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Changes in left ventricular mechanical and hemodynamic function during acute rejection of orthotopically transplanted hearts in dogs
Changes in left ventricular mechanical and hemodynamic function during acute rejection of orthotopically transplanted hearts in dogs During orthotopic cardiac transplantation in 10 non immunosuppressed dogs the donor left ventricle (LV) was equipped with endocardial piezoelectric crystals for direct ultrasound measurement of internal transverse diameter and an indwelling pressure transducer. Measurements made immediately postoperatively and then daily until death due to acute graft rejection included LV pressure and maximum dp/dt, end-diastolic and end-systolic internal diameters, the per cent shortening of diameter during systole, calculated ejection fraction, and the velocity of donor LV contraction. In addition, diastolic LV mechanics were characterized by the rate of filling, the prominence of the rapid filling phase of diastole, and the ratio of developed LV pressure to the increment in diameter during the total diastolic interval. Average survival was 6.2 (:to.8 S.E.) days. Developed LV pressure and maximum LV dp/dt remained within a normal range throughout the postoperative course except in three dogs studied immediately before death. Average end-diastolic diameter showed no significant changes throughout the postoperative interval, whereas end-systolic diameter decreased during postoperative recovery and then increased during rejection. The extent of diameter shortening during systole and calculated ejection fraction increased during recovery and fell during rejection. Indices of LV contraction velocity showed improvement after transplantation and then declined sharply during rejection. Changes in donor LV diastolic mechanics with advancing rejection suggested decreasing LV distensibility. These data indicate that the major functional components of acute cardiac allograft rejection responsible for hemodynamic deterioration consist of both impairment of ventricular contracile state and diminished ventricular compliance.
Edward B. Stinson, M.D., * Paul L. Tecklenberg, M.D., Jefferson F. Hollingsworth, M.D., Kent W. Jones, M.D., Robert Sloane, M.D., and Glen Rahmoeller, M.S., Bethesda, Md., and Stanford, Calif.
Studies of systemic hemodynamics during acute rejection of orthotopically transplanted hearts in dogs have shown that detectable deterioration of left ventricular pumping From the Clinic of Surgery, National Heart and Lung Institute, National Institutes of Health, Bethesda, Md., and the Department of Cardiovascular Surgery, Stanford University Medical School, Stanford, Calif. Received for publication Oct. 10, 1973. Address for reprints: Edward B. Stinson, M.D., Department of Cardiovascular Surgery, Stanford University Medical Center, Stanford, Calif. 94305. ·Established Investigator, American Heart Association.
performance at rest is a relatively late event in the course of rejection. 1 Significant decreases in stroke volume and cardiac output develop, on the average, approximately one day before death in nonimmunosuppressed recipients; impairment of left ventricular function is then progressive and, terminally, extreme limitation of stroke output is present. 1 Similar observations have been documented after heart transplantation in man," although in the clinical setting immunosuppressive treatment is usually associated with 783
784
The Journal 01
Stinson et at.
Thoracic and Card iovascular Surgery
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expansion of the time course of evident graft dysfunction during rejection episodes, in comparison to that seen in unmodified canine recipients. It is apparent that changes in left ventricular dimensions and /or extent of fiber shortening must necessarily occur in conjunction with impairment of external systolic work during acute cardiac rejection. However, the mechanics of donor left ventricular performance during this interval have not been described. In addition, alterations in the mechanics of ventricular diastole have also been suggested by physical findings which occur during acute graft rejection in man. v ' In order to define further the effects of acute reject ion on donor left ventricular mechanical and hemodynamic performance, we measured left ventricular pressure, internal transverse diameter, and derived variables after orthotopic transplantation in nonimmunosuppressed dogs. The results of this study substantiate the expectation that significant changes in such parameters of graft function are associated with acute rejection.
Methods Orthotopic cardiac transplantation was performed in 10 American foxhounds whose unrelated donors from the same breed were matched only for size.' At operation a single dose of digoxin was given intravenously, and antibiotics (penicillin and streptomycin) were administered daily postoperatively. Immunosuppressive drugs were not used. After excision and cooling of the donor heart, a miniature, solid-state pressure transducer* was inserted into the left ventricle through a small incision at the apex. Two 5 mm . diameter discs of lead titanate-zirconate crystal, mounted in Lucite housings, were firmly implanted on opposite endocardial surfaces of the left ventricle across the maximum transverse internal axis for continuous instantaneous measurement of diameter by direct ultrasound techniques." Wires for electrical pacing of the donor heart were sewn to the atrial appendages. All leads were passed from the chest incision through a subcutaneous tunnel to the back of the neck where they were exteriorized. Recipients were studied immediately after operation and extubation of the trachea, and then daily thereafter. At each study, performed in the right lateral position, a thr ee-lead electrocardiogram (ECG) (limb Leads I, II, and III) , left ventricular pressure (LVP) and first derivative (LV dp /dt) , and internal transverse left ventricular diameter (LVID) and first derivative (dD/dt) were recorded on a Brush 280 recorder] and on magnetic tapej for later playback. An example of these signals in one recipient , recorded 2 hours after transplantation, is shown in Fig. 1. All dogs were studied within 24 hours of death, but only three were studied within 6 hours of death. Postmortem examination of the grafts included gross inspection and routine histological study of representative sections of the left ventricle. 'Model P-22. Konigsberg Instruments, Pasadena, Calif. t Gould, Inc., Cleveland, Ohio. :j:Am pex FR 1300, Ampex Corp., Redwood City, Calif.
Volume 68 Number 5 November, 1974
Orthotopic cardiac transplantation
Pressure transducers were calibrated against a mercury column before and after implantation; static calibrations were linear from 0 to 300 mm. Hg and remained constant. Zero baselines, however, though constant with some gauges, were unreliable; they were therefore adjusted at each study to effect a left ventricular end-diastolic pressure of 5 to 10 mm. Hg, and only relative LVP events were measured (e.g., developed LVP or dP/ dt during systole, changes in LVP during diastole). The frequency response of the pressure monitoring system was flat (±5 per cent) to 80 c.p.s. LV dp/dt was obtained with an active differentiator having a linear frequency response and constant phase lag up to 80 c.p.s. The techniques for direct ultrasound measurement of LVIO and derivation of dO/dt have been described." Both end-diastolic (OJ)) and end-systolic (Ds) diameters were recorded, and the per cent systolic shortening of LVIO was calculated as Do - Ds Do
x 100.
