Download The sensation of dyspnea during exercise is not determined

391
JACC Vol. 28, No. 2
August 1996:391-5
The Sensation of Dyspnea During Exercise is Not Determined by the
Work of Breathing in Patients With Heart Failure
D O N N A M. M A N C I N I , MD, J O H N LA M A N C A , PHD, L I S A D O N C H E Z , RN, D A V I D H E N S O N , MD,*
S A N F O R D L E V I N E , MD*
New York, New York and Philadelphia, Pennsylvania
Objectives. The present study sought to investigate whether the
work of breathing was reduced after heart transplantation. Accordingly, the tension time index of the diaphragm was measured
in patients with heart failure and in transplant recipients.
Background. Patients with heart failure are frequently limited
by exertional dyspnea that may be due to the increased work of
breathing. After heart transplantation, exertional dyspnea is
markedly diminished. Whether work of breathing is reduced in
posttransplant recipients is unknown.
Methods. Nine patients with heart failure, six normal subjects
and six heart transplant recipients were studied. Transdiaphragmatic pressure was measured throughout exercise. Accessory
respiratory muscle oxygenation was assessed using near-infrared
spectroscopy. Peak oxygen consumption, time in inspiration, time
per breath and maximal inspiratory and expiratory pressures
were measured in all subjects.
Patients with heart failure are frequently limited by exertional
dyspnea. During exercise, these patients exhibit an excessive
ventilatory response that may result from excessive dead space
ventilation, increased lactic acidosis or decreased perfusion
(1,2). After heart transplantation, exertional dyspnea is dramatically improved. Whether this alleviation of exertional
dyspnea is related to improved lung compliance, increased
perfusion of respiratory or leg musculature, or both, or greater
respiratory muscle strength is unclear. To investigate which of
these mechanisms underlies the subjective improvement in
dyspnea after transplantation, the work of breathing estimated
from the tension time index of the diaphragm (3), accessory
respiratory muscle oxygenation and respiratory muscle
strength were measured in transplant recipients, patients with
heart failure and normal subjects at rest and during exercise. It
was hypothesized that diminished work of breathing after
transplantation would be a major contributor to the improveFrom the Divisionof Cardiology,ColumbiaPresbyterianMedicalCenter,
NewYork,NewYork;and *ThePhiladelphiaVeteransAdministrationMedical
Center,Philadelphia,Pennsylvania.Thisstudywassupportedby a Southeastern
PennsylvaniaAmericanHeartAssociationGrant-in-Aid,Philadelphia,Pennsylvania.
Manuscript received September 15, 1995; revised manuscriptreceived
January18, 1996,acceptedMarch12, 1996.
Addressforcorrespondence:Dr. DonnaM.Mancini,DivisionofCardiology,
ColumbiaPresbyterianMedicalCenter,622West168thStreet,NewYork,New
York 10032.
Results. The tension time index remained markedly abnormal
after heart transplantation both at rest ([mean _+ SD] normal
group 0.01 -+ 0.006, heart failure group 0.026 -+ 0.018, transplant group 0.058 -+ 0.015, p < 0.004) and at peak exercise
(normal group 0.03 -+ 0.02, heart failure group 0.10 -+ 0.03,
transplant group 0.10 -+ 0.04, p < 0.0001). Accessory respiratory
muscle deoxygenation was present only in patients with heart
failure (near-infrared absorbency changes [arbitrary units]: normal group -3 -+ 6, heart failure group 28 -+ 5, transplant group
-3.5 -+ 4.4, p < 0.0001).
Conclusions. Although heart transplantation alleviates dyspnea
in patients with heart failure, the work of breathing as assessed by
the tension time index of the diaphragm is not decreased. Amelioration of exertional dyspnea is achieved by other mechanisms,
such as improved respiratory muscle perfusion.
