Download Mechanical Alternans in Patients With Chronic Heart Failure

Journal of Cardiac Failure Vol. 7 No. 2 2001
Mechanical Alternans in Patients With Chronic
Heart Failure
MAKOTO KODAMA, MD,* KIMINORI KATO, MD,*
SATORU HIRONO, MD,* YUJI OKURA, MD,* HARUO HANAWA, MD,*
MASAHIRO ITO, MD,* KOICHI FUSE, MD,* TAKAAKI SHIONO, MD,*
KENICHI WATANABE, MD,† YOSHIFUSA AIZAWA, MD*
Niigata, Japan
ABSTRACT
Background: Clinical implications of mechanical alternans in patients with chronic heart
failure have remained uncertain. In this study, prevalence, characteristics, and prognostic
implications of mechanical alternans were investigated.
Methods and Results: Consecutive 51 patients with dilated cardiomyopathy underwent
diagnostic cardiac catheterization using a micromanometer-tipped catheter. Under basal
conditions, 7 of 35 patients with sinus rhythm showed mechanical alternans. Physiologic
tachycardia (110 bpm) induced mechanical alternans in another 15 patients with sinus rhythm
and in another 10 of 16 patients with atrial fibrillation. Low doses of dobutamine also induced
mechanical alternans in another 8 patients, but a high dose of dobutamine eliminated
mechanical alternans. Consequently, 40 patients (78%) showed mechanical alternans.
Mechanical alternans was always accompanied by alternating changes of positive dP/dt, a
parameter of contractility during isovolumetric contraction time, but negative dP/dt was
occasionally constant. Concordant mechanical alternans between both ventricles was more
prevalent than discordant alternans. The left ventricular end-diastolic volume indices and
end-systolic volume indices of patients with mechanical alternans were larger than those of
patients without. The left ventricular ejection fraction of patients with alternans was
significantly lower than that of patients without.
Conclusions: Mechanical alternans was highly prevalent in patients with chronic heart
failure. The origin of mechanical alternans seems to exist before or at the isovolumetric
contraction time.
Key words: mechanical alternans, chronic heart failure, dilated cardiomyopathy, dP/dt,
sarcoplasmic reticulum.
From the *First Department of Internal Medicine, Niigata University School of Medicine, and the †Department of Clinical Pharmacology, Niigata
College of Pharmacy, Niigata, Japan.
Supported in part by a grant for scientific research (10670636) from the Ministry of Education, Science, and Culture of Japan and a grant-in-aid
from the Tsukada Medical Science Foundation.
Manuscript received June 28, 2000; revised manuscript received January 31, 2001; revised manuscript accepted February 9, 2001.
Reprint requests: Makoto Kodama, MD, First Department of Internal Medicine, Niigata University School of Medicine, Asahimachi 1-757, Niigata
951-8510, Japan.
Copyright © 2001 by Churchill Livingstone威
1071-9164/01/0702-0006$35.00/0
doi:10.1054/jcaf.2001.24122
138
Mechanical Alternans in Chronic CHF O Kodama et al
Mechanical alternans is a mysterious phenomenon of
alternating strong and weak beats with a constant beat to
beat interval. The phenomenon has, for over a century,
been recognized in patients with severe congestive heart
failure caused by global left ventricular dysfunction
(1–3). Other conditions related to the appearance of
mechanical alternans are aortic stenosis (4), hypertrophic
obstructive cardiomyopathy (5), sudden increase of afterload (6,7), ischemia (8,9), abrupt fall of preload, and
the onset of a tachyarrhythmia (10–12). Experimental
studies showed that mechanical alternans can be provoked in either whole hearts, isolated muscle preparations, and cultured isolated cardiomyocytes (13–15).
Experimental preparations also showed that predisposing
factors to mechanical alternans are extremely rapid heart
rates, ischemia, negative inotropic interventions, cooling
of the muscle, reduction of the extracellular Ca2⫹ concentration, and acidosis. In spite of the great interests by
both physiologists and cardiologists, the precise mechanisms of human mechanical alternans and clinical implications of mechanical alternans still remain unclear.
