other forms of abnormal automaticity.3 4 5 Reentrant mechanisms require regions of abnormal action potential conduction, but little attention has been focused on conduction defects or the underlying electrical properties of myocardium that cause this phenomenon in hypertrophied tissue. Cable theory predicts that as cell diameter increases, as occurs in cardiac hypertrophy, conduction velocity will be increased. However, using isolated hypertrophied human myocardium, it has been found that a reduced conduction velocity accompanies cell enlargement, and it was proposed that this was due to an additional increase of Ri.6 The objective of the present study was to examine directly the hypothesis that hypertrophy is associated with increased Ri.
Several models of ventricular loading that induces left ventricular hypertrophy are available; these include models of renal artery stenosis,7 infrarenal aortic banding,8 and increased growth hormone secretion.9 Interpretation of the data may be difficult when these various models are compared. We have used a guinea pig model of thoracic aortic constriction that also demonstrates reduced action potential conduction in whole-heart preparations10 and most closely approximates the human condition associated with aortic stenosis.11 Multicellular tissue strands were used, so the resistivity estimations are macroscopic values rather than the properties of individual cells, but they represent the average intracellular pathway through which local circuits flow. The magnitude of the intracellular resistance is the sum of the sarcoplasmic resistance and that offered by intercellular junctions, and data analysis was extended to measure separately these two fractions. It is concluded that an increase of Ri does accompany the later stages of hypertrophic growth and that the increase can be attributed solely to a raised junctional resistance.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Animal Model of Left Ventricular Hypertrophy
Left ventricular hypertrophy was induced in Dunkin-Hartley guinea pigs, weighing 600 to 800 g, by placing a high-density plastic disk (internal diameter, 1.99 mm) around the ascending aorta under anesthesia (0.22 mL·kg-1 sodium pentobarbitone, followed by inhalation of a 49% N2O/49% O2/2% halothane mixture; the animals were subsequently allowed to recover. Postoperative analgesia was given after wound closure (50 µg·kg-1 subcutaneous buprenorphine). A sham operation, without clip placement, was performed as a control. Animals were divided into four groups: 50 days of constriction (n=8), 50 days after sham operation (n=9), 150 days of constriction (n=8), and 150 days after sham operation (n=6). Guinea pigs were killed by cervical dislocation, and the hearts were rapidly removed and placed in gassed Tyrode's solution at 37°C. No animals showed evidence of heart failure, liver and lung weights were normal, and the liver was free of ascites. Procedures were performed according to Guidance on the Operation of the Animals (Scientific Procedures) Act 1986, Her Majesty's Stationery Office, London, England.
Solutions
Experiments were carried out in Tyrode's solution (mmol/L):
NaCl 118, KCl 4.0, NaHCO3 24,
NaH2PO4 0.4, MgCl2 1.0,
CaCl2 1.8, glucose 6.1, and sodium pyruvate 5.0. The
solution was gassed at 37°C with 95% O2/5%
CO2, pH 7.35±0.03.
Longitudinal Impedance
The longitudinal impedance of subendocardial left
ventricular preparations (diameter, 0.88±0.02 mm;
n=31) was measured by constraining alternating current to flow along
the intracellular pathway. A three-chambered bath, separated by rubber
membranes, was used, and the preparation was pulled through tight holes
in the membranes with at least 1 mm protruding into the outer
chambers. The length of muscle in the central chamber was 3.0±0.7
mm. The central chamber contained mineral oil, and the outer chambers
contained Tyrode's solution. A thin layer of Tyrode's solution was
often trapped around the preparation, under the mineral oil, which
contributed to the overall extracellular space. The thickness was
measured with a binocular microscope (x80) and was variable
between being completely absent to 0.3 mm (mean±SD,
0.08±0.07 mm). The bath was placed on a water-heated aluminum
block at 37°C. Measurements were also made at 20°C to allow
comparison with values of Rc in myocyte
suspensions (see below) and to permit the temperature coefficient of
Rc to be calculated.
