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From the Division of Cardiology, Department of Internal Medicine,
University of Texas Southwestern Medical School and VA Medical Center, Dallas.
Correspondence to Paul A. Grayburn, MD, Division of Cardiology, UT Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX, 75235-9047. E-mail grayburn{at}ryburn.swmed.edu
Methods and Results—We studied the spontaneous variation in the
continuous-wave, Doppler-derived pressure gradient on 5 consecutive
days in 12 HOCM patients and 5 aortic stenosis control
subjects. While in some patients the day-to-day variability in resting
gradient was small, in others it varied markedly. The 95% confidence
interval for attributing a change in LVOT gradient to factors other
than random variation is ±32 mm Hg for resting gradient and
±50 mm Hg for provoked gradient. The mean coefficient of
variation for gradient across 5 days for the group was 0.52±0.33 for
resting gradient and 0.46±0.16 for provoked gradient. The day-to-day
variability in pressure gradient could not be explained by changes in
heart rate, blood pressure, or left ventricular
end-diastolic dimension, each of which had a coefficient of
variation <.11. Moreover, technical factors related to the
performance or interpretation of the studies did not account
for it because the coefficient of variation for gradient in aortic
stenosis was <10% and interobserver and intraobserver
agreement was excellent (r=.96 and .98,
respectively).
Conclusions—The LVOT pressure gradient varies considerably from
day to day in stable patients with HOCM. A single measurement of
pressure gradient is not adequate to define the severity of dynamic
LVOT obstruction in HOCM.
Because of its dynamic nature, the LVOT pressure gradient can vary
markedly with changes in preload, contractility, and
afterload.13 14 15 Paz et
al16 reported that ingestion of a small amount of
ethanol caused a 63% increase in the mean LVOT pressure gradient and a
fall in mean systolic blood pressure. In a double-blind,
placebo-controlled, crossover study of dual-chamber pacing for HOCM,
Nishimura et al10 reported a high degree of
variability between LVOT gradients obtained at baseline and 3 months
later in patients randomized to nonpacing therapy. As the authors
pointed out in the paper, this difference could either be due to a
placebo effect or to intrinsic variability of the dynamic obstruction
present in HOCM. Since loading conditions and
contractility fluctuate according to volume status,
autonomic system activity, diurnal changes in neurohormonal status, and
daily activity, the LVOT pressure gradient may exhibit considerable
temporal variability.
To our knowledge, no data exist regarding the day-to-day variability of
the LVOT gradient in patients with HOCM. Defining the magnitude of such
variability is important, particularly if improvement in LVOT gradient
is used to judge the efficacy of pacemaker or drug therapy for this
disorder. Therefore we performed this study to prospectively examine
the spontaneous day-to-day variability of rest and provoked LVOT
pressure gradient in stable patients with HOCM.
Study Design
Echocardiography
Standard M-mode echocardiographic examination at the
level of the mitral valve was used to assess the presence and the
severity of systolic anterior motion of the mitral valve.
Systolic anterior motion was graded as follows: 0, absent; 1+,
present with minimum distance between mitral valve and
ventricular septum during systole >10 mm; 2+, without
mitral-septal contact but with a distance <10 mm between mitral
valve and septum; 3+, brief mitral-septal contact (<30% of
echocardiographic systole); and 4+, prolonged
mitral-septal contact (>30% of systole).20
Provoked pressure gradient was obtained after giving 0.4 mg NTG
sublingually. All patients tolerated NTG, except one who refused it due
to a history of severe nitrate headaches and alternatively performed
the Valsalva maneuver. Blood pressure was obtained before and after
each minute of NTG intake. Continuous-wave Doppler examination of
LVOT was repeated once the systolic blood pressure had fallen
by >10 mm Hg.
Doppler recordings were reviewed independently and in
random order by two blinded observers (P.G. and S.H.). The observers
analyzed only those beats having a Doppler spectral signal
that was judged to represent the velocities across the LVOT and
for which there was sharp and unambiguous definition of the entire
waveform contour. Post–ectopic beat waveforms were disregarded. The
Doppler beam was assumed to be almost parallel (angle
Intraobserver variability was assessed by having one investigator
(P.G.) read the first 12 studies on two different occasions at least 4
weeks apart. Interobserver variability was assessed by having a second
investigator (S.H.) read the first 25 studies independently.