Similarly, an ejection fraction (EF) was calculated as
assuming a constant geometric factor relating the cube of LVIO to volume throughout the cardiac cycle. The maximum rate of change of LVIO was measured directly from the precalibrated derivative signal, and was divided by instantaneous LVIO to obtain peak circumferential fiber-shortening rate (Max VCF, in circumferences per second). Average systolic -dO/dt was derived from the diameter tracing, and was divided by average diameter, (Do + Ds), 2
to obtain the mean circumferential fibershortening rate (average VCF, in average circumferences per second). Left ventricular diameter at the end of the
785
early, rapid phase of diastolic filling (DR) was also measured, and the per cent of total diastolic filling contributed during this rapid filling phase (per cent RF) was calculated as DR - D, - - - x 100. Do - Ds
In addition, the average rate of diameter lengthening (millimeters per second) during rapid filling (+dD / dt), between points D s and D u , was determined directly from the diameter signal. For analysis, the results of studies done immediately after transplantation, at the time of maximum postoperative recovery (defined by the highest ejection fraction calculated on the second or third postoperative day*), and those performed closest to the time of death were combined. Group means, thus normalized, were compared by Student's t test for paired data with equal variance. Results
Postoperative survival ranged from 4 to 12 days; average survival was 6.2 (±0.8 S.E.) days. Histological changes indicative of severe acute rejection" were present in all donor hearts. Grossly, the ventricular walls were thickened and rubbery. ECG's, heart rate, and LVP (Fig. 2). Electrocardiographic voltage, determined as the algebraic sum of peak-to-peak QRS voltages in normally conducted complexes in Leads I, II, and III, showed no significant variation from the time of transplantation through postoperative recovery. During rejection, progressive decreases in voltage occurred in all animals; average voltage at the time of final study was 56 per cent of the early postoperative baseline level (P < 0.05). Junctional rhythm was present terminally in two dogs. Heart rate was maintained relatively con• Serial studies have shown that cardiac output and stroke volume increase to maximum levels in the majority of unmodified canine recipients on the second or third postoperative day.!
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The Journal of Thoracic and Cardiovascular Surgery
Stinson et al.
786
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Fig. 3. Mean values for LVID, per cent systolic shortening of LVID, and calculated ejection fraction.
stant by donor atrial pacing at approximately 150 beats per minute in most recipients throughout the first three postoperative days. During rejection, mean heart rate (unpaced in most) was 121 (±9.2) beats per minute (P < 0.01). Average developed LVP was highest immediately after transplantation ( 141 ± 6 mm. Hg); at the time of defined recovery it was significantly lower (120 ± 5.6 mm. Hg, P < 0.001). During rejection, developed LVP remained within a normal range in all but two of the three animals that were studied within 6 hours of death. Average developed LVP at the point of final study was 111 ± 10 mm. Hg. Peak LV dp/dt remained relatively stable throughout the postoperative course in most recipients. The slight decrease in the group mean during acute rejection, as compared to the recovery period, was of borderline statistical significance (P < 0.1), and was caused by low values observed in the three dogs studied within the terminal 6 hours. Absolute levels of peak LV dp/dt in donor hearts were generally comparable to normal (2,500 to 3,500 mm. Hg per second). LWD and systolic shortening of LVID (Fig. 3). Average end-diastolic LVID showed no significant changes throughout the postoperative course. The greatest changes observed in some individual dogs occurred from the time of transplantation through the first 2 to 3 postoperative days when end-diastolic diameter tended to increase (not consistently associated with decreases in heart rate). End-systolic LVID decreased slightly during the same interval and then rose significantly (P < 0.025) from the time of recovery to rejection. These changes in D s were associated with inverse variations in per cent systolic shortening of LVID and calculated ejection fraction. The former rose over the first 2 to 3 days from 22.6 ± 1.9 to 27.9 ± 2.2 per cent (P < 0.01) and then fell during rejection to 23 ± 1.5 per cent (P < 0.01). As expected, similar time course changes in calculated EF· were seen. Immediately postoperatively, EF was 53 ± 4 per cent, and
Volume 68
Orthotopic cardiac transplantation
Number 5
787
November, 1974
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then increased over the ensuing 2 to 3 days to 62 ± 4 per cent (P < 0.01); with rejection, EF declined to 54 ± 2.6 per cent (P < 0.025). Velocity of left ventricular contraction (Figs. 4 and 5). The maximum rate of systolic shortening of LVID was 57.3 ± 4.1 mm. per second immediately after transplantation. It then rose during recovery to 67.3 ± 2.2 mm. per second (P < 0.005). With acute rejection, maximum systolic -dD/dt decreased to 47.1 ± 3.2 mm. per second (P < 0.0005). Average systolic -dD/dt, and peak and average circumferential fiber-shortening rates showed similar changes. Average -dD/dt, which immediately after transplantation was 34.5 ± 2.6 mm. per second, rose to 44.6 ± 3.1 mm. per second at the time of recovery (P < 0.025). During rejection, measured average -dD/dt decreased to 36.3 ± 2.3 mm. per second (P < 0.025). Peak VCF increased from 2.9 ± 0.26 circumferences per second immediately postoperatively to 3.3 ± 0.4 circumferences per second during recovery (P < 0.1), and with rejection fell to 2.2 ± 2.3 circumferences per second (P < 0.005). Average VCF increased and decreased in a similar pattern, being 1.7 ± 0.13, 2.3 ± 0.41, and 1.7 ± 0.22 average circumferences per second at the time of
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Fig. 6. Mean values for the per cent of total diastolic expansion of LVID occurring during the early, rapid filling phase and the average rate of change of LVID during rapid filling (RF +dD/dt).
The Journal of
788
Stinson et al.
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Thoracic and Cardiovascular Surgery
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Fig. 8. Variations in the ratio of developed left ventricular pressure during diastole to the change in LVID during diastole (.<1P 1.<10) .
