Evidence for Functional Sympathetic Reinnervation of Left Ventricle and Coronary Arteries After Orthotopic Cardiac Transplantation in Humans
Background Structural sympathetic reinnervation of the transplanted human heart is believed to occur >1 year after cardiac transplantation. The functional effects of reinnervating neurons, however, are undefined.
Methods and Results To test directly for functional sympathetic reinnervation, we measured left ventricular or coronary hemodynamics in 11 patients ≤4 months after transplantation, in 45 patients ≥1 year after transplantation, and in 13 untransplanted, normally innervated patients. Sympathetic neurons were stimulated with left coronary injection of tyramine (10 μg/kg), which causes norepinephrine release from intact sympathetic nerve terminals. Reinnervation was defined as a measure of cardiac norepinephrine release after intracoronary tyramine injection. Left ventricular pressure was measured before and at 1-minute intervals after tyramine with a micromanometer-tipped catheter (Millar Instruments). Coronary blood flow velocity (CBFV) was measured with a 3F Doppler catheter (Numed), and coronary artery cross-sectional area was calculated using quantitative coronary angiography. In both early patients and patients studied ≥4 months after transplantation without reinnervation (late denervated), there was no change in left ventricular function in response to tyramine (ΔdP/dt=31±61 and 49±54 mm Hg/s, respectively; P=NS). In transplant recipients with reinnervation (late reinnervated), left ventricular dP/dt rose significantly (ΔdP/dt=210±97 mm Hg/s; P<.05) but less than in healthy patients (ΔdP/dt=577±66 mm Hg/s; P<.05). In both early and late denervated patients, there was no change in CBFV in response to tyramine (CBFV=1.02±0.1 and 1.0±0.1×basal, respectively; P=NS). In late reinnervated patients, CBFV fell significantly (CBFV=0.94±0.1×basal; P<.05). In healthy patients, CBFV fell even more (CBFV=0.88±0.1×basal; P<.05).
Conclusions Stimulation of reinnervating sympathetic neurons with tyramine in transplant recipients causes a significant but subnormal increase in dP/dt and a transient decrease in CBFV, suggesting that reinnervating sympathetic neurons can produce physiologically meaningful changes in left ventricular function and coronary artery tone.
Cardiac transplantation causes section of postganglionic neural axons innervating the heart and results in total cardiac denervation. Within days after transplantation, axonal degeneration caused by discontinuity with the nerve cell body1 (which resided outside the transplanted tissue block) leads to total depletion of cardiac norepinephrine stores2 and eventual disappearance of nerve terminals in the transplanted tissue3 (ie, wallerian degeneration).
Although sympathetic reinnervation occurs commonly in animal models, until very recently it was not believed to occur after human cardiac transplantation.4 5 6 Sympathetic reinnervation of transplanted human hearts, however, has been shown using two widely divergent methodologies.7 8 Studies from our laboratory have demonstrated that both tyramine (an agent that causes norepinephrine release from intact sympathetic nerve terminals) and sustained handgrip exercise (a reflex sympathetic stimulus) elicit norepinephrine release from the myocardium in the majority of transplant recipients surviving 1 or more years after transplantation.7 Patients studied less than 5 months after transplantation, however, failed to release norepinephrine from the myocardium in response to tyramine. Cardiac norepinephrine release could occur only if cardiac sympathetic neurons were contiguous with ganglionic nerve cell bodies in the nontransplanted thoracic ganglia and the central nervous system. In transplant recipients who demonstrated norepinephrine release, the magnitude of release increased for at least the first 5 years after transplantation, which suggests an ongoing process of sympathetic neural ingrowth. Using positron emission tomography, Schwaiger et al8 demonstrated uptake of a norepinephrine analogue (11C-hydroxyephedrine) in the anterolateral left ventricular wall in late transplant survivors but found no tracer uptake soon after transplantation.8 Taken together, these studies provide strong biochemical and spatial evidence for structural sympathetic reinnervation after human cardiac transplantation.
Studies in animals show that structural reinnervation causes partial return of sympathetic neural function.9 10 After reinnervation in dogs, heart rate and myocardial contractility increase during sympathetic stimulation with tyramine and during stellate ganglion excitation.9 10 The functional effects of reinnervation in humans have not been demonstrated, and several investigators have concluded from clinical studies that sympathetic reinnervation does not occur. Because sympathetic reinnervation is heterogeneous spatially and in magnitude, it is possible that the variability of response in late transplant recipients (some of whom were not reinnervated) might have precluded prior investigators from establishing the occurrence of functional reinnervation.
