International Journal of Cardiology, 33 (1991) 89-98 0 1991 Elsevier Science Publishers B.V. All rights reserved 0167-5273/91/$03.50

ADONIS 016752739100214P

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CARD10 01318

Coronary venous noradrenaline during coronary angioplasty

Alastair J. McCance and J. Colin Forfar Department of Cardiovascular Medicine, John Radcliffe Hospital, Oxford, U.K.

(Received 6 August 1990; revision accepted 18 April 1991)

McCance AJ, Forfar JC. Coronary venous noradrenaline during coronary angioplasty. Int J Cardiol 1991;33:89-98.

Coronary venous and arterial noradrenaline concentrations were measured during percutaneous transluminal coronary angioplasty in 14 patients. Coronary venous noradrenaline did not increase significantly during balloon inflation but was increased during early reperfusion in patients undergoing left anterior descending angioplasty (n = 81, from 157 + 38 pg/ml to 295 f 94 pg/ml (P < 0.05). Coronary blood flow, measured by thermodilution in 7 further patients during left anterior descending angioplasty, was 69 f. 9 ml / min, decreased to 80 f 3% of basal flow during balloon inflation (P < 0.01) and increased to 135 + 5% during early reperfusion (P < 0.01). It was estimated using these results that cardiac spillover of noradrenaline did not change during occlusion of the left anterior descending artery, but increased almost 3-fold during early reperfusion. During the period of balloon inflations, there was a modest increase in overall sympathetic tone, as assessed by total not-adrenaline spillover to plasma (400 &- 77 ng/min to 473 + 87 ng/min, P < 0.01). These results, suggesting an increase in release of noradrenaline during early reperfusion following brief occlusion of the left anterior descending artery, may be relevant to the genesis of reperfusion arrhythmias.

Key words: Noradrenaline; Coronary angioplasty; Reperfusion

Introduction

Percutaneous transluminal coronary angio- plasty is an increasingly popular method of coro- nary revascularization. The temporary obstruc- tion of coronary flow during inflation of the bal- loon catheter provides a useful human model of

acute coronary arterial occlusion and reperfusion. Ventricular arrhythmias may occur during infla- tion of the balloon and patients usually develop angina1 pain and objective evidence of ischaemia: ST segment elevation on the surface electrocar- diogram [2], a drop in coronary sinus pH [3], net cardiac lactate release [4] and segmental abnor- malities of wall motion [51.

In experimental animals, the sympathetic ner-

Correspondence to: Dr. A.J. McCance, Dept. of Cardiol-

ogy, Groby Road Hospital, Groby Road, Leicester LE3 9QE, U.K.

vous system has a profound effect upon the de- velopment of ventricular arrhythmias during my- ocardial ischaemia [6] but little is known of the

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response of the sympathetic nervous system to brief periods of coronary occlusion and reperfu- sion in man. We have used noradrenaline kinetics and differences in coronary venoarterial concen- trations of noradrenaline to assess overall and cardiac sympathetic activity in patients undergo- ing coronary angioplasty.

Patients and Methods

We studied 21 patients (18 male) aged 56 k 2 years. Patients with major single vessel coronary disease causing stable angina inadequately con- trolled by medical treatment, in whom there was felt to be a high chance of successful angioplasty, were eligible for the study. In the initial 14 pa- tients studied (13 male) plasma noradrenaline concentrations in arterial and coronary venous blood and radiotracer noradrenaline kinetics were measured. Repeated sampling of coronary venous blood at short intervals precluded the measure- ment of coronary blood flow in these patients. Therefore, in 7 subsequent patients (5 male) un- dergoing left anterior descending angioplasty, coronary blood flow was measured by thermodi- lution. These patients were similar to the previ- ous patients demographically and had similar coronary anatomy, with severe discrete lesions in the proximal or mid left anterior descending coronary artery. In the first group, the treated vessel was the left anterior descending artery in 8 patients, the left circumflex artery in 3, and the right coronary artery in 3. All patients had had diagnostic coronary arteriography performed on a previous occasion. Patients were studied fasting and had taken their usual medication on the morning of the study (P-blockers in 19, calcium antagonists in 11 and long-acting nitrates in 8). Premeditation with diazepam (5-10 mg intra- venously) and pethidine (25-50 mg intravenously) was given in the catheterization laboratory. All patients gave informed verbal consent to the study, which was approved by the Central Oxford Research Ethics Committee.