It was important to avoid a hypoxic core to the preparation because this would falsely increase Ri. Several lines of evidence indicated that this was so: (1) the preparation diameter was <1 mm; (2) the preparation never showed histological evidence of damage, as evidenced by gross cellular necrosis or enlarged extracellular space; (3) impedance measurements were stable for at least 30 minutes (below); and (4) aspiration of the adhering Tyrode's layer in the central chamber had a Po2 in excess of 65 kPa, and the Po2 in the outer chambers was 86.3±5.7 kPa (n=5).
Alternating current (frequency [f], 20 Hz to 300 kHz) was passed via
platinum black electrodes between the outer chambers. The resistance
(r) and capacitance (c) of the system were
recorded with a balanced Wien bridge (Wayne-Kerr 6425), assuming a
parallel rc configuration.12 13 Two complete
sets of recordings were made at 10-minute intervals; values
always agreed within 5%, and the average value was used. In three
separate preparations, six sets of recordings were made at
10-minute intervals; only the sixth varied by >5% from the others. At
the end of recordings, the preparation was immediately fixed
for histological estimation of muscle CSA (below).
Platinum black electrode resistance (re) and
capacitance (ce) were separately measured over
the same frequency range in a large volume of Tyrode's solution before
and after the experiment and varied by <5%. The resistivity of
Tyrode's solution was measured at 20°C and 37°C using the same
platinum black electrodes in a conductivity cell of known dimensions
(length, 1.0 cm; CSA, 0.070 cm2) and had values of 64±2
and 49±1 
·cm (n=5) at the two respective temperatures.
Polarization resistance (rp) and capacitance
(cp) of the electrode were calculated from
re and ce, assuming that
rp and cp lie in
series.14
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-1. rs and
xs were calculated from the measured
r and c values and corrected for the electrode
properties, rp and cp,
and 
is the radial frequency [=2
f]):
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and F). Values of specific resistivity
quoted in "Results" (uppercase R; units, ·cm)
were calculated from the above values using the length of the
preparation in the oil gap and the CSA of muscle in the
preparation12 : they thus represent a macroscopic
value of the specific resistivity of the intracellular compartment.
Isolated Myocytes
Left ventricular myocytes were prepared by perfusing
the coronary circulation with a
collagenase-containing solution. The heart was initially
perfused for 4 minutes at 40 mm Hg with a nominally
Ca2+-free solution (solution A, mmol/L): NaCl 120, KCl
5.4, MgSO4 5.0, sodium pyruvate 5.0, glucose 20, taurine
20, and HEPES 20, pH 6.95, followed by 2.0 minutes of perfusion with
solution A plus 200 nmol/mL CaCl2 and 0.3 mg/mL protease. A
final 5.0- to 7.0-minute perfusion was carried out in solution A plus
200 nmol/mL Ca2+, 0.33 mg/mL collagenase, and
0.6 mg/mL hyaluronidase. After perfusion, the atria and right
ventricular free wall were cut away, and the remainder was
chopped into small pieces and gently triturated and stored in solution
A plus 1.8 mmol/L CaCl2.
Measurement of Rc
Rc was estimated separately at 20°C by
measuring the impedance of myocyte suspensions over the range 20 Hz to
30 kHz in a Perspex chamber (CSA, 0.05 cm2) via platinum
black electrodes separated by 200 µm. Myocytes were suspended in
Tyrode's solution in which NaCl had been replaced by sucrose to
maximize current flow through the suspension; the resistivity of this
solution was 349±5 ·cm (n=4). Values of r and
c obtained from the Wien bridge were corrected for electrode
resistance and capacitance as described above and converted to
rs and xs values, which
were finally converted to specific values, Rs
and Xs (·cm), using the chamber CSA and
electrode separation. Resistance-reactance plots (see Fig 1B
) showed a
single dispersion attributable to the surface membrane as it was
completely removed by 10 µmol/L digitonin.15
Low-frequency (R1) and high-frequency
(R2) intercepts of the plot with the resistance
axis were estimated, and the value of R2 was
used to calculate Rc. Rc
values were calculated from Equation 316 :
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) and 150-day constricted guinea pig
(
). A, Zs (
Histology
Muscle samples were fixed in half-strength Karnovsky fixative at
4°C and processed in wax. Sections (3 µm) were cut and fixed
in hematoxylin and eosin for measurement of cell diameter and further
stained in trichrome MSB for connective tissue to estimate muscle
proportion in the cross section. CSA of the individual cells was
measured in the narrowest plane across the nucleus to avoid oblique
sections17 with an image acquisition system (Seescan). At
least 75 cells from each section were measured.