The purpose of the present study was to determine if stimulation of reinnervating sympathetic neurons can produce physiologically meaningful changes in left ventricular function and coronary artery tone.
Three groups of patients were studied. The first group was composed of 11 patients who had undergone orthotopic cardiac transplantation within 4 months (mean, 3.2 months; range, 2 to 4 months) of the study. Each patient was treated with cyclosporin A, azathioprine, and glucocorticoid immunosuppression; the protocol is described elsewhere.11 Three patients had prior episodes of rejection based on serial endomyocardial biopsies and clinical course, but none had rejection at the time of the study. In this early transplant group, we assumed total sympathetic denervation on the basis of prior studies in 20 patients evaluated less than 4 months after transplantation in whom no evidence of reinnervation was found.7 12
The second group was composed of 46 patients studied 1 or more years after orthotopic cardiac transplantation (mean, 37.9 months; range, 12 to 96 months) and treated with immunosuppressive drugs similar to those described above. Eleven patients had at least one prior episode of rejection, but none had rejection at the time of the study.
The third group consisted of 13 patients undergoing coronary angiography for a chest pain syndrome or pre–lung transplantation evaluation in whom normal cardiac innervation was assumed. None had significant coronary artery disease (coronary diameter stenosis, >30% by visual inspection), pulmonary artery hypertension (mean pulmonary artery pressure, >25 mm Hg), hypoxemia (Sao2, <90%), or carbon dioxide retention (Pco2, >45 mm Hg).
Patients were excluded from any group if they had diabetes mellitus, amyloidosis, serum creatinine concentration of >2.0 mg/dL, or any other diseases known to impair peripheral neural function. Patients who were taking β-adrenoreceptor antagonists, calcium channel antagonists, or nitrates had the drug withdrawn and held for at least five drug half-lives before the study.
From these patient groups, two catheterization research protocols were carried out during a routine surveillance cardiac catheterization. Each patient participated in only one protocol. All studies were approved by the University of Minnesota Institutional Review Board.
Assessment of Left Ventricular Innervation
Five early transplant recipients, 13 late transplant recipients, and 3 normally innervated, untransplanted patients were studied. After informed consent was obtained and patients were premedicated with diazepam (5 to 10 mg PO), all patients were studied in a fasting state. A pacing catheter (5F or 6F) was placed into the right atrium, and the heart was paced at 100 beats per minute. A micromanometer catheter (6F or 7F, Millar Instruments) was placed into the left ventricle via the right femoral artery. The left main coronary artery was cannulated with a 6F coronary catheter via the left femoral artery. In all late transplant patients, the coronary sinus was cannulated with a 5F catheter (model 7171, Cordis). Pressure from the left ventricle and the ECG were monitored continuously. For subsequent off-line analysis of left ventricular function, 10- to 20-second samples of left ventricular pressure were recorded on-line to an IBM AT microcomputer equipped with an analog-to-digital conversion board (AT-Codas, Data Q Instruments), and pressure was digitized at 2-millisecond intervals.
Basal left ventricular pressure and ECG were recorded twice within 1 minute (without intervention) to assess measurement variability. In late transplant recipients, baseline paired blood samples from the left main coronary artery (via the guiding catheter) and coronary sinus blood were taken for plasma norepinephrine assay. Next, tyramine (10 μg/kg in 8 mL 0.9% saline, Sigma Chemical Co) was infused into the left coronary artery at approximately 1 mL/s as a bolus to elicit a cardiac norepinephrine release from intact sympathetic nerve terminals. This dosage was chosen based on previous studies demonstrating myocardial release of norepinephrine without systemic effects.7 12 Left ventricular pressure was recorded at 1-minute intervals for 8 minutes after tyramine administration.
After tyramine stimulation, 3 patients had an increase in heart rate over the paced rate. In each patient, the sinus node artery arose from the circumflex artery. To control for the effect of an increase in heart rate on left ventricular pressures, these patients were paced at the peak heart rate attained after tyramine. This was done after a waiting period of more than 8 minutes to allow left ventricular function to return to basal levels because we demonstrated in a previous study that left ventricular norepinephrine release and its effect on heart rate last less than 7 minutes.7 12 Left ventricular pressure then was recorded twice at 1-minute intervals. These pressures were considered to be basal conditions.
