From the Division of Cardiology, Department of Medicine, Johns Hopkins
Medical Institutions, Baltimore, Md, and Medtronic, Inc, Minneapolis, Minn.
Correspondence to Peter H. Pak, MD, Johns Hopkins Hospital, Halsted 500, 600 N Wolfe St, Baltimore, MD 21287-6568. E-mail peterpak{at}welchlink.welch.jhu.edu
Methods and Results—Eleven patients with NYHA class III
symptoms, 5 with HCM, and 6 with hypertensive hypertrophy
and cavity obliteration, were studied by invasive conductance catheter
methods. No patient had coronary artery or primary
valvular disease. Pressure-volume relations were recorded
before and during VDD pacing by use of a short (75-millisecond) PR
interval to achieve preexcitation. Left ventricular cavity
pressure was simultaneously recorded at basal and
apical sites, with pressure at the basal site used to generate the
ESPVRs. VDD pacing shifted the ESPVR rightward, increasing
end-systolic volume by 45% (range, 17% to 151%;
P=0.002). Resting and provokable gradients declined by
20% (range, -56% to +3%) and 30% (range, -65% to -12%),
respectively (P<0.05). Preload declined by 3% to 10%
because of the short PR interval. Preload-corrected
contractility indexes and myocardial workload declined
by
Conclusions—VDD pacing shifts the ESPVR rightward in HCM patients
with cavity obliteration with or without obstruction, increasing
end-systolic volumes and reducing apical cavity compression and
cardiac work. These effects likely contribute to reduced
metabolic demand and improved symptoms.
Pacing is thought to generate mechanical benefits by limiting outflow
tract narrowing and dynamic obstruction because of asynchronous septal
activation.1 2 3 4 5 6 This hypothesis focuses on a
critical site of discoordinate activation (ie, proximal septum) and
thus predicts little benefit for patients without outflow tract
obstruction or SAM.
An alternative but related explanation is that pacing-induced
asynchrony results in net contractile depression and a rightward shift
of the ESPVR as shown in experimental studies in normal animal
hearts.8 9 The resulting increase in Ves can
greatly influence cavity gradients and SAM. Because the effect on Ves
would be present as long as a sufficient territory of muscle became
dyskinetic, VDD pacing may also be effective in patients without
outflow obstruction, such as those with HH-CO commonly seen in the
elderly.10 11
The present study tested the hypothesis that VDD pacing has its
primary mechanical effect on the systolic ventricle, shifting
the ESPVR rightward and thereby reducing cavity obliteration, outflow
gradients, and myocardial work. We reasoned that this mechanism would
apply similarly to HCM ventricles with rest gradients and SAM as well
as to HH-CO without obstruction and suggest a mechanism by which pacing
may convey sustained relief of symptoms.
Procedure
ESPVRs and EDPVRs were generated from data recorded during
transient rapid preload reduction by balloon obstruction of
inferior vena caval inflow (SP9516, Cordis). A 2.5F pacing
wire (Baxter) advanced through this catheter was positioned in the
right atrium for atrial sensing. Ventricular pacing was
achieved with a steerable quadripolar catheter placed at the right
ventricular apex. Pacing stimuli were provided by an
external dual-chamber pulse generator (Medtronic 5311B) in VDD mode,
with the AV delay set to the longest value that still yielded optimal
ventricular preexcitation as judged by QRS duration (mean,
75 milliseconds).
Data Analysis
The ESPVR was derived from the series of end-systolic PV points
derived from multiple cardiac cycles during transient preload
reduction. The time constant of isovolumic relaxation (
Preexcitation required a short AV delay potentially influencing preload
and thus chamber end-systolic volumes,
dP/dtmax, SW, and PVA. Therefore, data were also
calculated at matched EDV under both normal sinus rhythm and VDD pacing
conditions. Because multiple beats were obtained under both conditions
at varying preloads, beats could be selected at the highest matched
EDV. Preload-adjusted parameters are denoted by
end-systolic volume*, dP/dtmax*, SW*, and
PVA*.
