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(Circulation. 1999;100:807-812.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Ventricular Pacing With Premature Excitation for Treatment of Hypertensive-Cardiac Hypertrophy With Cavity-Obliteration
From the Division of Cardiology, Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, Maryland
Correspondence to David A. Kass, MD, Halsted 500, Johns Hopkins Hospital, 600 N. Wolfe Street, Baltimore, MD 21287. E-mail dkass{at}bme.jhu.edu
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Abstract |
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 Top Abstract IntroductionMethodsResultsDiscussionReferences |
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Background—Hypertensive left ventricular hypertrophy with supranormal systolic ejection and distal cavity obliteration (HHCO) can result in debilitating exertional fatigue and dyspnea. Dual-chamber pacing with ventricular preactivation generates discoordinate contraction, which can limit cavity obliteration and thereby increase potential ejection reserve. Accordingly, we hypothesized that pacing may improve exercise tolerance long-term in this syndrome.
Methods and Results—Dual-chamber pacemakers were implanted in 9
patients with exertional dyspnea caused by HHCO. Intrinsic atrial rate
was sensed, and ventricular preactivation was achieved by
shortening the atrial-ventricular delay. Pacing was on or
off for successive 3-month periods (randomized, double-blind,
crossover design), followed by 6 additional pacing-on months.
Metabolic exercise testing, quality-of-life assessment, and
rest and dobutamine-stress
echocardiographic/Doppler data were obtained. After
3 months of pacing-on, exercise duration rose from 324±133 to 588±238
s (mean±SD; P=0.001, with 7 of 9 patients improving
30%), and maximal oxygen consumption increased from 13.6±2.9 to
16.7±3.3 mL of O2 · min-1 ·
kg-1 (P<0.02). Both parameters
were little changed from baseline during the pacing-off period.
Improved exercise capacity persisted at 1-year follow-up. Clinical
symptoms and activities of daily living improved during the pacing-on
period and stayed improved at 1 year, but they were little changed
during the pacing-off period. Despite similar basal values, stroke
volume (P<0.001) and cardiac output
(P<0.02) increased with dobutamine
stimulation 2 to 3 times more after 1 year of follow-up as compared
with baseline.
Conclusions—Long-term dual-chamber pacing can improve exercise capacity, cardiac reserve, clinical symptoms, and activities of daily living in patients with HHCO. This therapy may provide a novel alternative for patients in whom traditional pharmacological treatment proves inadequate.
Key Words: pacing • hypertension • exercise • hypertrophy • heart failure
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Hypertension is a leading risk factor for the development of heart failure,1 2 3 particularly as age increases.2 As many as 30% to 40% of affected individuals have resting ejection fractions >50%, often with varying degrees of left ventricular (LV) hypertrophy.4 5 6 7 A subset of these patients develop severe hypertrophy with supranormal function and near-complete distal cavity obliteration during ejection.8 Such patients can experience profound exertional dyspnea and fatigue and intermittent pulmonary edema requiring hospitalization. Pharmacological therapy centers around ß-receptor and calcium-channel blockers, diuretics, and angiotensin-converting enzyme inhibitors, yet many patients remain symptomatic, and alternative approaches are needed.
Because heart failure symptoms occur in the absence of systolic abnormalities, the investigators focused on diastolic dysfunction to explain the pathophysiology of hypertensive hypertrophy with cavity obliteration.5 9 Another important factor, however, is the loss of systolic reserve. Once a heart ejects to very small cavity volumes at rest, it cannot reduce this volume further during stress demands, thereby limiting its reserve. Cardiac output can increase by the Frank-Starling mechanism, which risks diastolic pressure elevation in a hypertrophied heart, or by raising heart rate, which can compromise chamber filling time.10 Treatments that increase rest-end systolic volume, such as negatively inotropic ß-receptor and calcium-channel blockers,11 may improve reserve, as volumes can again decline under stress.