Cardiac alternans can be classified into mechanical
alternans and electrical alternans. Electrical alternans is
composed of QRS alternans and ST-T alternans. QRS
electrical alternans has been considered to be related to
incomplete activation of the heart or changes of the
ventricular activation process (16). Another possible
relating condition for QRS alternans is positional oscillation of the heart in massive pericardial effusion. ST-T
electrical alternans depends on the oscillation of the
action potential duration. This form of electrical alternans leads to the dispersion of refractory periods of the
myocardium. ST-T electrical alternans has been shown to
be able to predict the occurrence of polymorphic ventricular tachycardia, ventricular fibrillation, and sudden
cardiac death (17–20). Despite the clinical usefulness of
electrical alternans, prognostic implications of mechanical alternans in patients with chronic heart failure are still
unknown (21–23). The relevance among these subtypes
of cardiac alternans is also uncertain.
In this study, we examined the frequency and features
of mechanical alternans in patients with chronic heart
failure. We also analyzed the relationship between the
prevalence of mechanical alternans and left ventricular
function. Mechanisms and prognostic implications of
mechanical alternans in patients with chronic heart
failure were also discussed.
Methods
Patients
Fifty-one consecutive patients with mild-to-severe left
ventricular dysfunction, admitted to our hospital from
November 1989 to May 1995 because of chronic or
139
congestive heart failure, were included in the study
(Table 1). Underlying heart diseases consisted of idiopathic dilated cardiomyopathy and postmyocarditic dilated cardiomyopathy. Patients with active myocarditis,
significant valvular diseases, hypertensive heart diseases,
hypertrophic cardiomyopathy, or ischemic heart diseases
were excluded. Thirty-eight patients were men. Ages of
the patients ranged from 21 to 71. Thirty-five patients
had sinus rhythm, and the remainder had atrial fibrillation. The left ventricular end-diastolic volume indices
ranged from 63 to 276 mL/m2. The left ventricular
ejection fraction ranged from 13% to 59%. After admission to the hospital, congestive heart failure was controlled using diuretics, digitalis, and angiotensinconverting enzyme inhibitors. Cardiac catheterization
was performed after written informed consent was obtained from each patient. All patients were followed for
over 3.5 years or until death.
Hemodynamic Assessments
All patients initially underwent routine left and right
diagnostic catheterization using a femoral approach.
Diagnostic examinations contained pressure studies,
coronary arteriography, and left ventriculography. After
diagnostic procedures were undertaken, a 7F
micromanometer-tipped catheter (Millar Industries,
Houston, TX) was placed in the left ventricle. A 7F
thermodilution floating catheter was placed in the pul-
Table 1. Patient Characteristics
Total number
Men
Women
Age (yr)
Range
Mean
Underlying diseases
Dilated cardiomyopathy
Postmyocarditis
Uremic cardiomyopathy
Rhythm
Sinus
Atrial fibrillation
NYHA
1
2
3
4
Left ventricular function
LVEDVI range
Mean
LVESVI range
Mean
LVEF range
Mean
51
38
13
21–71
49 ⫾ 13
46
3
2
35
16
3
29
19
0
63–276
134 ⫾ 41
35–220
88 ⫾ 38
13–59
36 ⫾ 12
NYHA, New York Heart Association; LVEDVI, left ventricular
end-diastolic volume index; LVESVI, left ventricular end-systolic
volume index; LVEF, left ventricular ejection fraction.
140 Journal of Cardiac Failure Vol. 7 No. 2 June 2001
monary artery. A 5F pacing catheter was advanced to the
right atrium in patients with sinus rhythm and to the right
ventricle in patients with atrial fibrillation. Left ventricular pressure, the first derivatives of left ventricular
pressure (dP/dt), and pulmonary artery pressure were
recorded on a chart recorder during this study. Electrocardiography of surface limb leads were simultaneously
traced.
Definitions of Mechanical Alternans
Mechanical alternans was detected by direct pressure
measurement. Electrical alternans was evaluated from 2
surface limb leads, II and aVF. Several terms relating to
mechanical alternans were defined as follows. A magnitude of pressure difference of the strong beat and the
weak beat was defined as an alternating pressure. Large
alternans indicated mechanical alternans having 10 mm
Hg or more of an alternating pressure, which may be
recognized by physical examinations. Small alternans
indicated an alternating pressure less than 10 mm Hg.