In late transplant recipients, paired left main coronary artery and coronary sinus blood samples were drawn 30 seconds, 1 minute, and 2 minutes after intracoronary tyramine administration to assess left ventricular norepinephrine release. (We have shown previously that peak norepinephrine release occurs within 1 minute after tyramine administration.7 ) The method has been described in detail elsewhere.12
Assessment of Coronary Artery Reactivity
Six early transplant recipients, 33 late transplant recipients, and 10 normally innervated patients were studied. Following the routine procedures described above, the coronary sinus was cannulated with a 5F catheter as described above. A 5F or 6F pacing catheter was placed into the right atrium, and the heart was paced at 100 beats per minute. The left main coronary artery was cannulated with a 7F guiding catheter (Cordis Corp). Through the guiding catheter, a 3F Doppler catheter (Numed) was advanced into either the left anterior descending coronary artery or left circumflex artery until an acceptable signal of coronary blood flow velocity (CBFV) was obtained. The method has been described in detail elsewhere.13 The left anterior descending coronary artery was studied in 5 of 6 early and 24 of 32 late transplant recipients and in 5 of 10 normally innervated patients. Blood samples were taken from the coronary sinus and left main catheters to assess basal plasma norepinephrine concentration and oxygen saturation (OSM3, Radiometer). Basal heart rate, blood pressure, and CBFV were recorded, and an angiogram of the artery with the Doppler catheter was obtained to assess epicardial coronary caliber.
After basal measurements, tyramine (10 μg/kg in 8 mL 0.9% saline, Sigma Chemical Co) was infused as a bolus at approximately 1 mL/s into the left coronary artery. Heart rate, blood pressure, and CBFV were monitored continuously. Paired left main and coronary sinus blood samples for norepinephrine were drawn at 30 seconds, 1 minute, and 2 minutes after intracoronary tyramine administration. In addition, 1 minute after tyramine administration paired blood samples for oxygen saturation measurement were drawn from the left main coronary and coronary sinus, and a repeat angiogram was then obtained.
Measurement of Plasma Norepinephrine Concentration
Blood samples obtained from the left main coronary and coronary sinus were centrifuged at 2000 rpm for 12 minutes. The plasma was decanted and frozen at −70°C. Plasma norepinephrine concentration was subsequently determined by a radioenzymatic method that has been described elsewhere (Cat-a-Kit, Amersham Corp).14
Assessment of Cardiac Norepinephrine Release (Uptake)
Cardiac release or uptake of norepinephrine was assessed by subtracting the norepinephrine concentration in the blood entering the heart through the left main coronary from the norepinephrine concentration in the coronary sinus ([NE]CS-Ao).7 The effect of an intervention on cardiac norepinephrine release (uptake) was assessed by subtracting the cardiac norepinephrine release (uptake) during control conditions from the cardiac norepinephrine release (uptake) during the intervention (Δ[NE]CS-Ao). In the late transplant recipients, reinnervation was defined as Δ[NE]CS-Ao≥143 pg/mL (a threefold increase in the measurement variability of [NE]CS-Ao).7 In the early transplant patients, we assumed denervation based on the previous finding from our laboratory that 20 patients previously tested in this manner had no measurable norepinephrine release.7 12 In healthy, nontransplanted patients, we assumed that innervation was intact based on previous experience that all patients meeting the entry criteria had marked norepinephrine release.7 12
Assessment of Left Ventricular Function
At the time of catheterization, left ventricular pressure was digitized at 2-millisecond intervals and subsequently analyzed using commercial software (Data Q Instruments) and additional software developed in our laboratory. Left ventricular systolic and diastolic pressures, dP/dt, and dP/dt normalized to instantaneous pressure (dP/dt/P) were measured, and the time constant of early diastolic left ventricular relaxation (τ) was estimated according to the technique of Weiss et al.15
Assessment of Coronary Artery Cross-sectional Area
Angiograms of the coronary arteries were analyzed using quantitative angiography, which was performed using the CAAS-Reiber method (PIE DATA). The technique has been described in detail elsewhere.16 17 In brief, the lumen of the artery at the position of blood flow velocity measurement (Doppler catheter tip marker) was outlined using an automated edge-detection algorithm by an operator who was blinded to the clinical and experimental data. The lumen outline was corrected for magnification and radiographic pin-cushion distortion. The mean lumen diameter was determined for basal conditions and 1 minute after tyramine administration. Arteries were assumed to be circular, and cross-sectional area was calculated geometrically using the formula: cross-sectional area=(mean diameter)2 · π/4.