Dual-chamber cardiac pacing with atrial sensing and premature ventricular activation (VDD mode) may provide a nonpharmacological alternative. Pacing generates discoordinate contraction and, thus, inhibits cavity obliteration by increasing end-systolic volume.12 To date, studies of pacing therapy in hypertrophied hearts have almost exclusively targeted patients with asymmetric septal thickening, systolic anterior motion of the mitral valve, and outflow tract obstruction.13 14 15 16 17 However, this specific pathophysiology is not required to observe functional effects from VDD pacing, as patients with symmetric hypertensive hypertrophy and distal cavity obliteration (HHCO) display very similar ventricular mechanical responses.12
Accordingly, the present study was designed to test the hypothesis that long-term VDD pacing in patients with HHCO improves metabolic exercise performance and activities of daily living. As a secondary goal, we sought to determine potential mechanisms for such change, focusing on alterations in rest and adrenergic-stimulated cardiac reserve.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Patient Group
A total of 10 patients were recruited for the study over a period of 1.5 years. The sample size was set by Food and Drug Administration guidelines for a feasibility trial. One patient was diagnosed with primary hyperaldosteronism on the basis of data obtained shortly after pacemaker implantation and, therefore, was removed from the trial. Data from the 9 remaining patients are presented. All patients provided informed consent, and the study was approved by the Joint Committee on Clinical Investigation of the Johns Hopkins Medical Institutions.
All patients had documented exertional dyspnea (NYHA class III) despite hyperdynamic systolic function, with a mean estimated ejection fraction of 85.2±7.1%. Three patients had been previously hospitalized for pulmonary edema. The mean age of the 4 male and 5 female patients was 58±8 years. Four patients were black, and the others were white. All but one had well-documented histories of long-term, treated hypertension, spanning 18±7 years, with mean systolic and diastolic arterial pressures of 157±29.3 and 91.9±15.9 mm Hg, respectively. The only patient without a documented hypertension history had not seen a physician for most of her adult life; however, she had a family history of hypertension and no history of familial hypertrophic disease.
All patients had concentric hypertrophy, with mean septal
and LV free-wall thicknesses of 18.4±2.5 and 16.3±2.2 mm,
respectively. None of the patients had significant mitral
regurgitation or systolic anterior motion of
the mitral valve. Mean outflow velocity assessed by continuous-wave
Doppler was 244.2±114 cm/s, which is consistent with an
intracavitary pressure gradient of 28.5±29.7 mm Hg. This
gradient did not reflect outflow obstruction, but rather distal cavity
obliteration18 and, thus, pressure differences between
distal and basal LV regions.12 Figure 1
shows examples of echocardiogram images
demonstrating marked hypertrophy with near-obliteration of
the distal cavity at end-systole.
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Long-term medications included calcium-channel blockers (verapamil or diltiazem 240 to 300 mg/d; n=6), ß-blockers (atenolol or metroprolol 12.5 to 75 mg/d; n=5), angiotensin-converting enzyme inhibitors (captopril 10 to 40 mg/d; n=3), and diuretics (n=6).
Study Protocol
Baseline evaluation included metabolic exercise
testing, ECG, rest and dobutamine-stimulated
echo/Doppler studies, and the completion of a quality-of-life
questionnaire (Minnesota Living with Heart Failure [MLHF]). Patients
then received a permanent dual-chamber pacemaker (Thera-DR, Medtronic).
The atrial lead was used to sense intrinsic sinus rhythm, and the right
ventricular apical lead paced the heart. Premature
ventricular activation was achieved by setting the
pacemaker atrial-ventricular delay shorter than the
intrinsic PR interval (mean delay, 71 ms) (VDD mode). This delay was
the longest possible that achieved full preexcitation at rest and
during ambulation. Confirmation of capture during exercise was made
during metabolic stress testing. At discharge, the
pacemaker was either programmed on (VDD) or off (DDI, with low atrial
backup rate); the choice of pacing mode was randomized and
double-blinded. After 3 months, patients underwent repeat assessment,
and pacing was then switched to the alternate mode for the ensuing 3
months. After follow-up evaluation, pacing resumed in all patients for
an additional 6 months (total, 1 year), at which time final tests were
performed. This final test included a repeat rest and
dobutamine-stress echo/Doppler study.