Noradrenaline kinetics

l-[2,5,6- 3H]noradrenaline (New England Nu- clear, Boston, MA) was infused into a peripheral

vein throughout the angioplasty procedure, 12 PCi (0.44 MBq) as a bolus followed by 0.7 pCi(O.026 MBq)min-’ m-‘. Twenty-five minutes were allowed to reach steady state [7] before basal coronary venous and arterial blood samples were taken, as described below. Plasma nora- drenaline was measured by high performance liq- uid chromatography with electrochemical detec- tion and plasma [ 3H]noradrenaline concentration by liquid scintillation counting of alumina ex- tracts, as we have previously described in detail [7,8]. Noradrenaline clearance (the volume of plasma cleared of noradrenaline per unit time) and noradrenaline spillover (the amount of nora- drenaline entering plasma per unit time) were determined according to the following well de- scribed relationships [9]:

Whole body noradrenaline clearance (ml/min)

Infusion rate (dpm/min)

= Plasma [3H]noradrenaline (dpm/ml)

Whole body noradrenaline spillover (ng/min)

Infusion rate (dpm/min)

= Specific radioactivity of plasma noradrenaline (dpm/pg)

Cardiac NA spillover

= csPF x [(NA,s-NA,) + (NA, x NA,)]

where CSPF = coronary sinus plasma flow, NA, = fractional extraction of [3H]noradrenaline by the coronary circulation (the proportion of arte- rial i3H]noradrenaline extracted by the heart un- der steady state conditions), NA,, = coronary si- nus noradrenaline concentation, NA, = arterial noradrenaline concentration and dpm = disinte- grations per minute of [ 3H]noradrenaline.

For coronary venous blood sampling a size 7 French Gensini catheter was introduced into the coronary sinus via the right subclavian vein. Cor- rect placement was confirmed by the injection of a small quantity of contrast material. In patients undergoing left anterior descending angioplasty, the catheter was placed in the great cardiac vein

91

and in those undergoing right or circumflex an- gioplasty in the mid coronary sinus, so as to include venous drainage from the inferior surface of the heart. Coronary angioplasty was performed by the standard femoral approach. Balloon infla- tions were to a pressure of 4-6 atmospheres (median 6), for a duration of 60 seconds and there were 4-6 inflations per patient. Coronary venous samples were taken before the first bal- loon in~ation~ during the final 10 seconds of first inflation and 15, 30 and 60 seconds and five minutes after the first balloon deflation. The first 5 samples of this regimen were repeated for two or more subsequent balloon inflations in 11 of the 14 patients. Arterial blood samples were also taken from the angioplasty guiding catheter be- fore and after those balloon inflations during which coronary venous samples were taken. In all patients further arterial and coronary venous samples were taken 10 minutes after the final inflation. Sampling for more than one inflation was not possible for technical reasons in one patient each during left anterior descending, left circumflex and right coronary angioplasty. The surface electr~ardio~ram (lead I) and intra- arterial blood pressure were monitored continu- ously during the procedure.

Coronary sinus flow

In the second group of seven patients undergo- ing left anterior descending angioplasty a Bairn coronary sinus catheter (Electra-catheter Corpo- ration, Rahway, New Jersey) was inserted via the right subclavian vein and coronary sinus blood flow measured by continuous the~odilution, as we have previously described [7]. 0.9% saline was infused via a Harvard pump at 25 ml/min until equilibrium was reached and the infusion contin- ued during and for 2 minutes after each of two balloon inflations. The temperature data were stored on disc and coronary sinus blood flow was determined at 10 second intervals from the stan- dard equation using temperature signals inte- grated over a 5 second period.

Statistical analysis

Results during coronary occhrsion and reper- fusion were compared to baseline values using a

Wilcoxon signed rank test (two-tailed), with ap- propriate correction for multiple comparisons. Data are expressed in the text as mean + 1 SEM.

Results

Coronary angioplasty was successful (final coronary stenosis < 30% of the diameter of the treated vessel) in all but one case, where the posterior descending branch of the right coronas artery became occluded. Emergency surgery was not required. In the first group (catecholamine measurements) of the 8 patients undergoing left anterior descending angioplasty, 6 developed chest pain during balloon inflations and ST seg- ment elevation was observed in 5 of these. In the right and circumflex group all 6 patients devet- oped chest pain and ST segment elevation was observed in one. In the group undergoing mea- surement of coronary blood flow by thermodilu- tion, chest pain and ST segment elevation oc- curred in 6 of 7 patients.

