Functional significance of cardiac reinnervation in heart transplant recipients

Functional significance of cardiac reinnervation in heart transplant recipients

CLINICAL HEART TRANSPLANTATION Functional Significance of Cardiac Reinnervation in Heart Transplant Recipients Martin Schwaiblmair, MD,a Wolfgang von...

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CLINICAL HEART TRANSPLANTATION

Functional Significance of Cardiac Reinnervation in Heart Transplant Recipients Martin Schwaiblmair, MD,a Wolfgang von Scheidt, MD,a ¨ berfuhr, MD,b Sibylle Ziegler, PhD,c Markus Schwaiger, MD,c Peter U Bruno Reichart, MD,b and Claus Vogelmeier, MDa Background: There is accumulating evidence of structural sympathetic reinnervation after human cardiac transplantation. However, the functional significance of reinnervation in terms of exercise capacity has not been established as yet; we therefore investigated the influence of reinnervation on cardiopulmonary exercise testing. Methods: After orthotopic heart transplantation 35 patients (mean age, 49.1 ⫾ 8.4 years) underwent positron emission tomography with scintigraphically measured uptake of C11-hydroxyephedrine (HED), lung function testing, and cardiopulmonary exercise testing. Two groups were defined based on scintigraphic findings, indicating a denervated group (n ⫽ 15) with a HED uptake of 5.45%/min and a reinnervated group (n ⫽ 20) with a HED uptake of 10.59%/min. Results: The two study groups did not show significant differences with regard to anthropometric data, number of rejection episodes, preoperative hemodynamics, and postoperative lung function data. The reinnervated group had a significant longer time interval from transplantation (1625 ⫾ 1069 versus 800 ⫾ 1316 days, p ⬍ .05). In transplant recipients with reinnervation, heart rate at maximum exercise (137 ⫾ 15 versus 120 ⫾ 20 beats/min, p ⫽ .012), peak oxygen uptake (21.0 ⫾ 4 versus 16.1 ⫾ 5 mL/min/kg, p ⫽ .006), peak oxygen pulse (12.4 ⫾ 2.9 versus 10.2 ⫾ 2.7 mL/min/beat, p ⫽ .031), and anaerobic threshold (11.2 ⫾ 1.8 versus 9.5 ⫾ 2.1 mL/min, p ⫽ .046) were significantly increased in comparison to denervated transplant recipients. Additionally, a decreased functional dead space ventilation (0.24 ⫾ 0.05 versus 0.30 ⫾ 0.05, p ⫽ .004) was observed in the reinnervated group. Conclusions: Our study results support the hypothesis that partial sympathetic reinnervation after cardiac transplantation is of functional significance. Sympathetic reinnervation enables an increased peak oxygen uptake. This is most probably due to partial restoration of the chronotropic and inotropic competence of the heart as well as an improved oxygen delivery to the exercising muscles and a reduced ventilationperfusion mismatching. J Heart Lung Transplant 1999;18:838–845.

From the aDepartment of Internal Medicine I, and bDepartment of Cardiac Surgery, Klinikum Großhadern, University of Munich, Munich, Germany; cInstitute of Nuclear Medicine, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany. Submitted September 10, 1998; accepted May 24, 1999. Reprint requests: Martin Schwaiblmair, MD, Department of Inter-

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nal Medicine I, Klinikum Großhadern, University of Munich, Marchioninistr. 15, D— 81377 Mu ¨nchen. Fax: 0049-89-7095-8877; E-mail: [email protected]. Copyright © 1999 by the International Society for Heart and Lung Transplantation. 1053-2498/99/$–see front matter PII S1053-2498(99)00048-0

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ardiac transplantation results in total autonomic denervation of the heart. Although previously this was thought to be permanent, there is now accumulating evidence that sympathetic reinnervation occurs. In animal models sympathetic reinnervation is a common phenomenon.1–3 Studies focused on reinnervation of the transplanted human heart showed evidence of partial restoration of cardiac sympathetic nerve function.4 –11 However, the functional significance of reinnervation has not been adequately established, including the question of whether reinnervation influences the inotropic and chronotropic regulation. Exercise capacity after heart transplantation remains below normal due to graft rejection, immunosuppressive therapy, deconditioning, intrinsic skeletal muscle changes, and denervation.12–21 We hypothesized that exercise capacity may improve as a consequence of reinnervation. To evaluate this hypothesis we determined the functional significance of reinnervation. Standardized cardiopulmonary exercise testing was performed and the results compared to the data obtained with norepinephrine analogue C11-hydroxyephedrine (HED) scintigraphy.9 Positron-emission tomography (PET) allows the noninvasive regional determination of tracer amounts of HED in the myocardium.22 Thereby sympathetic reinnervation can be quantified.