120
Fig. 7. Serial recordings of LVIO in one recipient; death due to acute rejection occurred 5.5 days after transplantation. By day 4 (36 hours prior to de ath ), there was little further expansion of LVID after the early, rapid filling phase, even during long diastolic intervals induced by interruption of atrial pacing (day 5). Small deflections in LVID during the long diastolic interval are caused by contractions of the residual recipient left atrium.
operation, recovery , and rejection , respectively (P < 0.1 and < 0.01 for sequential differences). Contraction velocity normalized for end-diastolic LVID exhibited parallel changes, rising from 1.5 ± 0.12 to 1.9 ± 0.35 end-diastolic circumferences per second over the first 2 to 3 days (P < O. I) and then falling to 1.5 ± 1.8 end-diastolic circumferences per second during rejection (P < 0.025). Left ventricular diastolic filling (Fig. 6). Little variation in the pattern of left ventricular diastolic filling, as determined from transverse LVID, was observed during the first 2 to 3 days after transplantation. Average per cent RF remained in the range of 60 to 65 per cent. The average rate of diameter lengthening during early, rapid diastolic filling increased over this period , however , from 55 ± 11.3 to 66.7 ± 4.6 mm. per second (P < 0.1) . During acute rejection , striking changes in the pattern of diastolic filling developed
in all animals (Fig. 7). The early, rapid phase of filling accounted for an increasing proportion of the total increment in LVID during diastole ; slight or no expansion of LVID was seen during diastasis and donor atrial systole, even in the presence of prolonged diastolic intervals associated with continuing rises in left ventricular diastolic pressure (LVDP). Average per cent RF rose with rejection to 86.3 ± 4.1 per cent (range 65 to 100 per cent) (P < 0.0005) . Concurrently, the average rate of diameter lengthening during rapid filling decreased to 49.2 ± 3.8 mm. per second (P < 0.0005). In eight of the 10 recipients these changes were associated with a progressively more prominent early diastolic dip in LVP recordings. The ratio of developed LVP during diastole (end-diastolic pressure minus end-systolic pressure) to the total change in LVID averaged 1.2 ± during diastole (~P I ~D) 0.1 mm. Hg per millimeter immediately after transplantation. It then decreased to 1.0 ± 0.1 mm. Hg per millimeter on the second or third postoperative day (P < 0.1) . Terminally, ~P I ~D rose significantly to an average value of 1.6 ± 0.1 mm. Hg per millimeter (P < 0.025) (Fig. 8). Discussion Morphologic evidence of a progressive host immune response can often be detected in orthotopically transplanted cardiac grafts
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Orthotopic cardiac transplantation
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November, 1974
in nonimmunosuppressed dogs as early as 24 to 48 hours after operation. G Such early
histological changes, however, are not expressed in detectable impairment of graft function. On the contrary, both the present and previous studies' indicate that orthotopic cardiac graft performance at rest steadily improves over the early postoperative interval. Maximum values for stroke volume, cardiac output, and myocardial contraction velocity, near or within the ranges observed in normal dogs, are gradually attained over the first 2 to 4 postoperative days. The depression of donor heart function immediately after transplantation is probably not immunologically determined, inasmuch as a similar response is observed in autotransplanted hearts submitted to identical operative manipulations. Initial abnormalities of graft function include limitation of stroke volume and cardiac output; normal arterial blood pressure, however, is maintained by compensatory adjustments in peripheral vascular resistance. 1 The present study has demonstrated parallel alterations of donor left ventricular mechanical performance which are consistent with these previous hemodynamic findings. Thus, early after transplantation, the extent of shortening of transverse LVID, calculated ejection fraction, and peak myocardial contraction velocity were markedly low. Developed left ventricular pressure and peak left ventricular dp/dt (which under resting conditions may be prominently modified by the arterial blood pressure at the time of aortic valve opening), however, were comparable to normal. Indices of graft left ventricular mechanical function then improved significantly over the following 2 to 3 days. Again, these changes are consonant with previously documented hemodynamic improvement over the same interval in both allografts and autografts.' Early postoperative abnormalities of donor left ventricular diastolic events were less definite, but suggested an initial decrease in compliance, followed by significant
improvement during the ensuing 2 to 3 days. Changes in average dD/dt during the early, rapid filling phase of diastole and alterations of diastolic ~p / ~D were independent of variations in end-diastolic fiber length (DD) and probably left ventricular geometry (although this is unproved), and therefore may be interpreted as indices of left ventricular compliance.' The directional changes measured in this regard are consistent with the results of previous studies of the effects of temporary myocardial anoxia on left ventricular compliance; aortic cross-clamping for 20 to 45 minutes in dogs supported on cardiopulmonary bypass is followed by immediate" and extended" decreases in left ventricular compliance which may persist for 24 to 48 hours. Transplantation of the heart, which as presently performed necessitates more prolonged periods of hypothermic anoxia (45 to 75 minutes), would thus be expected to be associated with significant early postoperative alterations in compliance. During the first two to three postoperative days, normal values for donor left ventricular diastolicziP/ ~D (1.04 ± 0.17 mm. Hg per millimeter in this laboratory) were gradually reached in most although not all recipients. Trends toward normal pressure-todiameter ratios then became reversed, and progressively abnormal values were observed during advancing rejection. These findings and the data of Nelson and associates> suggest that decreased left ventricular distensibility is commonly present in cardiac allografts during the first few postoperative weeks. The latter workers found a subnormal maximum rate of change of left ventricular area during early, rapid diastolic filling by angiographic techniques in immunosuppressed canine recipients. During the late stage of acute, first-set cardiac rejection (i.e., the terminal 24 to 48 hours) in nonimmunosuppressed dogs, myocardial lesions include vascular congestion, capillary and venular rupture with extravasation of red blood cells, generalized myocardial edema, and myocyte necrosis (often with grossly evident myocardial in-
790
Stinson et at.
