Mechanism of the Bradycardia During Coronary Angiography
RICHARD
MD,
FACC
BRUCE MERRICK, BS HAROLD M. LOWE, MD,
J. FRINK,
FACC
Sacramento, California
From the Cardiopulmonary Department, Mercy General Hospital, Sacramento, Calif. This work was supported in part by a grant from the Sacramento Yolo-Sierra Heart Association, Sacramento, Calif. Manuscript accepted July 12, 1974. Address for reprints: Richard J. Frink, MD, 1014 40th St., Sacramento, Calif. 95819.
Bradycardia occurring during coronary angiography may be due to the direct effect of dye or to reflex vagai effects on pacemaker centers. Fifteen patients were classified according to the origin of the sinus nodal and atrioventricuiar nodal arteries. In patients with type A anatomy, both the sinus and the atrioventricuiar nodal arteries arose from the right coronary artery. in those with type B anatomy, only the atrioventricular nodal artery arose from the right coronary artery. Heart rate recordings were made during coronary angiography before and after selective infusion of atropine (0.2 mg) into the right coronary artery. in type A patients, the sinus bradycardia observed during right coronary dye injection was caused by a combination of both direct and rdflex effects on pacemaker tissue. Sinus bradycardia occurring with left coronary dye injections was entirely reflex in nature and was completely blocked with right coronary arterial injection of atropine. in type B patients, sinus bradycardia with right coronary dye injections was produced by reflex suppression of the sinus pacemaker. A junctional rhythm was consistently produced afler administration of atropine. Junctional bradycardia in type B patients was caused by direct suppression of the junctional pacemaker. Thus, angiographic dye appears to decrease heart rate both by a direct effect on pacemaker tissue and by reflex vagai suppression of the sinus pacemaker.
The injection of angiographic dye into the coronary arteries causes transient electrocardiographic and hemodynamic changes.1-6 These changes include bradycardia, hypotension, depression of first derivative of left ventricular pressure (dP/dt),2,4 prolongation of the P-R interval,5,6 widening of the QRS complex,6 marked repolarization changes3 and a shift in the electrical axis.3 Coronary angiographers have observed various degrees of bradycardia induced by dye injections into normal, abnormal and obstructed coronary arteries. The bradycardia is said to be eliminated by intravenous administration of atropine.4-6 Some authors have speculated that the explanation for the bradycardia lies within the’ confines of two major areas: (1) an ischemic or physical effect of the dye upon pacemaker tissue,1,2,7,8 or (2) a reflex vagal effect. 4-6 This study seeks to ascertain the mechanism of the bradycardia in man by correlating heart rate response with blood supply to the sinus and atrioventricular nodes. Before and after selective infusion of atropine into the right coronary artery, recordings of heart rate were made as angiographic dye was injected into the right and occasionally the left coronary arteries. Materials
and Methods
Twenty-five patients undergoing selective coronary angiography were studied for heart rate response. All studies were performed as part of the daily schedule of cardiac catheterization and coronary angiography (using the Sones technique) in patients with suspected heart disease. Nembutalm,
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100 mg, and atropine, 0.5 mg, were administered as premedication before the procedure. Heart rate recordings were made using an Electronics for Medicine photographic recorder (DR 12) at a paper speed of 50 mm/set. The coronary injections were filmed with a 35 mm Arriflex camera at 80 frames/set using a 5 inch image intensifier. The films were examined to establish the origin of the sinus node and atrioventricular node arteries and to detect significant occlusive coronary disease. Patients with valvu-
lar disease, cardiomyopathy or congenital heart disease were excluded. Patients with greater than 50 percent obstruction of the coronary arteries were excluded with the exception of one patient who had a normal right coronary artery but 70 percent obstruction in the left anterior descending branch distal to the origin of the first septal artery. Ventricular function studies included determihation of the first derivative of left ventricular pressure (dP/dt) and left ventricular end-diastolic pressure and performance of left ventricular cineangiography. The results were normal in all included cases. Patients were classified into two types on the basis of the blood supply to both the sinus and atrioventficular nodes. In type A, the blood supply to both nodes originated from the right coronary artery. In type B, the sinus nodal artery came from the circumflex branch whereas the right coronary artery gave rise to the atrioventricular nodal artery. Three major groups were studied. Group I: Fifteen patients, 10 classified as type A and 5 as type B, were studied by recording the heart rate during the infusion of dye into the right coronary artery before and after selective right coronary arterial injection of atropine. The atropine, 0.2 mg in 10 cc of normal saline solution, was infused slowly into the right coronary artery after the appropriate control heart rate recordings had been made. Heart rate response immediately after the infusion was also recorded. In 2 of these 15 patients, both classified as type A, heart rate recordings were made during left coronary arterial injections before and after right coronary arterial infusion of atropine. There were nine men in the group, ranging in age from 36 to 60 years (mean age 50), and six women with an age range of 44 to 52 years (mean age 49). Group II: Five patients were studied during the infusion of 8 to 10 ml of autogenous blood into the right coronary artery. This procedure was used to determine whether distension of the right coronary or the sinus nodal artery by the pressure of the injections contributed to the bradycardia.g All five patients were type A, with the sinus nodal artery originating from the proximal right coronary artery. This group did not undergo selective right coronary arterial injection of atropine. Group III: Five patients, all type A, had heart rate recordings made during left coronary injections. None had selective right coronary arterial injections of atropine. All five patients, plus the two from Group I who received right coronary arterial injections of atropine, underwent evaluation of left coronary arterial injections.