Statistics
Values are quoted as mean±SD. Statistical differences between
data sets were calculated by Student's t test. The null
hypothesis was rejected when P
.05.
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Results |
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Development of Left Ventricular Hypertrophy
Guinea pigs were divided into four experimental groups, those at 50 and 150 days after the operation, with or without aortic constriction. Aortic constriction significantly and progressively increased HBR compared with the sham operation; the data are shown in Table 1
. The increase of HBR in the constricted groups
was not due to a decrease of body weight (Table 1) and therefore
reflects an increase of heart weight. Table 1 also shows that
myocardial growth was mirrored by an increase of cell CSA. In the
constricted groups at 50 and 150 days after the operation, the HBRs and
the CSAs were both significantly increased compared with the
age-matched sham-operated control groups. In addition, the mean HBR
value after 150 days of constriction was significantly greater than
after 50 days of constriction, although this was not so for the
CSA.
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Measurement of Ri
Fig 1A
shows the impedance,
Zs, of two myocardial preparations in the
oil-gap chamber as a function of frequency between 20 Hz and 300 kHz;
one preparation was from a 50-day sham-operated animal (closed
symbols), and the other was from a 150-day constricted animal (open
symbols). In each case, impedance declines with increasing frequency,
leveling off toward a constant finite value at higher frequencies. The
plot is interpreted as one or more parallel rc circuits in
series with a resistance. For each rc circuit with a
different time constant (
=rc), there will be a specific
range of frequencies over which the impedance will decline. In Fig 1A, two phases of decline are apparent before attainment of a constant
value.
More accurate analysis was obtained by plotting, at each
frequency, the resistive (Rs) and reactive
(-Xs) components of Zs
as a function of each other. Fig 1B shows such plots using the data of
Fig 1A; points for lowest frequencies are on the right side, and each
time constant shows as a separate semicircular locus. Semicircles were
fitted to the left (higher frequencies) loci, and the intercepts with
the Rs axis are shown as
R1 and R2. The plots were
analyzed in terms of circuit elements in the longitudinal
pathway of the muscle preparations, in parallel with a resistive shunt,
Rec, which is present in the extracellular
space of the preparation and in the thin layer of Tyrode's solution
adhering to the muscle beneath the oil in the central chamber (see
below and Fig 1C).
Such plots do not specifically display frequency information, but the
values of some frequencies are shown on the plots. The time constant,
, of the parallel rc circuit generating a particular
dispersion is obtained from the relationship 2f*=1, where f* is
the frequency generating the maximum value of
-Xs in the locus. The low-frequency dispersion
exhibited a maximum reactance at 40 Hz, equivalent to a time
constant of 4 ms and similar to that of the myocardial membrane time
constant.18 Thus, the low-frequency dispersion was
interpreted as resulting from the surface membrane of the preparation
in the outer chambers, Rm and
Cm in Fig 1C.
The high-frequency dispersions (maximum reactance at 10 to 40 kHz) have
been interpreted as a junctional impedance between cells in the
longitudinal pathway.12 13 19 20 The residual resistance
at the higher frequencies was considered to result from the resistance
of the sarcoplasm. Fig 1C shows an equivalent circuit that was used to
analyze the
-Xs/Rs plots of
Fig 1B. Included in the circuit is a shunt resistance,
Rec, representing current flow
through the extracellular compartment of the preparation in the oil
gap. The low-frequency intercept of the left dispersion with the
resistance axis, R2, is a parallel combination
of Rec and the total intracellular resistivity,
Ri, where Ri is the sum
of Rc and Rj. The
high-frequency intercept, R1, is a parallel
combination of Rec and Rc
alone. The difference,
R2-R1, will therefore be
a function of Rj and Rec.
The values of the intercepts R1 and
R2 were determined in all preparations, along
with the preparation length in the oil gap, total CSA (including the
adherent layer of Tyrode's solution), and the proportion of CSA
occupied by muscle for calculation of the specific resistances in units
of ·cm. There were no significant differences in preparation
dimensions between each of the four experimental groups.