Whole body noradrenaiine kinetics

Arterial noradrenaline was 189 &_ 50 pg/ml before the commencement of angioplasty and in- creased during the period of balloon inflations to 210 4 46 pg/ml (P < 0.05) before the final infla- tion. Whole body noradrenaline spillover in- creased during the period of balloon inflations, from 400 rfr 77 ng/min to 473 rt 87 ng,/min (P < O.Ol), while whole body noradrenaline clearance did not alter (2.50 + 0.19 l/min at baseline and 2.49 + 0.19 I/min before the final balloon infla- tion). Ten minutes after the final inflation arterial noradrenaline (198 + 45 pg/ml) and whole body noradrenaline spillover (387 rfi 87 ng/min) had returned to baseline.

Concentrations of noradrenaline in the coronary sinus (Figs. 1 and 2)

In patients undergoing angioplasty of the left anterior descending artery, coronary venous nora- drenaline was 157 A- 38 pg/ml before the first balloon inflation. There was a trend for coronary venous noradrenaline to increase during the first

92

700. Gnrt cudlac

w-600

SW

500

400

300

200

100

&al Ooelusidn 15s 3bs 60s 5kllin

Reperfuslon

Fig. 1. Great cardiac venous noradrenaline (NA) concentra- tions during and after the first balloon inflation in 8 patients undergoing left anterior descending coronary angioplasty. Bars are median values. Conversion factor: Na-1 ng/ml= 5.91

nmol/l.

balloon inflation (to 194 k 45 pg/ml, P = 0.11) and there was a significant increase in the first early reperfusion period (within to 295 f 94 pg/ml, P = 0.02). By 60 seconds after reperfu- sion, coronary venous noradrenaline had de- creased to baseline levels 058 k 29 pg/ml) (Fig. 1). In patients undergoing angioplasty of the cir- cumflex or right coronary arteries, there were no significant changes in coronary sinus nora- drenaline (Fig. 21, although the numbers studied were small.

Reproducibility of coronary venous noradrenaline responses to coronary angioplasty (Fig. 3)

A striking feature of the results was the be- tween patient variability in the response of coro- nary venous noradrenaline to acute left anterior

descending coronary occlusion and reperfusion. All except one of the cases undergoing dilatation of the left anterior descending coronary artery developed chest pain and/or electrocardio- graphic changes, but the changes in great cardiac venous noradrenaline were highly variable (Fig. 1). Responses within individual patients, how- ever, were generally similar during repeated bal- loon inflations, although there was a tendency for the response to decline with later inflations. The raw data for the seven patients in whom sampling was repeated during more than one inflation of the balloon in the left anterior descending artery are shown in Fig. 3.

Coronary blood flow (Fig. 4)

In the seven patients in whom coronary blood flow was measured during angioplasty of the left anterior descending artery, basal coronary sinus blood flow was 69 & 9 ml/min. Coronary blood flow was quite variable between patients and was not normally distributed, being dependent on po- sition of the catheter and coronary venous anatomy, but was highly reproducible within pa- tients. During balloon inflation all patients

lQQQ-4 Circumflex

Basal ocdusian1563os6os 5 min

FbpMnk.n

Fig. 2. Coronary sinus noradrenaline (NA) concentrations during and after the first balloon inflation in patients under- going right (n = 3) or circumflex (n = 3) coronary angioplasty.

Bars are median values.

300

meat ardlsc VWOUS

F&W 200

Patients

-A . . . . . . 6 -4 c

Basal Ochsicn 15s 30s 60s 5 min

Fteperfusion

40(

Great cardiac venous

&ml)

30(

Patients

-E

. . . . . ..a F

t-4 G

, I I I I Basal Occlusion 15~30s 60s 5 mtn

Reperfusion

Fig. 3. Coronary venous noradrenaline (NA) concentrations during repeated balloon inflations in patients undergoing left anterior

descending coronary angioplasty (n = 7). Samples were not taken during all inflations in all patients and hence data from some

inflations is missing. 1 = first inflation; 2 = second inflation; 3 = third inflation: 4 = fourth inflation: S = fifth inflation.

showed a decline in coronary sinus blood flow to a mean of 80 k 3% of the control value (P < 0.01) and on reperfusion following balloon deflation reactive hyperaemia developed rapidly in all pa- tients. The peak of reactive hyperaemia (135 + 5% of control flow, P < 0.01) occurred 10 to 40 seconds (median = 30 set) after reperfusion and coronary flow usually remained above the base- line value for 5 minutes or longer. A representa- tive thermodilution record obtained during left anterior descending angioplasty is shown in Fig. 4.