Results
FIGURE 1. Case 2. Heart rate response before, during and after the injection of angiographic dye in the right coronary artery in a patient with type A anatomy. S-T and T wave changes provide evidence of maximal dye effect. A, before selective right coronary arterial injection of atropine. The control heart rate of 86 decreased to 50 beats/ min during the dye injection, then gradually returned to normal. The sinus pacemaker maintained control throughout injection and recovery phases. This tracing demonstrates the occurrence of sinus bradycardia but does not identify direct or reflex effects. The three lower strips are continuous. B, after selective right coronary arterial injection of atropine there was sinus tachycardia with a control heart rate of 104 beats/min. A decrease in heart rate to 96 beats/min occurred during the dye injection. This response, since reflex effects were blocked, was due to direct depression of pacemaker discharge by angiographic dye. The three lower strips are continuous.
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Type A: The heart rate response to the injection of angiographic dye into the right coronary artery of type A patients before and after selective right coronary atropinization is shown in Table IA. Sinus bradycardia developed in all patients during the dye infusion, both before and after infusion of atropine. The selective infusion of atropine produced an immediate increase in heart rate averaging approximately 25 percent. The sinus pacemaker consistently maintained rhythmic control after atropine infusion in all type A cases. l3efore administration of atropine, the heart rate decreased nearly 33 percent during the dye injection. After infusion of atropine, the heart rate during dye injection decreased approximately 17 percent. Atropinization cardiac slowing.
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A typical example of the heart rate response in a type A patient is shown in Figure 1. Figure 1A demonstrates the effect on heart rate and electrocardiographic configuration before administration of atropine. The rhythm remains sinus with marked T wave inversion during maximal effect of the dye. The heart rate decreases from a control rate of 86 to 50 beats/ min, then slowly returns to the control rate. Essentially the same effect is seen after administration of atropine (Fig. lB), the only differences being a more rapid rate at the beginning of the infusion and a lesser degree of sinus bradycardia. Type B: The results in patients with type B anatomy are shown in Table IB. Figure 2 illustrates the electrocardiographic changes in type B patients before and after administration of atropine. Certain similarities as well as significant differences between type A and B patients are apparent. First, before administration of atropine, sinus bradycardia developed in both types of patients during the infusion of dye (Fig. 1A and 2A). The magnitude of the bradycardia, 33 percent in type A and 24 percent in type B, was similar. Second, whereas an increase in sinus rate was always observed in type A patients after infusion of atropine, all type B patients manifested a juncTABLE
Control Heart Rate (Sinus Rhythm) (beats/min)
of Angiographic
Mean
11 12 13 14 15 Mean
ET AL.
tional rhythm that was always faster than the control sinus rate (Table IB, Fig. 2B). Third, bradycardia did occur with dye infusion after administration of atropine in type B patients but with certain specific features. The junctional pacemaker maintained control of the rhythm past the point of maximal bradycardia. Episodes of isorhythmic atrioventricular dissociation frequently occurred during the recovery phase; maximal bradycardia usually occurred within 3 to 6 seconds after the infusion was begun (Fig. 2B). The junctional rate at the point of maximal slowing was less than the control sinus rate in all cases. However, the magnitude of the hradycardia was essentially the same before infusion of atropine (25 fiercent) as after the infusion (26 percent) in type B patients. This finding contrasts with observations in type A patients, whose heart rate after infusion of atropine was reduced from 33 to 17 percent. The infusion of autogenous blood into the right coronary artery produced a mean decrease in heart rate of 2 percent in the five patients tested. Left coronary injection of atropine: The decrease in heart rate during left coronary injections in the seven type A patients was 34 percent, almost identical to the decrease after right coronary injec-
68 100 86 88 77 110 96 79 86 77 86.7 z!zl2.5
66 83 79 71 70 72.8 xk7.0
Dye into the Right Coronary
Change in Heart Rate (beats/min)
6450 96-66 79-50 88-69 7765 110-66 96-47 82-50 86-54 77-50 ...
66-50 83-65 79-44 71-69 70-49
...
Artery Dye lnjechon After Atropine
Heart Rate Response and Rhythm After Selective Right Coronary Atropine
Dye Injection Before Atropine
% Decrease _--___-._ A.
1 2 3 4 5 6 7 8 9 10
ANGIOGRAPHY-FRINK
I
Heart Rate Response After Injection
Case no.
DURING CORONARY
Change in Heart Rate (beats/min)
% Increase
.
Rhythm
-_. _.-.
Change in Heart Rate (beatq’min) --
% Decrease .____
Ten Patients with Type A Coronary Anatomy
22 31 36 21 16 40 51 39 37 35 32.8 zt11.3
66-91 91-124 77-105 86-94 80-104 110-130 92-116 80-83 79-96 65-91
... _.~_. ___
51 36 36 10 30 18 21 3 21 40 26.6 Ik15.01
Sinus Sinus Sinus Sinus Sinus Sinus Sinus Sinus Sinus Sinus
86-73 124-108 104-96 94-73 104-88 130-98 116-94 83-68 96-70 91-79
...
...
16.9 xt6.9
78-57 104-72 82-51 75-59 81-65
19 31 38 21 21 26.0 l t7.3
B. Five Patients with Type B CoronaryAnatomy ___~._~__. 24 66-78 18 Junctional 15 78-104 25 Junctional 44 75-82 9 Junctional 4 68-74 10 Junctional 30 68-81 19 Junctional 23.8 ... 16.2 ... 16.0 zk12.2
...