Total Ri in myocardial preparations from
sham-operated and constricted guinea pigs was measured at 20°C and
37°C; the values are shown in Table 2. In
sham-operated animals, 50- and 150-day postoperation values were not
significantly different at either 20°C or 37°C. After 50 days of
constriction, the mean value of Ri was also not
significantly different from the age-matched control group at 20°C or
37°C. However, at 150 days after the operation, values of
Ri in the constricted group were significantly
greater than in the sham-operated control group at both
temperatures.
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Estimation of Junctional and Sarcoplasmic Impedances
Separate values of sarcoplasmic, Rc, and
junctional, Rj, impedance were calculated to
determine which component was responsible for the increase of
Ri; the data are shown in Table 2, and the
37°C results are also shown in Fig 2. Fig 2, top,
shows Rc values, and Fig 2, bottom, shows the
corresponding values of Rj. At each temperature,
values of Rc were the same in control and
hypertrophied groups, both at 50 and 150 days after the operation.
Combining data from all experimental groups, Rc
was 147±76 ·cm at 20°C and 100±52 ·cm at 37°C. This
represents an average Q10 of 1.28 over this range of
temperatures. The Q10 of the specific resistivity of a 150 mmol/L
KCl solution has an average value of 1.23 over this range, calculated
from Onsager's limiting law for conductivity.21 The
similarity of Q10 values is consistent with considering the
sarcoplasm as a simple ionic solution.
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Calculated mean values of Rj mirrored changes to total Ri induced by hypertrophy. At 37°C, values of Rj at 50 days after surgery were not significantly different in the control and hypertrophied groups. However, after 150 days, compared with the control group, there was a significant increase in the hypertrophied group: at 20°C, the same pattern was observed. Therefore, the observed increase of Ri after 150 days of hypertrophy can be accounted for solely by an increase of junctional resistance.
Control Experiments
It is important to provide supportive evidence for the
interpretation of the longitudinal impedance data in terms of
sarcoplasmic and junctional impedances. This was carried out by two
experiments: (1) an independent estimate of Rc,
which was determined from suspensions of isolated myocytes, where the
junctional impedance would not be expected to contribute to the overall
impedance of the preparation, and (2) manipulation of junctional
impedance with n-heptanol, which has been demonstrated to
have a fairly specific effect on junctional
impedance.22
Myocyte Suspensions
In four preparations with a packing fraction of 0.32±0.02, the
high-frequency specific impedance, Zs, was
420±50 ·cm, which from Equations 3, and 4 (see "Materials and
Methods") yielded a value for Rc of 442±32
·cm in the sucrose-containing Tyrode's solution (see
"Materials and Methods"). An extensive study of the effect of
changes in Rec on the value of cytoplasmic
resistivity, Rc, has been carried out in
suspensions of isolated cells (rods)16 : ie,
1/Rc=0.5/Rec+constant. If
a similar relationship existed in these isolated myocytes, a value of
123±3 ·cm (n=4) was calculated for Rc at
20°C in normal Tyrode's solution (RTyr=68
·cm). This value was not significantly different from the above
value obtained for Rc at 20°C in the
longitudinal impedance measurements (147±76 ·cm).
Experiments With n-Heptanol
Values of Rc and Rj
were calculated at 20°C in further longitudinal impedance
measurements, after 30 minutes of pretreatment in gassed Tyrode's
solution containing 2 mmol/L n-heptanol. These values
were compared with those from five control experiments made on strips
immersed only in Tyrode's solution for 30 minutes. Fig 3 shows examples of two resistance-reactance plots
obtained in control Tyrode's solution (closed symbols) and 2
mmol/L heptanol Tyrode's solution (open symbols). The high-frequency
intercepts of the left loci, R1, are not greatly
different; however, the low-frequency intercept,
R2, of the heptanol-treated preparation is
larger than that for the control strip, suggesting a selective increase
of Rj. Values of Rc in
control and n-heptanol–treated strips were not
significantly different, 113±29 ·cm (n=5) and 147±24
·cm (n=6), respectively. However, Rj was
significantly greater in the n-heptanol–pretreated group
(200±47 versus 308±52 ·cm (P<.05). Therefore,
n-heptanol selectively increased the component of
Zs attributed to Rj,
providing support for the interpretation of the impedance data in terms
of the circuit elements of Fig 1C.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Left Ventricular Hypertrophy
The data show that constriction of the ascending aorta in guinea pigs produces cardiac hypertrophy, demonstrated by an increase of HBR. Such hypertrophy was reflected in an increase of cellular dimensions when expressed as the mean CSA in histological preparations. HBR also increased significantly between 50 and 150 days of constriction, whereas no such progressive increase was seen in the cellular CSA. Therefore, it is likely that part of the increased cardiac growth between 50 and 150 days of constriction results from an increase in the proportion of nonmyocardial tissue, but nevertheless, significant cellular hypertrophy can be demonstrated at both time intervals.
