Download Left atrial systolic and diastolic function accompanying chronic rapid

Left atrial systolic and diastolic function accompanying
chronic rapid pacing-induced atrial failure
BRIAN D. HOIT, YANFU SHAO, AND MARJORIE GABEL
Division of Cardiology, Department of Internal Medicine,
University of Cincinnati Medical Center, Cincinnati, Ohio 45267
dog; atrial function; left atrium; cardiac mechanics; heart
failure
EXPERIMENTAL MODELS of both sustained (e.g., 6 wk) and
short-term paroxysmal (e.g., 5 and 30 min) atrial
fibrillation induced by rapid pacing ($400 beats/min)
have been shown to result in impaired atrial contractility (16, 17, 19). Although we recently demonstrated
that after 1 wk of rapid atrial pacing, noninvasively
determined indexes of atrial booster pump function
were markedly impaired (9), the more chronic effects of
atrial tachyarrhythmia on invasively and noninvasively determined measures of atrial systolic and diastolic function are unknown. This gap in our knowledge
is particularly relevant insofar as chronic rapid atrial
pacing is a potentially important model for the study of
both the electrophysiological and mechanical consequences of atrial arrhythmias. For example, the model
has been used to demonstrate atrial remodeling and
sinus node dysfunction owing to chronic atrial fibrillation (4, 9, 19). Moreover, largely for methodological
reasons, the contributions of atrial function toward
cardiovascular performance and ventricular filling re-
main controversial (2, 7, 23). Thus the objective of the
current study was to examine the hypothesis that
long-term (6 wk), rapid (400 beats/min) atrial pacing
myopathy produces a model of isolated atrial myopathy
characterized by impaired atrial systolic and diastolic
function and unaltered ventricular function.
METHODS
Fourteen conditioned mongrel dogs were used in these
experiments. Eight dogs weighing 21–25 kg (23.7 6 1.7 kg)
were studied 6 wk after rapid (400 beats/min) atrial pacing.
Six dogs weighing 19–25 kg (22.8 6 2.4 kg) were instrumented with a right atrial pacemaker (see below) but were
unpaced; these sham-operated dogs served as controls.
Animals were anesthetized with pentobarbital sodium (30
mg/kg iv). A unipolar pacemaker (Medtronic; Bloomington,
MN) lead was sutured to the right atrial appendage through a
right lateral thoracotomy and small pericardiotomy. In eight
dogs, a pulse generator programmed at 400 beats/min was
implanted in the subcutaneous tissue over the back of the
neck. Six weeks after we instituted rapid pacing, the pacemaker was reprogrammed to 30 beats/min, and the animals
underwent hemodynamic study. The remaining six dogs had
the pacing lead and pulse generator (set at 30 beats/min)
implanted and served as controls. Sham dogs were studied
after a minimum of 2 wk after surgery. Long-acting diltiazem
(Cardizem 300 mg) was given daily to slow the ventricular
response (3:1 to 5:1) in all animals.
Hemodynamic studies were performed as described previously (14). Briefly, animals were anesthetized with pentobarbital sodium (30 mg/kg) and morphine sulfate (3 mg/kg sc)
and then intubated and ventilated with a positive-pressure
respirator (Harvard Apparatus, South Natick, MA). The
heart was exposed with a left lateral thoracotomy at the
fourth intercostal space and was suspended in a pericardial
cradle. A 7-Fr micromanometer with lumen (Millar Instruments, Houston, TX) was advanced into the left atrium via a
pulmonary vein; a second 7-Fr micromanometer with lumen
(Millar Instruments) was advanced into the left ventricle
through an apical stab wound. A femoral vein was cannulated
to administer intravenous fluids. An 8-Fr catheter with a
10-ml capacity balloon was advanced from the femoral vein
into the inferior vena cava just below the right atrium, and a
second balloon catheter was advanced from the jugular vein
into the superior vena cava.
Pairs of 3-MHz sonomicrometers (6-mm diameter, Triton
Technology, San Diego, CA) were sewn to the epicardial
anterior and posterior walls (long axis) and to the medial and
lateral walls (short axis) of the left atrium as previously
described (11, 14, 15). A pair of 3-MHz (7-mm diameter)
sonomicrometers were sewn to the anterior and posterior left
ventricular epicardium to measure the minor axis dimension.
The transit time of ultrasound between each crystal pair was
measured with a multichannel sonomicrometer (Triton Technology).