The term sustained alternans was defined when constant
alternating pressure exceeding 4 mm Hg continued
beyond 20 beats. When alternating pressure gradually
tapered and ultimately disappeared until 20 beats, the
term decay alternans was used. Only sustained alternans
was included in this study; decay alternans was ne-
glected. Biventricular alternans was detected by a simultaneous pressure recording of the left ventricle and the
pulmonary artery. Concordant alternans indicated that
both ventricular strong or weak beats coincided. When a
strong beat of 1 ventricle coincided with a weak beat of
the opposite ventricle, the term discordant alternans was
used. The phase reversal point was defined as a coupling
interval of a premature beat that showed phase reversal
effects on mechanical alternans. Demonstrable traces of
mechanical alternans are presented in Fig. 1. The left
panel shows aortic pressure of a female patient with
idiopathic dilated cardiomyopathy under sinus rhythm.
Her alternating pressure was extremely large, and her
peripheral pulse rate was half the heart rate. The right
panel shows a left ventricular pressure tracing of a male
patient with idiopathic dilated cardiomyopathy under
atrial pacing of 110 bpm. His left ventricular pressure
and pulmonary artery pressure showed concordant alternans, and the positive and the negative dP/dt of left
ventricular pressure also showed alternating changes.
Rapid Pacing
An abrupt tachycardia of extremely rapid heart rates
has been shown to be related to the initiation of mechanical alternans in clinical and experimental observations.
In this study, we tested physiologic tachycardia and did
Fig. 1. Demonstrable records of mechanical alternans. (A) Aortic pressure tracing of a female patient with idiopathic dilated
cardiomyopathy. Alternating pressure was 32 mm Hg. ST-T electrical alternans was also detectable. (B) Tracing of left ventricular
pressure and the first pressure derivatives from a male patient with idiopathic dilated cardiomyopathy. Both positive and negative
dP/dt showed alternating changes with left ventricular pressure. Pulmonary artery pressure exhibited concordant alternans with the
left ventricle. AO, aortic pressure; LA, left atrial pressure; LV, left ventricular pressure; PA, pulmonary arterial pressure; S, strong
beat; W, weak beat.
Mechanical Alternans in Chronic CHF O Kodama et al
141
not test extremely rapid heart rates. After diagnostic
catheterization, provocation of mechanical alternans by
right atrial pacing was carried out. The pacing rate was
110 bpm. In patients with atrial fibrillation, right ventricular pacing of 110 per minute was performed.
Intravenous Dobutamine
The effects of inotropic agents on the appearance of
mechanical alternans were investigated in this study.
Previous experimental observations suggested that impaired intracellular calcium cycling is essential in the
prevalence of mechanical alternans. Therefore, in this
study, effects of dobutamine that increase intracellular
calcium cycling were tested. Dobutamine was intravenously infused with an upward titration of the infusion
rate at 5-minute intervals. Stepwise dobutamine loading
was initiated at a dose of 2 µg/kg/min, then the dose was
increased to 4 and 8 µg/kg/min. Three minutes after the
start of dobutamine infusion, a constant pacing of 110 per
minute was started, and hemodynamic parameters were
measured at 5 minutes after dobutamine loading. All
study protocols were approved by the ethics committee
of Niigata University, Niigata, Japan.
Statistical Analysis
Data are presented as mean ⫾ 1SD. The unpaired
Student t test was used to calculate the statistical differences between 2 groups. Differences were considered
significant at P < .05. Relations between pressure alternans and dP/dt alternans were analyzed using the partial
correlation coefficients.