Statistical Analysis
Pressure Gradients
End-Systolic Pressure-Volume Relation
Group data are provided in Table 2
Diastolic Indexes
Energetics
Differences Between HCM and HH-CO
Regional Dyssynchrony and Pressure Gradient Reduction
Figure 4C
VDD Pacing and ESPVR Shift
Prior short-term clinical studies of HCM have not observed an increase
in Ves with pacing,15 16 but this may relate to
methodological limitations. Because of chamber geometric abnormalities,
small volume changes, especially at the apex, are difficult to assess
from echocardiographic images. The conductance catheter
method is better suited to evaluating small relative changes in volume
by use of multiple recording segments. This applies in HCM
hearts with abnormal geometry.13
Effects on Pressure Gradient and Cardiac Work
VDD pacing increases Ves while reducing overall cardiac work as indexed
by PVA*. Unlike negative inotropic drugs, this pacing effect on
workload was more directly targeted to distal regions of the heart
generating high systolic forces from midsystolic cavity
compression. By limiting cavity obliteration, pacing may diminish
isovolumic work in these regions, reducing energy consumption, and over
time, resulting in ventricular
remodeling.3 17 18 This concept is supported by
PET scan data from HCM patients treated with long-term pacing, which
has shown reduced oxygen uptake and higher metabolic
reserve in the obliterating region.19 20
Diastolic Parameters
AV sequential pacing slows relaxation in normal canine
hearts.23 However, the effect of pacing on active
relaxation in human HCM has been less consistent. Betocchi et
al16 reported that
Similarities of VDD Pacing and Other Therapies
Hypertensive Heart Disease
Study Limitations
A catheter can be entrapped in the obliterating apex, causing
artifactual pressure differences between the apex and the base.
However, we used a straight-tipped catheter with several side holes to
minimize the probability of entrapment. Furthermore, direct peak
instantaneous pressure gradients (55±31 mm Hg; range, 28 to
100 mm Hg) were highly correlated to those obtained noninvasively
by Doppler velocity (50±48 mm Hg; range, 0 to 120
mm Hg) by linear regression (r2=0.945 and
P<0.0001). The strength of the PESP contraction can vary
with the premature interval, and ideally this is fixed by use of
programmed electrical stimulation. Although this was not done in this
study, we carefully matched coupling intervals for the PESP
analysis so that valid comparisons of provokable gradients
could be made.
Conclusions
Received January 23, 1998;
revision received February 24, 1998;
accepted March 17, 1998.
© 1998 American Heart Association, Inc.
Clinical Investigation and Reports
Mechanism of Acute Mechanical Benefit From VDD Pacing in Hypertrophied Heart
Similarity of Responses in Hypertrophic Cardiomyopathy and Hypertensive Heart Disease
Abstract
Top
Abstract
Introduction
Methods
Results
Discussion
References
Background—Dual-chamber pacing can
improve symptoms in hypertrophic cardiomyopathy
(HCM), but the mechanism remains unclear. We hypothesized that pacing
generates discoordinate contraction and a rightward shift of the
end-systolic pressure-volume relation (ESPVR) and that benefits
from this mechanism do not depend on the presence of resting outflow
pressure gradients or obstruction. 
10% (P<0.001). Diastolic compliance
and relaxation time were unchanged. Pacing made apical pressure-volume
loops discoordinate, limiting cavity obliteration and reducing distal
systolic pressures. Results in both patient groups were
similar.
Key Words: pacing • cardiomyopathy • hypertrophy • hemodynamics
Introduction
Top
Abstract
Introduction
Methods
Results
Discussion
References
Dual-chamber pacing
may benefit HCM patients with intraventricular
gradients having symptoms refractory to medical
therapy.1 2 3 4 5 6 However, not all patients improve
symptomatically, and the amount of pressure gradient
decrease can be small.5 6 These facts have
tempered the enthusiasm for pacing therapy and highlighted the need for
better patient selection criteria and thus for a better understanding
of its mechanical effects.7
Methods
Top
Abstract
Introduction
Methods
Results
Discussion
References
Patients
The study group consisted of 11 patients, 5 with HCM and 6 with
HH-CO. All HCM patients had resting
intraventricular pressure gradients >30
mm Hg and asymmetric ventricular hypertrophy.