Statistical Analysis
Day-to-Day Variability of Resting Pressure Gradient
Systolic anterior motion of the mitral valve was present in
9 of the 12 HOCM patients and was generally mild to moderate. However,
the large increase in resting pressure gradient seen on a single day in
patients 8, 9, and 10 (Table 1
Day-to-Day Variability of Provoked LVOT Pressure Gradient
Control Subjects
Observer Variability
Factors that could account for such marked variability include (1)
day-to-day variation in hemodynamic conditions within
individual patients, (2) operator- and instrument-dependent
variables, (3) differences in interpretation of studies between
observers, and (4) intrinsic variability of pressure gradient. The
possible effect of each of these factors on the results of this study
is discussed in the following paragraphs.
Changes in heart rate and loading conditions occurring daily in
patients can influence the pressure
gradient.13 14 15 To limit the effects of these
hemodynamic changes to spontaneous day-to-day
variation, this study included only patients taking a stable dose of
cardioactive medications. The coefficient of variation for daily
changes in heart rate, systolic blood pressure, and left
ventricular-end diastolic dimension was <11%,
suggesting that the variability in pressure gradient observed in this
study was not due to major changes in day-to-day
hemodynamic conditions.
Several operator- and instrument-dependent factors may influence the
serial measurements of pressure gradient. The most important of such
factors is the ability of the sonographer to reproducibly align the
interrogating Doppler beam parallel to the LVOT systolic
flow. An unacceptably high error is induced in the estimation of
pressure gradient if the angle between the interrogating ultrasound
beam and the direction of blood flow is more than 20
degrees.20 To limit the influence of this
variable on the daily measurements of pressure gradient, all
echocardiograms were performed by experienced sonographers who were
trained to interrogate the LVOT systolic flow jet from multiple
acoustic windows with careful angulation of the transducer to isolate
the maximal velocity spectral profile. Aortic valve pressure gradients
in a control group of aortic stenosis patients were also
studied in a similar manner on 5 consecutive days to determine if the
observed variability in pressure gradient found in this study was
largely due to technical factors. Aortic valve pressure gradients did
not change significantly between studies in individual patients with
aortic stenosis, supporting the reliability and reproducibility
of the continuous-wave Doppler data in this study. Gain and filter
settings were also kept constant between studies for each patient.
Therefore the 52% variability in pressure gradient observed in this
study is not explained by variations in operator or instrument factors.
Moreover, these data may underestimate the magnitude of spontaneous
variability observed in clinical practice because the study was
performed under a rigorous protocol optimized for repeated
measurements.
There was excellent interobserver and intraobserver agreement for
pressure gradient measurements present in this study. Therefore, we
do not believe that the day-to-day variation in LVOT pressure gradient
is due to interpretive differences between observers.
Given that there was minimal variation in hemodynamic
conditions, technique, and observer measurements, we are left to
conclude that marked day-to-day variability in gradient is largely
intrinsic to hypertrophic cardiomyopathy. Moreover,
since all patients were clinically stable and had only mild symptoms at
the time of study, the finding of a high gradient on any given day does
not necessarily correlate with severity of disease.
Clinical Implications
Controversy exists as to the importance of the pressure gradient in
HOCM. Traditional teaching is that the gradient represents a
dynamic outflow tract obstruction that produces symptoms in a subset of
patients with this disorder.4 5 6 Supporting this
view is marked relief of symptoms after surgical myectomy in selected
patients.24 25 Alternatively, the fact that the
majority of left ventricular stroke volume is ejected
before to the development of the gradient has led some to conclude that
there is no true obstruction to left ventricular outflow
and that the gradient is a result of cavity
obliteration.26 27 The present study does not
directly address this controversy. However, if the gradient is not
important in the pathophysiology of HOCM, expensive therapies directed
at relieving LVOT obstruction, such as dual chamber pacing, may not be
warranted. Our data suggest that a decrease in LVOT gradient measured
at a single point in time after pacing therapy may be the result of
spontaneous variability and could lead to the erroneous conclusion of
therapeutic efficacy. Controlled clinical trials of pacing therapy in
HOCM are currently underway and should take into account the
spontaneous variability of pressure gradient.
Limitations
All but two of the patients in our study were already taking
medications for relief of symptoms at the time of enrollment. Due to
the outpatient nature of the study, and the unknown risk of drug
withdrawal, patients were continued on their medical treatment. The
time and dose of medication were kept constant and no new medications
were added during the study. Thus the results of this study do not
reflect the natural history of HOCM but rather indicate the variability
of daily measurements of LVOT gradient in patients on stable medical
therapy.
We only studied patients in sinus rhythm. Atrial fibrillation was
excluded because beat-to-beat variability in pressure gradient may
confound the ability to quantify day-to-day variability.
