Evolution of the chronotropic response to exercise after cardiac transplantation

Evolution of the Chronotropic Response Exercise After Cardiac Transplantation Christopher

D. Scott, MD, John H. Dark, MB, and Janet M. McComb,

to MD

The chronotropic response to exercise is abnormal in cardiac transplant recipients as a result of autonomic denervation. Differences in the response between recent transplant recipients and longer-term survivors have been described in previous cross-sectional studies. These changes have not been assessed directly using serial studies. The effect of sinus node dysfunction on the chronotropic response has not previously been determined. Thirty-one transplant reci ients underwent serial treadmill exercise tests usin x e chronotropic exercise assessment protocol 3 an d 6 weeks and 3 and 6 months after transplantation. Sinus node function was assessed using standard electrophysiologic techniques. The chronotropic response increased between 3 and 6 weeks after transplantation in all sub+ Six months after transplantation, there was a further marked in-

crease in the response in a subgroup of 5 sub’ects. These subjects also had a dramatic decrease in I! eart rate on cessation of exercise. Three subjects had abnormal sinus node function. Although heart mtes and chronotropic response were below avemge in these sub@&, 2 other sub’ects with normal sinus node function on electrophysio I ogic testing had lower heart mtes and worse chronotropic responses. Thus, the chronotropic response to exercise evolves over the first 6 weeks after cardiac transplantation in all sub’ects. In a number of recipients (16%), there is a mark J increase in chronotropic response between 3 and 6 months, which suggests efferent sympathetic reinnervation. There was no clear difference in chronotropic response between subjects with and without evidence of sinus node dysfunction. (Am J Cardiol 1995;76: 1292-l 296)

he chronotropic response to exercise is abnormal in T cardiac transplant recipients.‘” Absence of autonomic innervation results in delayed acceleration of heart

perature of 4°C. Twenty-eight subjects (90%) were men. The mean + SD recipient and donor ages were 33 + 10.4 and 46 f 12.4 years, respectively. Immunosuppression was achieved with cyclosporine, azathioprine, and prednisolone. Surveillance endomyocardial biopsies were performed at weekly intervals for 6 weeks, twice weekly for 12 weeks, monthly for 6 months, and thrice monthly thereafter. Further biopsies were performed if there was clinical suspicion of rejection. Biopsies were histologically graded using the Billingham classificationi All subjects gave fully informed written consent and all investigations were approved by the joint ethics committee of the University of Newcastle upon Tyne and Newcastle District Health Authority. Exercise testing: The heart rate response to exercise was tested in each subject at 3 and 6 weeks, and at 3 and 6 months after transplantation. A symptom-limited treadmill test was performed on each occasion using the chronotropic assessment exercise protocol.‘* Each test was preceded by a IO-minute rest period. Heart rate was recorded with a 6-lead rhythm strip every minute during exercise and for 5 minutes during recovery. Exercise tests were omitted whenever the general condition of the patient or specific complications made it difficult for the subject to exercise. All pacing systems were programmed to less than the spontaneous atria1 rate before exercise testing. Sinus node function tests: Sinus node function was assessed by electrophysiologic testing. The donor atrium was paced for 30 seconds at varying cycle lengths, and the sinus node recovery time (the interval between the last paced and the first spontaneous sinus beats) was measured. Decremental cycle lengths at 100 ms intervals were used, starting from just below the spontaneous sinus rate to a minimum of 400 ms. At least 1 minute elapsed between each pacing sequence. The corrected sinus node recovery time was calculated by subtracting the spontaneous cycle length from the sinus node recov-

rate early during exercise4 and a subnormal peak heart rate.7 Although ditferences in exercise response have been observed in cross-sectional studies between recent transplant recipients and longer-term survivors,7*x they have not been evaluated by serial studies in the same recipients. Early sinus node dysfunction is common after orthotopic cardiac transplantation,‘- ii although its frequency may have been overestimated.12 The resulting bradycardia frequently resolvesrn-rz and only a few recipients require long-term pacing.‘“-i5 Chronotropic competence is one aspect of sinus node function that has not previously been evaluated and may be helpful in determining need for pacing. This study observes serial changes in the chronotropic response to exercise in the first 6 months after cardiac transplantation. METHODS Patients: All 44 adults who underwent cardiac trans-