Control Values of the Intracellular Pathway
The specific value of Ri from control
hearts was 216±64 ·cm at 37°C and 373±103 ·cm at
20°C, similar to that obtained by DC cable analysis (eg,
Reference 1818 ; 152 ·cm, 37°C). Ri has
been modeled as a series combination of a sarcoplasmic resistance and a
junctional impedance. Rc was 100±52 and 147±76
·cm at 20°C and 37°C, respectively. An independent
measurement of Rc was made in isolated myocyte
suspensions to corroborate the above values, with the assumption that
the quantitative relationship between changes of
Rec and Rc was the same
in cardiac myocytes and the rods.16 However, the value of
123±3 ·cm at 20°C was very close to that obtained in the
longitudinal impedance experiments. The contribution that the
intercalated disks make to the Ri was also
calculated, assuming that the myocytes are simple cylinders, with
intercalated disks occupying the entire end region (116±35 ·cm
at 37°C and 233±89 ·cm at 20°C). Although this does not
reflect accurately the distribution of intercellular couplings, it
permits comparison with other experimental and theoretical studies that
use a similar model. Using the above values for
Rj and a length of guinea pig myocytes of
147±33 µm (n=50; authors' unpublished data, 1996), we obtained
a value for the specific disk resistance of 1.7 ·cm2
for the control myocardial tissue at 37°C, which compares well with
the value of 3 ·cm2 obtained by
Weidmann.23
The Intracellular Pathway in Myocardial Hypertrophy
After 150 days of aortic constriction in a guinea pig model of
myocardial hypertrophy, there is an increase of
Ri. This increase was attributed solely to an
increase of the junctional impedance between adjacent cells;
Rc was unchanged. There is no evidence for
alteration to cell length in this model of hypertrophy (K.
Ryder, personal communication, 1996), so that if the same calculation
for specific disk resistance is carried out, the value will increase to
4.0 ·cm2. The finding of an increased
Ri is at variance with that in a rat model of
renal artery stenosis, where no change was
measured.24 However, in this model there was no increase
of HBR, so that comparison with the above data is difficult.
Electrical connections between contiguous myocardial cells are mediated
by connexin proteins, which form functional pores. Alteration of
connexin electrical conductance can be mediated in two ways: (1) a
decrease of the conductance of existing connexins, mediated, for
example, by a fall of intracellular pH or pCa,25 and (2)
alteration of the number, distribution, and type of connexin subtypes.
An intracellular acidosis of 0.19 pH units accompanies left
ventricular hypertrophy in this
model26 ; however, using available quantitative
data,25 this would decrease conductance by only 4%.
This suggests that the important change in myocardial
hypertrophy is in connexin density and maybe in their
distribution and subtype. In human hypertrophied
myocardium, a reduction of connexin43 (the predominant
subtype) density has been reported,27 which would support
the above electrical data. However, it is important to note that the
distribution of connexins on the cell surface is very plastic with a
rapid turnover,28 so that a raised longitudinal impedance
could be achieved equally well by a redistribution of connexins from
the longitudinal to transverse axes. The
electrophysiological consequences of these
possibilities and means of distinguishing between them are discussed
below.