farction, especially in the subendocardial region and papillary muscles). 6, 11 Despite such severe histological changes, systolic performance of the donor left ventricle is often relatively well preserved until the terminal 24 hours.' At this time rapid, progressive limitation of stroke volume and cardiac output develop; death of the recipient is usually caused by low cardiac output.' In the present study there was depression of per cent systolic shortening of transverse LVID, calculated ejection fraction, and myocardial contraction velocity over the same interval. Developed LVP and peak dp/dt, however, were relatively well maintained, as is arterial blood pressure,' until terminal collapse of the recipient. Thus, during acute rejection, an increasing proportion of myocardial energy expenditure is directed toward maintenance of wall tension rather than fiber shortening. Of the primary determinants of cardiac output, i.e., heart rate, preload, afterload, and contractile state, it is the latter which would appear to be critically limiting during advanced rejection. Heart rate changes during rejection were generally minimal, and the slight changes which did occur in enddiastolic diameter were directionally opposite to those which would tend to decrease stroke volume according to the Frank-Starling principle. The relative stability of left ventricular and arterial pressure and transverse internal diameter during rejection suggest that ventricular afterload also remained fairly constant, although it has not been disproved that alteration of the viscous properties of the myocardium by the pathological changes noted above may have generated important increases in resistance to fiber shortening. The maintenance of myocardial force development, at a time when contraction velocity was significantly diminished, in turn implies that decay in contractility may be due predominantly to decreases in velocity of contractile element interaction; some loss of contractile elements, however, also must occur as a consequence of the destructive changes seen in myocardial fibers during advanced rejection.
The Journal af Thoracic and Cardiavascular Surgery
Ultrastructural abnormalities which may interfere with the contractile process have also been described in myocytes during acute rejection. Kosek, Hurley, and Lower" and co-workers found degenerative changes in mitochondria and dilatation of the transverse tubular system, as well as frank dissolution of myofibrils. Such lesions would be expected to be associated with altered production of energy substrates and possibly derangement of electromechanical coupling. In addition to the changes observed in donor left ventricular systolic mechanics during acute rejection, striking alterations in the pattern of diastolic filling, as judged from LVID, developed as well. With advancing rejection, an increasing proportion of the total increment of diameter during diastole occurred during the early, rapid filling phase. Terminally, approximately half the records of graft LVID showed 90 to 100 per cent of total diastolic filling to be contributed during the phase of early, rapid filling, with absent or only slight further expansion of diameter during diastasis and donor atrial systole. The resulting LVID waveforms had a characteristic "flat-topped" appearance (Fig. 7), remininscent of the "square root" sign of ventricular pressure curves in constrictive or restrictive heart disease. This was especially prominent at slow heart rates. During long diastolic intervals induced by interruption of rapid atrial pacing, LVID showed essentially no change (Fig. 7). Many of the pathological features observed in acutely rejected hearts would appear capable of altering the elastic properties of the ventricular myocardium: edema, cellular infiltration, vascular congestion, and interstitial hemorrhage. G The present study offers direct evidence for the functional effects of such lesions on donor left ventricular diastolic pressure-dimension relationships and patterns of diastolic filling. Thus, during rejection, higher increments in diastolic pressure were associated with given increases in diameter, the expansion of left ventricular diameter during diastole became progressively restricted to the early, rapid
Volume 68 Number 5
Orthotopic cardiac transplantation
791
November, 1974
phase of filling, and the average rate of diameter lengthening during rapid filling decreased. These changes were not associated with significant variation in end-diastolic diameter, and thus signify a decrease in ventricular compliance as a major functional component of acute cardiac rejection. It is noteworthy that modifications in graft left ventricular diastolic mechanics generally developed earlier in the course of rejection than did impairment of systolic performance. In fact, in most animals distortion of diastolic LVID tracings and decreases in electrocardiographic voltage appeared concurrently. This association may imply a common pathophysiological mechanism; myocardial edema and hemorrhage along with vascular congestion could constitute sufficient explanation for both functional abnormalities. Extrapolation of these findings to the clinical situation suggests that examination of diastolic ventricular wall movement by such techniques as apexcardiography or echocardiography might contribute to more sensitive diagnosis of early, acute graft rejection in man. Abnormalities of both systolic and diastolic donor left ventricular performance during rejection are immunologically determined through pathological changes which have been previously described. 6, 11 It should be emphasized, therefore, that in the clinical setting treatment of such alterations of graft function must be directed toward attenuation of the host immune response. Supportive therapy in the form of positive myocardial inotropic drugs may, of course, be provided for hemodynamic deterioration associated with impairment of graft contractile function. No supportive measure, however, is available for the amelioration of diastolic dysfunction.
REFERENCES
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Stinson, E. B., Griepp, R. B., Bieber, C. P., and Shumway, N. E.: Hemodynamic Observations After Orthotopic Transplantation of the Canine Heart, I. THoRAc. CARDIOVASC. SURG. 63: 344, 1972. Williams, G. M., DePlanque, B., Graham, W. H., and Lower, R. R.: Participation of Antibodies in Acute Cardiac Allograft Rejection in Man, N. Engl. I. Med. 281: 1145, 1969. Stinson, E. B., Dong, E., rr., Bieber, C. P., et al. : Cardiac Transplantation in Man. I. Early Rejection, J. A. M. A. 207: 2233, 1969. Schroeder, I. S., Popp, R. L., Stinson, E. B., et al.: Acute Rejection Following Cardiac Transplantation: Phonocardiographic and Ultrasound Observations, Circulation 40: 155, 1969. Stinson, E. B., Rahmoeller, G., and Tecklenberg, P. L.: Measurement of Internal Left Ventricular Diameter by a Tracking Sonomicrometer, Cardiovasc. Res. 8: 283, 1974. Kosek, I. C., Hurley, E. J., and Lower, R. R.: Histopathology of Orthotopic Canine Cardiac Homografts, Lab. Invest. 19: 97, 1968. Diamond, G., Forrester, I. S., Hargis, I., et al.: Diastolic Pressure-Volume Relationship in the Canine Left Ventricle, Circ. Res. 29: 267, 1971. Enright, L. P., Staroscik, R. N., and Reis, R. L.: Left Ventricular Function After Occlusion of the Ascending Aorta, I. THoRAc. CARDIOVASC. SURG. 60: 737, 1970. Levine, F. H., Copeland, I. G., Melvin, M. B., and Stinson, E. B.: Extended Evaluation of Anoxia on Ventricular Performance and Compliance, Circulation 46 (Suppl. II): 184, 1972. Nelson, R. J., Castagna, I. T., Nedelman, A. L., et al.: Hemodynamic Effects of Volume Loading in Dogs Following Cardiac Homotransplantation, Circulation 43 (Suppl. I): 130, 1971. Bieber, C. P., Stinson, E. B., and Shumway, N. E.: Pathology of the Conduction System in Cardiac Rejection, Circulation 39: 567, 1969.