Assessment of Coronary Blood Flow
The effect of tyramine on CBFV was expressed as the fractional change in basal blood flow velocity. The change in coronary blood flow was calculated as the quotient of (CBFV · arterial cross-sectional area)after tyramine and (CBFV · arterial cross-sectional area)basal. The change in coronary artery resistance was calculated as the quotient of (mean arterial pressureafter tyramine · coronary blood flowbasal) and (mean arterial pressurebasal · coronary blood flowafter tyramine) (ie, the fractional change in the basal resistance).
All data are presented as mean±SD, except where noted otherwise. Differences between the group mean values were assessed using ANOVA (statview II). Paired differences were assessed with a paired t test. Linear regression was determined by the least-squares method, and correlation was expressed with a Pearson correlation coefficient (statview II). Statistical significance was defined as a value of P<.05.
Effects of Reinnervation on Left Ventricular Function
Left Ventricular Norepinephrine Release
Of the 13 late transplant recipients studied, 9 had a peak cardiac norepinephrine gradient (Δ[NE]CS-Ao) after tyramine that exceeded 143 pg/mL, indicating left ventricular reinnervation. Of patients with a significant norepinephrine release (ie, outside the 99% confidence limits for repeated measurements), the mean increase in [NE]CS-Ao was 780±694 pg/mL (range, 187 to 1901 pg/mL). In each patient, the peak Δ[NE]CS-Ao occurred within 1 minute of tyramine administration and declined somewhat at the 2-minute sample, indicating that the peak response was sampled.
Measurement Variability for Parameters of Left Ventricular Function
Paired measurements of left ventricular dP/dt, dP/dt/P, τ, systolic pressure, and end-diastolic pressure were correlated closely (r=.98, .99, .86, .95, and .92, respectively). The 95% confidence intervals for repeat measurements were ±118 mm Hg/s, ±1.9 s−1, ±8.9 milliseconds, ±8.8 mm Hg, and ±2.3 mm Hg, respectively).
Under basal conditions, there were no significant differences among the four groups in any measurement of left ventricular function (dP/dt, dP/dt/P, τ, systolic pressure, or end-diastolic pressure; Table 1⇓ and Fig 1A⇓).
Effect of Tyramine on Left Ventricular Function
After tyramine administration, early transplant recipients showed no significant change in left ventricular dP/dt, suggesting functional denervation (Fig 1B⇑). The dP/dt in late persistently denervated transplant patients also failed to change after tyramine, suggesting persistent functional denervation. In late transplant recipients with biochemical evidence of ventricular reinnervation (norepinephrine release), however, dP/dt rose promptly and significantly after tyramine stimulation (ΔdP/dt=210±32 mm Hg/s). In normally innervated patients, dP/dt rose even more after tyramine (ΔdP/dt=577±38 mm Hg/s). In both late reinnervated transplant recipients and healthy patients, the rise in dP/dt peaked 1 minute after tyramine administration and fell to basal levels over the next 8 minutes (Fig 2⇓).
In general, heart rate did not change after tyramine infusion (either because the sinoatrial nodal artery arose from the right coronary artery or because the sinoatrial node was not reinnervated). There were, however, 3 patients in whom a significant increase in heart rate occurred, including 1 late denervated transplant recipient, 1 late reinnervated transplant recipient, and 1 normally innervated patient. When these patients were excluded from data analysis, the results were not significantly different (ΔdP/dt in late denervated transplant recipients=75±11 mm Hg/s, in late reinnervated patients=204±36 mm Hg/s, and in healthy patients=615±5 mm Hg/s).
The dP/dt/P rose significantly only in healthy patients. In late reinnervated transplant recipients, however, τ increased significantly, as did the peak systolic pressure. None of the other parameters of left ventricular function changed significantly between patient groups or in relation to basal values (Table 1⇑).