Cardiac noradrenaline kinetics (Fig. 5 1

Although the rapidly changing conditions dur- ing coronary angioplasty prevent new steady states being reached during balloon inflation and reper- fusion, some assessment of cardiac noradrenaline extraction was possible from the radiotracer re- sults in the first group of patients. Before angio- plasty, when steady state conditions did obtain, cardiac noradrenaline extraction was 59 k 3%. During occlusion calculated cardiac nora- drenaline extraction decreased to 5 1 +_ 3% (P <

Discussion

22 InhKate

20 t

101 I I I I I I I 0 30 60 90 120 150 180 210 240

Fig. 4. Representative thermodilution trace obtained during

left anterior descending coronary angioplasty. A decline in

coronary flow (temperature) is seen during balloon inflation

in both the coronary sinus and the great cardiac vein and after

balloon deflation the rapid occurrence of reactive hyperaemia

is clearly demonstrated. CS = coronary sinus; GCV = great

cardiac vein.

0.05) and during reperfusion cardiac nora- drenaline extraction was 46 k 3% and 44 * 4% after 30 and 60 seconds, respectively (P < 0.001 for both, versus pre-occlusion). In keeping with the time course of reactive hyperaemia demon- strated following brief coronary occlusion in those in whom, measured with thermodilution, extrac- tion of noradrenaline by the heart was decreased for at least 5 minutes after inflation of the bal- loon, being 45 k 4% five minutes after the first inflation.

Cardiac spillover of noradrenaline cannot be quantified in absolute terms, since coronary blood flow was not measured in the same patients as the measurements of catecholamines were made. Nevertheless some inferences can be made for angioplasty of the left anterior descending artery from the observed changes in concentrations of noradrenaline and cardiac extraction of nora- drenaline, and by assuming that similar changes in coronary blood flow occurred in all subjects undergoing angioplasty of the left anterior de- scending artery. Making this assumption, we esti- mate that cardiac spillover of noradrenaline did not change during inflation of the balloon in the left anterior descending artery but increased nearly threefold during early reperfusion (Fig. 5).

Acute coronary occlusion in man causes clini- cal evidence of autonomic imbalance within min- utes of the onset of myocardial ischaemia or infarction [ 101. Autonomic responses to transient myocardial ischaemia during coronary angioplasty have not been assessed. In anaesthetized dogs, coronary occlusion for up to 60 minutes did not cause spontaneous release of noradrenaline into coronary venous blood [ll-131. Similarly, we found no clear evidence of increased cardiac re-

90

60

70

‘Estimated cardiac NA spillover

30

20

10

P= 0.016

1 I

Basal Occlusion Reparfusion

Fig. 5. Estimated cardiac noradrenaline (NA) spillover during

left anterior descending angioplasty in 8 patients. Cardiac

noradrenaline spillover was estimated from the observed

changes in arterial and coronary venous noradrenaline and in

cardiac noradrenaline extraction and by assuming changes in

coronary blood flow were similar to those observed in seven

similar patients undergoing left anterior descending coronary

angioplasty (69 ml/min at baseline, 55 ml/min during balloon

inflation and 93 ml/min during early reperfusion).

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lease of noradrenaline during a one minute pe- riod of coronary occlusion in conscious man.

By contrast, an increase in great cardiac ve- nous noradrenaline, and in estimated cardiac noradrenaline spillover, was demonstrated during early reperfusion after occlusion of the left ante- rior descending artery. This increase in release of noradrenaline was short lived, coronary venous noradrenaline having returned to baseline 60 sec- onds after reperfusion. We cannot be certain whether it represents passive washout of nora- drenaline accumulated during coronary occlusion, or whether it was the result of a short burst of increased sympathetic activity.

We demonstrated no changes in cardiac re- lease of noradrenaline during occlusion and reperfusion of the right or circumflex coronary arteries. A local release of noradrenaline from ischaemic myocardium cannot be excluded in this small number of patients, however, since coro- nary sinus blood contains a sizeable proportion of blood draining from anterior left ventricular my- ocardium, which was not ischaemic in these cases. The results may, however, reflect real regional differences in the autonomic response to coro- nary occlusion and reperfusion, since there is clinical evidence that inferior ischaemia is often associated with vagal overactivity [lo]. Experi- mental evidence also exists that vagal receptors are more prominent on the inferior surface of the dog heart [14] and that activation of vagal effer- ent fibres may inhibit release of noradrenaline at a presynaptic level [15].

