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(Circulation. 1997;96:2959-2968.)
© 1997 American Heart Association, Inc.
Articles |
Adrenergic Control of the Force-Frequency and Relaxation-Frequency Relations in Patients With Hypertrophic Cardiomyopathy
From the First Department of Internal Medicine (H.I., Y.T., M.I., K.N., M.I., T.S.) and the Department of Clinical Laboratory Medicine (M.Y.), Nagoya (Japan) University School of Medicine.
Correspondence to Mitsuhiro Yokota, MD, PhD, Cardiovascular Section, Department of Clinical Laboratory Medicine, Nagoya University Hospital, 65 Tsurumai-cho, Showa-ku, Nagoya, 466 Japan. E-mail myokota{at}tsuru.med.nagoya-u.ac.jp
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Abstract |
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 Top Abstract IntroductionMethodsResultsDiscussionReferences |
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Background Exercise-induced enhancement of the force-frequency and relaxation-frequency relations has been studied in conscious animals but not in intact diseased human hearts.
Methods and Results We evaluated left
ventricular (LV) isovolumic contraction
(dP/dtmax) and relaxation (
) during atrial pacing and
dynamic exercise in 13 patients with nonobstructive hypertrophic
cardiomyopathy (HCM) and 7 control subjects to
investigate the influence of exercise on the force-frequency and
relaxation-frequency relations. Group A consisted of 6 patients in whom
the heart rate (HR)–dP/dtmax relation was markedly
enhanced during exercise (88±30%) compared with during pacing
(34±15%). Group B consisted of 7 patients in whom the
HR-dP/dtmax relation showed similar enhancement during
exercise (28±7%) and atrial pacing (28±11%). There was no
difference in the HR- (derivative method [TD] and pressure
half-time method [T1/2]) relation between pacing and
exercise in groups A and B. Both the mean maximal wall thickness and
the hypertrophy score in group B were greater than in group
A (27±5 versus 19±2 mm and 7±1 versus 5±1 points,
respectively; both P<.01). There was no difference in the
LV peak systolic pressure, end-diastolic pressure,
or the plasma level of catecholamines at baseline, at 50 W
of exercise, and at peak pacing between groups A and B. The
HR-dP/dtmax relation in the control group was markedly
enhanced during exercise (80±27%) compared with during pacing
(32±14%). The HR- relation in the control group was enhanced
during exercise (TD, 35±9%; T1/2, 34±8%) compared with
during pacing (TD, 12±7%; T1/2, 14±7%).
Conclusions Exercise-induced enhancement of the relaxation-frequency relation was inhibited in all HCM patients, regardless of the degree of LV hypertrophy. The patients without exercise-induced enhancement of the force-frequency relation had more severe LV hypertrophy than the patients with the enhancement, indicating that the adrenergic control of the force-frequency relation may, at least in part, depend on the severity of LV hypertrophy or the stage of HCM.
Key Words: cardiomyopathy • exercise • contractility
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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An increase in HR has been found to augment myocardial contractility (the force-frequency effect) and relaxation (the relaxation-frequency effect) in isolated mammalian heart muscle1 2 and intact anesthetized normal animals,3 4 but its effect in conscious animals is controversial. Some studies5 6 7 8 have suggested that an increased HR has minimal effects on contraction and relaxation, whereas others9 10 have observed significantly enhanced myocardial contractility and relaxation in response to an increased HR. Recent studies have shown that exercise-induced adrenergic stimulation enhances the force-frequency relation and the relaxation-frequency relation in conscious normal dogs.7 11 12 On the other hand, Eising et al8 have reported that ß-adrenergic stimulation–induced enhancement of the force-frequency relation was impaired in a pig model of cardiac failure.