Effects of Reinnervation on Coronary Artery Reactivity
Left Ventricular Norepinephrine Release
Of the 33 late transplant recipients studied, 24 had a peak cardiac norepinephrine gradient (Δ[NE]CS-Ao) after tyramine that exceeded 143 pg/mL, indicating left ventricular reinnervation. Of patients with a significant increase, the mean change in [NE]CS-Ao was 544±413 pg/mL (range, 151 to 1725 pg/mL).
Under basal conditions, there were no significant differences among the four groups in heart rate, mean arterial pressure, arterial cross-sectional area, or transcardiac arteriovenous oxygen difference (Table 2⇓).
Effects of Tyramine on Coronary Artery Tone
Thirty seconds after tyramine administration, both late reinnervated and healthy patients showed a significant decrease in CBFV compared with patients studied early after transplantation (Figs 3⇓ and 4⇓). There were no significant changes between groups in any other parameter. Of importance, mean arterial pressure after tyramine was unchanged from basal values in each group (Table 2⇑).
One minute after tyramine administration, CBFV rose to basal levels in healthy patients and late reinnervated transplant recipients, even though heart rate and arterial pressure were unchanged (Table 2⇑). Transcardiac arteriovenous oxygen difference tended to show increased oxygen extraction in the late reinnervated transplant recipients and normally innervated patients, but the difference did not reach statistical significance. Coronary artery cross-sectional area 1 minute after tyramine administration did not change in any group.
There was no relation in any group between the artery studied (left circumflex or left anterior descending coronary artery) and the change in CBFV 30 seconds after tyramine administration.
These data show that stimulation of reinnervating sympathetic neurons produces physiologically meaningful changes in both left ventricular function and coronary vasomotor tone, suggesting that clinically significant sympathetic reinnervation occurs in human cardiac transplant recipients. The present study also confirms previous studies in late heart transplant recipients demonstrating that tyramine causes myocardial release consistent with sympathetic reinnervation. These data demonstrate for the first time that sympathetic reinnervation after cardiac transplantation in humans has important physiological effects in terms of myocardial function and coronary artery tone. Although the effects in late transplant recipients were generally less than those seen in healthy control subjects, the magnitude of the response to neural stimulation varied significantly among late transplant recipients (from no response to near-normal changes). These results in humans are similar to those found in animal models of cardiac transplantation, which nearly uniformly demonstrate functional sympathetic neural reinnervation.9 10
Tyramine resulted in a transient reduction in CBFV in normally innervated patients and reinnervated transplant recipients, consistent with brief, rapid microvascular constriction because blood flow is regulated primarily in vessels <400 μm in diameter.18 The explanation for the transient coronary constriction in the setting of a more persistent norepinephrine release into the coronary sinus is not known. The change in blood flow velocity may reflect a balance of two effects of norepinephrine release: a direct microvascular constrictor effect and a metabolic dilator stimulus from increased myocardial metabolic demand due to an increase in inotropic state. Initial coronary constriction, therefore, might have been overridden by increased metabolic demand, returning coronary resistance to basal levels, but still higher than would be appropriate for the increased inotropic state. This view is supported by the trend for a widened transcardiac arteriovenous oxygen difference 1 minute after tyramine administration in late reinnervated and normal patients but not in late persistently denervated or early transplant recipients.
Although systolic left ventricular dP/dt increased significantly after tyramine-induced norepinephrine release in late reinnervated transplant recipients and healthy patients, the parameter of diastolic relaxation, τ, unexpectedly increased in reinnervated transplant patients (Table 1⇑). In contrast, normally innervated patients tended to have a decrease in τ (although not statistically significant). This finding in late transplant recipients may seem contrary to the prior findings that sympathetic stimulation improves diastolic relaxation. The increase in τ, however, may be caused by regional differences in reinnervation within the left ventricle.8 12 Heterogeneous changes in contraction velocity and relaxation might therefore increase the total amount of time taken for relaxation to occur throughout the entire ventricle, which would subsequently result in a higher τ value.