A feature of experimental studies on the re- sponse of the autonomic nervous system to coro- nary occlusion and reperfusion has been the vari- ability between animals. Schwartz et al. [16] re- ported that “susceptible” dogs (those which de- veloped ventricular fibrillation in response to the combined stimulus of treadmill exercise and cir- cumflex coronary occlusion) increased their heart rate after coronary occlusion while, in “resistant” dogs, the heart rate decreased. Thus, individual variability in susceptibility to ventricular fibrilla- tion in conscious dogs may be dependent upon the autonomic response to coronary occlusion. Animals which respond by activating vagal re- flexes are less likely to fibrillate than those whose

response is primarily sympathotonic. A striking variability in the coronary venous noradrenaline response to occlusion of the left anterior de- scending coronary artery and reperfusion has been demonstrated in the present study. Such heterogeneity may be important in determining individual susceptibility to serious ventricular ar- rhythmias in the setting of acute coronary occlu- sion and reperfusion.

Reperfusion arrhythmias

The sympathetic nervous system is widely be- lieved to play a role in the pathogenesis of ven- tricular arrhythmias following coronary occlusion, but much less is known about reperfusion ar- rhythmias. Lombardi et al. [17] have demon- strated enhanced cardiac sympathetic neural dis- charge by direct recording during the initial oc- clusion period of enhanced vulnerability, but reperfusion did not alter cardiac efferent sympa- thetic firing rate. Bilateral stellectomy, protective against the enhanced vulnerability of the occlu- sion period, increased reactive hyperaemia and caused increased vulnerability to ventricular ex- trastimuli during the reperfusion period. The role of the sympathetic nervous system in reperfusion arrhythmias has thus received comparatively little attention [18], but there is evidence that it may be important. Depleting myocardial reserves of cate- cholamines with 6-hydroxydopamine or reserpine decreased reperfusion arrhythmias [ 19,201 and a-adrenoreceptor antagonists are strikingly pro- tective against reperfusion arrhythmias in several experimental models [19,21,22]. Our findings may, therefore, be relevant to reperfusion arrhythmias in man, which are known to be a marker for successful thrombolysis in acute myocardial in- farction [23], but whose clinical importance is uncertain.

.Limitations

Patients remained on anti-angina1 medication and received premeditation before the proce- dure. It is possible that this could have blunted the sympathetic response to coronary occlusion and reperfusion but is unlikely to have enhanced

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it. We have previously shown that chronic p- blockade does not alter whole body nora- drenaline spillover [24].

The variability between patients in the re- sponse to coronary angioplasty makes it difficult to generalize, since some patients did not show any change in coronary venous noradrenaline. Since non-parametric statistics were used, the conclusion remains valid that, overall, there was a significant increase in coronary venous nora- drenaline during early reperfusion following left anterior descending occlusion, undue weight not being given to the one patient who showed a very dramatic rise in coronary venous noradrenaline during early reperfusion (Fig. 1). The absence of data on coronary flow in the patients in whom noradrenaline was measured means that the oc- clusions regarding cardiac noradrenaline spillover must be regarded as tentative. The flow re- sponses to coronary angioplasty, nonetheless, were notably consistent. There is no reason to believe that they would have been directionally different in the patients in whom flow could not be measured.

In conclusion, this study has demonstrated variable changes in great cardiac venous nora- drenaline concentrations and consistent changes in coronary flow in patients undergoing angio- plasty of the left anterior descending coronary artery. Overall, there was an increase in coronary venous noradrenaline during early reperfusion in these patients and some subjects showed a sub- stantial release at this time. This may have been due to short burst of increased cardiac sympa- thetic activity during early reperfusion or to washout of noradrenaline which had accumulated during balloon inflation. In either case, increased local concentrations of noradrenaline may be an important factor in the genesis of reperfusion arrhythmias.

Acknowledgements

We gratefully acknowledge the technical assis- tance of P.A. Thompson. This study was sup- ported by The British Heart Foundation. Prelimi- nary data from the manuscript were presented at

the spring meeting of the British Cardiac Society, April, 1989 [l].

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