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METHODS Study population The study population included 35 patients (4 women and 31 men) after orthotopic heart transplantation with a mean age of 49 ⫾ 8.4 years (range, 27 to 62 years). The patients were representatively selected for the whole spectrum of time intervals after transplantation. Acute rejection, significant graft vasculopathy (stenoses ⱖ 50%), and impaired systolic function were excluded by endomyocardial biopsy, coronary angiography, and ventriculography within 5 days before the investigation. The clinical data of the patients are shown in Table I. The underlying disease for transplantation was dilated cardiomyopathy in 69% and ischemic heart disease in the remaining 31%. None of the patients had undergone a structured postoperative rehabilitation program. The protocol was approved by the Ethics Committee of the University of Munich and written informed consent was obtained from all subjects.

Medication All patients were receiving maintenance immunosuppression with cyclosporine in combination with azathioprine (49%; denervated versus reinnervated group, 60% versus 40%) and prednisone (60%; denervated versus reinnervated group; 67% versus 55%). At the time of testing, no individual was treated with ␤-blockers. Cardioactive medication,

TABLE I Characteristics of the study group and preoperative hemodynamics. Group I: denervated patients. Group II: reinnervated patients (mean ⫾ SD). Number (n) Age (years) Gender (female/male) Diagnosis (dilated/ischemic) Time after transplantation (days) Donor heart age (years) Cold ischemic time (min) Rejection episodes Cyclosporine A (% of all cases) Azathioprine (% of all cases) Prednisone (% of all cases) PAPmean preoperative (mmHg) PCmean preoperative (mmHg) CI preoperative (L/min/m2) EF postoperative (%)

All

Group I

Group II

35 49.1 ⫾ 8.4 4/31 24/11 1341 ⫾ 1238 27.1 ⫾ 9.2 153 ⫾ 51 2.54 ⫾ 1.30 100 49 60 31.4 ⫾ 10.7 21.6 ⫾ 8.9 2.13 ⫾ 0.63 76.6 ⫾ 7.2

15 47.0 ⫾ 8.0 3/12 8/7 800 ⫾ 1316 26.1 ⫾ 9.5 156 ⫾ 74 2.33 ⫾ 1.18 100 60 67 29.7 ⫾ 9.4 19.4 ⫾ 7.3 2.26 ⫾ 0.65 76.7 ⫾ 5.5

20 51.9 ⫾ 8.6 1/19 16/4 1625 ⫾ 1069* 27.9 ⫾ 9.1 152 ⫾ 43 2.70 ⫾ 1.40 100 40 55 32.5 ⫾ 11.5 22.9 ⫾ 9.4 2.03 ⫾ 0.64 76.5 ⫾ 8.3

PAP, pulmonary artery pressure; PC, pulmonary capillary pressure; CI, cardiac index; EF, left ventricular ejection fraction. Significance between the two groups: * ⫽ p ⬍.05.

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used primarily for blood pressure control, included angiotensin-converting enzyme inhibitors in 82% (denervated versus reinnervated group, 67% versus 90%), calcium channel blockers in 42% (denervated versus reinnervated group, 40% versus 45%), and diuretics in 45% (denervated versus reinnervated group, 47% versus 45%) of the patients.

Pulmonary function testing (PFT) Pulmonary function tests included spirometry (FVC, forced vital capacity; FEV1, forced expiratory volume in 1 second) and determination of singlebreath carbon monoxide diffusing capacity (TLCO) (Body test, Jaeger, Germany). Quality control procedures and reference values followed the standards of the European Community for Coal and Steel (1993).23 A minimum of three measurements were taken with the best values used. Blood gases were analyzed at rest and during maximum work capacity using capillarized ear lobe blood (Radiometer ABL 520, Copenhagen, Denmark). The patients breathed room air.