The pressure waveforms from the micromanometers were
matched with those of the fluid-filled catheters. Analog
0363-6135/98 $5.00 Copyright r 1998 the American Physiological Society
H183
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Hoit, Brian D., Yanfu Shao, and Marjorie Gabel. Left
atrial systolic and diastolic function accompanying chronic
rapid pacing-induced atrial failure. Am. J. Physiol. 275
(Heart Circ. Physiol. 44): H183–H189, 1998.—The objective
of this study was to examine the hypothesis that long-term,
rapid atrial pacing produces a model of atrial systolic and
diastolic dysfunction but does not alter ventricular function.
Eight dogs were atrially paced at 400 beats/min (3:1–5:1
ventricular response) for 6 wk and subsequently instrumented with left atrial (LA) and left ventricular (LV) sonomicrometers and micromanometers. Data were compared with
those from six sham-operated controls at matched heart rates
and mean LA pressures of 10 mmHg. Dogs with rapid pacing
had slightly greater LA volume (10.3 6 4.0 vs. 7.9 6 4.4 ml)
and reduced ejection fraction (2.2 6 1.4 vs. 13.0 6 4.0, P ,
0.05), systolic ejection rate (0.3 6 0.1 vs. 2.8 6 1.2 vol/s, P ,
0.05), and reservoir fraction (0.07 6 0.04 vs. 0.35 6 0.06, P ,
0.05) compared with controls. LA diastolic chamber stiffness
was greater after rapid atrial pacing than before (stiffness
constant kc, 5.7 6 2.3 vs. 3.4 6 0.6, P , 0.05), and the ratio of
transesophageal echo-determined pulmonary venous systolic
to diastolic integrated flow (a measure of relative reservoir to
conduit function of the LA) was less in rapidly paced dogs
compared with control dogs (0.41 6 0.19 vs. 0.68 6 0.23, P ,
0.05). In contrast, rapid atrial pacing did not influence LV
systolic performance or lusitropy, because the LV pressure
time derivative and the time constant of LV relaxation were
similar in both groups. In this model of isolated atrial
myopathy, increased atrial stiffness and enhanced conduit
function compensate for impaired atrial booster pump and
reservoir functions.
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PACING-INDUCED ATRIAL FAILURE
Experimental Protocols
Hemodynamic studies. The heart rate was slowed with
10–20 mg DKAH 0264 (Boehringer Ingelheim), an agent that
inhibits the sinoatrial (SA) node If current without effects on
myocardial contractility (8). Constant heart rate was achieved
by right atrial pacing with the pacing rate selected to
eliminate competing rhythms and to permit separation of
active from passive atrial emptying. Atrioventricular (AV)
conduction, measured from the onset of the atrial pacing
spike to the R wave, was similar in atrial failure animals
compared with sham animals (179 6 17 vs. 174 6 15 ms).
Hemodynamic and dimension data were recorded under
steady-state baseline conditions and during abrupt increases
in LA pressure and volume generated by either bolus infusion
of phenylephrine (200–400 µg iv) or vena caval occlusion.
Cholinergic blockade was accomplished using atropine (0.02–
0.04 µg/kg iv).
In five rapidly paced dogs, data were obtained before and at
the peak effect of a rapid intravenous infusion of 1–2 g CaCl2.
Baseline measurements were taken after the animal had
recovered from preceding protocols, and peak effects were
taken at a steady hemodynamic state.
Steady-state hemodynamic, dimensional, and Doppler echocardiographic data were acquired at a mean LA pressure of
,10 mmHg for purposes of comparisons at a common atrial
pressure. Data were obtained both at matched LA pressure
and paced heart rates. All data were acquired with the
respirator turned off at end expiration.
In an additional four dogs, AV nodal block was produced by
transvenous radiofrequency ablation (Radionics, Burlington,
MA), and right atrial and ventricular pacemakers were
subsequently placed via a small pericardiotomy (see above)
and the transvenous route, respectively. In two dogs, the
atrial pacemaker was programmed to 400 beats/min and the
ventricular pacemaker was programmed to 100 beats/min;
the remaining animals served as sham controls and were
unpaced. At the end of 6 wk, the animals were studied with an
AV sequential pacemaker set at 72 beats/min with an AV
interval of 200 ms (Medtronic, Minneapolis, MN) in the
manner described for the larger study.