(J Am Coll Cardio11996;28:391-5)
ment in exertional dyspnea. Surprisingly, work of breathing
and respiratory strength were not significantly different after
transplantation. However, regional perfusion of respiratory
musculature was normalized, suggesting that amelioration of
this symptom is related to improved perfusion.
Methods
Patients. Nine patients with chronic congestive heart failure (eight men and one woman, mean [_+SD] age 62 _+ 10
years) were studied. The cause of heart failure was coronary
artery disease in six patients and dilated cardiomyopathy in
three. Five patients had New York Heart Association functional class III congestive heart failure, two class II and two
class I. Left ventricular ejection fraction averaged 18 _+ 7%.
All patients were receiving digoxin, diuretic agents and
angiotensin-converting enzyme inhibitors.
Six heart transplant recipients also participated in the study
(mean age 62 _+ 7 years, mean ejection fraction 58 _+ 11%,
peak oxygen consumption 21 _+ 2.7 ml/kg per rain). All
transplant recipients were male and were studied a mean of 2.7
years after transplantation. All patients were receiving cyclosporine A, prednisone and azathioprine. No patient had a
rejection episode within 1 month before the exercise test. Rest
hemodynamic measurements performed at the same time as a
routine surveillance endomyocardial biopsy within 1 month of
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MANCINI ET AL.
E X E R T I O N A L DYSPNEA IN H E A R T F A I L U R E
exercise revealed a mean pulmonary artery pressure of 16 +_
5 mm Hg, pulmonary capillary wedge pressure of 9 _+
2 mm Hg, cardiac output of 5.7 _+ 1.2 liters/rain and pulmonary
vascular resistance of 1.5 +__0.7 Wood units.
Six normal male subjects (mean age 50 + 7 years) also
participated in the study. No subject had a significant past
medical history. All patients and normal subjects were currently nonsmokers with normal pulmonary function tests.
The protocol was approved by the Human Studies Subcommittee at the Philadelphia Veterans Administration Medical
Center and the Committee on Studies Involving Human
Beings at the Hospital of the University of Pennsylvania.
Written informed consent was obtained from all subjects.
Exercise protocol. On arrival at the exercise laboratory,
maximal inspiratory and expiratory pressures were measured
three times at residual volume and total lung capacity, respectively. Near-infrared fiberoptic light guides were placed on the
sixth intercostal space at the anterior axillary line over the
serratus anterior muscle, an accessory inspiratory muscle.
Esophageal and gastric balloons were inserted after the nares
were anesthetized with 1% vicous lidocaine. The subjects were
then positioned upright on a Monarch exercise bicycle ergometer. A three-way Hans Rudolph valve was used for respiratory
gas analysis. Arterial saturation was monitored using an Ohmeda ear oximeter.
After a 3-rain rest period, all subjects performed a bicycle
exercise test. Exercise was begun at a work load of 0 W and
increased by 25-W increments every 3 min to the symptomlimited maximum. Blood pressure was measured by a cuff
sphygmomanometer at the end of each work load. Respiratory
gases, arterial saturation, heart rate, transdiaphragmatic pressure and near-infrared spectra were monitored throughout
exercise. Borg scale ratings of perceived dyspnea and fatigue
were obtained at each work load.
Near-infrared spectroscopy. Near-infrared spectroscopy
noninvasively assesses skeletal muscle oxygenation (2,4-6).
Both oxygenated and deoxygenated hemoglobin absorbs light
at 850 nm, whereas primarily deoxygenated hemoglobin absorbs light at 760 nm. Therefore, by monitoring the difference
in absorption noted at these two wavelengths, it is possible to
assess changes in hemoglobin oxygenation. The difference in
absorption at 760 to 850 nm was used to assess serratus
anterior muscle oxygenation. All studies were performed using
the same gain settings on the spectrometer. Absorption
changes were then expressed as arbitrary units of deviation
from a stable baseline value. The higher the arbitrary unit, the
greater the muscle deoxygenation. A negative value represents
an increase in oxygenation.