Edward B. Stinson, M.D., * Paul L. Tecklenberg, M.D., Jefferson F. Hollingsworth, M.D., Kent W. Jones, M.D., Robert Sloane, M.D., and Glen Rahmoeller, M.S., Bethesda, Md., and Stanford, Calif.
Studies of systemic hemodynamics during acute rejection of orthotopically transplanted hearts in dogs have shown that detectable deterioration of left ventricular pumping From the Clinic of Surgery, National Heart and Lung Institute, National Institutes of Health, Bethesda, Md., and the Department of Cardiovascular Surgery, Stanford University Medical School, Stanford, Calif. Received for publication Oct. 10, 1973. Address for reprints: Edward B. Stinson, M.D., Department of Cardiovascular Surgery, Stanford University Medical Center, Stanford, Calif. 94305. ·Established Investigator, American Heart Association.
performance at rest is a relatively late event in the course of rejection. 1 Significant decreases in stroke volume and cardiac output develop, on the average, approximately one day before death in nonimmunosuppressed recipients; impairment of left ventricular function is then progressive and, terminally, extreme limitation of stroke output is present. 1 Similar observations have been documented after heart transplantation in man," although in the clinical setting immunosuppressive treatment is usually associated with 783
784
The Journal 01
Stinson et at.
Thoracic and Card iovascular Surgery
I--I.oc - - l
I
EKG
LVP ImmHq)
LVDP (mmHq)
100r50 E EE AE E =n T f.f ff n ~ FF ff ~ o
LVID ( mmJ
dD/dt (mm/.oc)
--!-\f
10 t
20
o
2000 ( mm dpHq/ / dt .oc )
t- H -H I- ' -t
0
-2000
I
,
I
t~HE99~utlB~f:iff.E~
;~t .-7~r ~ . k- TiU
__ ~
WW~
+75[
Fig. 1. Representative recordings of ECG (atrial pacing) , LVP, LV dp/dt, LVlD, and dD/dt in a cardiac recipient 2 hours after transplantation.
expansion of the time course of evident graft dysfunction during rejection episodes, in comparison to that seen in unmodified canine recipients. It is apparent that changes in left ventricular dimensions and /or extent of fiber shortening must necessarily occur in conjunction with impairment of external systolic work during acute cardiac rejection. However, the mechanics of donor left ventricular performance during this interval have not been described. In addition, alterations in the mechanics of ventricular diastole have also been suggested by physical findings which occur during acute graft rejection in man. v ' In order to define further the effects of acute reject ion on donor left ventricular mechanical and hemodynamic performance, we measured left ventricular pressure, internal transverse diameter, and derived variables after orthotopic transplantation in nonimmunosuppressed dogs. The results of this study substantiate the expectation that significant changes in such parameters of graft function are associated with acute rejection.
Methods Orthotopic cardiac transplantation was performed in 10 American foxhounds whose unrelated donors from the same breed were matched only for size.' At operation a single dose of digoxin was given intravenously, and antibiotics (penicillin and streptomycin) were administered daily postoperatively. Immunosuppressive drugs were not used. After excision and cooling of the donor heart, a miniature, solid-state pressure transducer* was inserted into the left ventricle through a small incision at the apex. Two 5 mm . diameter discs of lead titanate-zirconate crystal, mounted in Lucite housings, were firmly implanted on opposite endocardial surfaces of the left ventricle across the maximum transverse internal axis for continuous instantaneous measurement of diameter by direct ultrasound techniques." Wires for electrical pacing of the donor heart were sewn to the atrial appendages. All leads were passed from the chest incision through a subcutaneous tunnel to the back of the neck where they were exteriorized. Recipients were studied immediately after operation and extubation of the trachea, and then daily thereafter. At each study, performed in the right lateral position, a thr ee-lead electrocardiogram (ECG) (limb Leads I, II, and III) , left ventricular pressure (LVP) and first derivative (LV dp /dt) , and internal transverse left ventricular diameter (LVID) and first derivative (dD/dt) were recorded on a Brush 280 recorder] and on magnetic tapej for later playback. An example of these signals in one recipient , recorded 2 hours after transplantation, is shown in Fig. 1. All dogs were studied within 24 hours of death, but only three were studied within 6 hours of death. Postmortem examination of the grafts included gross inspection and routine histological study of representative sections of the left ventricle. 'Model P-22. Konigsberg Instruments, Pasadena, Calif. t Gould, Inc., Cleveland, Ohio. :j:Am pex FR 1300, Ampex Corp., Redwood City, Calif.
Volume 68 Number 5 November, 1974
Orthotopic cardiac transplantation
Pressure transducers were calibrated against a mercury column before and after implantation; static calibrations were linear from 0 to 300 mm. Hg and remained constant. Zero baselines, however, though constant with some gauges, were unreliable; they were therefore adjusted at each study to effect a left ventricular end-diastolic pressure of 5 to 10 mm. Hg, and only relative LVP events were measured (e.g., developed LVP or dP/ dt during systole, changes in LVP during diastole). The frequency response of the pressure monitoring system was flat (±5 per cent) to 80 c.p.s. LV dp/dt was obtained with an active differentiator having a linear frequency response and constant phase lag up to 80 c.p.s. The techniques for direct ultrasound measurement of LVIO and derivation of dO/dt have been described." Both end-diastolic (OJ)) and end-systolic (Ds) diameters were recorded, and the per cent systolic shortening of LVIO was calculated as Do - Ds Do
x 100.