Patients with HH-CO had long-standing hypertension, concentric
hypertrophy, and middistal systolic cavity
obliteration. All 11 patients had NYHA class III heart failure symptoms
despite maximum tolerated doses of calcium channel and ß-adrenergic
blockers. These drugs (but not other types of antihypertensive
medicines) were withheld 24 to 48 hours before the study. No patient
had significant coronary artery or valvular disease.
All patients gave informed consent to this protocol, which was approved
by the Joint Committee on Clinical Investigation of the Johns Hopkins
Medical Institutions.
Detailed methods for PV catheterization study in
HCM patients have been previously reported.12 13
After routine right- and left-side catheterization, a
multielectrode conductance catheter (Webster Labs or Sentron) was
positioned inside the LV. The conductance catheter had an end hole and
2 distal side holes but no pigtail tip so that ventricular
ectopy could be minimized after placement within the obliterating apex.
Apical pressures were recorded through the side holes by use of a
fluid-filled manometer. LV pressures used for PV analysis were
measured by a 2F micromanometer (SPC-320, Millar
Instruments) inside a pigtail catheter placed in the proximal half of
the LV chamber. The volume was measured with the conductance catheter
connected to a stimulator/microprocessor (Sigma V, CardioDynamics) and
calibrated as previously reported.12 13 Although
no complications occurred in this study, 2 instances of
ventricular perforation occurred subsequently while the
straight-tipped conductance catheter was used in hypertrophied LV. New
catheter design should facilitate such studies.
Hemodynamic data were measured at steady state
and transient load reduction in sinus rhythm and VDD pacing modes and
digitized at 200 Hz for off-line analysis. Steady-state
parameters were derived from signal-averaged cardiac
cycles. End-systolic pressure was the pressure at maximal
instantaneous elastance P/(V-V0), where P and V
are LV pressure and volume, respectively, and V0
is the volume-axis intercept of the ESPVR. 
) was the
negative inverse slope of the pressure-dP/dt plot with the use of data
between dP/dtmin and 2 mm Hg above
end-diastolic pressure. EDPVRs were derived from
end-diastolic PV points from the variably volume-loaded
beats.12 13 These data were fit to the equation
P=P0+
(eßV-1) by
nonlinear regression analysis, where ß is the chamber
stiffness and is a scaling factor. Finally, the total
PVA14 was determined from the sum of cardiac SW
and the area bounded by the ESPVR and EDPVR between
V0 and Ves.
Within-group hemodynamic changes from VDD pacing
were analyzed by Student's paired t test, and
changes between groups were analyzed by the unpaired
t test. Data are presented as mean±SD.
Results
Top
Abstract
Introduction
Methods
Results
Discussion
References
Baseline Characteristics
Baseline clinical characteristics are provided in Table 1
. HCM patients were younger
(P<0.05), but the degree of LV hypertrophy was
similar in both groups. No HH-CO patients had SAM, whereas 3 HCM
patients did. HCM patients had rest
intraventricular gradients with a peak of
67±33 mm Hg (range, 32 to 100 mm Hg), whereas HH-CO
patients had no or small rest gradients (mean, 17±19 mm Hg). All
11 patients had resting systolic cavity obliteration and
gradients >70 mm Hg with PESP (Table 2).
View this table:
[in a new window]
Table 1. Baseline Clinical Characteristics
View this table:
[in a new window]
Table 2. Hemodynamic Effects of VDD Pacing
As reported previously,1 2 3 4 5 6 15 16 VDD pacing
reduced the resting intraventricular pressure
gradient in HCM patients (Figure 1A). In
HH-CO patients, pacing resulted in marked reduction in the inducible
PESP gradient (Figure 1B and 1C). On average, pacing reduced rest
gradients by 29±18% (range, 7% to 56%) in HCM (Table 2
) and PESP
gradients by 34±21% (range, 12% to 55%) and 32±28% (range, 12%
to 65%) in HCM and HH-CO patients, respectively.
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Figure 1. Effect of VDD pacing on rest and provokable
pressure gradients. Pressure tracings from the LV base and apex are
plotted along with the ECG. A, HCM patient with rest gradient. Note the
sharp increase in the pressure gradients on cessation of pacing
(arrow). B, HH-CO patient with a small rest gradient but a provokable
gradient >100 mm Hg at baseline. The gradient was provoked by
PESP (arrow). C, Same patient as in B. With VDD pacing, the provokable
gradient (arrow) is much reduced. Note the similar coupling intervals
before and after the extrasystole.