Consequences for the Electrical Properties of Myocardium
A consequence of a raised Ri will be a
reduced velocity of action potential propagation. Data using this
guinea pig model,10 as well as human hypertrophied
myocardium,6 show that when the preparation
behaves as a one-dimensional cable, conduction velocity is inversely
related to cell diameter. One-dimensional cable theory would predict
the opposite relationship between the two variables unless there
was also a concomitant rise of Ri, as
demonstrated in the present study. The magnitude of the rise of
Ri is important, because theoretical studies
have shown that an excessive increase can result in discontinuous
propagation. Using baseline variables similar to the experimental
values reported here, it has been shown that an increase of
Ri above 1000 ·cm results in deviation
from the behavior of a one-dimensional cable to one permitting
discontinuous propagation to occur.29 This conclusion is
of importance, since it has been suggested that discontinuous
propagation is an important precursor of reentrant behavior in
myocardium.30 Such high values of
Ri were not, on average, observed in the
present study; however, the fact that an increase of
Ri can be demonstrated does not preclude much
higher local changes or the possibility that it might reinforce other
factors that increase Ri, such as tissue
hypoxia.31 Thus, a combination of these two
conditions could produce the conditions for discontinuous propagation
more effectively than either condition alone. Studies are under way to
quantify the effects of hypoxia on the electrical properties
and action potential propagation in hypertrophied
myocardium.
The fact that the increase of Ri is due solely to a raised Rj has additional consequences. Myocardial resistivity is a heterogeneous property, which is greater in dimensions transverse to the longitudinal axis because of the asymmetrical connexin distribution. Factors such as heptanol, which increase Rj and preferentially attenuate transverse conduction,22 may increase the propensity for reentrant circuits to develop.32 If connexin conductance were to decrease equally in all dimensions during hypertrophy, such a condition may well arise; however, if redistribution were to occur, as discussed above, then the difference between longitudinal and transverse impedances would diminish. Thus, it is vital to differentiate between such possibilities, and this can be achieved by measuring the ratio of transverse to longitudinal conduction velocities and by use of a three-dimensional map of Ri in hypertrophied myocardium.12 Such measurements are also presently under way.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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We thank the British Heart Foundation for financial assistance and M. Turner for technical help.
Received October 7, 1996; accepted February 21, 1997.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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1. Kannel WB, Doyle JT, McNamara PM, Quickenton P, Gordon T. Precursors of sudden coronary death: factors related to the incidence of sudden death. Circulation. 1975;51:606-613.
2. Levy D, Anderson KM, Savage DD, Balkus SA, Kannel WB, Castelli WP. Risk of ventricular arrhythmias in left ventricular hypertrophy: the Framingham heart study. Am J Cardiology. 1987;60:560-565.[Medline] [Order article via Infotrieve]
3.
Pye MP, Cobbe SM. Mechanisms of cardiac
arrhythmias in cardiac failure and
hypertrophy. Cardiovasc Res. 1992;26:740-750.
4. Aguilar JC, Martinez AH, Conejos FA. Mechanisms of ventricular arrhythmias in the presence of pathological hypertrophy. Eur Heart J. 1993;14(suppl J):65-70.
5. Aronson RS, Ming Z. Cellular mechanisms of arrhythmias in hypertrophied and failing myocardium. Circulation. 1993;87(suppl VII):VII-76-VII-83.
6. McIntyre H, Fry CH. Electrophysiological properties of isolated, hypertrophied human myocardium. J Physiol (Lond). 1994;477:19P. Abstract.
7.
Brilla CG, Pick R, Tan LB, Janicki JS, Weber
KT. Remodeling of the rat right and left ventricles in
experimental hypertension. Circ Res. 1990;67:1355-1364.
8. Ryder KO, Bryant SM, Hart G. Membrane current changes in left ventricular myocytes isolated from guinea-pigs after abdominal aortic constriction. Cardiovasc Res. 1991;27:1278-1287.
9.
Xu XP, Best PM. Decreased transient outward
K+ current in ventricular myocytes from
acromegalic rats. Am J Physiol. 1991;260:H935-H942.
10.
Winterton SJ, Turner MA, O'Gorman DJ, Flores NA,
Sheridan DJ. Hypertrophy causes delayed conduction
in human and guinea-pig myocardium: accentuation during
ischaemic perfusion. Cardiovasc Res. 1994;28:47-54.
11. Weber KT, Clark WA, Janicki JS, Shroff SG. Physiologic versus pathologic hypertrophy and the pressure-overloaded myocardium. J Cardiovasc Pharmacol. 1987;10:537-549.