Postmortem Studies
At the end of the experiment, animals were euthanized
with a pentobarbital sodium overdose (65 mg/kg iv). The
hearts were immediately removed, divided into right and left
atria and right and left ventricles, and weighed on a balance
(Galaxy 400, Ohaus, Florham Park, NJ).
Data Analysis
LA variables. The LA dimension signals were analyzed as
previously described (11, 14, 15). Maximum LA dimension
(LAmax ) was taken as the largest atrial dimension corresponding to the V wave on the LA pressure tracing, LA end-diastolic
dimension (LAed ) was taken as the largest diameter immediately preceding the A wave of the LA pressure tracing, and LA
end systole (LAes ) was taken as the smallest dimension at the
end of LA contraction. Relative LA volume was estimated as a
general ellipsoid of revolution (14): LA volume 5 (p/
6)(SAX)2 · (LAX), where SAX is the short or mediolateral axis,
and LAX is the long or anteroposterior axis of the left atrium.
LA stroke volume was calculated as LA end-diastolic
volume minus end-systolic volume. LA ejection fraction was
calculated as 100 3 (LA stroke volume/LA end-diastolic
volume). The heart rate-corrected mean normalized systolic
ejection rate was calculated as the LA ejection fraction
divided by the heart rate-corrected LA ejection time; the
latter was defined as the time from LAed to LAes, divided by
the square root of the R-R interval (3).
LA pressure-volume loops were generated off-line by plotting instantaneous LA pressure and volume data from phenylephrine runs every 2 ms. The LA ‘‘A’’ loop represents active
LA contraction, and the ‘‘V’’ loop represents passive LA filling.
LA A and V pressure-volume loop areas were determined by
planimetry (Sigma plot, Jandel Scientific, San Rafael, CA) at
a common LA pressure of ,10 mmHg. The net work by the
atrium was computed by subtracting the V loop area from the
A loop area (14).
Table 1. Hemodynamic and LV function variables at a matched LAP of 10 mmHg
in myopathic and sham-operated dogs
AMYO
Sham
n
HR,
beats/min
LAP,
mmHg
LVSP,
mmHg
LV dP/dt,
mmHg/s
LVSF,
%
t,
ms
LV Stiffness
Constant, mmHg/ml
8
6
98 6 7
96 6 7
10.5 6 0.8
10.2 6 2.1
100 6 9
112 6 10
1,353 6 207
1,547 6 203
7.4 6 2.4
7.7 6 2.3
43.2 6 3.2
41.4 6 5.9
0.10 6 0.04
0.08 6 0.02
Data are means 6 SD; n 5 no. of dogs. AMYO, atrial myopathy; HR, heart rate; LAP, LA pressure; LVSP, left ventricular (LV) systolic
pressure; LV dP/dt, peak rate of rise of isovolumetric LVSP; LVSF, LV shortening fraction; t, time constant of isovolumic relaxation. * P , 0.05
vs. sham.
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signals for left ventricular (LV) and left atrial (LA) pressures
and atrial dimensions were digitized through an analog-todigital board (Data Translation, Marlboro, MA) interfaced to
an IBM AT computer with a 2-ms sampling frequency and
were stored on floppy disk.
Fluid-filled catheters were connected to Statham 23 dB
pressure transducers with zero pressure set at the level of the
mid right atrium. The electrocardiogram and analog signals
for pressures and dimensions were recorded on-line at slow
and rapid paper speeds (5, 25, and 100 mm/s) on a multichannel physiological recorder (Gould, Cleveland, OH).
A Hewlett-Packard biplane transesophageal imaging transducer was lubricated and advanced into the esophagus behind the atrium. The left upper pulmonary vein and mitral
valve were visualized in transverse and orthogonal longitudinal views. Color flow-directed Doppler identification of intracavitary flow was used in all instances. Transmitral flow was
obtained from apical four-chamber and orthogonal twochamber views with the sample volume placed within the left
ventricle between the opened mitral leaflet tips. Pulmonary
venous flow velocity was sampled from a left superior pulmonary vein, 1–2 cm proximal to the left atrium. Attempts were
made to maintain the angle between the ultrasound beam
and various flows within 30°.
Experiments were conducted in accordance with institutional guidelines and the Guide for the Care and Use of
Laboratory Animals put forth by the United States Department of Health and Human Services. The experimental
protocol was approved by the Institutional Animal Care and
Use Committee at the University of Cincinnati.
