JACC Vol. 28, No. 2 391
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. Ac- cordingly, 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. Transdiaphrag- matic 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.
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, trans- plant 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]: nor- mal 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. Ame- lioration of exertional dyspnea is achieved by other mechanisms, such as improved respiratory muscle perfusion.
(J Am Coll Cardio11996;28:391-5)
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 dra- matically 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 improve-
From the Division of Cardiology, Columbia Presbyterian Medical Center, New York, New York; and *The Philadelphia Veterans Administration Medical Center, Philadelphia, Pennsylvania. This study was supported by a Southeastern Pennsylvania American Heart Association Grant-in-Aid, Philadelphia, Pennsyl- vania.
Manuscript received September 15, 1995; revised manuscript received January 18, 1996, accepted March 12, 1996.
Address for correspondence: Dr. Donna M. Mancini, Division of Cardiology, Columbia Presbyterian Medical Center, 622 West 168th Street, New York, New York 10032.
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.
M e t h o d s
Patients. Nine patients with chronic congestive heart fail- ure (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 func- tional 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 cyclo- sporine 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
392 MANCINI E T AL. J A C C Vol. 28, No. 2 E X E R T I O N A L D Y S P N E A IN H E A R T F A I L U R E August 1996:391-5 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 cur- rently nonsmokers with normal pulmonary function tests.
The protocol was approved by the Human Studies Subcom- mittee 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, respec- tively. 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 ergome- ter. A three-way Hans Rudolph valve was used for respiratory gas analysis. Arterial saturation was monitored using an Ohm- eda 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 symptom- limited maximum. Blood pressure was measured by a cuff sphygmomanometer at the end of each work load. Respiratory gases, arterial saturation, heart rate, transdiaphragmatic pres- sure 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 ab- sorbs 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 esopha-
geal, 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 de- rived by electrical subtraction of esophageal pressure from gastric pressure.
During bicycle exercise, the subjects breathed through a mouth piece connected to a specially modified two-way non- rebreathing valve (Hans Rudolph). The subject inspired air through an inspiratory pneumotachygraph (model 3800, Hans Rudolph) connected to a variable-reluctance pressure trans- ducer (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 consid- ered significant. Data are expressed as mean value +_ SD.
R e s u l t s
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 quo- tient 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 respi- ratory 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 maxi-
mal inspiratory mouth pressures tended to be lower in trans- plant 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 (nor- mal 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 MANCINI ET AL. 393 August 1996:391-5 EXERTIONAL DYSPNEA IN HEART F A I L U R E
Table 1. Rest and Peak Exercise Measurements
Normal Subjects Patients With Heart Failure Transplant Recipients Rest Exercise Rest Exercise Rest Exercise Heart rate (beats/min) 82 ± 11 167 ± 11 85 ± 15 136 ± 18" 89 ± 21 138 -+ 20* Mean arterial BP (mm Hg) 96 _+ 6 140 + 9 90 ± 10 114 t 18' 107 ± 8 116 -+ 13" Vo 2 (ml/kg per min) 4.2 + 0.8 33 _+ 11 3.4 + 1.3 15.6 _~ 5.9* 4.3 ± 0.6 21 -+ 2.2*¢ VE (liters/rain) 11 ± 3 89 + 3 12 ± 3 49 ± 16" 15.0 + 1 53 ± 8* Respiratory rate (beats/min) 15 ± 4 32 + 9 18 + 5 39 ± 9 14 + 2 30 ± 6 RQ 0.78 ± 0.05 1.09 ± 0.15 0.77 ± 0.08 1.03 ± 0.15 0.9 ± (I.03 1.07 -+ 0.08 NIR (arbitra~ units) - 3 ± 6 28 ± 5* 3.5 ± 4.4? Arterial saturation (%) 97 ± 1 97 _+ 1 97 -+ 1 96 + 1 97 ± 1 96 + l
*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 signifi- cantly 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 per- ceived fatigue.
In the present study the tension time index of the dia- phragm 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. F~- .30 t ~ NORMAL (n=6) I I CHF (n=9) [NN TRANSPLANT (n=6) * p < O . 0 5 v s N o r m a l 3 ~ 2 0 -r +p(O.05 vs Transplant E~IO cO I O ~o I"-- - 1 0 ;
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 respira- tory 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 dia- phragm 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 hyperten- sion is an unlikely explanation for the increased work of breathing after heart transplantation because pulmonary ve- nous 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-
Figure 2. Plot of tension time index at rest and during exercise in normal subjects, patients with congestive heart failure (CHF) and transplant recipients. O. lO- X L~ E] Z L~ Z o 0.05 o"1 Z DJ 0.00 0 - - 0 NORMAL (n=6) O - - O CHF (n=9) A - - A TRANSPLANT (n=6) *p(0.05 vs NORMAL / ~ *
j l0 25 50 75 WORKLOAD (wotts) I 0 0
394 MANCINI ET AL. JACC Vol. 28, No. 2 EXERTIONAL DYSPNEA IN HEART FAILURE August 1996:391-5
Table 2. Borg Scale Ratings of Perceived Dyspnea and Fatigue
Normal Patients With Transplant Normal Patients With Transplant Work Load (W) Subjects Heart Failure Recipients Subjects Heart Failure Recipients 0 9.3 ± 1.8 7,5 -+ 1.2 7.8 ± 1.8 25 6.7 ± 0.8 10.3 ± 2.4* 8,8 ± 2* 6.8 _+ 1.1 10.3 ± 2.4* 9.2 ± 2.8* 50 7.3 ± 1.5 13.5 ± 3.0* 9,7 ± 2.5'1 7.5 ± 1.6 13.3 ± 3* 11 -2-_ 2.8* 75 9.2 ± 1.7 15.1 ± 2.9* 13.3 ± 2.3* 9 ± 1.8 14.1 ± 2.5* 14.8 + 2.7* Maximum 16.7 _+ 2 16.6 ± 1.4 15.3 ± 1.5 18 ± 1 17.8 ± 1.4 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 re- corded in the present study, previous studies in heart trans- plant 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 demon- strated 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 inspira- tory 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). Dimin- ished 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 re- lated to deconditioning are at least partially reversible.
Few studies have focused on skeletal muscle function after transplantation. Muscle biopsies from renal transplant recipi- ents 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 dur- ing 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 de- scribed during exercise in patients with heart failure (2) and in those with mitral stenosis (32) using near-infrared spectros- copy, a noninvasive technique that provides qualitative mea- surement of deoxygenated skeletal muscle hemoglobin by measuring the difference in absorbency of 760- to 850-nm light. Using this technique, we again observed progressive respira- tory muscle deoxygenation during exercise in patients with heart failure but not in normal subjects or transplant recipi- ents. These findings suggest that improved regional perfusion of the respiratory muscles occurs after heart transplantation. This improved muscle perfusion may be the primary mecha- nism 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 per- ceived dyspnea between patients with heart failure and trans- plant 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 incorpo- rate 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 previ- ously shown (31) that maximal voluntary ventilation and maximal sustainable ventilatory capacity are improved in trans- plant recipients. Thus, although the absolute amount of work may be the same, transplant recipients have the capacity to do greater amounts of work.
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Study limitations. The present study is limited by its cross- sectional 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 informa- tion 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 stimu- lation 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 pul- monary 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 pa- tients. Additional studies are warranted to identify the primary stimulus for dyspnea in patients with heart failure.
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