Results
Frequency of Mechanical Alternans
The prevalence of mechanical alternans in patients
with chronic heart failure was investigated under the
basal condition, rapid pacing of 110 per minute, and
stepwise dobutamine loading. Under the basal condition,
7 out of 35 patients with sinus rhythm (20%) showed
mechanical alternans (Fig. 2). Six patients (17%) showed
large alternans. Rapid pacing provoked mechanical alternans in another 15 patients with sinus rhythm and in
another 10 of 16 patients with atrial fibrillation. Five
patients with large alternans at rest were not enrolled in
further studies. Accordingly, 27 of 46 patients (59%)
showed mechanical alternans under rapid pacing. Dobutamine loading at a dose of 2 µg/kg/min was tested in 40
patients. Nineteen patients (48%) showed mechanical
alternans. A dose of 4 µg/kg/min of dobutamine was
tested in 38 patients, and 23 patients (61%) showed
mechanical alternans. Low doses of dobutamine, either 2
Fig. 2. Frequency of mechanical alternans under stepwise
provocation procedures. Pace indicates physiologic tachycardia. DOB indicates intravenous dobutamine infusion.
or 4 µg/kg/min, induced mechanical alternans in 8
patients for the first time, who did not show mechanical
alternans under either the basal condition or rapid pacing. Subsequently, a high dose of dobutamine at 8
µg/kg/min was tested and data, which were available for
evaluation, were collected from only 28 patients because
of tachycardia exceeding pacing rates or frequent premature beats. Mechanical alternans was observed in 8
patients (28%). Nobody showed for the first time, mechanical alternans under the high dose of dobutamine.
Consequently, 40 patients (78%) showed mechanical
alternans under either condition, basal, rapid pacing, or
low doses of dobutamine. Thus, rapid pacing and low
doses of dobutamine were frequently able to provoke
mechanical alternans in patients with chronic heart
failure, and high doses of dobutamine eliminated mechanical alternans. Large alternans was still rare under
the provocation procedures in patients with chronic heart
failure.
Alternans of the First Pressure
Derivatives
During sustained mechanical alternans, oscillation of
the positive and the negative dP/dt of left ventricular
pressure was investigated. When the alternating pressure
was large, both positive and negative dP/dt showed
alternating changes. When the alternating pressure was
small, positive dP/dt showed alternating strong and weak
beats, but negative dP/dt was occasionally constant. The
relation between the magnitude of alternating left ventricular pressure and the magnitude of alternating dP/dt
of each patient at maximum mechanical alternans are
plotted. Pressure alternans was related more lineally to
positive dP/dt than negative dP/dt. Positive dP/dt oscillated with mechanical alternans in all patients (Fig. 3). In
142 Journal of Cardiac Failure Vol. 7 No. 2 June 2001
alternans of both ventricles. In a male patient with
idiopathic dilated cardiomyopathy, biventricular discordant alternans was detected. In this case, both concordant
and discordant alternans were observed during a study,
and concordant alternans changed into discordant alternans after a premature ventricular contraction. The mean
right atrial pressure and the mean pulmonary arterial
pressure were constant before and after this transformation of mechanical alternans. These observations imply
that mechanical alternans of the left ventricle is independent of right ventricular stroke volume.
Effects of Premature Beats
Fig. 3. Relationship between pressure alternans and positive
dP/dt alternans.
6 patients, mechanical alternans was sustained without
oscillation of negative dP/dt (Fig. 4). As left ventricular
dP/dt is influenced by preload and afterload, strict
assessment of contractility and relaxation property during mechanical alternans may be incomplete in this
study. Otherwise, our observation implies that mechanical alternans depends not on the relaxation property of a
prior beat but on a contractile property during the
isovolumic contraction phase.
Biventricular Alternans
The appearance of biventricular alternans was investigated in 35 patients by simultaneous pressure recordings of the pulmonary artery and the left ventricle. Most
patients with chronic heart failure showed single ventricular alternans of the left ventricle (24 of 35, 69%).
Biventricular alternans was observed in 11 patients
(31%), and 10 of the 11 patients showed concordant
Fig. 4. Relationship between pressure alternans and negative
dP/dt alternans.
Effects of premature beats on mechanical alternans
were investigated. A premature beat, either supraventricular or ventricular, which appeared during a normal
pulse without alternans, frequently provoked decay mechanical alternans and sometimes provoked sustained
alternans in patients with chronic heart failure. A premature beat after a strong beat during sustained mechanical
alternans always exaggerated alternating pressure. However, a premature beat after a weak beat expressed
different effects on mechanical alternans according to the
coupling intervals. A premature beat with a relatively
long coupling interval after a weak beat attenuated
alternating pressure. A premature beat with a proper
coupling interval, that is a phase reversal point, after a
weak beat diminished mechanical alternans. A premature
beat with more shorter coupling intervals reversed the
alternating strong-weak phase and rather exaggerated the
alternating pressure.