18 15 8 22 16 25 20 14 26 13
A control heart rate (column 2) was recorded before any injection procedures were performed. Since right coronary injections came near the end of the procedure, the heart rate immediately before the right coronary injection (column 3) was sometimes slightly different from the original control heart rate. The same applies to the heart rate present at the time atropine was infused (column 5). Similarly, in column 8, the heart rate at the time of dye injection was slightly different from that achieved immediately after the infusion of atropine.
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FIGURE 2. Patient 12. Heart rate response in type B patient after the infusion of angiographic dye into the right coronary artery. A, before selective right coronary injection of atropine. Note heart rate change (sinus bradycardia) from 83 to 85 beats/min, and the corresponding S-T wave changes due to maximal dye effect. Essentially the same response occurred in type A patients before injection of atropine. The three lower strips are continuous. B, after selective injection of atropine into the right coronary artery there was a stable junctional heart rate of 94 beats/min. A decrease in heart rate from 94 to 71 beats/min occurred during the dye infusion. The rhythm remained junctional past the point of maximal bradycardia. lsorhythmic atrioventricular dissociation occurred briefly (bottom strip). The three lower strips are continuous.
tion in these same patients. In the two type A patients tested both before and after right coronary injection of atropine, the bradycardia was completely eliminated by the cholinergic blockade. Discussion Under normal circumstances the sinus node is the primary pacemaker of the heart.10 In abnormal physiologic conditions, the atrioventricular junctional region has been recognized as a secondary pacemaker center.ll All factors that directly or indirectly influence these two centers of cardiac rhythm should be given utmost attention when considering chronotropic responses of the heart. Mechanisms of Bradycardia After Dye Injection In our attempt to explain the bradycardia following the injection of angiographic dye into the 20
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right coronary artery, there are two primary considerations: (1) the direct effects of the dye on pacemaker tissue, and (2) the reflex vagal effects on pacemaker discharge. For our purposes, any heart rate response believed to be due to the physical or chemical properties of the dye, including anoxia, is considered a direct effect on pacemaker tissue. The stimulation of neurogenic receptors by the angiographic dye, which subsequently affects heart rate indirectly, is considered a reflex effect. Sinus nodal distension: The possible distension of the sinus nodal artery during the injection of dye is a secondary consideration. In dogs, such distension regularly produces transient bradycardia.12 Although so far unproved, the same reponse may occur in man. Since the sinus nodal artery arises from the proximal right coronary artery in type A patients, distension could conceivably occur during the injection of dye
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and contribute to the bradycardia. Our results, using autogenous blood instead of dye, demonstrate relatively little change, less than 5 percent, in heart rate. This response was not considered a significant factor in the production of the bradycardia. Vagal effects on sinus and atrioventricular nodes: Autonomic reflexes, particularly those affecting the sinus and atrioventricular nodes, are important in the control of heart rate and rhythm.13 Heavily concentrated areas of cholinergic nerve endings have been found in these regions and may be considered prime centers of reflex activity.14 The dual cholinergic innervation of both sinus and atrioventricular nodes is a well known clinical and experimental fact.‘” We assume that reflex effects producing bradycardia are caused by the stimulation of vagal receptors, activating an afferent limb that travels by way of the vagus nerve to the central nervous system and subsequently back by the efferent limb to both the sinus and atrioventricular nodes. The resulting bradycardia is primarily produced b> vagal effects on the sinus pacemaker. Vagal efferen~s may pass also to the atrioventricular nodal region, but the effects may not be evident because of the dominance of the sinus pacemaker. Bezold-Jarisch effect on chemoreceptors: Receptors of various types have been identified in both the atria and ventricles of experimental animals.15-18 A heavy concentration of receptors has been found in the region of the sinus and atrioventricular nodes.15 Some of these receptors are stimulated by pressure changes and by chemical stimulation.16 Chemical receptors have been found in the heart, primarily in the left ventricle of experimental animals,18 which, when stimulated by various means, give rise to the Bezold Jarisch effect or reflex.1s-22 This reflex response is characterized by both bradycardia and hypotension. The bradycardia produced by the injections of angiographic dye may be the human counterpart of the Bezold-Jarisch reflex. In our study, the types of receptors that were stimulated and their precise location are not known. Theoretically, if chemoreceptors are limited to the left ventricle and do respond to angiographic dye, a left coronary injection would be expected to stimulate them and produce reflex changes in heart rate. Our results with left coronary injections support this reasoning. Left coronary injections in type A patients produced the same degree of bradycardia as did right coronary injections, yet little or no dye circulated to the sinus or atrioventricular node. Elimination of the bradycardia in two of these patients by selective right coronary injection of atropine definitely suggests a reflex response. Firm conclusions on this point should not be drawn since only two patients were studied after right coronary injection, but other reasonable alternative explanations are lacking. Right vs. left coronary arterial dye injection: The right coronary artery in all patients in this study supplied blood to at least a portion of the inferior wall of the left ventricle and inferior intraventricular septum. A right coronary injection may therefore be