Cardiopulmonary exercise testing (CPX) An incrementally progressive, symptom-limited cardiopulmonary exercise test was performed. The individuals were tested at least 2 hours after their last meal, using an electronically braked cycle ergometer (Ergotest, Jaeger, Germany). Heart rate and rhythm were monitored by an electrocardiograph. The participants were connected to a twoway, low-resistance y-mouthpiece and a pneumotachograph breathing room air. The expired air was collected continuously in a Douglas bag. O2 and CO2 were analyzed every 15 seconds (Eos-Sprint, Jaeger, Germany). Before each test, the pneumotachograph and gas analyzers were calibrated using a graduated syringe and test gases with known concentrations. Maximum workload (P) was defined as the highest work level reached and maintained for at least a full minute. The predicted value of P was derived from Lo ¨llgen et al.24 Similarly, for maximum ˙ O2) and heart rate (HR), peak oxygen uptake (V ˙ maximum ventilation (Ve), the highest readings of each parameter were used. At rest and during maximum exercise, functional dead space ventila˙ d/V ˙ t) and alveolar-arterial oxygen difference tion (V (P(A-a)O2) were calculated based on the PaCO2. The ˙ d/V ˙ t values were obtained using standard formula. V P(A-a)O2 at end-exercise was determined based on direct measurement of arterial PaO2 and PaCO2 using the alveolar gas equation. The anaerobic threshold (AT) was evaluated with the V-slope

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method, and we measured the ventilatory equivalent ˙ e/V ˙ CO2) at the anaerobic for carbon dioxide (V threshold. After 5 minutes of adaptation to the mouthpiece, P was increased in 30-watt slopes every 3 minutes up to the point of exhaustion (inability to maintain a constant speed and/or intolerable dyspnea) according to a modified Bruce protocol using a cycle ergometer. Reference values were derived from Wasserman et al.25

Positron emission tomography The radiolabeled catecholamine analogue HED was synthesized according to Rosenspire et al.22,26 Imaging was performed with a CTI/Siemens 951R PET scanner (Knoxville, TN). For qualitative assessment of myocardial perfusion N13-ammonia (370 MBq) was injected and after a waiting period of 4 minutes PET images (duration 10 min) of the myocardial blood flow distribution were acquired. After allowing for physical decay of N13-ammonia, HED (740 MBq) was injected as a slow bolus over 30 seconds and data acquisition was initiated over 40 minutes.9 Attenuation corrected, transaxial images were reconstructed with a spatial resolution of 9 mm. Circumferential activity profiles were used to quantify regional tracer distribution. From the dynamic PET images, retention was defined as HED activity at 40 minutes divided by the integral of the blood activity curve.27 Based on results in completely denervated hearts, areas with HED retention below 7%/min were defined to be denervated.9

Statistics All data were presented as mean ⫾ standard deviation (SD). Differences between groups were determined by two-tailed unpaired Student’s t-tests or rank-based Mann-Whitney test (time after transplantation). The rank sum test was used to define the difference between the groups due to the wide variability in time following transplantation. A p value ⬍ .05 was regarded as significant. The statistical computations were performed using SPSS/PC⫹ software.

RESULTS Study population, preoperative hemodynamics, and pulmonary function test As shown in Table I, there were no significant differences between the two groups in the anthropometric or preoperative hemodynamic data studied. The reinnervated group had a significant longer time from transplantation (1625 ⫾ 1069 versus 800 ⫾ 1316 days, p ⬍ .05). When patients

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TABLE II Scintigraphic data, pulmonary function test, and blood gas analysis. Group I: denervated patients (n ⫽ 15). Group II: reinnervated patients (n ⫽ 20) (mean ⫾ SD). Positron emission tomography HEDmax (%/min) Pulmonary function test FVC (%pred) FEV1 (%pred) TLCO (%pred) Blood gas analysis PaO2 at rest (mmHg) PaO2 during exercise (mmHg)