Mechanical Alternans and Clinical
Characteristics
Clinical characteristics of patients who showed mechanical alternans under either rest, mild tachycardia, or
low doses of dobutamine (n ⫽ 40) were compared with
those of patients without alternans under any conditions
(n ⫽ 11) (Table 2). Patients with mechanical alternans
had a higher score for the New York Heart Association
functional class than those without. The left ventricular
end-diastolic pressure and the pulmonary capillary
wedge pressure were higher in patients with alternans
than those without. The cardiac indices were not different
between both groups. The left ventricular end-diastolic
volume indices and end-systolic volume indices of patients with mechanical alternans were significantly larger
than those of the patients without. The left ventricular
ejection fraction in patients with alternans was lower
than those without. There were, in this study, 8 patients
with preserved systolic function whose left ventricular
ejection fraction were over 45%. Three of these patients
showed mechanical alternans, and 5 patients did not
Mechanical Alternans in Chronic CHF O Kodama et al
143
Table 2. Comparison of Clinical Characteristics, Cardiac Function, and Prognosis Between Patients With and Without
Mechanical Alternans
With Alternans
Number
Men/women
Age (yr)
NYHA 1
2
3
LVEDVI (mL/m2)
LVESVI (mL/m2)
LVEF (%)
LVEDP (mm Hg)
PCW (mm Hg)
CI (L/min/m2)
Mortality
Death of heart failure
Sudden death
Noncardiac death
40
31/9
48.6 ⫾ 13.2
1 (3%)
21 (52%)
18 (45%)
141.7 ⫾ 44.5
96.5 ⫾ 40.1
33.3 ⫾ 10.2
9.6 ⫾ 6.8
9.6 ⫾ 6.2
2.7 ⫾ 0.8
10 (25%)
7
3
0
Without Alternans
11
7/4
48.2 ⫾ 14.3
2 (18%)
8 (73%)
1 (9%)
110.4 ⫾ 19.9
60.9 ⫾ 18.3
45.3 ⫾ 11.5
4.7 ⫾ 2.8
6.2 ⫾ 2.1
2.8 ⫾ 0.6
2 (18%)
0
1
1
Statistical Difference
NS
NS
P < .003
P < .0003
P < .02
P < .002
P < .005
NS
NS
NYHA, New York Heart Association; LVEDP, left ventricular end-diastolic pressure; PCW, pulmonary capillary wedge pressure; CI, cardiac index;
NS, not significant.
show. Although there was no difference in the total
mortality, death from heart failure was more frequent in
patients with mechanical alternans.
Discussion
Until now, many observations concerning mechanical
alterations have been reported, but both mechanisms and
clinical implications of this phenomenon are still unknown. In this report, we showed a few unique findings
concerning mechanical alternans of patients with chronic
heart failure. The first is that mechanical alternans is rare
at the resting condition, and its prevalence increases
dramatically by physiologic tachycardia and low doses
of ␤-adrenoceptor stimulants. The next is that mechanical alternans is always accompanied by alternating
changes of positive dP/dt and is able to continue without
oscillation of negative dP/dt.
The precise prevalence of mechanical alternans in
patients with chronic heart failure has been unknown.
Hada et al (22) investigated the frequency of mechanical
alternans in 100 patients with dilated cardiomyopathy
using echocardiography. They found sustained alternans
in 10 patients and decay alternans in another 7 patients.
Their conclusion was that there was no difference in the
severity of disease in patients with mechanical alternans
compared with those without. Schaefer et al (23) reported the prevalence of mechanical alternans in 104
patients with miscellaneous heart diseases by direct
pressure measurement. The study used rapid atrial pacing
as a provocation maneuver of mechanical alternans.
Overall, 29 patients developed mechanical alternans,
containing both decay and sustained, under either the
basal condition or rapid atrial pacing. Our study included
only patients with chronic heart failure; focused on only
sustained alternans; detected it by a direct pressure
recording of the left ventricle simultaneously with the
first pressure derivatives; and used mild, maybe physiologic, provocation procedures. Many physicians have
felt that pulsus alternans must be strictly related to heart
failure and to a poor prognosis. However, there is no
systematic study concerning these points until now (21).