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expected to circulate dye to and possibly stimulate any chemoreceptors located in the left ventricle. Thus, the heart rate response with a right as well as with a left coronary injection may reflect reflex suppression of pacemaker discharge. Since the volume of ventricular muscle supplied by the right coronary artery is considerably less than that supplied by the left coronary artery, the magnitude of the reflex response may be less with the right coronary injection. In our studies, this proved to be correct. The reflex effect of a left coronary injection was double that of a right coronary injection in type A patients. The intracardiac route of the Bezold-Jarisch reflex in dogs has been determined to be along the left coronary artery, exiting near the left coronary ostia.20 This may be true also of the left coronary artery in man. Since the human right coronary artery supplies the inferior wall of the left ventricle in 90 percent of cases2a the possibility that afferents travel with the right coronary artery and exit from the heart near the right coronary atria should be considered. Response in Type A Patients to Right Coronary Injections Heart rate response was quite consistent in that sinus bradycardia was produced by each right coronary injection (Fig. 1A). Since the dye circulated to both the sinus and atrioventricular nodes, the bradycardia may have been caused by direct or reflex effects, or both.24 Deciding which effect was operative was aided by cholinergic blockade of both sinus nodal and atrioventricular junctional regions by selective right coronary injection of atropine. The production of sinus tachycardia (an average of 26.6 percent increase in heart rate) indicates, we believe, effective vagal blockade of at least the sinus pacemaker. This blockade did not interfere with pacemaker dominance, nor did it eliminate the bradycardia during right coronary injections (Fig. 1B). This result would not have occurred if the bradycardia operated entirely by reflex. We believe the bradycardia in type A patients during a right coronary injection is the result of both reflex and direct effects, each contributing equally to the bradycardia. Response in Type B Patients to Right Coronary Injections We interpret the consistent production of a junctional rhythm rather than a sinus tachycardia after right coronary injection of atropine as concrete evidence of a separate blood supply to the sinus and atrioventricular nodal regions in type B patients. A right coronary injection in this instance is considered a selective atrioventricular nodal infusion maneuver. In man this is as close as one can come to a selective atrioventricular nodal arterial injection.25 The heart rate response must be interpreted in light of this anatomic difference between type A and B patients. Heart rate response before atropine: The infusion of dye produced a sinus bradycardia very similar to that seen in type A patients (Fig. 1A and 2A). The
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mechanism of the bradycardia cannot be the same because dye does not circulate to the sinus node: Direct depressant effects of dye on the sinus pacemaker therefore cannot explain the bradycardia. The only possible explanation for the slowing of sinus nodal discharge is reflex suppression. Direct conduction across the free atria1 wall would occur much too slowly to produce these effects. The reflex must originate with receptors located in the distribution of the right coronary artery, and the reflex effect must occur very quickly since the sinus pacemaker remains in control throughout injection and recovery. Atrioventricular dissociation did not occur. Heart rate response after atropine: The major response to this maneuver was a shift in the dominant pacemaker from the sinus nodal to the atrioventricular junctional region, with an increase in the heart rate (Fig. 2B). The cholinergic blockade of all efferent nerves surrounding the junctional pacer prevented any reflex change in heart rate. Any change in the firing rate of this junctional pacemaker could have been due only to the direct effects of the dye. The receptors and afferent nerves were not blocked nor were any efferent nerves to the sinus node blocked. The infusion of dye into the right coronary artery produced a junctional bradycardia of the same magnitude as that produced before infusion of atropine when the sinus node was the dominant pace-
maker. These data lead us to believe that the bradycardia in type B patients, just as in type A, was due to a combination of both direct and reflex effects. In type A patients the two effects were additive, whereas in type B they were nonadditive but equal or equivalent. This may expl:iin why the magnitude of the bradycardia was slightly less in type B than in type A patients before administration of atropine. Before infusion of atropine, the discharge rate of the sinus pacemaker was suppressed entirely by reflex, masking any direct effects at the atrioventricular junction. After the infusion, the sinus pacemaker failed to emerge when the junctional rate fell below the control sinus rate during the maximal dye effect (Fig. 2B). This is the second piece of evidence indicating reflex suppression of sinus nodal function in type B patients. A junctional heart rate, faster than the sinus rate, occurred after administration of atropine in type B patients (Fig. 2B). The observed firing rate of the junctional pacemaker in most clinical situations is reported to be between 40 to 60 beats/min2s and is often referred to as the “inherent” firing rate of the atrioventricular junctional pacer. Our work suggests that the inherent firing rate of this pacemaker, free from vagal influence, may be faster than 40 to 60 beats/min. The evidence also implicates vagal efferent connections in relation to pacemaker dominance.