12.
Chapman RA, Fry CH. An analysis of the
cable properties of frog ventricular
myocardium. J Physiol (Lond). 1978;283:263-282.
13.
Freygang WH, Trautwein W. The structural
implications of the linear electrical properties of cardiac Purkinje
strands. J Gen Physiol. 1970;55:524-547.
14. Schwan HP. Determination of biological impedances. In: Nastuk WL, ed. Techniques in Biological Research, VI. New York, NY/London, UK: Academic Press Inc; 1963:pt B.
15. Fry CH, Powell T, Twist VW, Ward JPT. Net calcium exchange in adult rat ventricular myocytes: an assessment of mitochondrial calcium accumulating capacity. Proc R Soc Lond B Biol Sci. 1984;223:223-238.[Medline] [Order article via Infotrieve]
16.
Falk G, Fatt P. Passive electrical properties of
rod outer segments. J Physiol (Lond). 1968;198:627-646.
17.
Baandrup U, Olsen EGJ. Critical analysis
of endomyocardial biopsies from patients suspected
of having cardiomyopathy, 1: morphological and
morphometric aspects. Br Heart J. 1981;45:475-486.
18.
Weidmann S. Electrical constants of
trabecular muscle from mammalian heart.
J Physiol (Lond). 1970;210:1041-1054.
19.
Ohba M, Sakamoto Y, Tokuno H, Tomita T.
Impedance components in longitudinal direction in the guinea-pig taenia
coli. J Physiol (Lond). 1976;256:527-540.
20.
Bortoff A, Sillin LF. Changes in intercellular
electrical coupling of smooth muscle accompanying atrophy and
hypertrophy. Am J Physiol. 1986;250:C292-C298.
21. Robinson RA, Stokes RH. Electrolyte Solutions. London, England: Butterworths; 1955.
22.
Delmar M, Michaels DC, Johnson T, Jalife J.
Effects of increasing intracellular resistance on transverse and
longitudinal propagation in sheep epicardial muscle. Circ
Res. 1987;60:780-785.
23.
Weidmann S. The diffusion of radiopotassium
across intercalated disks of mammalian cardiac muscle.
J Physiol (Lond). 1966;187:323-342.
24. Keung ECH, Keung C-S, Aronson RS. Passive electrical properties of normal and hypertrophied rat myocardium. Am J Physiol. 1982;243:H917-H926.
25. Firek L, Weingart R. Modification of gap junction conductance by divalent cations and protons in neonatal rat heart cells. J Mol Cell Cardiol. 1995;22:1633-1643.
26. Wallis WRJ, Wu C, Sheridan DJ, Fry CH. Intracellular pH and H+ buffering capacity in guinea-pig left ventricular hypertrophy induced by constriction of the thoracic aorta. Exp Physiol. 1997;82:227-230.[Abstract]
27.
Peters NS, Green CR, Poole-Wilson PA, Severs NJ.
Reduced content of connexin43 gap junctions in ventricular
myocardium from hypertrophied and ischemic human
hearts. Circulation. 1993;88:864-875.
28.
Darrow BJ, Laing JG, Lampe PD, Saffitz JE, Beyer
EC. Expression of multiple connexins in cultured neonatal rat
ventricular myocytes. Circ Res. 1995;76:381-387.
29.
Rudy Y, Quan W-L. A model study of the effects
of the discrete cellular structure on electrical propagation in cardiac
tissue. Circ Res. 1987;61:815-823.
30.
Spach MS, Dolber PC, Heidlage JF. Influence of
the passive anisotropic properties of directional differences in
propagation following modification of the sodium conductance in human
atrial muscle: a model of reentry based on anisotropic
discontinuities. Circ Res. 1988;62:811-832.
31.
Wojtczak J. Contractures and increase in
internal longitudinal resistance of cow ventricular muscle
induced by hypoxia. Circ Res. 1979;44:88-95.
32. Spach MS, Josephson ME. Initiating reentry: the role of non-uniform anisotropy in small circuits. J Cardiovasc Electrophysiol. 1994;5:182-209.[Medline] [Order article via Infotrieve]
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