We made no attempt to simultaneously measure the pressure
gradient using catheter-based techniques. Several studies in the past
have already validated continuous-wave Doppler assessment of
pressure gradient against the catheter-based methods of measuring
pressure differences across the LVOT in patients with
HOCM.18 29
As shown in Table 1
Conclusions
Received July 23, 1997;
revision received October 6, 1997;
accepted October 7, 1997.
© 1998 American Heart Association, Inc.
Clinical Investigation and Reports
Spontaneous Variability of Left Ventricular Outflow Tract Gradient in Hypertrophic Obstructive Cardiomyopathy
Abstract
Top
Abstract
Introduction
Methods
Results
Discussion
References
Background—Improvement in the left
ventricular outflow tract (LVOT) gradient has been used as
a means of assessing response to therapy in patients with hypertrophic
obstructive cardiomyopathy (HOCM). To our
knowledge, no data exist regarding the spontaneous day-to-day
variability of the LVOT gradient in patients with HOCM. Defining the
magnitude of such variability is critical to properly understand how
much improvement in LVOT gradient must be present to invoke a
therapeutic response.
Key Words: cardiomyopathy • echocardiography • hypertrophy • hemodynamics • pressure
Introduction
Top
Abstract
Introduction
Methods
Results
Discussion
References
Hypertrophic
cardiomyopathy is a complex disorder characterized
by a broad spectrum of morphological, functional, and genetic
abnormalities.1 2 3 4 5 6 7 The phenotypic expression of
this disorder is variable and includes asymmetric septal
hypertrophy, concentric hypertrophy, and apical
hypertrophy with or without an LVOT gradient. Clinical
presentation is also diverse, ranging from absence of
symptoms to sudden cardiac death.5 6 7 In clinical
practice, measurement of the LVOT gradient is often used to evaluate
the severity of disease, the presence or absence of LVOT obstruction,
and the efficacy of treatment.5 6 7 8 9 10 11 12
Methods
Top
Abstract
Introduction
Methods
Results
Discussion
References
Study Patients
The study was approved by the Institutional Review Board at the
University of Texas Southwestern Medical Center and the Veterans
Affairs Medical Center at Dallas. All patients gave written informed
consent. The diagnosis of HOCM was confirmed in all patients by a
previous echocardiogram demonstrating a hypertrophied nondilated
ventricle in the absence of a secondary cause, along with a resting or
provoked pressure gradient across the LVOT.17
Patients were ineligible for the study if they had atrial fibrillation,
an indwelling pacemaker, or an unstable medical condition that could
result in alteration of the loading conditions. Patients with
concomitant valvular heart disease of aortic stenosis,
aortic regurgitation, or mitral stenosis, as
well as those with mitral regurgitation thought to be
caused by a primary valvular abnormality, were also excluded
from the study. A control group of five patients with varying severity
of aortic stenosis was also studied.
Serial echocardiograms were performed on 5 consecutive days for
each patient. To ensure blinded reading, the studies were labeled with
a preassigned random study number instead of the patient's name. Each
study was done at approximately the same time of day by the same
technician using the same instrument. Patients were asked to take their
medications at the same time each day. Medication dosage was kept
constant during the study period. On each day, blood pressure and heart
rate were measured after 10 minutes of supine rest.
Echocardiograms were performed in the partial left lateral
decubitus position with the use of standard imaging planes and a
commercially available instrument (Hewlett-Packard Sonos 2500 or
Vingmed 800C). For each individual patient, the same echo machine and
instrument settings were used for each of the five subsequent
examinations to keep the imaging conditions constant between studies.
Standard two dimensional echocardiography was
performed with the use of a 2.5-MHz transducer. Continuous-wave
Doppler examination was performed with the use of a 1.9-MHz
nonimaging transducer. Examination was done from multiple imaging
planes, using careful transducer angulation to isolate maximum velocity
across the LVOT.18 19 Particular effort was made
to isolate a spectral profile showing a relatively slow increase in
velocity culminating in a delayed peak velocity in mid-systole, a
characteristic waveform of HOCM patients (Fig 1
). Gain and filter settings were
adjusted to obtain the signal with the highest audible frequency, the
maximal peak velocity, and optimal signal-to-noise ratio. These gain
and filter settings were recorded and kept constant for each
subsequent study on that patient. Particular care was taken to
distinguish the LVOT signal from that of mitral regurgitation by direct
visualization of color Doppler on two-dimensional image and by
recognizing that mitral regurgitation jet is characterized by earlier
onset, more abrupt initial increase in velocity and higher peak
velocity than the outflow tract signal.18 19
View larger version (72K):
[in a new window]
Figure 1. Top, Continuous-wave Doppler signal at rest
showing a peak velocity of 2.2 m/s, corresponding to a gradient of
19 mm Hg. Bottom, After sublingual NTG, the peak velocity
increases to 4.0 m/s, corresponding to a gradient of 64 mm Hg.