Figure 2 shows example
pressure-volume loops and relations measured under normal sinus rhythm.
Both forms of hypertrophy were characterized by a steep
ESPVR (Table 2), with values averaging nearly 4 to 5 times that
observed in normal hearts. Figure 3 shows
data from the same 2 hypertrophy patients during VDD
pacing. Control relations (Figure 2) are superimposed for comparison.
Pacing induced a rightward ESPVR shift with little slope change.
View larger version (16K):
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Figure 2. Baseline PV loops in normal sinus rhythm during
transient preload reduction caused by inferior vena caval
occlusion. A, Normal subject included for comparison
purposes. B, HCM patient. C, HH-CO patient. Note
the steep ESPVRs in these patients.
View larger version (21K):
[in a new window]
Figure 3. PV loops during VDD pacing for the same HCM and
HH-CO patients as in Figure 2 . The baseline ESPVRs and EDPVRs are
reproduced in dashed lines for comparison. A, HCM patient. B, HH-CO
patient. Note the rightward displacement of the ESPVRs caused by pacing
without a significant change in the slope. The EDPVRs are
superimposable with or without pacing.. The ESPVR shift was indexed by the
end-systolic volume determined at a matched
end-systolic pressure of 100 mm Hg. That pressure rose by
39% in HCM and by 96% in HH-CO patients (both P<0.05).
Ves* (preload-adjusted Ves) increased similarly. Ees tended to decline
in both groups, but this did not achieve statistical significance.
Evidence for a net negative contractile effect was supported by
dP/dtmax*, which declined by 7% in HCM and 14%
in HH-CO patients (both P<0.05). By virtue of the need for
a short AV delay, pacing reduced preload volume in both groups. This
reduction, combined with the rightward ESPVR shift, led to an 18%
decline in stroke volume (P<0.05).
LV end-diastolic pressure decreased, along with
preload volume (P=0.04 in HCM patients). Peak filling rate
normalized to EDV rose slightly in HCM patients (P=0.02)
even though neither nor chamber stiffness was altered.
Total myocardial work indexed by PVA at a matched
end-diastolic volume (PVA*) was reduced by VDD pacing. In
HCM patients, this decline was somewhat greater (14%) than in HH-CO
patients (7%), but changes were significant in both groups. The ratio
of SW to PVA (mechanical work efficiency) remained unchanged.
Although the 2 patient groups reflected different
hypertrophic disease conditions, there were important similarities. For
example, all ventricles had cavity obliteration and elevated baseline
Ees, and their response to pacing was very similar. The only
parameter with a significantly different response to pacing
was EDV, which declined less in HH-CO patients (3% versus 12%,
P<0.05). The contribution of atrial contraction to net
chamber filling fell from 44±16% in HCM at baseline to 12±9% with
VDD pacing (P=0.03), whereas it decreased from 33±19% to
23±15% (P=0.27) in HH-CO patients, consistent with
the greater preload decline in HCM.
Regional dyssynchrony at the site of apical pacing was examined
from apex-segment PV loops. Figure 4A
shows the time plot of this apical volume signal under normal sinus
rhythm versus VDD conditions. The bent arrow indicates pacing
stimulation and shows the consequent early onset of contraction in the
apical territory. By midsystole, however, this region was stretched by
the late-activated myocardium (arrowhead),
increasing apical volume. This prevented the heart from contracting to
a small Ves during VDD pacing. Figure 4B displays these data as
regional PV loops. Whereas the control loop had a normal configuration,
with positive external work, the loop with VDD pacing was a figure
eight, with little early ejection and subsequent systolic
bulging.
View larger version (25K):
[in a new window]
Figure 4. Apical segment volume plots of an HH-CO patient.