Transdiaphragmatic pressures. Measurement of esophageal, gastric and transdiaphragmatic pressures was performed
at rest and during exercise. Esophageal and gastric pressures
were directly measured by 100- to ll0-cm catheters custom
fitted with 10-cm latex balloons according to the method of
Milic-Emili et al. (7). Transdiaphragmatic pressure was derived by electrical subtraction of esophageal pressure from
gastric pressure.
JACC Vol. 28, No. 2
August 1996:391-5
During bicycle exercise, the subjects breathed through a
mouth piece connected to a specially modified two-way nonrebreathing valve (Hans Rudolph). The subject inspired air
through an inspiratory pneumotachygraph (model 3800, Hans
Rudolph) connected to a variable-reluctance pressure transducer (model MP45-871, Validyne Engineering). Expired gas
was directed through the respiratory valve into the expiratory
pneumotachygraph (model 3800, Hans Rudolph) and then into
a 6:1 mixing chamber. Ventilatory frequency, total ventilatory
cycle duration and inspiratory time per cycle were derived from
these signals. The time tension index of the diaphragm as
defined by Bellemare and Grassino (3) was derived for each
breath as the product of the inspiratory duty cycle and the
mean transdiaphragmatic pressure divided by the maximal
voluntary transdiaphragmatic pressure.
Statistical analysis. Data from patients with heart failure,
transplant recipients and normal subjects at rest and during
exercise were compared with Student nonpaired and paired t
tests or two-way repeated-measures analysis of variance, as
appropriate. The relations between variables were examined
by linear regression analysis. A value of p < 0.05 was considered significant. Data are expressed as mean value +_ SD.
Results
Exercise measurements. Rest heart rate, mean arterial
blood pressure, oxygen consumption, respiratory quotients and
arterial saturation were comparable in patients with heart
failure, transplant recipients and normal subjects (all p = NS)
(Table 1). At peak exercise, heart rate, mean arterial blood
pressure and oxygen consumption were significantly reduced
both in patients with heart failure and in transplant recipients
compared with that in normal subjects. The respiratory quotient at peak exercise was similar in all three groups. Arterial
desaturation was not observed in any of the groups.
Near-infrared spectroscopy. At all exercise work loads, 760
to 850 nm absorption was significantly greater in patients with
heart failure than in normal subjects or transplant recipients.
Only patients with heart failure demonstrated accessory respiratory muscle deoxygenation (peak exercise [arbitrary units]:
normal group - 3 +- 6, heart failure group 28 _+ 5, transplant
group -3.5 +- 4.4, p < 0.001) (Fig. 1). No significant change
occurred in the 850-nm signal throughout exercise in any of the
groups, indicating that total blood volume was unchanged
during exercise.
Transdiaphragmatic pressure measurements. Rest maximal inspiratory mouth pressures tended to be lower in transplant recipients than in patients with heart failure and normal
subjects but did not reach statistical significance (normal group
117 +__ 9.2 mm Hg, heart failure group 104 +__ 15 mm Hg,
transplant group 81 _+ 14 mm Hg, p = NS). Similar results
were observed for maximal expiratory mouth pressures (normal group 228 + 8 mm Hg, heart failure group 201 +
31 mm Hg, transplant group 178 ~ 21 mm Hg, p = NS).
The inspiratory duty cycle (time in inspiration divided by
time/breath) was comparable between all three groups. The
JACC Vol. 28, No. 2
August 1996:391-5
MANCINI ET AL.