Long-term medications were continued throughout the study, and medication adjustments by the patients' primary care physicians were permitted. During the initial 6 months (blinded, crossover protocol), changes were made in only 2 patients; the diuretic dose was increased in both and the atenolol dose was increased (75 to 100 mg/d) in one. As these changes were made shortly after pacemaker implantation, they applied similarly during much of the protocol (specifically for on versus off comparisons). During the second 6-month period, the ß-blocker dose was doubled in 2 additional patients, and captopril was converted to lisinopril in a third.
Testing Procedures
Metabolic testing was performed during maximal
effort upright treadmill exercise with continuous ventilatory
gas-exchange monitoring (MedGraphics). Exercise followed a Naughton
protocol, with a fixed treadmill rate of 2.0 mph and incremental
elevations of 3.5 degrees every 3 minutes. These data were used to
obtain total exercise duration; the peak rate of oxygen consumption
(maximal 
O2), reflecting the
oxygen transport capacity of the circulatory system; and the
O2 at the anaerobic
threshold. The anaerobic threshold is the exercise level at
which energy production from anaerobic
metabolism becomes significant, and it is an endurance
measure for exercise and activities of daily living.19
Lastly, peak exercise heart rate, systolic blood pressure, and
the maximal rate-pressure product (RPPmax)
were determined.
Echocardiographic and Doppler studies were performed at baseline and after 1 year to assess wall thickness, chamber diameter, fractional shortening, LV mass (area/length method),20 and LV outflow tract mean flow velocity, which was determined by continuous-wave Doppler. The latter provided an estimate of intracavitary pressure gradients associated with hyperdynamic contraction.21 Dobutamine stress-echocardiography was performed to assess cardiac reserve. Patients received intravenous dobutamine in incremental doses to maximal tolerated levels (7.5 to 40 µg · kg-1 · min-1). Dobutamine stress results were compared at a matched dose in all but 2 patients. In these 2 patients, 1-year follow-up data were recorded only at the 40 µg · kg-1 · min-1 dose, versus the 30 and 20 µg · kg-1 · min-1 doses used at baseline in each, respectively. The average dose used for baseline and 1-year studies was 25±12.8 versus 29±13.6 µg · kg-1 · min-1, respectively (P=0.2).
Chamber-diameter and wall-thickness measurements were made under rest conditions using commercial software. The ECG was not displayed on the echocardiographic monitor; therefore, analysis was blinded to pacing conditions (on versus off). All echodimension and flow-gradient data were determined at the time of the procedure, and the technician was blinded to prior results. Baseline and dobutamine-stimulated stroke volume and cardiac output were determined from either aortic flow velocityxaortic root-area or cavity volumes calculated from biplane images. These data were an average from at least 3 separate cycle determinations performed by a single observer blinded to data source.
Statistical Analysis
For the randomized, blinded portion of the study
(baseline, pacing on, and pacing off), data were analyzed by
repeated-measures analysis of variance (RMANOVA), with protocol
period and patient number treated as categorical variables.
Post-hoc testing of individual mean differences due to protocol period
was performed using a Tukey test. Data after 1 year were
analyzed separately because the latter 6-month period was
unblinded and the duration of contiguous pacing varied with initial
randomization. For this comparison, data were assessed by a
nonparametric Wilcoxan test. Data are presented as
mean±SD.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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VDD Pacing and Exercise Performance
Four patients were randomized to have pacing on during the first 3 months, and the remaining patients had active pacing during the second 3 months. Exercise capacity improved during the pacing-on period in nearly all patients. Figure 2
provides
individual and summary data comparing exercise duration, maximal
O2, and
RPPmax at initial baseline to pacing-on and
pacing-off periods. Randomization order is coded in the figure. With
active pacing, total exercise duration lasted an average of 82%
longer, from 324±133 to 588±239 s (P=0.001 by
RMANOVA with multiple comparisons test). Although there was
heterogeneity in this response, 7 of 9 subjects
experienced 30% improvement in exercise duration. Maximal
O2 increased 24%: from
13.5±2.9 to 16.7±3.3 mL of O2 ·
min-1 · kg-1
(P=0.05), with all but 2 patients experiencing
at least a 10% increase.