plantation between October 1991 and January 1993 were considered for the study; 31 were recruited. Seven subjects died in the early postoperative period, I required prolonged intensive care, 3 were unable to walk on a treadmill because of arthritis, and 2 refused consent. All subjects underwent orthotopic transplantation using the standard atria1 anastomosis technique described by Lower et al.lh The donor heart was perfused and topically cooled with St. Thomas’s cardioplegia solution at a ternFrorn the Regional Cardro!horacic Centre. Freeman IHospital. New castle upon‘Tyne. United Kingdom. This work was supported by a arant from .Ihe British Hecrt Foundation. London. United Kinadom. Gonuscript recei,ved (May 9, 1995, revlied manuscript receivevd and accepie: Auvusi 5.. 1995. Address or reprmtb. Jane: M. McComb, MD, Regional Cardiothoracic Centre, Freeman Hospital, Newcustle upon Tyne. NE7 7DN, United Kingdom.

1292

THli

AAMKICAN

JOURNAL

OF CARDIOLOGY”

VOl

76

DECEMBER

15.

1995

TABLE I Group

Exercise

Dota Time

After

3 Weeks Resting heart rate (beats/min) Duration of exercise (s) Peak heart rate (beats/min) Increase in heart rate (beats/min) Peak heart rate reserve (%) Values

are expressed

87 485 110 23 27

* * f * *

13 120 12 8 9

(64-110) (240-85 (84-131) (7-41) (1 l-46)

Transplantation

3 Months 98 730 127 29 40

1)

zt 11 * 128 ZJZ16 * 13 +c 18

6 Months

(77-125) (51 l-935) (98-151) (11-59) (12-80)

----

100 774 133 27 50

2 * * zt zt

13 130 21 14 26

(76-121) (547-992) (88-169) (11-55) (11-124)

CIS mecln * 1 SD (range).

ery time. Sinus node function was considered abnormal if the corrected maximal sinus node recovery time was >S25 ms.‘” Analysis of exercise response: Results were analyzed in terms of both absolute changes in heart rate and heart rate reserve, defined as maximal age-predicted heart rate (220 beats/min, recipient age) minus resting heart rate.‘” The estimated workload was similarly measured in absolute terms and by calculation of the metabolic reserve, defined as estimated oxygen consumption (METS) at peak exercise minus that at rest. The expected response of a normal innervated heart would be to achieve 100% of the calculated heart rate reserve at peak exercise.‘* Statistical methods: Analyses were performed using Statgraphics (version 2.6, STSC Inc., Rockville, Maryland) statistical software. Serial changes in the chronotropic response. decrease in heart rate during recovery, and exercise duration after transplantation were assessed by l-way analysis of variance. Mann-Whitney U tests were used to analyze ditferences in the chronotropic response and exercise capacity due to acute rejection. Associations between operative ischemic time, donor or recipient ages, and subsequent chronotropic response were assessed by linear correlation analysis.

r I

2

20 I

n

I

I

I

I

3

6

12

24

Time

after

transplantation

(weeks)

FIGURE 1. Change over time in peak chronotropic response 31 subjects after transplantation. Vertical bars, SEM.

in

RESULTS Twenty-live subjects completed all 4 exercise tests as planned. Six subjects missed a single test owing to temporary inability to exercise (2 at week 3 and 4 at month 6). No subject missed >l test. Two subjects received permanent pacemakers during the study, but the atria1 rate was successfully programmed to less than the spontaneous rate before exercise in each instance. Exercise

response

and

time after

60 -t

e, f t az

transplantation:

Changes over time in exercise capacity, and resting and peak heart rate after transplantation are summarized in Table I. All increased significantly over time after transplantation (p
I

1

0

25

X Metabolic

I

I

50

75

1

100

reserve

FIGURE 2. Differences over time in the chronotropic response during exercise after transplantation in 31 subjects. Vertical bars, SEM; circles, 3 weeks; squares, 6 weeks, stars, 3 months; and diamonds, 6 months after transplantation.