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PACING-INDUCED ATRIAL FAILURE
Table 2. LA function variables at a matched LAP of 10 mmHg in myopathic and sham-operated dogs
AMYO
Sham
n
LAmax ,
ml
LASV,
ml
LAEF,
%
MNSER,
vol/s
Res10
k,
mmHg/ml
kc ,
mmHg/ml
8
6
9.7 6 5.2
7.9 6 4.4
20.21 6 0.3*
0.86 6 0.50
23.0 6 4.9*
13.0 6 4.0
20.49 6 0.66*
2.8 6 1.2
0.05 6 0.05*
0.35 6 0.06
0.97 6 0.05*
0.50 6 0.14
5.7 6 2.3*
3.4 6 0.6
Data are means 6 SD; n 5 no. of dogs. AMYO, atrial myopathy; Sham, sham-operated dogs; LAmax , maximal left atrial volume; LASV, LA
stroke volume; LAEF, LA ejection fraction; MNSER, mean normalized systolic ejection rate; Res10, reservoir volume fraction at a LA pressure
of 10 mmHg; k, atrial stiffness constants calculated with a pressure offset; kc , normalized stiffness constant. * P , 0.05 vs. sham.
respectively. LV fractional shortening (LVFS) was defined as
[(LVEDD 2 LVESD)/LVEDD]. LV volume was estimated from
the LV epicardial sonomicrometer diameter (D) as volume 5
(D3 )(p/6). LV diastolic chamber compliance was estimated by
fitting end-diastolic LV pressure and volume data to the
exponential curve equation, P 5 AekV.
Echo Doppler variables. Diastolic transmitral waveforms
were analyzed for the peak and integral early (E) and late (A)
velocities and their ratios (E/A); owing to the relatively slow
heart rates, the early and late waveforms did not overlap.
Fractional early (EFx ) and fractional late velocity (AFx ) were
derived as E/(E 1 A) and A/(E 1 A), respectively.
Pulmonary venous waveforms were analyzed for the peak
and integrated systolic (J) and diastolic (K) velocities, and
their respective ratios (J/K) were derived. When necessary,
integrals were calculated by dropping a vertical line to the
baseline from the intersection of the systolic and diastolic
waveforms. The fractional pulmonary venous velocity time
integral during ventricular systole (Jvti/[Jvti 1 Kvti]) was
taken as the reservoir fraction, and the fractional pulmonary
venous velocity time integral during diastole (Kvti/[Jvti 1 Kvti])
was taken as the conduit fraction (12, 21).
Statistical Analysis
Hemodynamic, dimension, and echocardiographic data in
atrial myopathic and sham-operated dogs were compared
with unpaired t-tests. Calcium chloride data were compared
with paired t-tests. All data are means 6 SD. A P value ,0.05
was taken to indicate statistical significance.
Fig. 1. High-fidelity left ventricular
(LV) and left atrial (LA) pressure and
dimension signals, rate of LV pressure
change (LV dP/dt), and electrocardiogram (ECG) in sham-operated control
dogs (A) and in dogs after production of
rapid pacing atrial failure (AMYO) (B).
Note absence of atrial pressure generation and atrial dimension shortening
during atrial systole in AMYO.
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The atrial diastolic dynamic chamber stiffness constant (k)
(modulus of chamber stiffness) was determined by fitting LA
pressure-volume data at LAmax to the exponential curve
equation, P 5 AekV (Delta Graph, Deltapoint, Monterey, CA),
where P is LA pressure, the constant A is the y intercept, e is
the base of the natural logarithm, and V is LA volume. A
range of atrial pressure and volume was derived from either
phenylephrine boluses or vena caval occlusion. To normalize
for the effects of LA volume and pressure on atrial compliance, stiffness constants (kc ) were calculated as the slope of
the linear relationship between V(dP/dV) versus P, where
dP/dV 5 kP (18). Atrial stiffness constants were also calculated using an offset term Po; thus P 5 Po 1 Ae kV (Origin,
Microcal Software).
In addition to booster pump function, the left atrium serves
as a reservoir for LV filling during ventricular systole.
Therefore, the increase in LA volume from minimum (at the
time of mitral valve closure) to maximum (at the time of
mitral valve opening) represents the reservoir volume of the
atrium (6). The LA reservoir function was assessed by the
reservoir volume fraction at a LA pressure of 10 mmHg,
which was computed as the maximum minus minimum LA
volume divided by the minimum LA volume.
