8. Kronik G, Mosslacher H. Positive contrast echocardiography in patients with patent foramen wale and normal right heart hemodynamics. Am J Cardiol 1982;49:1806-1809. 9. Lynch JJ, Schuchard GH, Gross CM, Warm LS. Prevalence of right-to-left shunting in a healthy population: detection by Valsalva maneuver contrast echocardiography. Am J Cardiol 1984;53:1478-1480. 10. Dubourg 0, Bourdaria JP, Farcot JC, Gueret P, Terdjman M, Ferrier A, Rigaud M, Bardet JC. Contrast echocardiographic visualization of cough-induced right to left shunt through a patent foramen ovale. J Am Coil Cardiol 1984;4:587-594. 11. Pollick C, Sullivan H, Cujec B, Wilansky S. Doppler color-flow imaging assessment of shunt size in atria1 septal defect. Circulation 1988;78:522-528. 12. Dexter L, Haynes FW, Burwell CS, Eppinger EC, Sagerson RP, Evans JM.

Exercise Hemodynamics Rebreathing Techniques

The pressure and oxygen content of blood in the right auricle, right ventricle, and pulmonary artery in control patients, with observations on the oxygen saturation and source of pulmonary capillary blood. J Clin Invest 1974;26:554-560. 13. Hugenholtz PG, Schwark T, Monroe RG, Gamble WJ, Hawk AJ, Nadas AS. The clinical usefulness of hydrogen gas as an indicator of left-to-right shunts. Circulation 1963:33:542-X1. 14. Levin AR, Spach MS, Boineau JP, Canent RV Jr., Capp MP, Jewett PH. Atria1 pressure flow dynamics and atria1 septal defects (secundum type). Circulation 1968;37:476. 15. Simpson IA, Valdes-Cruz LM, Sahn DJ, Murillo A, Tamura T, Chung KJ. Doppler color flow mapping of simulated in vitro regurgitant jets: evaluation of the effects of orifice size and hemodynamic variables. J Am Coil Cardiol 1989; 13:1195-1207.

and Oxygen Delivery Measurements in Heart Transplant Patients

Using

Robert L. Jensen, PhD, Frank G. Yanowitz, MD, and Robert 0. Crapo, MD

he cardiorespiratory responseto graded exercise in cardiac transplant patients differs from that in normal subjectspartly becausedenervatedhearts are much less responsiveto changesin autonomic nervous system input. Previous studies with transplant patients have shown a delayed and often diminished heart rate responseto exercise compared with normal subjects.1,2Although it has been assumedthat increasesin stroke volume, using the Frank-Starling mechanism, compensatefor the delayed heart rate responseduring exercise, little is known about the matching of cardiac output (0, ) to oxygen uptake (902) in cardiac transplant patients. During exercise the metabolic requirements of skeletal muscle, a function of the work load and the sizeof the active musclemass,are the major determinants of or and systemic 02 transport3 The relation between & and 902 in normal subjectsduring exercise has been studied extensively and found to be relatively constant at 5 to 6 liters of blood flow, Qr, per liter of change in 902 /min. 4-6This is approximately a 1:1 ratio between exercise-inducedincreasesin 02 transport relative to levels at rest. Becausethe normal heart relies primarily on an increase in heart rate to increase or during exercise,with only minimal change in stroke volume, it is reasonableto expectthat the transplant patient will have a suboptimal responseto exercise.This study was conducted to determine the characteristics of the

T

From the Pulmonary Division, LDS Hospital, Salt Lake City, Utah 84143, and the Department of Medicine, University of Utah, Salt Lake City, Utah. This study was supported in part by the American Heart Association/Utah Affiliate, Salt Lake City, and the LDS HospitalDeseret Foundation, Salt Lake City, Utah. Manuscript received September 10, 1990; revised manuscript received and accepted February 2s. 1991.