Group I

Group II

Significance

5.45 ⫾ 0.47

10.59 ⫾ 0.59

93.30 ⫾ 15.80 97.10 ⫾ 16.10 83.70 ⫾ 16.50

99.10 ⫾ 10.50 101.00 ⫾ 13.30 88.2 ⫾ 0.90

NS NS NS

83.70 ⫾ 7.30 91.70 ⫾ 6.00

85.20 ⫾ 10.00 94.40 ⫾ 7.20

NS NS

HED, C11-hydroxyephedrine uptake; FVC, forced vital capacity; FEV1, forced exspiratory volume in 1 second; TLCO, diffusing capacity; PaO2, arterial oxygen partial pressure; pred, predicted; NS, not significiant.

with and without reinnervation were compared, no significant differences in static and dynamic lung volumes and in diffusing capacity could be demonstrated (Table II).

Positron emission tomography All patients had regional N13-ammonia values within 2.5 SD of normal flow. The HED images, however, were markedly different from control. In healthy individuals the myocardial retention of HED averages 16.6 ⫾ 2.3 and is homogenous throughout the left ventricle.9 None of the transplant recipients showed a homogeneous tracer accumulation of HED throughout the ventricle. Two groups were defined. One group of 15 patients demonstrated little HED uptake (5.45 ⫾ 0.47%/ min; range, 3.8 – 6.9%/min), with no pronounced

regional pattern across the myocardium. The mean maximal retention in this group was well below the published value in normals and represented complete denervation in these patients.9 In 20 patients, areas of regional HED retention higher than 7%/ min, located in the anterior wall, were identified. They were classified as reinnervated (10.59 ⫾ 0.59%/min; range, 7.3–16.4%/min).

Cardiopulmonary exercise testing Cardiovascular and ventilatory data from graded maximum exercise testing are shown in Tables III and IV and Figure. Comparing the groups with and without reinnervation, significant differences could be demonstrated with respect to P (113 ⫾ 27 versus 81 ⫾ 32 watts, p ⫽ .007), maximum HR (137 ⫾ 15 ˙ O2 versus 120 ⫾ 20 beats/min, p ⫽ .012), peak V

TABLE III Cardiopulmonary exercise testing. Group I: denervated patients (n ⫽ 15). Group II: reinnervated patients (n ⫽ 20) (mean ⫾ SD). P (watts) HR at rest (/min) HRmax (/min) ˙ O2 (L/min) V ˙ O2 (mL/min/kg) V O2-pulse (mL/min/beat) AT (L/min) AT (mL/min/kg) ˙ e (L/min) V ˙ d/V ˙t V P(A-a)O2 (mmHg) EQCO2-AT

Group I

Group II

Significance

80.70 ⫾ 32.30 94.20 ⫾ 14.10 119.90 ⫾ 19.80 1.22 ⫾ 0.45 16.10 ⫾ 4.80 10.20 ⫾ 2.70 0.72 ⫾ 0.20 9.51 ⫾ 2.10 48.80 ⫾ 13.90 0.30 ⫾ 0.05 31.40 ⫾ 6.40 36.20 ⫾ 4.80

113.00 ⫾ 27.20 97.00 ⫾ 11.90 136.80 ⫾ 14.50 1.67 ⫾ 0.38 21.00 ⫾ 4.00 12.40 ⫾ 2.90 0.89 ⫾ 0.17 11.20 ⫾ 1.80 62.40 ⫾ 15.50 0.24 ⫾ 0.05 27.40 ⫾ 7.30 32.20 ⫾ 3.10

p ⫽ .007 NS p ⫽ .012 p ⫽ .002 p ⫽ .006 p ⫽ .031 p ⫽ .009 p ⫽ .046 p ⫽ .014 p ⫽ .00 NS p ⫽ .019

˙ O2, peak oxygen uptake; O2-pulse, oxygen-pulse; AT, anaerobic threshold; V ˙ e, peak minute ventilation; P, work capacity; HR, heart rate; V ˙ d/V ˙ t, functional dead space ventilation during peak exercise; P(A-a)O2, alveolar-arterial oxygen difference during peak exercise; V EQCO2-AT, ventilatory equivalent for carbon dioxide at the anaerobic threshold; NS, not significant.