References I. MacAlpln RN, Weidner WA, Kattus, AA Jr, et al: Electrocardiographic changes during selective coronary cineangiography. Circulation 34:627-637, 1966 2. Benchimol A, McNally EM: Hemodynamic and electrocardiographic effects of selective coronary angiography in man. N Engl J Med 274:1217-1224, 1966 3. Coskey RL, Magldson 0: Electrocardiographic response to selective coronary arteriography. Br Heart J 29512-519, 1987 4. Carson RP, Lazzara R: Hemodynamic responses initiated by coronary stretch receptors with special reference to coronary arteriography. Am J Cardiol 25571-578, 1970 5. DeMaria A, Amsterdam EA, Zelis I?, et al: Cardiac rhythm and QRS axis changes during coronary angiography. Relation to coronary anatomy and to the divisions of the left bundle (abstr). Clin Res 20:204, 1972 6. Massumi RA, DeMaria A, Amsterdam EA, et al: Electrocardiographic (ECG) and His bundle studies during coronary angiography (CA) (abstr). Clin Res 20:396, 1972 7. Benchimol A, McNally EM: Atrial pacing during selective coronary angiography. Br Heart J 29:767-769, 1967 8. White CW, Eckberg DL, Abboud FM: Influence of contrast media on the sinus node (abstr). Circulation 48: Suppl ll:ll-38, 1972 9. James TN: Pulse and impulse in the sinus node. Henry Ford Hosp Med J 15275-299, 1967 10. Meek WJ, Eyster JAE: Experiments on the origin and propagation of the impulse in the heart. IV. The effect of vagal stimulation and of cooling on the location of the pacemaker within the sino-auricular nod& Am J Physiol34:368-383, 1914 Il. Hoffman BF: The genesis of cardiac arrhythmias. Prog Cardiovast Dis 8:319-329, 1986 12. James TN, Nadeau RA: Sinus bradycardia during injection directly into the sinus node artery. Am J Physiol 204:9-15, 1963 13. James TN; Cardiac innervation: anatomic and pharmacologic
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relations. Bull NY Acad Med 43:1041-1086, 1967 14. James TN, Spence CA: Distribution of cholinesterase within the sinus node and AV node of the human heart. Anat Ret 155: 151-162, 1966 15. Colerldge HM, Coleridge JCG, Kidd C: Cardiac receptors in the dog with particular reference to two types of afferent ending in the ventricular wall. J Physiol 174:323-339, 1964 16. Brown AM: Mechanoreceptors in or near the coronary arteries. J Physiol 177:203-214, 1965 17. Sleight P, Wlddicombe JG: Action potentials in fibers from receptors in the epicardium and myocardium of the dog’s left ventricle. J Physiol 181:235-258, 1965 18. Dawes GS: Studies on veratrum alkaloid. VII. Receptor areas in the coronary arteries and elsewhere as revealed by the use of veratridine. J Pharmacol Exp Ther 89:325-342, 1947 19. Sleight P: A cardiovascular depressor reflex from the epicardium of the left ventricle in the dog. J Physiol 173:321-343, 1964 20. Frink RJ, James TN: Intracardiac route of the Bezold-Jarisch reflex. Am J Physiol 221:1464-1469, 197 1 21. Shepherd JT: lntrathoracic baroreflexes. Mayo Clin Proc 48: 426-437, 1973 22. Linden RJ: Function of cardiac receptors Circulation 48:463479, 1973 23. James TN; Anatomy of the Coronary Arteries. New York, Hoeber, 1961, p 93 24. Adams DF, Paulin S: Effect of radiographic contrast media in selective injections into the sinus node artery. Radiology 91: 719-724, 1968 25. James TN, Bear ES, Frink RJ, et al: Selective stimulation, suppression, or blockade of the atrioventricular node and His bundle. J Lab Clin Med 76:240-256, 1970 28. Stock JPP: Diagnosis and Treatment of Cardiac Arrhythmias. New York, Appleton-Century-Crofts, 1970, p 38
Volume 35
RICHARD
MD,
FACC
BRUCE MERRICK, BS HAROLD M. LOWE, MD,
J. FRINK,
FACC
Sacramento, California
From the Cardiopulmonary Department, Mercy General Hospital, Sacramento, Calif. This work was supported in part by a grant from the Sacramento Yolo-Sierra Heart Association, Sacramento, Calif. Manuscript accepted July 12, 1974. Address for reprints: Richard J. Frink, MD, 1014 40th St., Sacramento, Calif. 95819.
Bradycardia occurring during coronary angiography may be due to the direct effect of dye or to reflex vagai effects on pacemaker centers. Fifteen patients were classified according to the origin of the sinus nodal and atrioventricuiar nodal arteries. In patients with type A anatomy, both the sinus and the atrioventricuiar nodal arteries arose from the right coronary artery. in those with type B anatomy, only the atrioventricular nodal artery arose from the right coronary artery. Heart rate recordings were made during coronary angiography before and after selective infusion of atropine (0.2 mg) into the right coronary artery. in type A patients, the sinus bradycardia observed during right coronary dye injection was caused by a combination of both direct and rdflex effects on pacemaker tissue. Sinus bradycardia occurring with left coronary dye injections was entirely reflex in nature and was completely blocked with right coronary arterial injection of atropine. in type B patients, sinus bradycardia with right coronary dye injections was produced by reflex suppression of the sinus pacemaker. A junctional rhythm was consistently produced afler administration of atropine. Junctional bradycardia in type B patients was caused by direct suppression of the junctional pacemaker. Thus, angiographic dye appears to decrease heart rate both by a direct effect on pacemaker tissue and by reflex vagai suppression of the sinus pacemaker.