cardiovascular responseto upright bicycle exercise in cardiac transplant patients. In particular, the & to 902 relation during exercisein the transplant patients was comparedwith that of normal subjectsto determine if @Jwasappropriately matchedto 902 during exercise. The acetylene rebreathing system used to measure pulmonary capillary blood flow (0, ) and i/oz during exercise was developed in our laboratory.7 Measurements of & have been compared with simultaneously measured indicator dye dilution (Cot~).~,~ Triebwasser et all9 showed excellent correlation (r = 0.94) between COm and & with a slope not different from identity, and Kally et al8 showed a similar correlation (r = 0.97), and that & insignificantly overestimates Cot, by 2 f 9% in normal lungs and that in patients with obstructive lung disease & again insignificantly overestimates COm by 6 f 15%. Because of the high degree of accuracy and precision of & with COm, we made calculations such as stroke volume and cardiac index using & as the value for &. Gas concentrations were measured with a Perkin-Elmer MGA-1100 mass spectrometer (Pomona, California) and calculations for & were made according to the method described by Sackner et al.tO Lung tissue volume value was estimated from a study of normal subjects.‘l Test gas composition was 0.79% acetylene, 9.18% helium, 39.00% 02 and 60.03% nitrogen. Calibration was performed initially and after every other rebreathing measurement with the gravimetrically mixed test gas and room air. Room air values were assumed to be 20.94% 02,0.94% argon, 0.04% carbon dioxide and 78.08% nitrogen. The initial rebreathing test gas volume was 1,000 ml for men and 800 ml for women. Rebreathing gas volume was increased by 200

BRIEF REPORTS 129

TABLE I Hemodynamic

Pt. No.

Age&r) & sex

Variables Resting HR (beats/min)

Max.HR (beats/min)

AHR* (beaUminI

Max.i/O, (ml/kg/min)+

Max.& (liter/min)

Max.CI (liter/min/m2)

Max. C,-,,, (ml/100 ml blood)

Max.SV (ml)

Max. Exercise (watts)

6.3 9.8 5.2 5.2 6.0 6.2 4.9 4.3 6.0 ir 1.7

12.5 10.7 10.3 12.3 11.3 11.3 15.3 13.7 12.2 f 1.7

156 142 103 86 96 84 63 50 98 f 36

125 125 75 50 100 100 100 75 94?26

16.5 13.7 13.5 13.8 14.7 13.0 14.0 11.8 16.3 12.9 13.6 14.0 2 1.4

107 133 116 137 92 127 121 75 117 75 106 109 -+ 21

200 250 200 250 175 150 200 125 300 125 175 195 rt 55

Transplant Patients 1 2 3 4 5 6 7 8 MeanSD

29M 26M 41M 47M 20M 21M 40M 24F 31-t-10

70 71 90 111 99 104 125 117 98?20

90 118 104 127 126 150 151 137 125+21

20 47 14 16 27 46 26 20 27 f 13

18.0 25.3 12.2 14.5 17.1 17.3 20.2 16.6 17.6 2 3.9

14.1 16.8 10.7 10.9 12.1 12.6 9.5 6.9 11.7 it 3.0

Normal Subjects 1 2 3 4 5 6 7 8 9 10 11 MeanSD

47M 29M 28M 31M 28M 29M 27M 33F 35M 42M 38F 332

7

68 70 87 65 74 77 70 84 65 106 77 76 f 13

155 181 161 162 173 133 164 174 185 170 172 1662

14

87 111 74 77 99 56 94 90 140 64 95 90 rt23

37.5 40.4 31.8 41.4 36.1 22.3 42.2 28.6 49.2 27.8 22.5 34.5 k 8.6

16.6 24.0 18.6 22.2 15.9 16.9 19.9 13.1 21.7 12.8 18.2 18.2 k 3.6

8.9 11.6 9.0 11.2 8.8 7.9 11.2 8.3 11.2 7.6 8.1 9.4 f 1.5

*AHR = change in heart rate from rest to maximal heart rate. ‘Standard

temperature

C(e-v)on=

arterid-WOUS

strokevolume;

and pressure, dry.

oxygen contentdifference;CI = cardiac index; HR = heart rate; Max. = maximal;& = pulmonarycapillaty blood flow; SD = standard deviation;SV =

V02 = oxygen uptake.

ml at each exercise level up to 2,400 ml and thereafter increased by 100 ml for each additional exercise level. Rebreathing was initiated at functional residual capacity and continued for 8 to 12 breaths while gas concentrations were digitized and stored for off-line process&g. Pulmonary capillary blood flow was estimated from the natural log of the acetylene disappearance curve.tO Analysis was started from the breath where the concentration of helium became constant, typically the second to fourth breath, and continued through the next 4 breaths. The rebreathing protocol required a minimum of 8 breaths to mix and analyze the test gas. i/oz in ml of Oz/kg/min was estimated as the total volume of the rebreathing compartment (lungs, rebreathing volume and dead space) multiplied by the concentration change of 02 in the compartment over the same time interval. & was calculated and divided by the time of the interval in minutes. These values were then normalized to body weight in kilograms as ml of 02/min/kg. Eight patients who had undergone cardiac transplantation and 1 I normal volunteers were studied. Consent forms approved by the Human Subjects Review Committee at LDS Hospital were read and signed by each participant. After height and weight were measured, the subjects were seated on a Sie130