EXERTIONAL DYSPNEA IN HEART F A I L U R E
393
Table 1. Rest and Peak Exercise Measurements
Normal Subjects
Heart rate (beats/min)
Mean arterial BP (mm Hg)
Vo 2 (ml/kg per min)
VE (liters/rain)
Respiratory rate (beats/min)
RQ
NIR (arbitra~ units)
Arterial saturation (%)
Rest
Exercise
82 ± 11
96 _+ 6
4.2 + 0.8
11 ± 3
15 ± 4
0.78 ± 0.05
167 ± 11
140 + 9
33 _+ 11
89 + 3
32 + 9
1.09 ± 0.15
-3 ± 6
97 _+ 1
97 ± 1
Patients With Heart Failure
Rest
85 ±
90 ±
3.4 +
12 ±
18 +
0.77 ±
Exercise
15
10
1.3
3
5
0.08
136 ± 18"
114 t 18'
15.6 _~ 5.9*
49 ± 16"
39 ± 9
1.03 ± 0.15
28 ± 5*
96 + 1
97 -+ 1
Transplant Recipients
Rest
89 ±
107 ±
4.3 ±
15.0 +
14 +
0.9 ±
Exercise
21
8
0.6
1
2
(I.03
138 -+ 20*
116 -+ 13"
21 -+ 2.2*¢
53 ± 8*
30 ± 6
1.07 -+ 0.08
3.5 ± 4.4?
96 + l
97 ± 1
*p < 0.05 versus normal subjects. ?p < 0.05 versus patients with congestive heart failure. Data presented are mean value ± SD. BP = blood pressure; NIR = the
difference in 760- to 850-nm absorption; RQ = respiratory quotient; VE = expired volume; Vo 2 oxy,gen consumption.
tension time index (transdiaphragmatic pressure times time in
inspiration divided by total time/breath) was increased at rest
and throughout exercise in patients with heart failure and
transplant recipients compared with that in normal subjects
(Fig. 2). At maximal exercise, the tension time index was
0.10 _+ 0.03 for patients with heart failure, 0.10 _+ 0.04 for
transplant recipients and 0.03 _ 0.02 for normal subjects (p <
0.001). In one patient in whom transdiaphragmatic pressures
were measured before and after transplantation, a trend
toward increasing tension time index at rest and during
exercise was also observed.
Ratings of perceived dyspnea and fatigue. Dyspnea was the
primary limiting symptom in two patients with heart failure, no
transplant recipients and three normal subjects. In patients
with heart failure, Borg scale ratings of dyspnea were significantly greater than in normal subjects at the same absolute
work load and tended to be significantly greater than in heart
transplant recipients. At maximal work load, Borg scale ratings
of dyspnea were comparable between all groups (Table 2).
Similar results were observed for Borg scale ratings of perceived fatigue.
Discussion
provide a measure of the work of breathing in normal subjects
and in patients with heart failure and transplant recipients (3).
The study demonstrates that in heart transplant recipients, the
work of breathing as assessed from the tension time index of
the diaphragm is not decreased. Respiratory. muscle strength is
unchanged. However, regional perfusion of accessory respiratory muscles improves significantly and is comparable to the
normal response.
Chronic venous pulmonary hypertension in patients with
heart failure leads to fibrotic changes in the lung parenchyma
and blood vessels and results in decreased lung compliance and
bronchoconstriction (8,9). These changes increase the energy
costs of respiration. Indeed, at rest and during exercise,
patients with heart failure exhibit an increased tension time
index (10) and increased work of breathing (11). In our group
of transplant recipients, the tension time index of the diaphragm remained elevated at rest and throughout exercise
compared with that in normal subjects but was similar to that
in patients with heart failure. Persistent pulmonary hypertension is an unlikely explanation for the increased work of
breathing after heart transplantation because pulmonary venous hypertension reverses by 1 month (12). All our patients
were studied at least 6 months after transplantation, and all
had normal rest hemodynamic measurements within the pre-
In the present study the tension time index of the diaphragm was used to approximate the oxygen cost/breath and to
Figure 1. Near-infrared absorbency changes at maximal exercise in
normal subjects, patients with congestive heart failure (CHF) and
transplant recipients.