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TABLE IV Cardiopulmonary exercise testing in cardiac transplant recipients more than 1 year after transplantation. Group I: denervated patients (n ⫽ 9). Group II: reinnervated patients (n ⫽ 19) (mean ⫾ SD). P (watts) HR at rest (/min) HRmax (/min) ˙ O2 (L/min) V ˙ O2 (mL/min/kg) V O2-pulse (mL/min/beat) AT (L/min) AT (mL/min/kg) ˙ e (L/min) V ˙ d/V ˙t V P(A-a)O2 (mmHg) EQCO2-AT

Group I

Group II

84.40 ⫾ 41.00 94.00 ⫾ 12.40 121.10 ⫾ 18.30 1.21 ⫾ 0.49 16.00 ⫾ 5.20 9.90 ⫾ 3.00 0.75 ⫾ 0.23 9.95 ⫾ 3.40 47.90 ⫾ 13.20 0.30 ⫾ 0.06 31.80 ⫾ 5.50 35.60 ⫾ 7.30

109.50 ⫾ 22.00 98.00 ⫾ 11.90 136.40 ⫾ 12.20 1.63 ⫾ 0.35 20.40 ⫾ 3.50 12.10 ⫾ 2.90 0.88 ⫾ 0.17 11.00 ⫾ 1.90 61.80 ⫾ 14.80 0.25 ⫾ 0.05 27.70 ⫾ 7.20 32.40 ⫾ 3.20

Significance

p p p

p p

NS NS ⫽ .048 ⫽ .011 ⫽ .026 NS NS NS ⫽ .034 ⫽ .049 NS NS

˙ e, peak minute ventilation; P, work capacity; HR, heart rate; VO2, peak oxygen uptake; O2-pulse, oxygen pulse; AT, anaerobic threshold; V ˙ d/V ˙ t, functional dead space ventilation; P(A-a)O2, alveolar-arterial oxygen difference; EqCO2-AT, ventilatory equivalent for carbon V dioxide at anaerobic threshold; NS, not significant.

(21.0 ⫾ 4 versus 16.1 ⫾ 5 mL/min/kg, p ⫽ .006), peak oxygen-pulse (O2-pulse) (12.4 ⫾ 2.9 versus 10.2 ⫾ 2.7 mL/min/beat, p ⫽ .031), AT (11.2 ⫾ 1.8 ˙e versus 9.5 ⫾ 2.1 mL/min/kg, p ⫽ .046), and peak V (62.4 ⫾ 15.5 versus 48.8 ⫾ 13.9 L/min, p ⫽ .014). ˙ d/V ˙ t (0.24 ⫾ 0.05 versus 0.30 ⫾ 0.05, p ⫽ .004) and V ˙ ˙ Ve/VCO2 (32.2 ⫾ 3.1 versus 36.2 ⫾ 4.8, p ⫽ .019)

were significantly reduced in the reinnervated group. To eliminate a possible influence of transient early postoperative denervation-independent causes of reduced exercise capacity, we also analyzed the data obtained from patients who had been transplanted more than 1 year before evaluation. Again, we could demonstrate significant differences be-

FIGURE Correlation between scintigraphically measure uptake of C11-hydroxyephedrine (SED) and maximum heart rate (r ⫽ 0.36/p ⫽ .04)/peak oxygen uptake during exercise (r ⫽ 0.37/p ⫽ .03) in 35 heart transplant recipients.

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tween the two groups (reinnervated group versus denervated group) according to HRmax (136 ⫾ 12 ˙ O2 versus 121 ⫾ 18 beats/min, p ⫽ .048), peak V (20.4 ⫾ 3.5 versus 16.0 ⫾ 5.2 mL/min/kg, p ⫽ .026), ˙ e (61.8 ⫾ 14.8 versus 47.9 ⫾ 13.2 L/min, p ⫽ peak V ˙ d/V ˙ t (0.25 ⫾ 0.05 versus 0.30 ⫾ 0.06, .034), and V p ⫽ .049) during maximum exercise (see Table 4).