An immediate response to exercise (measured at 25% of metabolic reserve) was initially absent in all subjects. The increase in variation in peak chronotropic response was further investigated by analysis of subgroups. An enhanced exercise response was arbitrarily defined as achievement of ~75% of heart rate reserve at peak exercise 6 months after transplantation, and was observed in 5 subjects (16%). When these subjects were analyzed separately, it became apparent that they were entirely responsible for both the increase in mean heart rate response and the increased variation (Figure 3). Significant differences between these 5 subjects and the remaining subjects were present throughout the study, and became greater with time. Heart rate changes during recovery: A similar, although reciprocal, pattern of changes was seen in recovery after exercise. Figure 4 illustrates the decrease in heart rate 5 minutes after exercise at the indicated times after transplantation. Again, there is a marked change in recovery of heart rate between 3 and 6 months, accompanied by a substantial increase in variation. Figure 5 shows the individual 5-minute decreases in heart rate at 3 and 6 months, and indicates that the subjects identified as having an enhanced exercise response also had a more rapid decrease in heart rate. However, unlike the exercise response, the difference was not apparent until 6 months after transplantation. Exercise response in subjects with sinus node dysfunction: Three subjects had sinus node dysfunction dur-

ing the study, 1 on 2 separate occasions. Table II lists the chronotropic responses in these subjects. Heart rates were lower and exercise responses less than average in the 2 subjects with early sinus node dysfunction (3 weeks after transplantation). However, subjects with normal sinus node function had lower peak heart rates and less chronotropic response. One of 2 subjects with sinus node dysfunction developed presyncope, which resolved

immediately after temporary pacing at 120 beats/min. The chronotropic response in the subject with late sinus node dysfunction was above average in all respects. When suggested definitions of chronotropic incompetence for the innervated heart*“~*t were compared with these data, it was apparent that none was useful in distinguishing subjects with normal and abnormal sinus node function. Both subjects with early sinus node dysfunction failed to achieve a peak heart rate of >I20 beats/min20 3 weeks after transplantation, but 76% of all subjects had chronotropic incompetence by this definition. No subject with sinus node dysfunction achieved a heart rate of ~85 beats/min at a workload of 4 METS.*’ Exerciseresponseand rejection, ischemictime, donor and recipient ages: Three subjects underwent exercise

testing 6 weeks after transplantation at a time when they were subsequently shown to have had moderate rejection. The response was significantly impaired, with peak heart rates of 92, 104, and 107 compared with 127 f 13 beats/min in the remaining subjects (p = 0.01). The percent heart rate reserves used were 18%, 36%, and 22% compared with 41 f 11.2% in other subjects (p = 0.03). The difference was not due to impaired exercise capacity. Exercise times were similar: 713, 768, and 457 seconds compared with 661 + 153 seconds. No correlations were noted between operative ischemic time, donor or recipient ages, and the chronotropic response to exercise at any time after transplantation. No direct correlation between corrected maximal sinus node recovery time and exercise response was identified.

DISCUSSION Changesin exercise responseand recovery with time after transplantation: This is the first serial study of

changes in exercise response after transplantation. Previous cross-sectional studiesx* compared recipients I to 2 months and 212 months after transplantation. The results of these studies were compatible with our findings of higher resting and peak heart rates and better

f 'E E Y 0" P

120

-6 1 100

z z

60

z z &

60

ii L 2 L = 3 I

n

40

2o

J 1

-16

I

I

I

1

3

6

12

24

Time after FIGURE 3. Changes in peak with an enhanced response jeck (dad &c/es]; ve&a/

1294

THE AMERICAN

transplantation

3

(weeks)

OF CARDIOLOGY”

6

Time after

chronotro ic response in 5 subieck (open circ & s] and in 26 other subbars, SEM; ‘p 4.01; **p cO.001.

JOURNAL

-

VOL. 76

FIGURE recovery SEM.

4. Change and afkr

DECEMBER

15.

24

12

transplantation

lwreksl

over time in heart rak aher 5 minutes transplantation in 31 subieck. Ver!ica/

1995

of bars,

TABLE

II Chronotropic

Response

in Four

Subjects

With

Sinus

Time 3 Weeks Subject number Corrected SNRT (ms) Resting heart rate (beats/min) Duration of exercise (s) Heart rate at peak exercise (beats/min) Increase in heart rate (beats/min) Peak heart rate reserve (%) Symptomatic SNRT = sinus node

recovery

competence

After

Transplantation

3 Weeks

15 565 70 264 90 20 16

Dysfunction

3 Months

6 Months

16

16 1,460 96 976 150 54 77 No

33 1,325 64 367 98 34 34 No

Yes

1,825 81 915 149 68 80 No

time.