Similarly, an ejection fraction (EF) was calculated as
assuming a constant geometric factor relating the cube of LVIO to volume throughout the cardiac cycle. The maximum rate of change of LVIO was measured directly from the precalibrated derivative signal, and was divided by instantaneous LVIO to obtain peak circumferential fiber-shortening rate (Max VCF, in circumferences per second). Average systolic -dO/dt was derived from the diameter tracing, and was divided by average diameter, (Do + Ds), 2
to obtain the mean circumferential fibershortening rate (average VCF, in average circumferences per second). Left ventricular diameter at the end of the
785
early, rapid phase of diastolic filling (DR) was also measured, and the per cent of total diastolic filling contributed during this rapid filling phase (per cent RF) was calculated as DR - D, - - - x 100. Do - Ds
In addition, the average rate of diameter lengthening (millimeters per second) during rapid filling (+dD / dt), between points D s and D u , was determined directly from the diameter signal. For analysis, the results of studies done immediately after transplantation, at the time of maximum postoperative recovery (defined by the highest ejection fraction calculated on the second or third postoperative day*), and those performed closest to the time of death were combined. Group means, thus normalized, were compared by Student's t test for paired data with equal variance. Results
Postoperative survival ranged from 4 to 12 days; average survival was 6.2 (±0.8 S.E.) days. Histological changes indicative of severe acute rejection" were present in all donor hearts. Grossly, the ventricular walls were thickened and rubbery. ECG's, heart rate, and LVP (Fig. 2). Electrocardiographic voltage, determined as the algebraic sum of peak-to-peak QRS voltages in normally conducted complexes in Leads I, II, and III, showed no significant variation from the time of transplantation through postoperative recovery. During rejection, progressive decreases in voltage occurred in all animals; average voltage at the time of final study was 56 per cent of the early postoperative baseline level (P < 0.05). Junctional rhythm was present terminally in two dogs. Heart rate was maintained relatively con• Serial studies have shown that cardiac output and stroke volume increase to maximum levels in the majority of unmodified canine recipients on the second or third postoperative day.!
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stant by donor atrial pacing at approximately 150 beats per minute in most recipients throughout the first three postoperative days. During rejection, mean heart rate (unpaced in most) was 121 (±9.2) beats per minute (P < 0.01). Average developed LVP was highest immediately after transplantation ( 141 ± 6 mm. Hg); at the time of defined recovery it was significantly lower (120 ± 5.6 mm. Hg, P < 0.001). During rejection, developed LVP remained within a normal range in all but two of the three animals that were studied within 6 hours of death. Average developed LVP at the point of final study was 111 ± 10 mm. Hg. Peak LV dp/dt remained relatively stable throughout the postoperative course in most recipients. The slight decrease in the group mean during acute rejection, as compared to the recovery period, was of borderline statistical significance (P < 0.1), and was caused by low values observed in the three dogs studied within the terminal 6 hours. Absolute levels of peak LV dp/dt in donor hearts were generally comparable to normal (2,500 to 3,500 mm. Hg per second). LWD and systolic shortening of LVID (Fig. 3). Average end-diastolic LVID showed no significant changes throughout the postoperative course. The greatest changes observed in some individual dogs occurred from the time of transplantation through the first 2 to 3 postoperative days when end-diastolic diameter tended to increase (not consistently associated with decreases in heart rate). End-systolic LVID decreased slightly during the same interval and then rose significantly (P < 0.025) from the time of recovery to rejection. These changes in D s were associated with inverse variations in per cent systolic shortening of LVID and calculated ejection fraction. The former rose over the first 2 to 3 days from 22.6 ± 1.9 to 27.9 ± 2.2 per cent (P < 0.01) and then fell during rejection to 23 ± 1.5 per cent (P < 0.01). As expected, similar time course changes in calculated EF· were seen. Immediately postoperatively, EF was 53 ± 4 per cent, and
Volume 68
Orthotopic cardiac transplantation
Number 5
787
November, 1974
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then increased over the ensuing 2 to 3 days to 62 ± 4 per cent (P < 0.01); with rejection, EF declined to 54 ± 2.6 per cent (P < 0.025). Velocity of left ventricular contraction (Figs. 4 and 5). The maximum rate of systolic shortening of LVID was 57.3 ± 4.1 mm. per second immediately after transplantation. It then rose during recovery to 67.3 ± 2.2 mm. per second (P < 0.005). With acute rejection, maximum systolic -dD/dt decreased to 47.1 ± 3.2 mm. per second (P < 0.0005). Average systolic -dD/dt, and peak and average circumferential fiber-shortening rates showed similar changes. Average -dD/dt, which immediately after transplantation was 34.5 ± 2.6 mm. per second, rose to 44.6 ± 3.1 mm. per second at the time of recovery (P < 0.025). During rejection, measured average -dD/dt decreased to 36.3 ± 2.3 mm. per second (P < 0.025). Peak VCF increased from 2.9 ± 0.26 circumferences per second immediately postoperatively to 3.3 ± 0.4 circumferences per second during recovery (P < 0.1), and with rejection fell to 2.2 ± 2.3 circumferences per second (P < 0.005). Average VCF increased and decreased in a similar pattern, being 1.7 ± 0.13, 2.3 ± 0.41, and 1.7 ± 0.22 average circumferences per second at the time of
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Fig. 6. Mean values for the per cent of total diastolic expansion of LVID occurring during the early, rapid filling phase and the average rate of change of LVID during rapid filling (RF +dD/dt).
The Journal of
788
Stinson et al.
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Fig. 8. Variations in the ratio of developed left ventricular pressure during diastole to the change in LVID during diastole (.<1P 1.<10) .