An increased HR produced by atrial pacing has a positive inotropic
effect in healthy human subjects.13 14 Feldman et
al14 reported that patients with dilated
cardiomyopathy showed little or no enhancement in
LV dP/dtmax and the time constant of isovolumic relaxation
() during atrial pacing–induced tachycardia. The
inotropic response to rapid pacing, evaluated in terms of
pressure-volume relations, was recently reported to be diminished in
patients with symptomatic hypertensive
hypertrophy.15 Both diastolic and
systolic functions of HCM has been reported to diminish at
increased HR in isolated muscle16 and intact
humans.17 Most studies have evaluated
diastolic dysfunction in terms of the elevation in the LV
end-diastolic pressure or tension and systolic
dysfunction in terms of the decrease in force generation or shortening.
However, the force-frequency and relaxation-frequency relations during
exercise have not been assessed in HCM patients. We recently found that
the effect of exercise-induced adrenergic stimulation on relaxation was
blunted in patients with nonobstructive HCM, who were different from
patients in the present study, compared with patients with
hypertensive hypertrophy,18 suggesting that
the response of relaxation to exercise-induced adrenergic stimulation
may, at least in part, depend on the pathogenesis or the cause of LV
hypertrophy.
Although specific missense mutations of sarcomeric proteins, such as
myosin heavy chain, troponin T, 
-tropomyosin, and C-protein, have
been reported in patients with familial HCM,19 20 21 HCM is a
primary cardiac disease characterized by LV hypertrophy
without an identifiable cause. The clinical course and prognosis differ
considerably from patient to patient. Sudden death has occurred in some
asymptomatic patients during physical
exercise.22 23 LV outflow obstruction does not appear to
be a determinant of sudden death,22 23 24 but abnormal
cardiac performance during exercise is believed to be an
important contributing factor.23 However, the effect of
exercise-induced adrenergic stimulation on LV inotropic and lusitropic
properties in patients with HCM remains largely unexplored.
Accordingly, the aim of the present study was to examine the effect of exercise-induced adrenergic stimulation on the force-frequency and relaxation-frequency relations in patients with HCM. HR-induced changes in LV inotropic and lusitropic properties were evaluated in patients with nonobstructive HCM and a control group consisting of patients without coronary artery disease and with normal LV function.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The protocols were approved by the appropriate institutional review committee. Written informed consent was obtained from all subjects.
Patient Population
We studied 13 patients with nonobstructive HCM (mean age, 55
years; range, 37 to 64 years). All patients were suspected of having LV
hypertrophy on routine company medical examination on the
basis of an ECG and/or echocardiography and had
occasional mild breathlessness or atypical chest pain. All patients
were newly diagnosed and had not previously taken cardioactive
medications. Of the 13 patients, 5 had an identifiable family history
of HCM in a second-degree relative. All patients had normal sinus
rhythm on ECG and normal LV ejection fraction on left ventriculograms
(mean, 73%; range, 64% to 82%) without an elevation of LV
end- diastolic pressure (mean, 10 mm Hg; range, 6
to 16 mm Hg) at baseline. HCM was diagnosed by established
clinical, hemodynamic, and
echocardiographic criteria.21 No
significant intraventricular pressure gradient was
detected at rest or during provocative maneuvers (the
Valsalva maneuver and isoproterenol infusion) following completion of
the study protocol in any patients with HCM. Patients with apical
hypertrophy, as indicated by a spade-shaped configuration
on left ventriculography, were excluded. We also studied 7 patients
with normal LV function who had been referred for evaluation of
atypical chest pain as the control group. Control subjects had normal
ECGs, left ventriculograms, and echocardiograms. None of the study
subjects had valvular heart disease or >50% coronary
artery stenosis as determined by coronary
arteriography.
Assessment of LV Hypertrophy
Two-dimensional echocardiographic studies were
performed with conventional equipment, and images were recorded on
0.5-in VHS videotape recorders. Images were obtained in the
parasternal long- and short-axes views and apical 2- and 4-chamber
views. Echocardiographic analysis was performed
by a single individual who was unaware of the results of this study.