THEAMERICANJOURNALOFCARDIOLOGY

VOLUME

68

mens electronically braked bicycle ergometer, the seat height was adjusted appropriately, and shoes were placed in toe clips. Each subject was then instructed in the use of a pneumatic balloon valve, which switched the subject from room air into the rebreathing circuit at the end of a normal expiration. Duplicate measurements of & and ~OZ were performed with the subject sitting on the bicycle at rest. The exercise protocol began at 25 Wfor 3 minutes and increased 25 Wevery 3 minutes thereafter until the patient was exhausted. This was a modified Bruce protocol that probably did not allow steady states to be reached at each 3-minute interval. Rebreathing tests were performed during the last minute of each exercise level. Blood pressure was recorded during every other work load. Electrocardiographic monitoring was performed to measure heart rate and observe for arrhythmias. A venous blood sample was drawn after exercise and analyzed for hemoglobin content. Resting and maximal exercise mean values were tested for differences between the normal and transplant subjects. Plots of VOz versus work load, i/O* versus & PO2 versus heart rate, PO2 versus stroke volume, PO2 versus arterial-venous 02 content difference (C(a - v)Oz) were constructed. Linear regression between the variables was performed to determine the change in each of the variables with changes in PO,. JULY

1,1991

ml of OdlOO ml of blood, respectively, p = 0.0863). However, at the 25-W level of exercise, the transplant patients demonstrated a significantly higher C(a v)Oz difference than control subjects (8.92 f 1.70 us 7.84 f 0.91, respectively, p = 0.0487). The transplant patients had a significantly lower stroke volume, expressed in ml/beat, than the control subjects at exercise levels of 575 W (respectively, 67 f 22 us 94 f 18 atrest,p=O.O001;89f33vs112f19at25W,p= 0.0336;94f28vs113f17at50W,p=0.0350;92f 27 us 115 f 20 at 75 W, p = 0.0316). There was no significant difference in stroke volumes at maximal exercise levels between transplant patients and control subjects (98 f 36 us 109 f 21 ml/beat, p = 0.1515). Figure 1 compares the & to PO2 relation of the transplant patients with the normal group. There was no significant difference in the mean slopes of these linear relations by analysis of covariance (5.593 f 0.475 for transplant patients us 5.403 f 0.130 for control subjects), suggesting that &- was adequately matched to 02 consumption in the transplant patients. Significant differences were found by analysis of covariance between the transplant patients and the normal subjects for stroke index versus PO, consumption (p = 0.0005) andfor C(a - v)Oz versus PO2 consumption (p = 0.0329).

The slope coefficients were compared between normal subjects and transplant patients by analysis of covariante to check for significant differences between the relations with i/02. Table I lists all relevant data for the transplant patients and the control group. The 8 transplant patients (7 men) had a mean age of 31 f IO years (range 20 to 47), and the 11 normal subjects (I 0 men) had a mean age of 33 f 7 years (range 27 to 47). The exercise studies in the transplant group were performed at a mean duration of 11.2 months (range 2 to 30) after operation. At rest, heart rates in the transplant group averaged 98 f 20 beatslmin and were significantly higher than the normal subjects who averaged 76 f 13 beats/ min (p = 0.0045). Maximal heart rates were lower in the transplant patients than in the normal subjects (125 f 21 us 166 f 14 beatslmin, respectively, p = 0.0095) as were the exercise-induced heart rate increments (27 f 13 us 90 f 23 beatslmin, respectively, P = 0.0010). Maximal work rates were significantly greater in the normal than in the transplant group (94 f 26 us 195 f 55 W, respectively, p = 0.00001). Analysis of the hemodynamic variables listed in Table I reveals that normal subjects achieved sign@cantly higher values than transplant patients for maximal PO* (ml/kg/min, 34.5 f 8.6 us 17.6 f 3.9 respectively, p = 0.0006), maximal & (18.2 f 3.6 us 11.7 f 3.0 Eiterslmin respectively, p = 0.0007) and maximal cardiac index (9.4 f 1.5 us 6.0 f 1.7 literslmin/m2, respectively, p = 0.0005). Maximal PO2 tended to be smaller in the transplant group than in control subjects, although the difference between groups did not reach statistical significance (12.2 f 1.7 us 14.0 f 1.4

Our data indicate that the cardiac transplant patients were significantly impaired in their cardiovascular responseto dynamic exercisewhen comparedwith normal subjects. The lower values for maximal work load achieved and maximal \iO, reflect, in part, a state of chronic deconditioning associatedwith their preoperative history of cardiomyopathy and congestiveheart failure. Moreover, none of the patients were engagedin formal