The injection of angiographic dye into the coronary arteries causes transient electrocardiographic and hemodynamic changes.1-6 These changes include bradycardia, hypotension, depression of first derivative of left ventricular pressure (dP/dt),2,4 prolongation of the P-R interval,5,6 widening of the QRS complex,6 marked repolarization changes3 and a shift in the electrical axis.3 Coronary angiographers have observed various degrees of bradycardia induced by dye injections into normal, abnormal and obstructed coronary arteries. The bradycardia is said to be eliminated by intravenous administration of atropine.4-6 Some authors have speculated that the explanation for the bradycardia lies within the’ confines of two major areas: (1) an ischemic or physical effect of the dye upon pacemaker tissue,1,2,7,8 or (2) a reflex vagal effect. 4-6 This study seeks to ascertain the mechanism of the bradycardia in man by correlating heart rate response with blood supply to the sinus and atrioventricular nodes. Before and after selective infusion of atropine into the right coronary artery, recordings of heart rate were made as angiographic dye was injected into the right and occasionally the left coronary arteries. Materials
and Methods
Twenty-five patients undergoing selective coronary angiography were studied for heart rate response. All studies were performed as part of the daily schedule of cardiac catheterization and coronary angiography (using the Sones technique) in patients with suspected heart disease. Nembutalm,
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100 mg, and atropine, 0.5 mg, were administered as premedication before the procedure. Heart rate recordings were made using an Electronics for Medicine photographic recorder (DR 12) at a paper speed of 50 mm/set. The coronary injections were filmed with a 35 mm Arriflex camera at 80 frames/set using a 5 inch image intensifier. The films were examined to establish the origin of the sinus node and atrioventricular node arteries and to detect significant occlusive coronary disease. Patients with valvu-
lar disease, cardiomyopathy or congenital heart disease were excluded. Patients with greater than 50 percent obstruction of the coronary arteries were excluded with the exception of one patient who had a normal right coronary artery but 70 percent obstruction in the left anterior descending branch distal to the origin of the first septal artery. Ventricular function studies included determihation of the first derivative of left ventricular pressure (dP/dt) and left ventricular end-diastolic pressure and performance of left ventricular cineangiography. The results were normal in all included cases. Patients were classified into two types on the basis of the blood supply to both the sinus and atrioventficular nodes. In type A, the blood supply to both nodes originated from the right coronary artery. In type B, the sinus nodal artery came from the circumflex branch whereas the right coronary artery gave rise to the atrioventricular nodal artery. Three major groups were studied. Group I: Fifteen patients, 10 classified as type A and 5 as type B, were studied by recording the heart rate during the infusion of dye into the right coronary artery before and after selective right coronary arterial injection of atropine. The atropine, 0.2 mg in 10 cc of normal saline solution, was infused slowly into the right coronary artery after the appropriate control heart rate recordings had been made. Heart rate response immediately after the infusion was also recorded. In 2 of these 15 patients, both classified as type A, heart rate recordings were made during left coronary arterial injections before and after right coronary arterial infusion of atropine. There were nine men in the group, ranging in age from 36 to 60 years (mean age 50), and six women with an age range of 44 to 52 years (mean age 49). Group II: Five patients were studied during the infusion of 8 to 10 ml of autogenous blood into the right coronary artery. This procedure was used to determine whether distension of the right coronary or the sinus nodal artery by the pressure of the injections contributed to the bradycardia.g All five patients were type A, with the sinus nodal artery originating from the proximal right coronary artery. This group did not undergo selective right coronary arterial injection of atropine. Group III: Five patients, all type A, had heart rate recordings made during left coronary injections. None had selective right coronary arterial injections of atropine. All five patients, plus the two from Group I who received right coronary arterial injections of atropine, underwent evaluation of left coronary arterial injections.
Results
FIGURE 1. Case 2. Heart rate response before, during and after the injection of angiographic dye in the right coronary artery in a patient with type A anatomy. S-T and T wave changes provide evidence of maximal dye effect. A, before selective right coronary arterial injection of atropine. The control heart rate of 86 decreased to 50 beats/ min during the dye injection, then gradually returned to normal. The sinus pacemaker maintained control throughout injection and recovery phases. This tracing demonstrates the occurrence of sinus bradycardia but does not identify direct or reflex effects. The three lower strips are continuous. B, after selective right coronary arterial injection of atropine there was sinus tachycardia with a control heart rate of 104 beats/min. A decrease in heart rate to 96 beats/min occurred during the dye injection. This response, since reflex effects were blocked, was due to direct depression of pacemaker discharge by angiographic dye. The three lower strips are continuous.
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Type A: The heart rate response to the injection of angiographic dye into the right coronary artery of type A patients before and after selective right coronary atropinization is shown in Table IA. Sinus bradycardia developed in all patients during the dye infusion, both before and after infusion of atropine. The selective infusion of atropine produced an immediate increase in heart rate averaging approximately 25 percent. The sinus pacemaker consistently maintained rhythmic control after atropine infusion in all type A cases. l3efore administration of atropine, the heart rate decreased nearly 33 percent during the dye injection. After infusion of atropine, the heart rate during dye injection decreased approximately 17 percent. Atropinization cardiac slowing.
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A typical example of the heart rate response in a type A patient is shown in Figure 1. Figure 1A demonstrates the effect on heart rate and electrocardiographic configuration before administration of atropine. The rhythm remains sinus with marked T wave inversion during maximal effect of the dye. The heart rate decreases from a control rate of 86 to 50 beats/ min, then slowly returns to the control rate. Essentially the same effect is seen after administration of atropine (Fig. lB), the only differences being a more rapid rate at the beginning of the infusion and a lesser degree of sinus bradycardia. Type B: The results in patients with type B anatomy are shown in Table IB. Figure 2 illustrates the electrocardiographic changes in type B patients before and after administration of atropine. Certain similarities as well as significant differences between type A and B patients are apparent. First, before administration of atropine, sinus bradycardia developed in both types of patients during the infusion of dye (Fig. 1A and 2A). The magnitude of the bradycardia, 33 percent in type A and 24 percent in type B, was similar. Second, whereas an increase in sinus rate was always observed in type A patients after infusion of atropine, all type B patients manifested a juncTABLE
Control Heart Rate (Sinus Rhythm) (beats/min)
of Angiographic
Mean
11 12 13 14 15 Mean
ET AL.
tional rhythm that was always faster than the control sinus rate (Table IB, Fig. 2B). Third, bradycardia did occur with dye infusion after administration of atropine in type B patients but with certain specific features. The junctional pacemaker maintained control of the rhythm past the point of maximal bradycardia. Episodes of isorhythmic atrioventricular dissociation frequently occurred during the recovery phase; maximal bradycardia usually occurred within 3 to 6 seconds after the infusion was begun (Fig. 2B). The junctional rate at the point of maximal slowing was less than the control sinus rate in all cases. However, the magnitude of the hradycardia was essentially the same before infusion of atropine (25 fiercent) as after the infusion (26 percent) in type B patients. This finding contrasts with observations in type A patients, whose heart rate after infusion of atropine was reduced from 33 to 17 percent. The infusion of autogenous blood into the right coronary artery produced a mean decrease in heart rate of 2 percent in the five patients tested. Left coronary injection of atropine: The decrease in heart rate during left coronary injections in the seven type A patients was 34 percent, almost identical to the decrease after right coronary injec-
68 100 86 88 77 110 96 79 86 77 86.7 z!zl2.5
66 83 79 71 70 72.8 xk7.0
Dye into the Right Coronary
Change in Heart Rate (beats/min)
6450 96-66 79-50 88-69 7765 110-66 96-47 82-50 86-54 77-50 ...