DISCUSSION We performed a study comparing the results of standardized exercise testing with the reinnervation status in 35 patients after orthotopic heart transplantation. Besides the increased heart rate during exercise in the reinnervated patients, we found significantly improved cardiopulmonary function as evidenced by increased values of work capacity, peak oxygen uptake, and anaerobic threshold. These changes were accompanied by an improved ventilation-perfusion ratio during exercise in the reinnervated group. This is one of the first studies suggesting functional significance of sympathetic reinnervation. To prove functional significance of reinnervation, a longitudinal study of a cohort that progresses from denervation to reinnervation would be needed. The primary limitation of our study is its cross-sectional design. The efficient uptake and storage of the catecholamine analog HED by sympathetic nerve terminals is the basis for scintigraphic visualization of catecholamine uptake.26,28 The scintigraphic findings in our study are in agreement with previously published data indicating evidence for regional catecholamine uptake in transplant recipients several years after transplantation.9 Homogeneous N13-ammonia uptake, representing uncompromised blood flow, proves that heterogeneous HED patterns are not caused by differences in blood delivery but by actual differences in catecholamine retention. Experimental results in animals proved that tissue HED uptake in the left atrium is comparable to the uptake found in the basal part of the left ventricle.29 Due to limitations in resolution, it is only possible to image adequately the left ventricular wall and it is impossible to visualize sinus node reinnervation from PET images. Conclusively, in humans, sympathetic atrial reinnervation cannot be visualized by HED scintigraphy. The significantly higher heart rate during maximum exercise in the reinnervated group is nevertheless an indicator for sympathetic atrial reinnervation, although all of our patients reached a normal heart rate during exercise. Several studies have demonstrated increased heart rates at maximum exercise in patients late after transplanta-

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tion compared with data obtained during the first post-transplant year.30 –33 Increases in maximum heart rate over time after transplantation have been used as evidence supporting reinnervation.6 It was postulated that there may be a time component in the reinnervation process.7 Lord et al,34 measuring reinnervation by heart rate response to intracoronary tyramine, showed that functional sympathetic efferent reinnervation of the sinus node occurred in some patients after transplantation, and this was associated with improved heart rate response during exercise, as well as with increased total workload. Similar results were obtained by Mandak et al35 showing a significant correlation between maximum heart rate and peak oxygen uptake in 60 heart transplant patients. A reduced maximum heart rate may represent an important reason why exercise performance remains blunted.31 Partial reinnervation with improved heart rate response to exercise could contribute to increased oxygen uptake and anaerobic threshold. Study data from Osada et al36 and Scott et al33 indicate that the inability of cardiac transplant recipients to achieve normal exercise performance may not solely be caused by a limitation of heart rate responsiveness. Maximum inotropic ventricular stimulation depends on local norepinephrine release from intact sympathetic nerve terminals.37 Denervated hearts only depend on circulating catecholamines, and therefore cannot achieve a maximal inotropic stimulation. Koglin et al2 showed that restoration of neuronal uptake profoundly alters the inotropic effect of circulating catecholamines. We therefore suggest that this partial restoration of the ventricular sympathetic innervation leads to the potential of local norepinephrine release from sympathetic nerve terminals and may be responsible for the improved oxygen uptake and elevated oxygenpulse during exercise as a consequence of improved maximum stroke volume. In addition, increased heart rate can directly mediate increased contractility (and therefore stroke volume) via the forcefrequency relationship. Burke et al4 showed that stimulation of reinnervated sympathetic neurons with tyramine in transplant recipients causes a significant but subnormal increase in the left ventricular dP/dt ratio (change in pressure/change in time), suggesting that reinnervated sympathetic neurons can produce physiologically meaningful changes in left ventricular inotropy. Moreover, if the reinnervation enables an improvement in cardiac output during exercise and thus influences the energy demand of working muscles, we suggest that the