A, Signal-averaged, steady-state apical segment volumes at baseline and
during pacing plotted against time. B, Apical
dyskinesis shown in a PV plot. Apical segment PV loops at baseline (C)
and during pacing (D) during transient inferior vena caval
occlusion. See text for details. and 4D demonstrates the consequences of apical discoordinate
motion on systolic cavity. In the control state, lowering
preload led to a marked increase in late systolic apical
pressure because of cavity obliteration, with substantial isovolumic
work performed by the distal myocardium. In contrast, the
discoordinate apex with VDD pacing did not develop late
systolic pressure increases because the cavity no longer
obliterated in midsystole.
Discussion
Top
Abstract
Introduction
Methods
Results
Discussion
References
This study demonstrates for the first time in humans that
dual-chamber pacing with preexcitation of the hypertrophied ventricle
induces a rightward shift of the ESPVR resulting from discoordinate
motion at the site of premature activation. This increases Ves at any
given end-systolic pressure and thus significantly reduces
intraventricular pressure gradients and myocardial
work. PV analysis enabled us to adjust for load changes induced
by pacing. As predicted by this model, the mechanical response is
virtually the same in HCM as HH-CO patients, suggesting that
obstruction is not a prerequisite for gradient reduction by pacing and
that pacing may help HH-CO patients who do not have outflow tract
obstruction.
The rightward ESPVR shift observed in the present study is
analogous to that reported in normal canine
hearts.9 As shown in Figure 4 and reported by
others,8 this shift results from dyssynergy in
chamber mechanical contraction. As shown in Figure 2, both HCM and
HH-CO ventricles undergo minimal Ves change over a broad
physiological loading range, reflecting ESPVR
steepness. Thus, only small changes in Ves are likely needed to
influence SAM and distal cavity pressure. Although small, the rightward
ESPVR shift from pacing reflected a substantial rise in Ves compared
with baseline. Achieving a similar Ves without pacing would require a
30% increase in preload that would also raise LV
end-diastolic pressures >40 mm Hg.
The present study confirms prior reports showing VDD pacing
reduces intraventricular pressure gradients in the
short term in patients with HCM.1 2 3 4 6 15 16
Furthermore, the pressure gradient was similarly reduced even when
generated by cavity obliteration rather than by outflow tract
obstruction, suggesting that the mechanism did not depend on
obstructive physiology.
Diastolic abnormalities contribute prominently to the
clinical course and symptoms of patients with LV
hypertrophy, and Ca2+ channel
blockers are thought to provide benefit in part by enhancing filling
dynamics, relaxation, and chamber
distensibility.21 22 However, these agents (and
ß-adrenergic blockers) do not alter chamber compliance in the short
term.12 In this sense, they are no different from
pacing, which also does not alter the diastolic PV relation
in the short term. The present data provide the first direct
analysis of such effects under variable loading
conditions. increases with pacing,
whereas Nishimura et al15 found no change at the
optimal AV delay. There were no significant changes in the
present study as well. These disparities are likely the result of
differences in the site of intraventricular
pressure measurement, heterogeneity of the HCM
substrate and load (gradient) reduction from pacing, and sample size.
Although relaxation was unchanged, pacing increased the peak filling
rate normalized for EDV. This pacing influence on filling was likely
related to increases in the early filling gradient caused by the
shortened PR interval as shown by Nishimura et
al.15 This short-term change likely resolves with
longer-term pacing as suggested in long-term
studies.3
In contrast to filling indexes, which may return to prepacing
levels with long-term pacing, systolic indexes with long-term
VDD pacing often remain impaired. The dP/dtmax
remains lower, and the end-systolic dimension by
two-dimensional echocardiogram is greater than the
baseline.3 These changes likely contribute to
symptomatic improvement rather than cause symptom
deterioration. The first line of therapy for symptomatic
HCM patients with intraventricular gradients has
been negative inotropic agents, such as ß-adrenergic and calcium
channel blockers or disopyramide. All these agents decrease
contractility and thereby diminish
intraventricular pressure gradients. However,
because pacing at the right ventricular apex reduces
contractility by causing temporal and spatial
asynchrony in contraction, its effects on the pressure gradient are
additive15 to the negative inotropic agents that
act more globally. Ves also increases after septal
myotomy-myectomy,24 and catheter-based septal
reduction may also increase Ves.25 Thus, a common
mechanism for relief of pressure gradients in HCM may be an increase in
Ves with or without generalized contractile depression.