66-50 83-65 79-44 71-69 70-49
...
Artery Dye lnjechon After Atropine
Heart Rate Response and Rhythm After Selective Right Coronary Atropine
Dye Injection Before Atropine
% Decrease _--___-._ A.
1 2 3 4 5 6 7 8 9 10
ANGIOGRAPHY-FRINK
I
Heart Rate Response After Injection
Case no.
DURING CORONARY
Change in Heart Rate (beats/min)
% Increase
.
Rhythm
-_. _.-.
Change in Heart Rate (beatq’min) --
% Decrease .____
Ten Patients with Type A Coronary Anatomy
22 31 36 21 16 40 51 39 37 35 32.8 zt11.3
66-91 91-124 77-105 86-94 80-104 110-130 92-116 80-83 79-96 65-91
... _.~_. ___
51 36 36 10 30 18 21 3 21 40 26.6 Ik15.01
Sinus Sinus Sinus Sinus Sinus Sinus Sinus Sinus Sinus Sinus
86-73 124-108 104-96 94-73 104-88 130-98 116-94 83-68 96-70 91-79
...
...
16.9 xt6.9
78-57 104-72 82-51 75-59 81-65
19 31 38 21 21 26.0 l t7.3
B. Five Patients with Type B CoronaryAnatomy ___~._~__. 24 66-78 18 Junctional 15 78-104 25 Junctional 44 75-82 9 Junctional 4 68-74 10 Junctional 30 68-81 19 Junctional 23.8 ... 16.2 ... 16.0 zk12.2
...
18 15 8 22 16 25 20 14 26 13
A control heart rate (column 2) was recorded before any injection procedures were performed. Since right coronary injections came near the end of the procedure, the heart rate immediately before the right coronary injection (column 3) was sometimes slightly different from the original control heart rate. The same applies to the heart rate present at the time atropine was infused (column 5). Similarly, in column 8, the heart rate at the time of dye injection was slightly different from that achieved immediately after the infusion of atropine.
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FIGURE 2. Patient 12. Heart rate response in type B patient after the infusion of angiographic dye into the right coronary artery. A, before selective right coronary injection of atropine. Note heart rate change (sinus bradycardia) from 83 to 85 beats/min, and the corresponding S-T wave changes due to maximal dye effect. Essentially the same response occurred in type A patients before injection of atropine. The three lower strips are continuous. B, after selective injection of atropine into the right coronary artery there was a stable junctional heart rate of 94 beats/min. A decrease in heart rate from 94 to 71 beats/min occurred during the dye infusion. The rhythm remained junctional past the point of maximal bradycardia. lsorhythmic atrioventricular dissociation occurred briefly (bottom strip). The three lower strips are continuous.
tion in these same patients. In the two type A patients tested both before and after right coronary injection of atropine, the bradycardia was completely eliminated by the cholinergic blockade. Discussion Under normal circumstances the sinus node is the primary pacemaker of the heart.10 In abnormal physiologic conditions, the atrioventricular junctional region has been recognized as a secondary pacemaker center.ll All factors that directly or indirectly influence these two centers of cardiac rhythm should be given utmost attention when considering chronotropic responses of the heart. Mechanisms of Bradycardia After Dye Injection In our attempt to explain the bradycardia following the injection of angiographic dye into the 20
January 1975
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right coronary artery, there are two primary considerations: (1) the direct effects of the dye on pacemaker tissue, and (2) the reflex vagal effects on pacemaker discharge. For our purposes, any heart rate response believed to be due to the physical or chemical properties of the dye, including anoxia, is considered a direct effect on pacemaker tissue. The stimulation of neurogenic receptors by the angiographic dye, which subsequently affects heart rate indirectly, is considered a reflex effect. Sinus nodal distension: The possible distension of the sinus nodal artery during the injection of dye is a secondary consideration. In dogs, such distension regularly produces transient bradycardia.12 Although so far unproved, the same reponse may occur in man. Since the sinus nodal artery arises from the proximal right coronary artery in type A patients, distension could conceivably occur during the injection of dye
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and contribute to the bradycardia. Our results, using autogenous blood instead of dye, demonstrate relatively little change, less than 5 percent, in heart rate. This response was not considered a significant factor in the production of the bradycardia. Vagal effects on sinus and atrioventricular nodes: Autonomic reflexes, particularly those affecting the sinus and atrioventricular nodes, are important in the control of heart rate and rhythm.13 Heavily concentrated areas of cholinergic nerve endings have been found in these regions and may be considered prime centers of reflex activity.14 The dual cholinergic innervation of both sinus and atrioventricular nodes is a well known clinical and experimental fact.‘” We assume that reflex effects producing bradycardia are caused by the stimulation of vagal receptors, activating an afferent limb that travels by way of the vagus nerve to the central nervous system and subsequently back by the efferent limb to both the sinus and atrioventricular nodes. The resulting bradycardia is primarily produced b> vagal effects on the sinus pacemaker. Vagal efferen~s may pass also to the atrioventricular nodal region, but the effects may not be evident because of the dominance of the sinus pacemaker. Bezold-Jarisch effect on chemoreceptors: Receptors of various types have been identified in both the atria and ventricles of experimental animals.15-18 A heavy concentration of receptors has been found in the region of the sinus and atrioventricular nodes.15 Some of these receptors are stimulated by pressure changes and by chemical stimulation.16 Chemical receptors have been found in the heart, primarily in the left ventricle of experimental animals,18 which, when stimulated by various means, give rise to the Bezold Jarisch effect or reflex.1s-22 This reflex response is characterized by both bradycardia and hypotension. The bradycardia produced by the injections of angiographic dye may be the human counterpart of the Bezold-Jarisch reflex. In our study, the types of receptors that were stimulated and their precise location are not known. Theoretically, if chemoreceptors are