Note the late peaking waveform, which is characteristic of HOCM. 
<20°)
to systolic flow in the LVOT, therefore no angle correction was
used in the estimation of the pressure gradient. LVOT pressure gradient
was estimated by utilizing the modified Bernoulli equation:
P=4 V2, where P is pressure
gradient in mm Hg and V is maximal flow velocity in m/s. For
each study, an average of the three highest velocity beats was
obtained.
The values for LVOT pressure gradient were plotted for all
patients and were observed to follow a gaussian distribution. Mean LVOT
pressure gradient for each patient was calculated from the values
obtained on 5 consecutive days. This mean gradient was considered to
represent the true pressure gradient. Day-to-day variation from
the mean was determined by subtracting each day's value from the mean
value of all 5 days. The 95% confidence intervals for day-to-day
variation were determined as 2 standard deviations from the mean
difference. In addition, the coefficient of variation (standard
deviation divided by the mean) for the 5 consecutive daily measurements
of pressure gradient was calculated for each patient as an index of
spontaneous variability. Similarly, coefficients of variation for blood
pressure, heart rate, left ventricular
end-diastolic dimension, and provoked LVOT pressure
gradient were calculated. Linear regression was used to assess whether
patients who have a higher mean pressure gradient across their LVOT
have a greater day-to-day variability. Finally, interobserver and
intraobserver variability were assessed by linear regression with
Bland-Altman analysis.21
Results
Top
Abstract
Introduction
Methods
Results
Discussion
References
Patient Group
The study population consisted of 12 patients with HOCM, ranging
in age from 34 to 77 years. There were 7 men and 5 women. All patients
were clinically stable and in sinus rhythm. Patients on a stable dose
of cardioactive medication were included in the study. Medications for
HOCM included calcium channel blockers (n=6), ß-blockers (n=2), and
both a calcium blocker and a ß-blocker (n=2). Two patients were not
taking any medication for HOCM. The dose range of ß-blockers was
equivalent to 50 to 150 mg of metoprolol, and the dosage range of
calcium channel blockers was equivalent to 120 to 360 mg of
verapamil. All patients except for one were
symptomatic. Dyspnea was present in all
symptomatic patients. Eight patients suffered from
exertional presyncope, stable angina, and palpitations. Only 2 patients
had a history of a complete syncopal event in the past. Of the 12
patients, 5 were New York Heart Association functional class 1, 6 were
class 2, and 1 was class 3. All patients had asymmetric septal
hypertrophy. Mean septal thickness was 1.8±0.3 cm (range,
1.4 to 2.2 cm). Systolic anterior motion of the mitral
valve was present in 9 patients. The mean rest LVOT pressure
gradient by continuous-wave Doppler
echocardiography was 27±27 mm Hg (range, 3
to 108 mm Hg). Individual values for resting and provoked
gradient in each patient are given in Table 1. The coefficients of variation for
heart rate, systolic blood pressure, LV
end-diastolic dimension, and rest and provoked gradients
are listed in Table 2.
View this table:
[in a new window]
Table 1. Daily Measurements of Resting and Provoked Gradient
in HOCM
View this table:
[in a new window]
Table 2. Coefficients of Variation for Day-to-Day
Measurements in HOCM Patients
The difference between each day's resting gradient and the mean
for all 5 days for each patient is illustrated in Fig 2. While in some patients, the day-to-day
variability in resting gradient was small, in others it varied
markedly. The 95% confidence interval for attributing a change in
resting LVOT gradient to factors other than random variation was
±32 mm Hg. In individual patients, the coefficient of variation
for resting gradient over the 5-day study period ranged from 0.11 to
1.18 (mean, 0.52±0.33). We found no significant correlation between
the coefficient of variation of resting pressure gradient and the
magnitude of the mean gradient (r2=.15,
P=.22).
View larger version (20K):
[in a new window]
Figure 2. Change in rest LVOT gradient from the mean value
over 5 consecutive days for each HOCM patient. The
y-axis shows the difference between the mean for all 5
days and each day's rest gradient (mean minus daily). The 95%
confidence interval (2 standard deviations) is ±32 mm Hg. 
) was accompanied by a corresponding
increase in systolic anterior motion score from 1 to 2+ to
4+.