O2 at the
anaerobic threshold increased from 8.6±0.97 to 11.4±1.9
mL of O2 ·
min-1 · kg-1
(P=0.005). RPPmax
rose 46%, from 15.6±3.2 to 22.8±3.3 mm Hg ·
beats/s · 103 (P=0.002),
indicating that prolonged exercise duration and maximal
O2 were associated with
enhanced total cardiac work. Resting RPP was similar for all
periods.
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None of these or any other exercise performance indexes were
altered from baseline during the 3-month pacing-off period. All but one
patient had a lower maximum
O2 during pacing-off than
pacing-on. Paired comparisons made solely between pacing-on versus
pacing-off data revealed significant differences in exercise duration
(P=0.024) and maximum
O2 (P=0.01).
Improved exercise capacity was generally sustained at the 1-year
follow-up (Table 1). Exercise duration
and RPPmax remained substantially increased over
baseline (and pacing-off period) at 1 year. Maximal
O2 was not significantly
elevated; however, an 18% decline in resting
O2 existed (P=0.007). In
addition, O2 at the
anaerobic threshold tended to increase
(P=0.05). These results suggested an
improvement in exertional efficiency. Initially, 8 of 9 patients
developed dyspnea and 3 developed dizziness during exercise, which led
to its termination. After 1 year of therapy, only 1 patient developed
either symptom (P<0.001; 
2 test),
and the most common reason for stopping exercise was leg fatigue.
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Pacing and Quality of Life Assessment
Figure 3 displays the total MLHF
questionnaire scores during the initial controlled crossover portion of
the study. The baseline MLHF score was 67.7±22.6 and it improved to
33.4±27.7 during the pacing-on period (P=0.008). In
contrast, the score was 47.2±27.6 during the pacing-off period
(P=0.18 versus baseline by RMANOVA). Symptomatic
improvement was also generally sustained at 1 year (33.4±23.8;
P=0.008). There was evidence of a substantial placebo
effect, as MLHF score also declined considerably in the 5 patients who
had pacing off during the initial 3 months (74.6 versus 42.6;
P=0.057). However, unlike the pacing-on period, no
corresponding changes in metabolic exercise data existed
during the pacing-off period in these subjects.
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Echocardiographic/Doppler Data
Table 2 provides baseline and
1-year follow-up echocardiographic/Doppler data.
Resting chamber diameter at the papillary muscle level increased and
average midwall thickness declined; thus, the radius/thickness ratio
increased. These changes were modest but significant. A corresponding
6.4±5.7% decline in wall mass occurred (P<0.05). Resting
stroke volume, cardiac output, and fractional shortening did not
significantly change between baseline and 1-year follow-up. Similarly,
diastolic function assessed by the early-to-late filling
ratio and E-wave deceleration time was not significantly altered.
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In contrast to rest function, cardiac reserve assessed during
dobutamine stimulation was increased after 1 year of pacing
therapy. Figure 4 displays absolute
stroke volume and cardiac output at the 2 observation times:
before and after receiving matched or nearly matched
dobutamine doses. The 2 patients who received slightly
higher doses at 1 year (see Methods) did not display the larger changes
in either parameter. At baseline, LV stroke-volume change
with dobutamine varied, and it was not significant overall
(8.1±21 mL). In contrast, stroke volume rose by 30±24 mL
(P=0.001) after 1 year (P=0.009 versus baseline
response). The improvement in dobutamine response was not
related to a change in resting stroke volume between the initial and
final studies (P=0.84). Likewise, baseline cardiac output
increased more with dobutamine after 1 year of pacing
(+4.8±5.2 L/min; P=0.02) than it did during the initial
study (+2.4±3.1 L/min, P=0.04; P=0.02
versus 1-year response). Further evidence that functional
reserve was altered was found in the maximal tolerated
dobutamine doses. Initially, only 3 patients tolerated a 40
µg · kg-1 ·
min-1 dose, with all 9 experiencing anginal-type
chest pain and 6 developing dyspnea. In contrast, all patients
tolerated the higher dose after 1 year of follow-up, with only 1
experiencing anginal-type pain and none developing dyspnea.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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This study demonstrates for the first time that long-term VDD pacing can improve exercise capacity, clinical symptoms, and the daily living activity of patients with severe exertional dyspnea and fatigue due to HHCO. In two-thirds of the patients, exercise duration increased substantially after 1 year (>50% in each; mean, 162%), and all but one improved at least 15%. The data further supports the hypothesis that VDD pacing increases systolic ejection reserve, and this may contribute to enhanced exercise capacity.