All patients had adequate echogenecity to allow reliable wall thickness
measurements in all segments needed for calculating
hypertrophy score. The measurements were made at end
diastole. The degree of LV hypertrophy was
evaluated semiquantitatively by use of the scoring system proposed by
Wigle et al,25 with a maximum of 10 points: 1 to 4 points
for septal hypertrophy based on the magnitude of the
thickness, up to 4 points for the length of asymmetric
hypertrophy determined from the parasternal and apical
views, and 2 points for the anterolateral extension of
hypertrophy determined from the short-axis view. This
scoring system was reported to correlate well with the Spirito-Maron
index by magnetic resonance imaging.26 We also assessed
MWT on the basis of the method proposed by Spirito and
Maron.27 In the parasternal short-axis plane, the LV was
divided into four segments (the anterior and posterior
ventricular septum and the lateral and poterior LV free
walls). Wall thickness was measured at the levels of both mitral valve
and the papillary muscles in each of the four ventricular
segments. The segment of the wall that showed the greatest thickness
was considered to represent the MWT.
Catheterization Procedures
A 6F pigtail angiographic high-fidelity
micromanometer-tipped catheter (model SPC-464D,
Millar Instruments) was advanced into the left ventricle through the
right brachial artery for measurement of LV pressure. The
micromanometer pressure was matched to the pressure
of the fluid-filled lumen. A 20-gauge catheter was placed in the left
brachial artery for measurements of arterial pressure. A 6F
bipolar pacing catheter was introduced through the right subclavian
vein and positioned in the right atrium. A 7F triple-lumen thermistor
Swan-Ganz catheter (Baxter Healthcare Co) was positioned in the
pulmonary artery through the right brachial vein. After bicycle
ergometer exercise tests were completed, selective coronary
angiography and left ventriculography were performed.
Study Protocol
Pacing Study
After all catheters were in place and baseline
hemodynamic data were being collected, right atrial
pacing was initiated at 80 bpm and increased by 10 bpm increments to a
maximum of 120 bpm for 3 minutes each. A modified 12-lead ECG,
arterial pressure, LV pressure, and the first derivative of
LV pressure (dP/dt) were recorded continuously during pacing. No
patients demonstrated right or left bundle-branch block or
second-degree AV block during right atrial pacing.
Exercise Study
Exercise testing was performed with patients in the supine
position on a bicycle ergometer, as described
previously,28 at least 30 minutes after completion of the
pacing study. The workload was initiated at 25 W for 3 minutes and then
increased to 50 W. The test was stopped after patients had exercised
for 6 minutes. A modified 12-lead ECG was recorded and
hemodynamic measurements were obtained at rest and at
the end of each 3-minute exercise stage.
Micromanometer pressure signals and a bipolar
standard ECG lead were re- corded continuously with a
multichannel recorder (MR-40, TEAC Co). No patients developed an
outflow tract gradient as assessed by Doppler
echocardiography,21 and none
demonstrated right or left bundle-branch block on the modified 12-lead
ECG during exercise.
Data Analysis
LV pressure signals were digitized at 3-ms intervals and
analyzed with software developed in our laboratory with a
32-bit microcomputer system. LV pressure data at baseline, at each
pacing rate, and at 7 to 10 points during exercise were selected for
analysis. To compensate for changes in the intrathoracic
pressure during breathing, steady-state measurements were averaged over
a 12-second recording period that spanned multiple respiratory
cycles. Extrasystolic and postextrasystolic
beats were excluded from analysis.
We used the ratio of the LV dP/dt to developed LV pressure at a developed LV pressure of 40 mm Hg [(dP/dt)/DP40], which is relatively insensitive to changes in preload and afterload, as an index of contractility.29
To evaluate LV isovolumic relaxation, was calculated in two ways.
The first method is the direct measurement of the pressure half-time
(T1/2) as described by Mirsky.30 The time
constant T1/2 was computed for each acquisition as the time
required for the pressure at the time of dP/dtmin to
decline to one half of its value at dP/dtmin. The second
method is a modification of that described by Raff and
Glantz31 in which (TD) is determined from the negative
inverse slope of the pressure-dP/dt plot using data between
dP/dtmin and a pressure equal to 5 mm Hg above the
previous LV end-diastolic pressure. The correlation
coefficients (r) were generally between.993 and.995, and the
lowest r value was.991.