chronotropic response in long-term survivors compared with recent recipients. The serial nature of the present study provides more reliable data and its time scale more detailed information about early changes in the exercise response. The improvement in chronotropic response between the third and sixth weeks after transplantation has not previously been described. The reasons for this change are unclear. The gradual development of presynaptic catecholamine supersensitivity after autonomic denervation at surgery is a possible explanation. This is established in subjects studied between 1 and 3 months after transplantation. 22 Serial studies of catecholamine sensitivity over the first 6 weeks after transplantation would be required to contirrn this hypothesis. The enhanced exercise response seen 6 months after transplantation in some subjects suggests efferent sympathetic reinnervation. Although further enhancement of presynaptic supersensitivity may explain this enhanced response, the rapid decrease in heart rate during the recovery period seen in these subjects is more in keeping with a rapidly acting direct neural mechanism. The suggestion of an improved heart rate response to exercise in the same subjects from as early as 3 weeks after transplantation does not support this conclusion because such rapid structural sympathetic reinnervation is unlikely. However. the relatively small differences in early exercise response should be interpreted with caution because of the division of the group using an arbitrary criterion and the small numbers involved. Furthermore, the rapid decrease in heart rate during recovery seen at 6 months is not evident at 3 months. The combined pattern of exercise response and recovery seen in these 5 subjects is comparable to that in a previous report* and has previously been attributed to efferent sympathetic reinnervation. An alternative explanation is that an enhanced early exercise response mediated by another mechanism may be predictive of future sympathetic reinnervation. However: a potential mechanism for this hypothesis is not evident. There have been no previous reports of transplant recipients with this pattern of exercise response or with other evidence of sympathetic reinnervation at such an early stage after transplantation. Chronotropic

Node

and sinus node dysfunction:

This study has shown that definitions of chronotropic competence suggested for innervated hearts”‘~2* are not MISCElIANECUS/CI

applicable to the denervated transplanted human heart. Although the chronotropic response in subjects with sinus node dysfunction was relatively poor, it was clearly not different from subjects with normal sinus node function. Thus, exercise testing is not helpful in the early assessment of sinus node function after heart transplantation. Heinz et a12” reported 32 transplant recipients who exercised between 1 and 3 months after transplantation. Their subjects with early sinus node dysfunction had significantly impaired exercise responses. Despite having regained sinus rhythm, it is likely that some or all of these patients had persistent sinus node dysfunction.24 Exercise testing may therefore be better able to distinguish normal and abnormal sinus node function 6 weeks to 3 months after transplantation. The few subjects in this study with early sinus node dysfunction preclude a similar analysis. The importance of chronotropic incompetence in transplant recipients is unclear. This study has shown that heart rate alone predicts neither exercise capacity nor the development of symptoms. Differences in stroke

01

2.

-g .g =. oz.2 1 9)

-5

-I

..:..

m

: 0 al ee 30

l e

-10

..:..

@

.‘. 010

-15

: 00

0.0 l

-25 00 0 l

-35 0

-40

6

$

Time after transplantation FIGURE

(months)

5. Decrease in heart mk during recovery 6 months antation in sub$cts with an enhanced exercise circles] and in 26 other subjects (closed circles).

1RONOTROPIC

RESPONSE

AFTCR

TRANSPlANTATlON

1295

volume due to variation in ventricular compliance may be more important. Implications for permanent pacing policy: Routine use of rate-responsive pacemakers in transplant recipients with sinus node dysfunction is illogical because of similar chronotropic responses without limitation of exercise in other recipients. Rate-responsive pacemakers should probably be reserved for patients who have symptomatic chronotropic incompetence and who have been shown to benefit from temporary pacing during exercise. Determinants of chronotropic response in transplant recipients: This study suggests that acute rejection may

cause impairment of the chronotropic response to exercise despite a normal exercise capacity in a few subjects. The lack of correlation with corrected maximal sinus node recovery time suggests that intrinsic sinus node function is not a primary determinant of the chronotropic exercise response. Early changes in catecholamine sensitivity and later direct sympathetic reinnervation in some subjects are more likely to be important.

1. Shaver JA. Leon DF, tiray S, Leonard 11, Bahnson HT. Hemodynamic ohservations after cardiac transplantation. ,Y End/ J Med 1969;281:822-827. 2. Stinson EB, Griepp RB. Schroeder JS. Dong E, Shumway NE. Hemodynamic observations one and two years after cardiac transplantation in man. Circdarim

lY72:45:

I 183-I 194.