LV variables. The time constant of LV relaxation was
derived from the high-fidelity LV pressure tracing using the
method of Weiss et al. (26). Data from five end-expiratory
beats were digitized by hand (Sigma Plot) and averaged. LV
dP/dt was obtained by electronic differentiation of the highfidelity LV pressure signal. LV end-diastolic (LVEDD) and
end-systolic (LVESD) dimensions were taken as the maximum and minimum LV external sonomicrometer dimensions,
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PACING-INDUCED ATRIAL FAILURE
RESULTS
Hemodynamic, LV, and LA Functional Variables
Hemodynamic and LA functional data are presented
in Tables 1 and 2 and representative examples of each
are shown in Fig. 1. When compared with shamoperated controls at matched heart rates, rapidly paced
(i.e., 400 beats/min for 6 wk) dogs had a slightly greater
LAmax dimension and diastolic stiffness constant and
significantly reduced reservoir volume; importantly,
atrial systolic shortening was absent. In contrast, LV
systolic pressure, peak positive dP/dt, the LV diastolic
kc, and the time constant of LV isovolumic relaxation
were similar. Thus, despite maintenance of LV systolic
and diastolic function, LA systolic function was markedly impaired after 6 wk of rapid pacing.
LA pressure volume loops in rapidly paced dogs were
characterized by a single clockwise V loop, with an area
of 4.0 6 3.7 mmHg/ml (Fig. 2B). In contrast, a typical
figure-eight shape, with a counterclockwise A loop and
a clockwise V loop, was seen in sham control dogs (Fig.
2B); the A and V loop areas in these animals were 3.2 6
2.8 and 3.9 6 2.5 mmHg/ml, respectively. V loop areas
were similar in rapidly paced dogs and sham control
dogs.
Table 3. LA atrial hemodynamics in dogs
with atrioventricular nodal blockade
and atrioventricular sequential pacing
HR,
LV dP/dt, LAmax , LASV, LAEF, MNSER, Res10,
beats/min mmHg/s
ml
ml
%
vol/s
ml
AMYO
Dog 1
Dog 2
Sham
Dog 3
Dog 4
72
72
1,325
1,500
15.7
8.2
0.1
0.0
1.0
0.0
0.31
0.00
0.05
0.11
72
72
1,875
1,250
9.5
15.2
1.5
1.4
17.8
9.9
6.87
4.09
0.35
0.24
The results for the four animals with AV nodal
ablation and right atrial and ventricular pacemakers
(Table 3) confirm those reported for dogs receiving
calcium channel blockers.
Echocardiographic Data
Diastolic transmitral velocities after 6 wk of rapid
atrial pacing and in control dogs are summarized in
Table 4. Transmitral and LA appendage Doppler flow
at a matched LAP about 10 mmHg in myopathic
and sham-operated dogs
AMYO (n 5 8)
Sham (n 5 6)
MF
Peak E, cm/s
Peak A, cm/s
Peak E/A
Evti
Avti
E/Avti
EFx
AFx
E 1 Avti
60.8 6 24.9
15.3 6 8.0
3.4 6 1.8
4.1 6 1.2
0.6 6 0.4
8.1 6 3.0
0.88 6 0.04
0.12 6 0.04
4.3 6 0.8
HR, beats/min
LAP, mmHg
Peak J, cm/s
Peak K, cm/s
Peak J/K
Jvti
Kvti
J/Kvti
Res Fx
Cond Fx
94 6 9
12.0 6 1.8
24.0 6 6.1
49.9 6 14.6
0.50 6 0.13
3.3 6 1.1
9.1 6 3.5
0.41 6 0.19
0.27 6 0.09
0.73 6 0.09
78.5 6 6.9
50.2 6 14.8*
1.6 6 0.4*
5.3 6 2.0
3.1 6 1.7*
1.8 6 0.3*
0.64 6 0.03*
0.36 6 0.03*
8.4 6 3.9*
PVF
97 6 16
11.0 6 1.4
41.3 6 4.0*
57.3 6 14.3
0.75 6 0.22*
6.1 6 1.3*
9.4 6 2.3
0.68 6 0.23*
0.40 6 0.08*
0.60 6 0.07*
Values are means 6 SD; n, no. of dogs. MF, transmitral flow; PVF,
pulmonary venous flow; E, early diastolic velocity; A, late diastolic
velocity; vti, velocity time integral; Fx, fractional filling; J, systolic
velocity; K, diastolic velocity; Res, reservoir function; Cond, conduit
function. Other abbreviation as in Table 1. * P , 0.05 vs. sham.