LV end-systolic and end-diastolic volumes were determined by biplane ventriculography and calculated by the area-length method.32
Plasma Concentrations of Catecholamines
Blood samples (7 mL) were collected from the brachial artery at
rest, at 120 bpm of pacing, and at 50 W of exercise and well
centrifuged at 5000 rpm at 4°C for 10 minutes. Plasma samples
(3 mL) were stored at -70°C until assayed. The plasma level of
catecholamines was analyzed by a radioenzymatic
assay with a commercial kit.
Statistical Analysis
Results are expressed as the mean±SD. One-way factorial ANOVA
was used to compare baseline characteristics and
hemodynamic variables at 120 bpm of pacing and at
50 W of exercise among groups. Within-group comparisons were performed
for the hemodynamic changes during exercise and pacing
with two-way repeated measures ANOVA. When a significant difference was
present, intergroup comparisons were made with Scheffé's
multiple comparison test. The force-frequency and relaxation-frequency
relations were assessed by the nonlinear least-squares fitting
technique as appropriate. Between-group comparisons of the regression
curves were determined by ANCOVA, with individual differences
analyzed by Scheffé's multiple comparison test. A value
of P<.05 was considered statistically significant.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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No complications were associated with the pacing or the exercise protocol. No patients complained of dyspnea or chest pain during either protocol. A representative illustration of waveforms from one control subject is depicted at baseline, 120 bpm of pacing, and 50 W of exercise (Fig 1
). The HR was
significantly correlated with the LV dP/dtmax
(r=.98±.22) and the T1/2
(r=.93±.39) during atrial pacing and exercise in control
subjects and HCM patients (Figs 2 through 4).
The slopes of the regression curves for HR–LV dP/dtmax
relation and the HR-T1/2 relation were significantly
steeper during exercise than during atrial pacing in control subjects
(P<.05, Fig 2).
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indicates during atrial
pacing; 
, during exercise.
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Subgroup Classification
We divided the HCM patients into two groups on the basis of the
comparative analysis of the force-frequency relation during
pacing and exercise. Group A consisted of 6 patients in whom the slope
of the regression curve for the HR–LV dP/dtmax relation
was significantly steeper during exercise than during atrial pacing
(P<.05, Fig 3
), showing that the force-frequency relation
was enhanced by exercise-induced adrenergic stimulation. Group B
consisted of 7 patients in whom the slope of the regression curve for
the HR–LV dP/dtmax relation was similar during pacing and
during exercise (Fig 4), showing that the force-frequency relation was
not enhanced by exercise-induced adrenergic stimulation. The relation
between HR and the LV (dP/dt)/DP40 was identical to HR–LV
dP/dtmax (data not shown). The slope of the regression
curve for the HR- T1/2 relation was similar during exercise
and during atrial pacing in all HCM patients.
Baseline Characteristics
Both groups A and B had increased wall thickness, with the greater
hypertrophy present in group B (Table 1). The LV hypertrophy score
was significantly higher in group B than in group A. All 3 patients
whose LV hypertrophy score was <4 belonged to group A, and
all 5 patients whose LV hypertrophy score was 
7 belonged
to group B. The LV end-systolic and end-diastolic
volumes were decreased and the LV ejection fraction was increased in
groups A and B compared with the control group.
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Hemodynamic Variables at Rest, 120 bpm of
Pacing, and 50 W of Exercise
There were no differences in resting hemodynamic
variables between before atrial pacing and before exercise in any
group (Table 2). In the control group,
the LV dP/dtmax and LV (dP/dt)/DP40 both
increased by 32% during pacing at a rate of 120 bpm; T1/2
decreased by 14% and TD decreased by 12%. Exercise induced
significant increases in the LV dP/dtmax, LV
(dP/dt)/DP40, and LV peak systolic and
end-diastolic pressures compared with at rest (80%, 74%,
21%, and 56%, respectively). Exercise also induced a significant
decrease in T1/2 and TD compared with at rest (34% and
35%, respectively).