Medical treatment for HH-CO patients shares many similarities with
that for HCM patients. In particular, both types of patients are often
helped by ß-receptor and calcium channel blockers. The present
study showed that VDD pacing could increase Ves for the short term and
decrease provokable pressure gradients in HH-CO patients. If the
increase in Ves is important in improving symptoms in HCM patients by
reducing intraventricular gradients and myocardial
workload, then VDD pacing should benefit HH-CO patients as well. Only 1
prior study has evaluated a group of HCM patients without resting
pressure gradients, and it reported no improvement from dual-chamber
pacing.26 However, these patients had reduced
ejection fraction and likely did not have cavity obliteration, because
there were no provokable pressure gradients. We would agree that pacing
has little role in patients in whom Ves is already high enough to
prevent cavity obliteration or outflow obstruction.
This study examined short-term hemodynamic
responses to VDD pacing in HCM and HH-CO patients in the
catheterization laboratory at rest in the supine
position. Therefore, it cannot predict the efficacy of long-term pacing
in these patients on its own. However, existing published data on the
long-term use of pacing in HCM do indicate that it can relieve symptoms
and lower the intraventricular pressure difference.
Nevertheless, gradient reduction cannot be used as the sole index of
efficacy, because some HCM patients have significant reduction in the
pressure gradient without symptomatic
improvement,5 6 possibly because of the
heterogeneity of HCM, labile nature of the pressure
gradient, and simultaneous load changes with pacing.
Long-term prospective, randomized, and double-blinded studies are
currently underway to examine pacing effects in both HCM and HH-CO
patients. Preliminary 6-month results suggest that long-term pacing in
HH-CO patients increases exercise time and produces sustained
symptomatic relief.27
VDD pacing increases Ves in the short term because of a rightward
shift of the ESPVR, reduces intracavitary pressure gradients, and
lowers total chamber workload in HCM patients. These effects likely
underlie symptomatic improvement in select patients with
HCM. Because similar mechanical effects are induced in patients with
HH-CO, individuals with this disorder may also benefit from VDD pacing
therapy. Current randomized trials are addressing this hypothesis.
Selected Abbreviations and Acronyms
EDPVR
=
end-diastolic pressure-volume relation
EDV
=
end-diastolic volume
Ees
=
LV end-systolic elastance
ESPVR
=
end-systolic pressure-volume relation
HCM
=
hypertrophic cardiomyopathy
HH-CO
=
hypertensive hypertrophy and cavity obliteration
LV
=
left ventricle
PESP
=
postextrasystolic potentiation
PV
=
pressure-volume
PVA
=
PV area
SAM
=
systolic anterior motion of the mitral valve
SW
=
stroke work
Ves
=
end-systolic volume
Acknowledgments
This study was supported by a grant from Medtronic, Inc (Dr
Kass), NIA grant AG:12249 (Dr Kass), and an ACC/Merck Fellowship
(Dr Pak).
References
Top
Abstract
Introduction
Methods
Results
Discussion
References
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D. A. Kass, C.-H. Chen, M. W. Talbot, C. E. Rochitte, J. A. C. Lima, R. D. Berger, and H. Calkins Ventricular Pacing With Premature Excitation for Treatment of Hypertensive-Cardiac Hypertrophy With Cavity-Obliteration Circulation, August 24, 1999; 100(8): 807 - 812. [Abstract] [Full Text] [PDF]
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B. J. Maron, R. A. Nishimura, W. J. McKenna, H. Rakowski, M. E. Josephson, and R. S. Kieval Assessment of Permanent Dual-Chamber Pacing as a Treatment for Drug-Refractory Symptomatic Patients With Obstructive Hypertrophic Cardiomyopathy : A Randomized, Double-Blind, Crossover Study (M-PATHY) Circulation, June 8, 1999; 99(22): 2927 - 2933. [Abstract] [Full Text] [PDF]
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D. A. Kass, C.-H. Chen, C. Curry, M. Talbot, R. Berger, B. Fetics, and E. Nevo Improved Left Ventricular Mechanics From Acute VDD Pacing in Patients With Dilated Cardiomyopathy and Ventricular Conduction Delay Circulation, March 30, 1999; 99(12): 1567 - 1573. [Abstract] [Full Text] [PDF]
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