Study Limitations
This study was designed as a feasibility trial and was,
therefore, limited in sample size. Although clearly a limitation, the
randomized, blinded, crossover design enhanced the power of the study,
enabling delineation of changes beyond those from a placebo effect. We
also intentionally restricted the entry criteria to generate a fairly
homogeneous population. Although mean changes were often
large, not every patient benefited similarly, and some had only modest
gains. Confirmation of the present results in a much larger cohort
is needed, particularly to define which patients are mostly likely to
benefit. Lastly, 4 patients had their ß-blocker and/or
diuretic dose increased between the initial and final studies,
and some effect on the results cannot be ruled out. However, it could
not have altered comparisons between randomized pacing on and off
periods because the medication changes occurred either very early or
after this period was completed. Furthermore, the 3 patients on higher
ß-blocker doses after 1 year displayed negligible differences in
basal heart rate or cardiac output and did not have discernibly
improved symptoms, exertional capacity, or
dobutamine-stimulated reserve compared with other
patients.
Mechanisms of Improved Functional Reserve
In a recent study of patients with HHCO or familial
hypertrophic cardiomyopathy, apical pacing
generated discoordinate wall motion at the pacing site, shifting the
end-systolic pressure-volume relation rightward.12
The result was an increase in LV end-systolic volume at any
given arterial or volume load, which exceeded that normally
obtainable by these hearts in the absence of pacing. Sympathetic
activation of the heart during stress decreases end-systolic
volumes, shifting the end-systolic pressure-volume
relation leftward. By increasing basal end-systolic
volumes and not directly inhibiting sympathetic drive, VDD pacing may
restore some of this reserve capacity.
Reduction of distal cavity compression may also improve
mechanoenergetics, because once the distal chamber is at near-zero
volume, subsequent systolic force contributes little to
ejection but can increase cardiac internal work. Preventing cavity
obliteration can reduce this wasted energy12 and might
underlie reported declines in blood flow and flow
heterogeneity.22 We could not directly
demonstrate increased end-systolic volumes in our patients
given the complex end-systolic geometry. However,
end-diastolic dimension increased and stroke volume
(derived by Doppler flow) remained unchanged, suggesting this
increase occurred. Additional evidence was provided by the decline in
mean outflow flow velocity, indicating reduced cavity obliteration.
Lastly, exercise duration remained considerably prolonged at 1 year,
despite little change in maximal
O2. This is
consistent with enhanced exercise efficiency that could reflect
better conditioning, and/or more effective
cardiovascular reserve.
The effects of VDD pacing on diastolic function remain unclear. We previously reported chamber compliance was unchanged by acute VDD pacing,12 but no data exist regarding long-term pacing. If anything, relaxation prolongs with discoordinate contraction from pacing23 and, given the role of diastolic dysfunction in hypertrophic disorders, this has raised concerns.17 24 Yet, we found VDD pacing improved exercise function and symptoms without a demonstrable benefit (or worsening) of diastolic function. This suggests that while diastolic abnormalities undoubtedly contribute to exercise intolerance in patients with HHCO, they are not the only factor. As noted, these patients also had limited systolic reserve capacity associated with basal hyperejection, and this may play a greater role in their symptoms.