3. Clark DA. Schroeder JS, Griepp RB. Stinson EB, Dong E, Shumway NE, Harrison DC. Cardiac transplantation in man. Review of first three years’ expricnce. Am .I hid lY73;5456>576. 4. Pope SE. Stinron EB, Daughters GT, Schroeder JS, Ingels NB, Alderman EL. Exercise response of the denervated heart in long term cardiac transplant recipicm. Am J Cur&/ lY80:46:213-218. 5. Savin WM, Haskell WL. Schroeder JS, Stinson EB. Cardiorespiratory responses of cardiac transplant patients to graded. symptom limited exercise. Ciwularion 1980:62:55XI. 6. Savin WM, Schroeder JS. Haskell WL. Response of cardiac transplant recipients to static and dynamic exercise: a review. J Hearr ~rumplan~ 1984;1:72-19.

1296

THE AMERICAN

JOURNAL

OF CARDIOIOGYx

VOL. 76

7. Quipg RJ. Roux MB, Gauthier DF. Creager MA, Hartley H. Colucci WS. Mechanism of attenuated peak heart rate response IO exercise after orthotopic heart transplantation. J Am Cdl Curdid 19X9; 14~338-344. 8. Rudah I.. Pllugielder PW. Mcnkis AH, Notick RJ. McKenzie FN. Kostuk WJ. Evolution of heart rate responsivcners after orthotopic hean transplantation. Am J Curdid I99 I ;68:232-236. 9. Mackintosh AF. Carmichael DJ, Wren C. Gory-Pearce R, English TAH. Sinus node function in the first three weeks after cardiac transplantation. Br Hurt J 1982:

48:.5X4-58X. 10. Heinz G. Hirsch1 M, Buxhaum P, Lauder G. Laczkovics A. Sinus node dysfunction after onhotopic cardiac transplantation: postoperative incidence and long term implications. PACE 1992: IS:73 I-737. 11. Jacquet L. Ziady G. Stein K. Griffith B. Armitage J, Hardesty R. Kormos R. Cardiac rhythm disturbances early after onhotopic heart transplantation: prevalence and clinical importance of the observed abnormalities. JAm Co// Cdiol 1990:lh:

832-X37. 12. Scotr CD. Dark JH. MoComb JM. Sinus node function after cardiac trdnsplantation. J Am Cd/ Cur&/ 1994~24: I33t I34 I. 13. Miyamoto Y. Cunihs El. Kormos RL. Armitagr JM, Hardesty RL. Griffith BP. Bradyarrhythmia after heart transplantation. Circulution lYYO:R2(suppl IV):IV313-IV-317. 14. Scott CD, McComh JM, Omar I, Dark JII. Bexton RS. Long teno pacing after heart transplantation is usually unnecessary. PACE 1991;14: 1792-1796. 15. Scotr CD, McComb JM. Dark JH. Bcxton RS. Permanent pacing after cardiac transplantation. Rr Hvurr J 1993:60:399403. 16. Lower RR, Stofer KC. Shumway NE. Homovital transplantation of the hean. J Thoruc Curdiovmc Surg I961 ;4 I : I9&202. 17. Billingham ME. Diagnosis of cardiac rcjecction by endomyocardial biopsy. J Heurt 7iun.vl,lunr I98 I ; I :2S-30. 18. Wilkoff BL, Cowy J, Blackhum G. A mathematical model of the cardiac chronotropic response to exercise. J Ekcvrophpiol l989;3: 176-l 80. 19. Narula OS, Samer P, Javier RP. Significance of the sinus node recovery time. Circukurion lY72;45: 140-l 5X. 20. Rosenquist M. Atrial pacing for sick sinus syndrome. C/in Cardid 1990:13:

43-47. 21. Wienh

RD, Lafia P, Marder CM, Evans RG. Kennedy HL. Chronotropic incompetence in clinical exercise testing. Am J Curdid 19X4:54:74-78. 22. Gilbert EM, Eiswenh CC. Mealey PC, Larrabee P. Henick CM, Bristow MR. Beta adrenergic supersensitivity of the transplanted human heart is pre-synaptic in origin. Circukurion 1989;79:34&349. 23. Heinz G. Radosztics S. Kratochwill C. Krciner G, Buxbaum P, Grimm M. Sunder-Plwmann G. Laufer G, Lawkovics A. Gossinger H. Exercise chromttnpy in patienls with normal and impaired sinus node function after cardiac transplantation. PACE 1003: 16: l7Y3-1799. 24. Heinr G. Kratochwill C. Buxbaum P. Krcinrr G. Laufcr G. Gossinger H, Laclkovics A. Long term intrinsic pacemaker function in patients paced for sinus node deficiency abler cardiac transplantation. /‘ACE 1992;15:206-2067.

DECEMBER

1.5. 1995