Figure 2. Plot of tension time index at rest and during exercise in
normal subjects, patients with congestive heart failure (CHF) and
transplant recipients.
0 - - 0 NORMAL(n=6)
F~- .30 t ~
O--O
*+
NORMAL(n=6)
I I CHF (n=9)
[NN TRANSPLANT(n=6)
X
L~
E]
Z
L~
*p<O.05 v s N o r m a l
3 ~ 2 0 -r +p(O.05 vs Transplant
O. lO-
CHF (n=9)
A - - A TRANSPLANT(n=6)
*p(0.05 vs NORMAL
cO
I
O
~o
I"--
o 0.05
o"1
Z
DJ
J
0.00
-10;
*
jl
Z
E~IO
/~
0
25
50
WORKLOAD(wotts)
75
I00
394
MANCINI ET AL.
EXERTIONAL DYSPNEA IN HEART FAILURE
JACC Vol. 28, No. 2
August 1996:391-5
Table 2. Borg Scale Ratings of PerceivedDyspnea and Fatigue
Dyspnea
Work Load (W)
Normal
Subjects
0
25
50
75
Maximum
6.7 ± 0.8
7.3 ± 1.5
9.2 ± 1.7
16.7 _+ 2
Patients With
Heart Failure
9.3 ±
10.3 ±
13.5 ±
15.1 ±
16.6 ±
1.8
2.4*
3.0*
2.9*
1.4
Fatigue
Transplant
Recipients
Normal
Subjects
7,5 -+ 1.2
8,8 ± 2*
9,7 ± 2.5'1
13.3 ± 2.3*
15.3 ± 1.5
6.8 _+ 1.1
7.5 ± 1.6
9 ± 1.8
18 ± 1
Patients With
Heart Failure
10.3 ±
13.3 ±
14.1 ±
17.8 ±
2.4*
3*
2.5*
1.4
Transplant
Recipients
7.8 ± 1.8
9.2 ± 2.8*
11 -2-_2.8*
14.8 + 2.7*
18.3 ± 1.5
*p < 0.05 versus normal subjects, tp < 0.05 versus patients with heart failure. Data presented are mean value ± SD.
ceding month. Thus, at least at rest, the elevated tension time
index was not related to persistent pulmonary hypertension.
Although exercise hemodynamic measurements were not recorded in the present study, previous studies in heart transplant recipients have shown elevated pulmonary pressures
during exercise (13,14). Therefore, we cannot exclude that
exercise-induced pulmonary hypertension did not contribute to
elevated tension time index during exercise. However, it is
more likely that irreversible structural changes occur in the
lung that increase respiratory work through a decrease in lung
compliance. Analysis of lung biopsies in adolescents with
mitral stenosis after successful surgical therapy has demonstrated irreversible lung changes (15). No longitudinal studies
have been performed in patients with heart failure to assess the
reversibility of lung parenchymal changes. Persistent fibrotic
changes resulting in an increased work of breathing would not
preclude some improvement in lung compliance. Previously,
Hosenpud et al. (16) compared spirometric results before and
after transplantation and noted improvements in lung volumes
and flow rates. This posttransplantation improvement was
attributed to a combination of reduced cardiac size, interstitial
edema and pleural effusions. Thus, in transplant recipients
with the same mean transdiaphragmatic pressure, the change
in volume should be greater. Improved static and dynamic lung
compliance probably contributes to an alleviation of dyspnea
in transplant recipients despite no alteration in the absolute
work of the diaphragm.
Respiratory muscle strength assessed from maximal inspiratory and expiratory mouth pressures tended to be lower in
transplant recipients than in patients with heart failure or
normal subjects but did not achieve statistical significance.
Maintenance therapy with corticosteroids in our transplant
recipients may have contributed to this trend. Skeletal muscle
metabolic, enzymatic and histochemical abnormalities have
been described in patients with heart failure (1%21). Diminished skeletal muscle endurance (22) and generalized muscle
atrophy (23) have also been described in patients with heart
failure. To what extent these intrinsic muscle changes are
reversible is unclear, although presumably those changes related to deconditioning are at least partially reversible.