Our study targeted patients with increased basal LV outflow velocity consistent with modest intracavitary pressure gradients from distal-wall compression. It is important to emphasize again that none of the patients had outflow obstruction. Rather, the velocities and estimated gradients reflected a small resting end-systolic volume that limited any further reduction with exercise. It remains possible, if not likely, that patients who only cavity-obliterate during exercise would still benefit from VDD pacing. Lastly, the same pathophysiology occurs in elderly individuals with hypertrophic disease,8 many of whom have systolic hypertension. VDD pacing in individuals with refractory exertional dyspnea might also prove useful.
Comparison with Pacing Therapy for Familial Hypertrophic
Cardiomyopathy
The usefulness of pacing to treat familial hypertrophic
cardiomyopathy with asymmetric septal
hypertrophy and intraventricular cavity
gradients has been the focus of several recent studies and
reviews.13 14 15 16 17 24 25 The primary hypothesis is that by
altering the ventricular activation sequence, pacing limits
septal motion, reducing outflow gradients and improving
symptoms.24 Initial, non-placebo–controlled studies
suggested consistent success,16 25 whereas
subsequent trials using controlled/crossover designs similar to that
used in the present study have been less consistent. For
example, Nishimura et al13 reported only modest
changes in exercise duration (414 versus 342 s), no change in
maximal O2, and no
clinical improvement in >30% of patients. Exercise capacity was also
unchanged in the recent, larger Pacing in Hypertrophic
Cardiomyopathy trial,15 although it
rose 21% in those patients with <10 minutes of exercise time at
baseline.
With this background, the current study is intriguing in that
exercise capacity improved in most patients and generally was
associated with objective improvement in metabolic and
hemodynamic performance. Furthermore, reduced
symptoms and enhanced exercise capacity were sustained with long-term
treatment, which makes it less likely to reflect a placebo effect. The
difference may lie in particular characteristics of the study
population. In the present study, all patients had substantial
baseline exertional disability, with an exercise duration <6 minutes
and maximal O2<14 mL of
O2 · kg-1 ·
min-1, and none had outflow tract obstruction,
mitral regurgitation, malignant arrhythmias, or
cavity distortion caused by asymmetric disease. Echocardiograms in
these individuals were generally similar, with symmetric
hypertrophy and distal cavity obliteration.
Ventricular pacing generates regional discoordinate motion
at the pacing site, thereby limiting cavity compression.12
In patients with HHCO, the symmetry and more distal distribution of
hypertrophy could, thereby, enhance the efficacy of apical
pacing. In contrast, patients with proximal septal
hypertrophy may depend more on a timing delay between an
apical pacing stimulus and septal shortening, and such timing could
vary considerably among patients.
Conclusions
Congestive failure is a leading cause of
cardiovascular morbidity and mortality in older adults,
yet nearly 40% of these individuals have preserved ejection
fraction.9 In a subset of individuals with hypertensive,
supranormal ejection and near-cavity obliteration, VDD pacing may offer
a useful adjunct to pharmacological therapies. Further multicenter
trials are needed to confirm the present findings and define the
criteria for predicting patients most likely to benefit.
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Acknowledgments |
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Supported by grants from the National Public Health Clinical Research Center (RR00052), Medtronic, Inc (to D.A.K.), and the National Aging Institute (AG-12249; to D.A.K.)
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Footnotes |
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Dr. Chen was a visiting fellow from the National Yang-Ming Medical College and Veterans General Hospital, Taipei, Taiwan.
Received April 14, 1999; revision received May 21, 1999; accepted May 24, 1999.
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 B. A. Borlaug, V. Melenovsky, S. D. Russell, K. Kessler, K. Pacak, L. C. Becker, and D. A. Kass Impaired Chronotropic and Vasodilator Reserves Limit Exercise Capacity in Patients With Heart Failure and a Preserved Ejection Fraction Circulation, November 14, 2006; 114(20): 2138 - 2147. [Abstract] [Full Text] [PDF]
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