Potential Study Limitations
Although the present study demonstrates that tyramine-induced sympathetic stimulation affects ventricular function and coronary vasomotor tone in both transplanted and healthy hearts, tyramine itself is not an endogenous, physiological stimulus. We have shown previously, however, that norepinephrine is released from regenerating sympathetic neurons in transplanted hearts in response to sustained handgrip (a reflex stimulus for sympathetic discharge) and that all patients with reflexively induced norepinephrine release have tyramine-induced norepinephrine release.7 Each of the parameters studied (coronary blood flow and left ventricular function) are influenced significantly by systemic hemodynamics. The use of reflex stimuli to elicit cardiac sympathetic discharge in the present study would have led to hemodynamically induced changes in coronary blood flow and left ventricular function that would have been independent of the effects of neural stimulation alone, making difficult the interpretation of changes in left ventricular function or coronary tone. By administering intracoronary tyramine, it is possible to stimulate the cardiac sympathetic neurons without changing systemic hemodynamics. The possibility that tyramine itself affected vasomotor tone or left ventricular function is not likely as there was no response to tyramine in transplant patients studied early after transplantation or in those patients without ventricular norepinephrine release late after transplantation.
Another potential limitation is that transplanted hearts may be supersensitive to adrenergic stimulation, amplifying the effects of neurally released norepinephrine. Several studies have documented an increased response of both human and animal transplanted hearts to adrenergic stimulation due to either an increase in β-adrenoreceptor density or presynaptic supersensitivity.19 20 It is possible, therefore, that the observed changes in left ventricular function or coronary resistance in reinnervated transplant recipients were out of proportion to the degree of reinnervation. Alternatively, the expected response from a physiological neural discharge would be amplified similarly.
An unexpected result was the lack of constriction of epicardial coronary arteries in response to tyramine-induced norepinephrine release in all patients, including the normally innervated control patients. Tyramine failed to constrict the epicardial arteries of all patients, including those normally innervated, suggesting that it is not related to innervation status. This finding is surprising because epicardial vasoconstriction has been demonstrated to occur after physiological sympathetic stimulation in healthy patients.21 One possible explanation is that angiography was performed before the epicardial arteries constricted. In one prior study, the coronary arteries of dogs were unchanged 1 minute after infusion with methoxamine (a potent α-agonist) but constricted by 2 minutes.22 It is also possible that sympathetically induced conduit artery constriction occurs via release of multiple neurotransmitters, and it is unclear whether tyramine causes release of all of them, particularly neuropeptide Y.23 24 25 In addition, norepinephrine causes mixed α- and β-adrenergic stimulation.26 Because none of the patients we studied were taking β-adrenoreceptor antagonists, it is possible that the dilating effects of β-adrenoreceptor stimulation balanced the constricting effects of α-adrenoreceptor stimulation.
Finally, reinnervation is regionally heterogeneous within the ventricle,12 27 28 and it is possible that some of the coronary arteries studied were not reinnervated, despite reinnervation elsewhere in the ventricle as demonstrated by norepinephrine release. Misclassification of individual arteries (reinnervated and denervated) would have decreased our ability to detect changes in vasoreactivity due to reinnervation. Similarly, reinnervation occurs in a base-to-apex distribution in a dog model,28 and it is likely that the distal perfusion fields of the arteries we studied were less reinnervated than the proximal beds.
The primary implication of the present study is that stimulation by tyramine of regenerating sympathetic neurons in transplanted hearts can affect both left ventricular contractility and coronary vasomotor tone in a manner similar to that seen in healthy hearts. It is important, however, that the magnitude of the response of coronary tone and left ventricular function was variable among reinnervated patients. Therefore, one should anticipate wide variance in the clinical manifestations of reinnervation.
A second implication of the present study is that the use of transplanted hearts as a model of denervation is inappropriate unless the study is performed soon after cardiac transplantation. Previous studies in humans of left ventricular function or coronary vasomotor tone using chronically transplanted hearts as denervated controls will require reconsideration.
Finally, evidence in humans that severed sympathetic neurons can regenerate and have end-organ effects similar to those of normally innervated hearts has potential implications for other organ transplantation (lung, kidney, pancreas, and liver). The occurrence and effects of reinnervation in these conditions deserve study.
We thank the Cardiac Transplantation and Cardiac Catheterization Teams of the University of Minnesota for their assistance in the performance of these studies. We also thank Thomas H. Rector, PhD, for his statistical assistance and Susan S. Meyer, BS, MBA, for her expertise in quantitative coronary angiography.
- Received June 15, 1994.
- Accepted August 9, 1994.
- Copyright © 1995 by American Heart Association
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