The difference between each day's provoked gradient and the mean
for all 5 days for each patient is illustrated in Fig 3. Again, in some patients the day-to-day
variability of provoked gradient was small, whereas in others it varied
markedly. The 95% confidence interval for attributing a change in
provoked LVOT gradient to factors other than random variation was
±50 mm Hg. In individual patients, the coefficient of variation
for provoked gradient over the 5-day period ranged from 0.23 to 0.71
(mean, 0.46±0.16). We found no significant correlation between
coefficient of variation of provoked gradient and the magnitude of the
mean provoked gradient (r2=.16,
P=.20).
View larger version (21K):
[in a new window]
Figure 3. Change in provoked LVOT gradient from the mean
value over 5 consecutive days for each HOCM patient. The
y-axis is the difference between each day's provoked
gradient and the mean for all 5 days. The 95% confidence interval
(2 standard deviations) is ±50 mm Hg.
Day-to-day values of pressure gradient across the aortic valve for
the five control patients with aortic stenosis were obtained in
a similar manner as that of HOCM patients. The difference between each
day's resting gradient and the mean for all 5 days is illustrated in
Fig 4. The 95% confidence interval (±2
SD) was 5 mm Hg for the control group. The coefficient of
variation averaged 8±5% (range, 3% to 13%).
View larger version (16K):
[in a new window]
Figure 4. Change in aortic valve gradient from the mean
value over 5 consecutive days in each aortic stenosis patient.
The y-axis is the difference between each day's rest
gradient and the mean for all 5 days. The 95% confidence interval (2
standard deviations) is ±5 mm Hg.
An excellent correlation was found for rest gradient measurements
between different observers (r=.96) and the same observer at
different readings (r=.98). By Bland-Altman
analysis, the mean difference in interobserver and
intraobserver pressure gradient measurements was 0±5 mm Hg and
1±3 mm Hg, respectively. Similarly, a close correlation and
strong agreement was also found for provoked gradient
(r=.99, mean difference=-2±5), and (r=.95, mean
difference=0±5) for interobserver and intraobserver variability,
respectively.
Discussion
Top
Abstract
Introduction
Methods
Results
Discussion
References
Reduction in pressure gradient across the LVOT has been reported
as objective evidence of therapeutic success in patients
HOCM.8 9 10 11 12 To our knowledge, this is the first
study to systematically address the magnitude of spontaneous day-to-day
variability of pressure gradient in HOCM patients. We found the
coefficient of variation for repeated measurements of resting and
provoked gradient to be 0.52 and 0.46, respectively. This marked
variation in LVOT gradient was not associated with a change in symptoms
in most patients.
Wide spontaneous fluctuations in pressure gradient from one day to
another in HOCM, as reported in this study, indicate that a single
measurement of pressure gradient is not adequate to describe the
severity of LVOT obstruction. On the basis of our findings, we propose
that the LVOT pressure gradient be assessed on at least three separate
occasions and averaged in these patients. Such an approach would not be
novel to clinical practice, since the diagnosis of hypertension is not
made unless the patient's blood pressure is elevated on two different
measurements, on at least two separate occasions to account for the
spontaneous variation in blood pressure.22 23 In
addition to improving assessment of the individual patient, averaging
the LVOT gradient on 3 separate days would also help to distinguish
therapeutic benefit or disease progression from spontaneous variation.
This is important for clinical decision making in individual patients
and in clinical trials evaluating new therapies aimed at reducing the
pressure gradient in HOCM.
It is difficult to accurately measure left ventricular
afterload in the setting of HOCM. Noninvasive measures of afterload,
such as end-systolic wall stress, use cuff systolic
blood pressure as a surrogate marker for
intraventricular systolic
pressure.28 Such an approach would be inaccurate
in HOCM since the cuff systolic pressure may not reflect the
true intraventricular systolic pressure.
Although we did not find a significant change in systolic blood
pressure between studies in individual patients, we also cannot
completely eliminate the possibility of changes in afterload between
studies. , some patients on given days did not increase their
gradient with provocation. This may be due to inadequate
hemodynamic change with NTG or failure to collect the
Doppler data until maximal hemodynamic effect had
subsided.
The LVOT pressure gradient varies considerably from day to day in
stable patients with HOCM. A single measurement of pressure gradient is
not adequate to define the severity of dynamic LVOT obstruction in
HOCM.
Selected Abbreviations and Acronyms
HOCM
=
hypertrophic obstructive cardiomyopathy
LVOT
=
left ventricular outflow tract
NTG
=
nitroglycerin
References
Top
Abstract
Introduction
Methods
Results
Discussion
References
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