26 24 -

Normals

22 -

&I

20 18 -

X l

= i/O2 x 5.25

5.48

Normal Subjects Transplant Patients

16 -

FIGURE 1. Regressians of pulmonary capilary blood tlow (0) plotted against oxygen delivery (302) for both normal subjfscts and heart transplant patients.

z
100 beats/min were due to increasing sympathetic tone. Studiesby Rowell14and others15J6have also shown that plasma norepinephrine, an index of sympathetic activity, begins to rise during exercisewhen heart rates approach 100 beats/min. From theseobservations, it can be concluded that the higher heart rates at rest in transplant patients were due to the absenceof parasympathetic innervation, and that the blunted heart rate responseto exercisewasdue to the absenceof sympathetic innervation. The delayed heart rate increase during exercisehasbeenshownto occur asa result of circulatory catecholaminesreleasedfrom the adrenal medulla.r Kavanah et all7 showed that the cardiovascular responseto exercisetesting in transplant patients improved significantly after a structured exercisetraining program. Not only were peak power outputs and maximal 02 uptakes higher after training, but the heart rate response wasalsoimproved. Resting heart rateswere lower, maximal heart rates higher and heart rate increasesgreater after 1 to 2 years of training, suggestingthat the denervated transplanted heart adaptsto chronic physical activity much like a normal heart does.However, this tendency to normalize the heart rate responseafter training

132

THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 68

could not be explained by reinnervation. The authors speculatedthat the lower resting heart rates after training may be causedby reduced levelsof circulatory catecholamines at rest and that the higher maximal heart rates may result from increasedmyocardial sensitivity to circulatory catecholaminesat peak exercise. Although there is considerableintersubject variability, the relation between (ir and 902 during exercisein normal subjects is reasonably stable (low intrasubject variability) and linear in the submaximal exerciserange.3 Previous studies have shown that the slope of the & to VO? relation is approximately 5 to 6 liters/min per liter of VOZ.~-~ Yamaguchi et alI8 demonstrated a rather wide intersubject variability in the & to VO2 relation due to individual variations in resting and exercisehemodynamics. In their study of supine exercise, the mean slope of the Qr to 902 relation was 7.8 f 1.3, significantly steeperthan those reported by others,4-6but may have partly been due to the use of a noninvasive (ear lobe) sensingto derive dye dilution. Our data, derived from the acetylene rebreathing technique and measured during upright exercise,were similar to previous studies and revealed no significant differences between the Qr to VO2 slopesof transplant patients and normal subjects.Even though the transplant patientshavealtered hemodynamicresponsesto exercise, they are able to maintain their 02-carrying capacity within normal ranges.

1. PopeSE, StinsonEB, DaughtersGT, SchroederJS, Ingels NB, Alerman EL. Exerciseresponseof the denervatedheart in long-term cardiac transplant recipients. Am J Cardiol 1980;46:213-218. 2. Laboritz AJ, Drimmer AM, McBride LR, Pennington DG, Willman VL, Miller LW. Exercisescapacity during the first year after cardiac transplantation. Am J Cardiol 1989;64:642-645.

3. ClausenJP. Circulatory adjustmentsto dynamic exerciseand effects of physical training in normal subjectsand in patientswith coronary artery disease.Prog Cardiouasc Dis 1976;18:459-495. 4. Durand J, Mensch-DecheneJ. Physiologicmeaningof the slopeand intercept of the cardiac output-oxygenconsumptionrelationship during exercise. Bull Eur Physiopath Respir 1979;15:91?-998.

5. Faulkner JA, Heigenhauser GF, Schork MA. The cardiac output-oxygen uptake relationship of men during graded bicycle ergometry. Med Sci Sports 1977;9:148-154.

6. Mahaney GN, Blackie SP, Morrison NJ, Fairbarn MS, Wilcox PG, Pardy RL. Cardiac output at rest and in exercisein elderly subjects.Med Sci Sports Exec 1989:21:293-297.

7. Farney RJ, Morris AH, Gardner RM, Armstrong JD. Rebreathingpulmonary capillary and tissue volume in normals after saline infusion. J Appl Physioi 1911;43:246-253. 8. Kallay MC, Hyde RW, Smith RJ, Rothbard RL, Schreiner BF. Cardiac output by rebreathing in patientswith cardolpulmonarydiseases.J Appl Physiol 1987;63:201-210. 9. TriebwasserJH, JohnsonRL, Burpa RP, Campbell JC, Reardon WC, Blomqvist CG. Noninvasive determination of cardiac output by a modified acetylene rebreathing procedureutilizing massspectrometermeasurements.Aviat Space Environ Med 1977;48:203-209.