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In group A, atrial pacing increased both the LV dP/dtmax
and LV (dP/dt)/DP40 by 34% (Fig 5). Exercise also induced significant
increases in the LV dP/dtmax and LV
(dP/dt)/DP40 (88% and 87%, respectively). In group B, the
LV dP/dtmax and LV (dP/dt)/DP40 increased
significantly at 120 bpm of pacing (by 28% and 28%, respectively) and
at 50 W of exercise (by 28% and 29%, respectively) compared with at
rest. Changes in LV end-diastolic pressure from baseline to
50 W of exercise were similar between groups A and B (Fig 6). All patients in groups A and B had
greater T1/2 than control subjects at rest.
T1/2 was significantly prolonged at rest, at 120 bpm of
pacing, and at 50 W of exercise in group B compared with group A. But
changes in T1/2 were similar during atrial pacing and
exercise in group A (an 11% decrease during pacing and an 18%
decrease during exercise) and group B (a 9% decrease during pacing and
a 12% decrease during exercise). TD showed similar changes.
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) in LV
end-diastolic pressure (LVEDP) for 120 bpm of pacing and 50
W of exercise among the three groups. LVEDP during exercise increased
more markedly in the HCM groups than in the control group, but the
difference did not exist between the two HCM groups. *P<.05
vs control group.
Changes in the Plasma Levels of Catecholamines
Exercise-induced increases in the plasma level of
norepinephrine were observed in all groups. There were no
significant differences among groups in the plasma levels of
norepinephrine at rest (control, 219±35 pg/mL;
group A, 227±18 pg/mL; group B, 234±26 pg/mL), at 120
bpm of pacing (control, 235±38 pg/mL; group A, 239±26
pg/mL; group B, 252±41 pg/mL), or at 50 W of exercise
(control, 476±86 pg/mL; group A, 507±103 pg/mL; group
B, 485±61 pg/mL). Plasma levels of epinephrine were
also similar in all groups.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The present study presents a novel finding regarding both the force-frequency and the relaxation-frequency relations during atrial pacing and dynamic exercise in HCM patients. The exercise-induced enhancement of the relaxation-frequency relation was inhibited in all HCM patients, regardless of the degree of LV hypertrophy. On the other hand, we could divide the HCM patients into two groups on the basis of the difference in the force-frequency relation between during atrial pacing and exercise. One group consisted of patients with exercise-induced enhancement of the force-frequency relation, and the other consisted of patients without exercise-induced enhancement of the force-frequency relation. Patients without exercise-induced enhancement of the force-frequency relation had more severe LV hypertrophy than patients with exercise-induced enhancement of the force-frequency relation. In contrast, the force-frequency and the relaxation-frequency relations during atrial pacing were similar in all HCM patients and control subjects. These results indicate that the adrenergic control of the force-frequency relation may, at least in part, depend on the severity of LV hypertrophy or the stage in HCM and that the impaired adrenergic control of the relaxation-frequency relation might precede the impaired adrenergic control of the force-frequency relation in HCM patients.
Adrenergic Control of the Force-Frequency and Relaxation-Frequency
Relations in Control Subjects
The primary effect of exercise on myocardial
contractility is direct enhancement of myocardial
contraction caused by stimulation of myocardial ß-adrenergic
receptors.33 34 35 Recent studies have suggested that
ß-adrenergic control of the force-frequency relation is at least as
important as its effect on myocardial
contractility.35 Previous studies have
shown that ß-adrenergic stimulations induced by
exercise11 12 or dobutamine
infusion7 enhanced the force-frequency and
relaxation-frequency relations in normal conscious dogs.