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elevated anaerobic threshold in the reinnervated group may be an indicator for an increased cardiac output. Although the effects were generally less than those seen in healthy control subjects, the improved exercise capacity seen in our study— despite the fact of wide variance in scintigraphic and clinical manifestation of reinnervation—may be ascribed to improved left ventricular function during exercise due to partial restoration of neuronal control of inotropy and chronotropy. As we did not measure cardiac output during exercise (either invasively or noninvasively) we do not know with certainty if the improved exercise capacity in the reinnervated group is associated with an increased heart rate response and an increased inotropy. A comparison of the changes of the ejection fraction or the stroke volume response to exercise would more specifically evaluate the effects of reinnervation on inotropy. Our transplant recipients did not show clear abnormalities in resting or exercise gas exchange as measured by arterial blood gases and alveolararterial oxygen difference during exercise. On the other hand, the denervated patients have evidence of a mildly elevated dead space ventilation at peak exercise, a valuable indication for the ventilationperfusion mismatch during exercise.38 It is speculated that persistent denervation causes reduced perfusion to ventilated alveoli during exercise, and consequently alveoli must be ventilated to a proportionately higher degree to remove carbon dioxide and maintain arterial carbon dioxide partial pressure at a normal level.25 It is known, that heart transplant recipients achieve their maximum exercise capacity and maximum heart rate by 1 year after transplantation.13,35,36,39,40 The improvement in exercise capacity in the reinnervated group could be attributable to postoperative recovery and reconditioning and therefore be a question of the time interval from transplantation rather than reinnervation. To exclude the influence of postoperative rehabilitation effects, we therefore investigated the influence of reinnervation in patients that had been transplanted at least 1 year before evaluation. Again exercise capacity and peak oxygen uptake were higher in the reinnervated group indicating a clear causal relationship to the reinnervation of the transplanted heart. Peak oxygen pulse and aerobic threshold did not show significant differences more than 1 year after transplantation, suggesting that they are not influenced by reinnervation. Additionally, it is possible that the sample size of our study is too small to

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show significant differences in some cardiopulmonary exercise testing parameters, or we can speculate that changes of the microcirculation could influence a diminished exercise capacity in longterm transplant recipients. Furthermore it is known that several anthropometric and clinical characteristics may have an important influence on the exercise capacity of transplant patients.12–21,41 However, in all clinical data investigated, including dosages and levels of immunosuppressive therapy (especially in cyclosporine and prednisone), there were no significant differences in denervated and reinnervated patients. Considering the limited sample size in our study, we cannot exclude that relevant differences between the study group are overlooked. In conclusion, in transplanted patients with evidence for reinnervation using HED retention, maximum workload and peak oxygen uptake were increased in combination with an improved heart rate response to exercise. Keeping in mind the limitations of a cross-sectional study, our results nevertheless suggest an association between reinnervation imaging on PET scans and functional measures, and support the hypothesis that sympathetic reinnervation has clinical consequences. REFERENCES 1. Jenkins G, Parry D, Foulsham L, Yacoub M, Singer D. Is cardiac reinnervation in heart transplant recipients functionally significant? Insight from studies of diurnal blood pressure variability and cardiac mass. Transplant Proc 1997; 29:571. 2. Kaye M, Randall W, Hageman G, Geis W, Priola D. Chronology and mode of reinnervation of the surgically denervated canine heart: functional and chemical correlates. Am J Physiol 1977;233:H431–7. 3. Norvell J, Lower R. Degeneration and regeneration of the nerves of the heart after transplantation. Transplantation 1973;15:337– 44. 4. Burke M, McGinn A, Homans D, Christensen B, Kubo S, Wilson R. Evidence for functional sympathetic reinnervation of left ventricle and coronary arteries after orthotopic cardiac transplantation in humans. Circulation 1995;91:72– 8. 5. DeMarco T, Dae M, Yuen-Green M, Kumar S, Sudhir K, Keith F, Amidon T, Rifkin C, Klinski C, Lau D, Botvinick E, Chatterjee K. Iodine-123 metaiodobenzylguanidine scintigraphic assessment of the transplanted human heart: evidence for late reinnervation. J Am Coll Cardiol 1995;25:927. 6. Kaye D, Esler M, Kingwell B, McPherson G, Esmore D, Jennings G. Functional and neurochemical evidence for partial cardiac sympathetic reinnervation after cardiac transplantation in humans. Circulation 1993;88:1110 – 8. ¨ berfuhr P, Scheidt Wv. Time-dependent 7. Koglin J, Gross T, U decrease of presynaptic inotropic supersensitivity: physiological evidence of sympathetic reinnervation after heart transplantation. J Heart Lung Transplant 1997;16:621– 8. 8. Parry D, Foulsham L, Jenkins G, Wharton J, Marron K, Banner N, Yacoub M. Incidence and functional significance

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