Few studies have focused on skeletal muscle function after
transplantation. Muscle biopsies from renal transplant recipients receiving maintenance corticosteroids have demonstrated
reduced myofibrillar volume and a decreased capillary/fiber
ratio (24,25). Braith et al. (26) recently described a reduction
in skeletal muscle strength in heart transplant recipients up to
18 months after transplantation. Metabolic abnormalities during exercise have been reported in patients up to 1 year after
transplantation (27). Bussieres-Chafe et al. (28,29) described
an increase in mitochrondrial enzyme activity and fiber size
from serial percutaneous calf biopsies in 13 patients 1 year
after transplantation. Decreased respiratory muscle endurance
in transplant recipients has also been described (30,31). Thus,
both muscle endurance and strength tend to be reduced in
transplant recipients.
Accessory respiratory muscle deoxygenation has been described during exercise in patients with heart failure (2) and in
those with mitral stenosis (32) using near-infrared spectroscopy, a noninvasive technique that provides qualitative measurement of deoxygenated skeletal muscle hemoglobin by
measuring the difference in absorbency of 760- to 850-nm light.
Using this technique, we again observed progressive respiratory muscle deoxygenation during exercise in patients with
heart failure but not in normal subjects or transplant recipients. These findings suggest that improved regional perfusion
of the respiratory muscles occurs after heart transplantation.
This improved muscle perfusion may be the primary mechanism by which dyspnea is relieved.
After heart transplantation, the symptom of dyspnea is
greatly decreased in patients with heart failure. However,
quantification of dyspnea using a unidimensional scale during
bicycle exercise demonstrated only small differences in perceived dyspnea between patients with heart failure and transplant recipients and only at submaximal work loads. Ratings of
perceived dyspnea remained higher in transplant recipients
than in normal subjects. Use of alternate scales that incorporate a more multidimensional measure of dyspnea may have
yielded different results. The dyspnea index, which normalizes
minute ventilation by maximal capacity, would probably have
been reduced in transplant recipients because we have previously shown (31) that maximal voluntary ventilation and
maximal sustainable ventilatory capacity are improved in transplant recipients. Thus, although the absolute amount of work
may be the same, transplant recipients have the capacity to do
greater amounts of work.
JACC Vo]. 28, No. 2
August 1996:391-5
MANCINI ET AL.
EXERTIONAL DYSPNEA IN HEART FAILURE
Study limitations. The present study is limited by its crosssectional nature and the small sample size. However, the
findings in this small homogeneous group were extremely
consistent. Moreover, the one patient with longitudinal data
demonstrated a slightly increased tension time index after
transplantation.
Exercise hemodynamic measurements were not obtained.
However, several previous studies have adequately described
the hemodynamic response to exercise in these patient groups
(13,14). Transplant recipients will demonstrate an improved
hemodynamic response with lower pulmonary pressures and a
higher cardiac output that is intermediate between normal
subjects and patients with heart failure. Lung compliance
measurements were also not recorded. Although this information would have aided our understanding of the findings, the
observation that work of the diaphragm remains elevated after
transplantation is important. Other possible etiologies for
improvement in dyspnea after transplantation, such as stimulation of airway and lung parenchymal receptors, were not
investigated. Further studies will be needed to further clarify
the mechanisms underlying the relief of dyspnea in patients
with heart failure after transplantation.
Clinical implications. The present study implies that pulmonary work of breathing is not the major determinant of
dyspnea in patients with heart failure. Other mechanisms, such
as decreased lung compliance or decreased muscle perfusion,
may represent the primary stimuli for dyspnea in these patients. Additional studies are warranted to identify the primary
stimulus for dyspnea in patients with heart failure.
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