120
Fig. 7. Serial recordings of LVIO in one recipient; death due to acute rejection occurred 5.5 days after transplantation. By day 4 (36 hours prior to de ath ), there was little further expansion of LVID after the early, rapid filling phase, even during long diastolic intervals induced by interruption of atrial pacing (day 5). Small deflections in LVID during the long diastolic interval are caused by contractions of the residual recipient left atrium.
operation, recovery , and rejection , respectively (P < 0.1 and < 0.01 for sequential differences). Contraction velocity normalized for end-diastolic LVID exhibited parallel changes, rising from 1.5 ± 0.12 to 1.9 ± 0.35 end-diastolic circumferences per second over the first 2 to 3 days (P < O. I) and then falling to 1.5 ± 1.8 end-diastolic circumferences per second during rejection (P < 0.025). Left ventricular diastolic filling (Fig. 6). Little variation in the pattern of left ventricular diastolic filling, as determined from transverse LVID, was observed during the first 2 to 3 days after transplantation. Average per cent RF remained in the range of 60 to 65 per cent. The average rate of diameter lengthening during early, rapid diastolic filling increased over this period , however , from 55 ± 11.3 to 66.7 ± 4.6 mm. per second (P < 0.1) . During acute rejection , striking changes in the pattern of diastolic filling developed
in all animals (Fig. 7). The early, rapid phase of filling accounted for an increasing proportion of the total increment in LVID during diastole ; slight or no expansion of LVID was seen during diastasis and donor atrial systole, even in the presence of prolonged diastolic intervals associated with continuing rises in left ventricular diastolic pressure (LVDP). Average per cent RF rose with rejection to 86.3 ± 4.1 per cent (range 65 to 100 per cent) (P < 0.0005) . Concurrently, the average rate of diameter lengthening during rapid filling decreased to 49.2 ± 3.8 mm. per second (P < 0.0005). In eight of the 10 recipients these changes were associated with a progressively more prominent early diastolic dip in LVP recordings. The ratio of developed LVP during diastole (end-diastolic pressure minus end-systolic pressure) to the total change in LVID averaged 1.2 ± during diastole (~P I ~D) 0.1 mm. Hg per millimeter immediately after transplantation. It then decreased to 1.0 ± 0.1 mm. Hg per millimeter on the second or third postoperative day (P < 0.1) . Terminally, ~P I ~D rose significantly to an average value of 1.6 ± 0.1 mm. Hg per millimeter (P < 0.025) (Fig. 8). Discussion Morphologic evidence of a progressive host immune response can often be detected in orthotopically transplanted cardiac grafts
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Orthotopic cardiac transplantation
789
November, 1974
in nonimmunosuppressed dogs as early as 24 to 48 hours after operation. G Such early
histological changes, however, are not expressed in detectable impairment of graft function. On the contrary, both the present and previous studies' indicate that orthotopic cardiac graft performance at rest steadily improves over the early postoperative interval. Maximum values for stroke volume, cardiac output, and myocardial contraction velocity, near or within the ranges observed in normal dogs, are gradually attained over the first 2 to 4 postoperative days. The depression of donor heart function immediately after transplantation is probably not immunologically determined, inasmuch as a similar response is observed in autotransplanted hearts submitted to identical operative manipulations. Initial abnormalities of graft function include limitation of stroke volume and cardiac output; normal arterial blood pressure, however, is maintained by compensatory adjustments in peripheral vascular resistance. 1 The present study has demonstrated parallel alterations of donor left ventricular mechanical performance which are consistent with these previous hemodynamic findings. Thus, early after transplantation, the extent of shortening of transverse LVID, calculated ejection fraction, and peak myocardial contraction velocity were markedly low. Developed left ventricular pressure and peak left ventricular dp/dt (which under resting conditions may be prominently modified by the arterial blood pressure at the time of aortic valve opening), however, were comparable to normal. Indices of graft left ventricular mechanical function then improved significantly over the following 2 to 3 days. Again, these changes are consonant with previously documented hemodynamic improvement over the same interval in both allografts and autografts.' Early postoperative abnormalities of donor left ventricular diastolic events were less definite, but suggested an initial decrease in compliance, followed by significant
improvement during the ensuing 2 to 3 days. Changes in average dD/dt during the early, rapid filling phase of diastole and alterations of diastolic ~p / ~D were independent of variations in end-diastolic fiber length (DD) and probably left ventricular geometry (although this is unproved), and therefore may be interpreted as indices of left ventricular compliance.' The directional changes measured in this regard are consistent with the results of previous studies of the effects of temporary myocardial anoxia on left ventricular compliance; aortic cross-clamping for 20 to 45 minutes in dogs supported on cardiopulmonary bypass is followed by immediate" and extended" decreases in left ventricular compliance which may persist for 24 to 48 hours. Transplantation of the heart, which as presently performed necessitates more prolonged periods of hypothermic anoxia (45 to 75 minutes), would thus be expected to be associated with significant early postoperative alterations in compliance. During the first two to three postoperative days, normal values for donor left ventricular diastolicziP/ ~D (1.04 ± 0.17 mm. Hg per millimeter in this laboratory) were gradually reached in most although not all recipients. Trends toward normal pressure-todiameter ratios then became reversed, and progressively abnormal values were observed during advancing rejection. These findings and the data of Nelson and associates> suggest that decreased left ventricular distensibility is commonly present in cardiac allografts during the first few postoperative weeks. The latter workers found a subnormal maximum rate of change of left ventricular area during early, rapid diastolic filling by angiographic techniques in immunosuppressed canine recipients. During the late stage of acute, first-set cardiac rejection (i.e., the terminal 24 to 48 hours) in nonimmunosuppressed dogs, myocardial lesions include vascular congestion, capillary and venular rupture with extravasation of red blood cells, generalized myocardial edema, and myocyte necrosis (often with grossly evident myocardial in-
790
Stinson et at.
farction, especially in the subendocardial region and papillary muscles). 6, 11 Despite such severe histological changes, systolic performance of the donor left ventricle is often relatively well preserved until the terminal 24 hours.' At this time rapid, progressive limitation of stroke volume and cardiac output develop; death of the recipient is usually caused by low cardiac output.' In the present study there was depression of per cent systolic shortening of transverse LVID, calculated ejection fraction, and myocardial contraction velocity over the same interval. Developed LVP and peak dp/dt, however, were relatively well maintained, as is arterial blood pressure,' until terminal collapse of the recipient. Thus, during acute rejection, an increasing proportion of myocardial energy expenditure is directed toward maintenance of wall tension rather than fiber shortening. Of the primary determinants of cardiac output, i.e., heart rate, preload, afterload, and contractile state, it is the latter which would appear to be critically limiting during advanced rejection. Heart rate changes during rejection were generally minimal, and the slight changes which did occur in enddiastolic diameter were directionally opposite to those which would tend to decrease stroke volume according to the Frank-Starling principle. The relative stability of left ventricular and arterial pressure and transverse internal diameter during rejection suggest that ventricular afterload also remained fairly constant, although it has not been disproved that alteration of the viscous properties of the myocardium by the pathological changes noted above may have generated important increases in resistance to fiber shortening. The maintenance of myocardial force development, at a time when contraction velocity was significantly diminished, in turn implies that decay in contractility may be due predominantly to decreases in velocity of contractile element interaction; some loss of contractile elements, however, also must occur as a consequence of the destructive changes seen in myocardial fibers during advanced rejection.