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Fig. 2. LA pressure volume loops in
sham-operated control dogs (A) and in
dogs after production of rapid pacing
atrial failure (B), hand-smoothed for
illustration. Note single loop (corresponding to V loop) in atrial myopathy
and characteristic figure-eight appearance with nearly equal A and V loops in
a sham control dog. Arrows indicate
temporal sequence in which atrial pressure and volume change. MVO, time of
mitral valve opening; MVC, time of
mitral valve closure.
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PACING-INDUCED ATRIAL FAILURE
Table 5. Calcium effects on hemodynamic and LV and LA functional variables in atrial myopathic dogs
HR,
beats/min
LAP,
mmHg
LVSP,
mmHg
LV dP/dt,
mmHg/s
LVSF,
%
t,
ms
LAmax ,
ml
LASV,
ml
LAEF,
%
MNSER,
vol/s
97 6 16
94 6 21
10.6 6 4.9
14.6 6 5.1
100 6 7*
127 6 22
1,320 6 256*
1,860 6 233
6.0 6 2.0*
7.7 6 2.7
42.8 6 3.5
41.1 6 4.7
8.1 6 1.7
8.8 6 2.0
0.09 6 0.07*
0.39 6 0.15
1.2 6 0.9*
4.7 6 1.8
0.30 6 0.37*
0.85 6 0.19
Base
Ca21
Values are means 6 SD; n, 5 dogs. * P , 0.05 vs. Ca21.
Calcium Chloride Protocol
The effects of calcium chloride infusion in dogs with
rapid pacing-induced atrial myopathy and in normal
historical control dogs are shown in Tables 5 and 6. At
similar heart rates and mean LA pressures, calcium
produced a significant increase in LV systolic pressure,
dP/dtmax, and fractional shortening but did not change
the time constant of LV isovolumic relaxation. In
contrast to its effects on ventricular systolic function,
calcium infusion produced only a small, albeit significant, increase in atrial systolic shortening.
LA and Ventricular Mass
LA mass was 18.4 6 5.1 g in the rapidly paced dogs
and 16.7 6 4.3 g in sham control dogs (P 5 not
significant). In addition, the LA mass, either corrected
for body weight (0.78 6 0.20 vs. 0.71 6 0.11 g/kg) or LV
mass (0.16 6 0.04 vs. 0.14 6 0.02), was similar in
rapidly paced dogs vs. sham control dogs.
DISCUSSION
The principal finding of this study is that 6 wk of
rapid (400 beats/min) atrial pacing and a normal
ventricular rate response produce an isolated atrial
cardiomyopathy characterized by impaired booster
pump and reservoir functions and increased chamber
stiffness and relative conduit function. The model mimics the effects of rapid atrial tachycardias, such as atrial
flutter and fibrillation independently of ventricular
function; this is important insofar as in our previous
study (14), ventricular dysfunction produced compensatory increases in LA function. Further studies are
needed to determine whether the atrial myopathy
observed in this study may be modulated by the
adaptive (and directionally opposite) LA functional
changes that occur in response to coexisting LV dysfunction.
The loss of atrial booster pump function at the paced
heart rates as assessed by sonomicrometry precluded
measurement of atrial ‘‘A’’ wave pressure-volume loop
areas and atrial systolic elastance; indeed, atrial ejection phase indexes indicated that the LA body failed to
shorten during atrial systole. Thus net atrial work (A-V
loop area) was negative in atrial myopathic dogs; these
data indicate that net work was performed on the left
atrium and suggest that atrial efficiency is considerably reduced in this model (24). The altered Doppler
filling indexes confirm the severe impairment of atrial
contractile function in these animals. However, further
work is needed to determine the effect of atrial inefficiency on LV systolic performance.