This study showed that the prevalence of sustained
alternans under physiologic stimulation was associated
with the severity of left ventricular dysfunction.
Several theories have been proposed as the cause of
mechanical alternans. Mechanical alternans has been
initially considered to occur from alternating ventricular
filling patterns depending on the Frank-Starling mechanism (24). However, a regional discordant alternans of
the left ventricle had been reported (25). Experimental
studies have also shown that mechanical alternans can be
provoked in the isometric contraction models under
constant preload (13,14). These findings can deny the
possibility of the Frank-Starling mechanism as a cause.
An incomplete relaxation theory has been formulated
by the observation that a weak beat came out after a
small end-diastolic volume with high end-diastolic pressure, and a strong beat began from a large end-diastolic
volume with low end-diastolic pressure in some experimental models (26–28). However, this was not a rule in
this study of human mechanical alternans. A strong beat
appeared after various end-diastolic pressures, higher or
the same as, and occasionally lower compared with a
weak beat. The absolute value of the minimum negative
dP/dt of strong beats was larger than that of weak beats.
Partial asystole of the left ventricle has been considered to be a cause of mechanical alternans (29). If
144 Journal of Cardiac Failure Vol. 7 No. 2 June 2001
mechanical alternans of patients derived from a partial
asystole, alternating changes of the QRS morphology
would be observed on electrocardiography. Additionally,
as strong beats derived from full activation of the left
ventricle by this theory, it would show the same intensity
as the normal pulse without mechanical alternans. None
of the 40 patients showed alternating changes of the QRS
morphology during mechanical alternans in this study.
The intensity of normal beats was just a middle value
between strong beats and weak beats. Strong beats were
always more intense than normal beats in this study.
Accordingly, the partial asystole theory is unlikely.
The primary oscillation of mechanical alternans may
exist in the action potential duration (30). If the oscillation of the action potential duration is the primary event,
this form of mechanical alternans should be accompanied by ST-T electrical alternans and alternating changes
of left ventricular relaxation property. From our study,
ST-T electrical alternans was detected in only 3 out of 40
patients with sustained mechanical alternans. During
mechanical alternans, alternating changes of positive
dP/dt was more evident than alternating changes of
negative dP/dt. Therefore, the theory of alternating action
potential duration is unlikely.
Oscillation of afterload may be another potential origin
of mechanical alternans. From our observation, alternating change of positive dP/dt was evident during mechanical alternans. Positive dP/dt is a parameter of myocardial
contractility during the isovolumetric contraction time,
before opening of aortic valve. In a few patients with large
mechanical alternans, weak beats could not open the aortic valve (total alternans). Accordingly, primary origin of
mechanical alternans seems to exist on the isovolumetric
contraction time or more before.
Several experimental studies showed that the primary
event of mechanical alternans was alternating amounts of
Ca2⫹ sparks from the sarcoplasmic reticulum
(9,14,15,31–34). This form of mechanical alternans
showed heart rate dependency. In this study, some
features of human mechanical alternans produced by
premature beats agreed with theoretical mechanical alternans depending on Ca2⫹ sparks (31,35). However, we
cannot explain the reason why low doses of dobutamine
provoked mechanical alternans. Ca2⫹ sparks alternans
leads to the oscillation of the initial tension development
of myocardium. Alternating changes of cytosolic Ca2⫹
amounts can influence the calcium-dependent ion currents, which could subsequently lead to ST-T electrical
alternans (36,37). Because direct evidence of Ca2⫹
sparks alternans could not be obtained in this clinical
study, further study will be necessary.
Mechanical alternans is rare under a resting condition
in patients with chronic heart failure, and its prevalence
increases dramatically under physiologic tachycardia or
mild ␤-adrenergic stimulation. Mechanical alternans is
more prevalent in patients with severe left ventricular
dysfunction. Although the precise mechanisms of mechanical alternans is still uncertain, its origin may depend
on the abnormal Ca2⫹ handling in failing myocardium.
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