The Journal af Thoracic and Cardiavascular Surgery
Ultrastructural abnormalities which may interfere with the contractile process have also been described in myocytes during acute rejection. Kosek, Hurley, and Lower" and co-workers found degenerative changes in mitochondria and dilatation of the transverse tubular system, as well as frank dissolution of myofibrils. Such lesions would be expected to be associated with altered production of energy substrates and possibly derangement of electromechanical coupling. In addition to the changes observed in donor left ventricular systolic mechanics during acute rejection, striking alterations in the pattern of diastolic filling, as judged from LVID, developed as well. With advancing rejection, an increasing proportion of the total increment of diameter during diastole occurred during the early, rapid filling phase. Terminally, approximately half the records of graft LVID showed 90 to 100 per cent of total diastolic filling to be contributed during the phase of early, rapid filling, with absent or only slight further expansion of diameter during diastasis and donor atrial systole. The resulting LVID waveforms had a characteristic "flat-topped" appearance (Fig. 7), remininscent of the "square root" sign of ventricular pressure curves in constrictive or restrictive heart disease. This was especially prominent at slow heart rates. During long diastolic intervals induced by interruption of rapid atrial pacing, LVID showed essentially no change (Fig. 7). Many of the pathological features observed in acutely rejected hearts would appear capable of altering the elastic properties of the ventricular myocardium: edema, cellular infiltration, vascular congestion, and interstitial hemorrhage. G The present study offers direct evidence for the functional effects of such lesions on donor left ventricular diastolic pressure-dimension relationships and patterns of diastolic filling. Thus, during rejection, higher increments in diastolic pressure were associated with given increases in diameter, the expansion of left ventricular diameter during diastole became progressively restricted to the early, rapid
Volume 68 Number 5
Orthotopic cardiac transplantation
791
November, 1974
phase of filling, and the average rate of diameter lengthening during rapid filling decreased. These changes were not associated with significant variation in end-diastolic diameter, and thus signify a decrease in ventricular compliance as a major functional component of acute cardiac rejection. It is noteworthy that modifications in graft left ventricular diastolic mechanics generally developed earlier in the course of rejection than did impairment of systolic performance. In fact, in most animals distortion of diastolic LVID tracings and decreases in electrocardiographic voltage appeared concurrently. This association may imply a common pathophysiological mechanism; myocardial edema and hemorrhage along with vascular congestion could constitute sufficient explanation for both functional abnormalities. Extrapolation of these findings to the clinical situation suggests that examination of diastolic ventricular wall movement by such techniques as apexcardiography or echocardiography might contribute to more sensitive diagnosis of early, acute graft rejection in man. Abnormalities of both systolic and diastolic donor left ventricular performance during rejection are immunologically determined through pathological changes which have been previously described. 6, 11 It should be emphasized, therefore, that in the clinical setting treatment of such alterations of graft function must be directed toward attenuation of the host immune response. Supportive therapy in the form of positive myocardial inotropic drugs may, of course, be provided for hemodynamic deterioration associated with impairment of graft contractile function. No supportive measure, however, is available for the amelioration of diastolic dysfunction.
REFERENCES
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3
4
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6
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11
Stinson, E. B., Griepp, R. B., Bieber, C. P., and Shumway, N. E.: Hemodynamic Observations After Orthotopic Transplantation of the Canine Heart, I. THoRAc. CARDIOVASC. SURG. 63: 344, 1972. Williams, G. M., DePlanque, B., Graham, W. H., and Lower, R. R.: Participation of Antibodies in Acute Cardiac Allograft Rejection in Man, N. Engl. I. Med. 281: 1145, 1969. Stinson, E. B., Dong, E., rr., Bieber, C. P., et al. : Cardiac Transplantation in Man. I. Early Rejection, J. A. M. A. 207: 2233, 1969. Schroeder, I. S., Popp, R. L., Stinson, E. B., et al.: Acute Rejection Following Cardiac Transplantation: Phonocardiographic and Ultrasound Observations, Circulation 40: 155, 1969. Stinson, E. B., Rahmoeller, G., and Tecklenberg, P. L.: Measurement of Internal Left Ventricular Diameter by a Tracking Sonomicrometer, Cardiovasc. Res. 8: 283, 1974. Kosek, I. C., Hurley, E. J., and Lower, R. R.: Histopathology of Orthotopic Canine Cardiac Homografts, Lab. Invest. 19: 97, 1968. Diamond, G., Forrester, I. S., Hargis, I., et al.: Diastolic Pressure-Volume Relationship in the Canine Left Ventricle, Circ. Res. 29: 267, 1971. Enright, L. P., Staroscik, R. N., and Reis, R. L.: Left Ventricular Function After Occlusion of the Ascending Aorta, I. THoRAc. CARDIOVASC. SURG. 60: 737, 1970. Levine, F. H., Copeland, I. G., Melvin, M. B., and Stinson, E. B.: Extended Evaluation of Anoxia on Ventricular Performance and Compliance, Circulation 46 (Suppl. II): 184, 1972. Nelson, R. J., Castagna, I. T., Nedelman, A. L., et al.: Hemodynamic Effects of Volume Loading in Dogs Following Cardiac Homotransplantation, Circulation 43 (Suppl. I): 130, 1971. Bieber, C. P., Stinson, E. B., and Shumway, N. E.: Pathology of the Conduction System in Cardiac Rejection, Circulation 39: 567, 1969.