Dobutamine caused a dose-dependent upward shift of the
force-frequency relation during atrial pacing; at higher heart rates,
the inotropic effect was greater than that seen with
dobutamine alone. In conscious dogs, ß-adrenergic
blockade resulted in a reduction in the resting LV dP/dtmax
and the prevention of the early increase in the LV dP/dtmax
in response to exercise without ischemia, despite a modest
increase in HR.33 In the present study, we observed
that the exercise-induced adrenergic stimulation enhanced the
myocardial response of contractility and relaxation to
an increased HR in control subjects, indicating that regulation of the
force-frequency and relaxation-frequency relations by altered
ß-adrenergic stimulation during exercise is important for normal
physiological control of myocardial
contractility and relaxation as well as at
rest.35
The mechanisms involved in the adrenergic control of the force-frequency and relaxation-frequency relations are related primarily to increased Ca2+ availability to the myofilaments. In cardiac muscle, contraction-relaxation cycle is tightly controlled by the regulated release and removal of Ca2+ by the SR. It is well known that increased cAMP resulting from ß-adrenergic stimulation results in phosphorylation of sarcolemmmal Ca2+ channels by cAMP-dependent PKA, enhancing Ca2+ entry.36 PKA also phosphorylates phospholamban, which causes a disinhibition of SR Ca2+-ATPase, leading to accelerated relaxation.37 These alterations of the intracellular Ca2+ handling may be one of the major mechanisms of inotropic and lusitropic responses to exercise-induced adrenergic stimulation in the control subjects of the present study.
Impaired Adrenergic Control of the Force-Frequency and
Relaxation-Frequency Relations in HCM
In the present study, the force-frequency and
relaxation-frequency relations were preserved during atrial pacing in
all HCM patients. However, exercise-induced enhancement of the
relaxation-frequency relation was inhibited in all HCM patients.
Furthermore, the HCM patients were divided into two groups on the basis
of the difference in the force-frequency relation between during pacing
and during exercise. The patients without exercise-induced enhancement
of the force-frequency relation had more severe LV
hypertrophy than the patients with the enhancement. These
findings demonstrate that the adrenergic control of the force-frequency
relation was impaired in HCM patients with severe LV
hypertrophy and that the adrenergic control of the
relaxation-frequency relation was impaired in all HCM patients
regardless of the degree of LV hypertrophy. The possible
mechanisms of impaired adrenergic control of the force-frequency and
relaxation-frequency relations in HCM patients may include abnormal
intracellular Ca2+ handling, nonuniformity, and/or
ischemia in hypertrophied myocardium.
The subcellular mechanisms of impaired myocardial Ca2+ handling in HCM are the subject of ongoing study.16 38 39 40 41 42 No abnormalities in the number of ß-adrenoreceptors or adenylate cyclase activity have been observed in HCM patients and the WKY/NCrj rat model for HCM.38 39 There have been reports of abnormalities, including impaired intracellular Ca2+ transients, indicating delayed Ca2+ reuptake of SR with an increase in the end-diastolic intracellular Ca2+,16 an increase in the number of sarcolemmal Ca2+ ion channel,38 and a reduction in the enzyme activity and gene expression of the SR Ca2+-ATPase and sarcolemmal Ca2+-ATPase pumps.40 41 42 These data suggested that the Ca2+ overload and Ca2+ deposition caused by impaired Ca2+ sequestration by SR may have been responsible for the inhibited effect of exercise on the relaxation-frequency relation in the HCM patients in the present study. In the severe hypertrophied heart, the density of the Ca2+ release channels in SR (the ryanodine receptors) is reported to be decreased without changes in the binding affinity.43 This abnormality may have contributed to the impaired adrenergic control of the force-frequency relation in the HCM patients with severe LV hypertrophy. Further studies are needed to confirm these possibilities.
Nonuniformity should be considered as one of the potential mechanisms for our observations. A recent study44 45 has documented enhanced regional asynchrony of diastolic wall motion in HCM patients, which related to the prolonged LV relaxation. The possible causes of nonuniformity in HCM are considered to include the heterogeneity of regional load, metabolic condition, and wall stiffness.44 Ischemia in hypertrophied myocardium also affected regional nonuniformity.46 Therefore, our observations may be affected by the degree of nonuniformity as well as ischemia in the both HCM groups. Further studies are needed to clarify this issue.