The present study also indicates that decreased
diastolic LA compliance (increased stiffness constant),
impaired atrial reservoir function (decreased reservoir
fraction), and relative increases in the conduit-toreservoir capacity as assessed from the pulmonary vein
Doppler occur in the absence of LA hypertrophy. To
compare chamber stiffnesses of left atria with different
unstressed volumes, we performed a volume normalization and compared stiffness over a common level of LA
pressure. Thus the observed differences did not result
from differences in operative compliance. The contribu-
Table 6. Calcium effects on hemodynamic and LV and LA functional variables in historical control dog
Base
Ca21
LVSP,
mmHg
LV dP/dt,
mmHg/s
HR,
beats/min
LASV,
ml
LAEF,
%
MNSER,
vol/s
115 6 14
134 6 21*
1,214 6 122
1,800 6 363*
106 6 9
103 6 5
0.8 6 0.2
1.3 6 0.3*
11.3 6 2.7
19.0 6 4.1*
2.1 6 0.6
2.8 6 0.8
Values are means 6 SD; n, 7 dogs. See Refs. 11 and 14 for additional information. * P , 0.05 vs. baseline.
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Table 4. Late transmitral (A) peak and integral velocities were both significantly smaller in rapidly paced
dogs than control dogs; however, the early transmitral
(E) peak and integral velocities were similar. Accordingly, the early-to-late ratio of transmitral flow was
significantly increased. When expressed as fractional
filling, there was a significantly greater contribution of
early velocity (EFx ) and a smaller contribution of late,
systolic (AFx ) transmitral flow velocity in rapidly paced
dogs than control dogs. In addition, the sum of Evti and
Avti of mitral flow (a surrogate of stroke volume) was
significantly less in the rapidly paced than shamoperated animals.
The peak and integrated systolic flow velocities were
significantly less and the peak and integrated diastolic
flow velocities were similar in rapidly paced and control
dogs. Thus the ratios of peak and integrated systolic to
diastolic pulmonary vein flow velocities (estimates of
relative reservoir to conduit function) were significantly less in atrial myopathic than control dogs; in
addition, the reservoir fraction was less and the conduit
fraction was greater.
H188
PACING-INDUCED ATRIAL FAILURE
Limitations
There are several potential limitations of this study.
First, we used calcium channel blockers to slow the
ventricular response. Although these agents depress
myocardial contractility, a recent study suggests that
impaired atrial contractility after short-term atrial
fibrillation is attenuated by calcium channel blockade.
Therefore, it is important that both sham-operated
control dogs and experimental animals were given
diltiazem; verapamil was avoided in these animals
because of the frequency-dependent myocardial depression associated with its use (1). Moreover, the findings
in the dogs studied with AV nodal blockade and atrial
and ventricular pacemakers support the conclusions of
the larger study. Second, improper alignment of LV
epicardial and LA diameter gauges produce inaccurate
estimates of absolute LV and LA volume, respectively.
However, the analytic methods we employed are not
dependent on absolute volume determinations. Third,
because of the complex instrumentation required, terminal hemodynamic studies were performed in anesthetized, open chest animals. Despite the cardiodepression
and blunted reflexes associated with anesthesia (25),
time-dependent hemodynamic changes are qualitatively similar in conscious and anesthetized animals. A
related potential problem relates to the loss of pericardial influences on reservoir and conduit functions in the
terminal studies. Although we recently demonstrated
that the pericardium reduces atrial compliance and
that pericardial restraint increases directly with atrial
volume (13), the present study was performed with a
widely opened pericardium; thus, pericardial effects
cannot account for our findings. Nevertheless, it is
important that data are extrapolated cautiously from
these animal models in human disease. Finally, the use
of a simple monoexponential to describe diastolic pressure and volume behavior is potentially limited because it has little physiological basis (5). However, we
were primarily interested in demonstrating that for a
similar range of LV diastolic pressures and volumes,
there was no difference in a frequently used parameter
of chamber stiffness.
In conlusion, despite these limitations, we have
shown that rapid pacing produces an atrial myopathy
characterized by impaired atrial systolic function, diastolic stiffness, and altered atrial reservoir to conduit
functions in the context of normal ventricular function.
Simultaneous rapid atrial and ventricular pacing should
be feasible with experimentally produced AV block and
will allow the investigation of a range of atrial and
ventricular functions that accompany human atrial
arrhythmias.
We gratefully acknowledge the expert secretarial assistance of
Norma Burns and the assistance of Jim Reese and Chris Kirk from
Medtronics. DKAH 0264 was kindly donated by Boehringer Ingelheim Pharmaceuticals.
This work was supported in part by American Heart Association
Grant-in-Aid 9650695N.
Address for reprint requests: B. D. Hoit, Division of Cardiology,
Univ. of Cincinnati Medical Center, PO Box 670542, Cincinnati, OH
45267-0542.
Received 3 October 1997; accepted in final form 19 March 1998.
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