10. SacknerMA, Markwell G, Atkins N, Birch SJ, FernandezRJ. Rebreathing

JULY 1, 1991

techniquesfor pulmonary capillary blood flow and tissuevolume.J Appl Physiol 1980;49:910-915. 11. Crapo RO, Morris AH, Gardner RM. Referencevaluesfor pulmonary tissue volume, membranediffusion capacity, and pulmonary capillary blood volume. Bull Europ Physiopath Resp 1982;18:893-899. 12. Rowe11LB, Human Circulation Regulation During Physical Stress.New York: Oxford University, 1986221. 13. RobinsonBF, Epstein SE, BesserGD, Braunwald E. Control of hear rate by the autonomicnervoussystem:studiesin man on the interrelation betweenbaroreceptor mechanismsand exercise. Circ Res 1966;19:400-411. i4. Rowe11LB. Reflex control of regional circulation in man. J Autonomic Nem Sys 1984;11:101-114.

Morbidity

of Endomyocardial

15. Escourrou P, JohnsonDG, Rowe11LB. Hypoxemia increasesplasma catecholamineconcentrationin exercisionhumans.J Appl Physiol Respirat Environ Exercise Physiol 1984;57:1507-1511. 16. ChristensenNJ, Brandsborg0. The relationship betweenplasmacatecholamine concentration and pulse rate during exercise and standing. Eur J Clin Invest 1973;3:299-306. 17. KavanaghT, JacoubMH, M&ens DJ, KennedyJ, Campbell RB, Sawyer P. Cardiorespiratory responsesto exercise training after orthotopic cardiac transplantation Circulation 1988;77:162-171. 18. Yamaguchi I, Komatsu E, Miyazawa K. Intersubject variability in cardiac output-02 uptake relation of men during exercise. J Appl Physiol 1986; 61:2168-2174.

Biopsy in Cardiomyopathy

Randall C. Starling, MD, MPH, Douglas B. Van Fossen, MD, Donald F. Hammer, MD, and Donald V. Unverferth, MD* he transvenoustechnique of endomyocardial biopsy was developedover 15 years ago.1-3Before the proliferation of heart transplant centers,this procedure was performed at only a limited number of transplant and heart failure centers in the United States. Complication rates for endomyocardial biopsy are quoted in the published reports, but detailed analyses in specitlc patient populations are lacking.4-6One retrospective study has suggestedthat the procedural risks differ in transplant and nontransplant patient populations.7 The performance of endomyocardial biopsy to exclude cardiac allograft rejection is an acceptedindication in heart transplant recipients. The merit of endomyocardial biopsy in diagnosing myocarditis and evaluating cardiomyopathy has been questionedbecausethe diagnostic sensitivity of the procedure is limited and the results will not significantly influence patient management.8-11Therefore, clarification of the risks of this procedure in patients with unexplained heart failure allows clinicians to make informed decisionsregarding the risk/ benefit ratio of the procedure in specific patients. This study documents the procedural complications of endomyocardial biopsy in 706 consecutivepatients with cardiomyopathy evaluated at a single institution.

T

Records of a consecutive series of patients with cardiomyopathic heart failure who underwent right ventricular endomyocardial biopsy between July 1981 and June 1990 were reviewed. All procedural compli-

Froin the Division of Cardiology, Room 647 Means Hall, Department of Internal Medicine, the Ohio State University College of Medicine,

1654Upham Drive, Columbus,Ohio 43210-1228.This study was supported in part by grants from the Central Ohio Chapter of the American Heart Association,Columbus,Ohio, and the JamesD. Casto Research Fund, Columbus, Ohio. Manuscript received November 2, 199D;revised manuscript receivedand acceptedFebruary 14,1991. *Deceased.

cations were documented by a research nurse who observed the patient during and after the procedure (up to 24 hours). Since 1985, all procedures and complications have been logged in a computerized data base (474 of the 706 cases). All individual patient records were reviewed manually to be certain all complications were documented. Indications for the procedure included: (I) to rule out myocarditis, (2) to assess restrictive physiology, (3) to rule out coexistent myopathy in patients with valvular heart disease, (4) to rule out associated cardiac muscle involvement in patients with systemic disease, and (5) to assess heart failure of unknown etiology. Virtually all the patients tested had dilated or restrictive cardiomyopathy. A small group of patients (