Hittinger et al47 demonstrated selective subendocardial hypoperfusion and profound selective depression in subendocardial wall thickening during exercise in dogs with LV hypertrophy. And severe myocardial hypertrophy can affect diastolic function by subendocardial ischemia in HCM patients.17 Myocardial ischemia, which has been revealed by abnormal thalium perfusion,48 affected intracellular Ca2+ handling and regional nonuniformity.46 Relaxation seems to be more sensitive to myocardial ischemia than contraction.49 50 Taken together, myocardial ischemia may also explain the impairment of the adrenergic control of the force-frequency and relaxation-frequency relations in the HCM patients with severe LV hypertrophy.
Study Limitations
There are several limitations to the present study. First, we
used the LV dP/dtmax as an index of
contractility of the intact human heart, but LV
dP/dtmax is preload dependent. Although the change of LV
end-diastolic pressure from the resting condition to peak
exercise was similar in groups A and B, the change of the LV
dP/dtmax was greater in group A than in group B. We also
calculated LV (dP/dt)/DP40, which is relatively insensitive
to changes in preload and afterload,29 as an index of
contractility; the change in this index was similar to
the change in the LV dP/dtmax. Therefore, the difference in
the change of LV dP/dtmax and LV (dP/dt)/DP40
during exercise between groups A and B cannot be ascribed to loading
condition but rather to a true degree in the inotropic state. Second,
the use of a simple exponential model to characterize the time course
of the fall in LV pressure provides only an approximation. The
assumption of a monoexponential pressure decline for
calculation of may not be appropriate in ventricles in which there
is significant asynchrony of contraction and relaxation, as is the case
in HCM patients.51 Thus, we also applied T1/2
as the time constant of isovolumic relaxation, which is an index of a
nonexponential curve-fitting model according to the recommendation of
Mirsky.30 Changes in TD were consistent with
changes in T1/2 in the present study.
Clinical Implications
Sudden death can occur during physical exercise in some HCM
patients.22 23 The determinants and the mechanisms of
sudden death in these patients have not been clarified but may be
multifactorial and may differ among patients. A previous study
demonstrated that the risk of sudden death was significantly higher in
HCM patients with and without LV outflow obstruction who had a positive
result on a single Master's two-step test.22 LV outflow
obstruction does not appear to be a determinant of sudden
death,22 23 24 but abnormal cardiac performance
during exercise is believed to be an important factor.23
In the present study, we first demonstrated that the
exercise-induced enhancement of the relaxation-frequency relation was
inhibited in all HCM patients, regardless of the degree of LV
hypertrophy, and that the exercise-induced enhancement of
the force-frequency relation was inhibited in patients with severe LV
hypertrophy. The degree of LV hypertrophy has
been found to be related to the occurrence of sudden death in HCM
patients.27 Therefore, the impaired responses of LV
inotropic and lusitropic properties to exercise-induced adrenergic
stimulation may be one of the potential mechanisms of sudden death.
In conclusion, exercise-induced enhancement of the relaxation-frequency relation was inhibited in all HCM patients, regardless of the degree of LV hypertrophy. The patients without exercise-induced enhancement of the force-frequency relation had more severe LV hypertrophy than the patients with exercise-induced enhancement of the force-frequency relation. These results indicate that the adrenergic control of the force-frequency relation may, at least in part, depend on the severity of LV hypertrophy or the stage in HCM.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported in part by a grant-in-aid for scientific research from the Ministry of Education, Science, and Culture of Japan to Dr Yokota. Financial support from the Fukuda Memorial Foundation to Drs Yokota and Izawa is gratefully acknowledged. We are grateful to Drs Hirofumi Kanda, Takeshi Machii, Ryozo Kato, Takaharu Fujimura, Sahoko Ichihara, and Kazushige Shigemura for their cooperation; Nobuyuki Kitagawa for his valuable technical advice; Norio Sugimoto for his valuable statistical advice; and Sadako Ichihashi for manuscript preparation.
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Footnotes |
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Presented in part at the 69th Scientific Sessions of the American Heart Association, New Orleans, La, November 12, 1996, and printed in abstract form (Circulation. 1996;94(suppl I):I-502.)
Received April 15, 1997; revision received June 6, 1997; accepted June 19, 1997.
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