limited to the left ventricle and do respond to angiographic dye, a left coronary injection would be expected to stimulate them and produce reflex changes in heart rate. Our results with left coronary injections support this reasoning. Left coronary injections in type A patients produced the same degree of bradycardia as did right coronary injections, yet little or no dye circulated to the sinus or atrioventricular node. Elimination of the bradycardia in two of these patients by selective right coronary injection of atropine definitely suggests a reflex response. Firm conclusions on this point should not be drawn since only two patients were studied after right coronary injection, but other reasonable alternative explanations are lacking. Right vs. left coronary arterial dye injection: The right coronary artery in all patients in this study supplied blood to at least a portion of the inferior wall of the left ventricle and inferior intraventricular septum. A right coronary injection may therefore be
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expected to circulate dye to and possibly stimulate any chemoreceptors located in the left ventricle. Thus, the heart rate response with a right as well as with a left coronary injection may reflect reflex suppression of pacemaker discharge. Since the volume of ventricular muscle supplied by the right coronary artery is considerably less than that supplied by the left coronary artery, the magnitude of the reflex response may be less with the right coronary injection. In our studies, this proved to be correct. The reflex effect of a left coronary injection was double that of a right coronary injection in type A patients. The intracardiac route of the Bezold-Jarisch reflex in dogs has been determined to be along the left coronary artery, exiting near the left coronary ostia.20 This may be true also of the left coronary artery in man. Since the human right coronary artery supplies the inferior wall of the left ventricle in 90 percent of cases2a the possibility that afferents travel with the right coronary artery and exit from the heart near the right coronary atria should be considered. Response in Type A Patients to Right Coronary Injections Heart rate response was quite consistent in that sinus bradycardia was produced by each right coronary injection (Fig. 1A). Since the dye circulated to both the sinus and atrioventricular nodes, the bradycardia may have been caused by direct or reflex effects, or both.24 Deciding which effect was operative was aided by cholinergic blockade of both sinus nodal and atrioventricular junctional regions by selective right coronary injection of atropine. The production of sinus tachycardia (an average of 26.6 percent increase in heart rate) indicates, we believe, effective vagal blockade of at least the sinus pacemaker. This blockade did not interfere with pacemaker dominance, nor did it eliminate the bradycardia during right coronary injections (Fig. 1B). This result would not have occurred if the bradycardia operated entirely by reflex. We believe the bradycardia in type A patients during a right coronary injection is the result of both reflex and direct effects, each contributing equally to the bradycardia. Response in Type B Patients to Right Coronary Injections We interpret the consistent production of a junctional rhythm rather than a sinus tachycardia after right coronary injection of atropine as concrete evidence of a separate blood supply to the sinus and atrioventricular nodal regions in type B patients. A right coronary injection in this instance is considered a selective atrioventricular nodal infusion maneuver. In man this is as close as one can come to a selective atrioventricular nodal arterial injection.25 The heart rate response must be interpreted in light of this anatomic difference between type A and B patients. Heart rate response before atropine: The infusion of dye produced a sinus bradycardia very similar to that seen in type A patients (Fig. 1A and 2A). The
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mechanism of the bradycardia cannot be the same because dye does not circulate to the sinus node: Direct depressant effects of dye on the sinus pacemaker therefore cannot explain the bradycardia. The only possible explanation for the slowing of sinus nodal discharge is reflex suppression. Direct conduction across the free atria1 wall would occur much too slowly to produce these effects. The reflex must originate with receptors located in the distribution of the right coronary artery, and the reflex effect must occur very quickly since the sinus pacemaker remains in control throughout injection and recovery. Atrioventricular dissociation did not occur. Heart rate response after atropine: The major response to this maneuver was a shift in the dominant pacemaker from the sinus nodal to the atrioventricular junctional region, with an increase in the heart rate (Fig. 2B). The cholinergic blockade of all efferent nerves surrounding the junctional pacer prevented any reflex change in heart rate. Any change in the firing rate of this junctional pacemaker could have been due only to the direct effects of the dye. The receptors and afferent nerves were not blocked nor were any efferent nerves to the sinus node blocked. The infusion of dye into the right coronary artery produced a junctional bradycardia of the same magnitude as that produced before infusion of atropine when the sinus node was the dominant pace-
maker. These data lead us to believe that the bradycardia in type B patients, just as in type A, was due to a combination of both direct and reflex effects. In type A patients the two effects were additive, whereas in type B they were nonadditive but equal or equivalent. This may expl:iin why the magnitude of the bradycardia was slightly less in type B than in type A patients before administration of atropine. Before infusion of atropine, the discharge rate of the sinus pacemaker was suppressed entirely by reflex, masking any direct effects at the atrioventricular junction. After the infusion, the sinus pacemaker failed to emerge when the junctional rate fell below the control sinus rate during the maximal dye effect (Fig. 2B). This is the second piece of evidence indicating reflex suppression of sinus nodal function in type B patients. A junctional heart rate, faster than the sinus rate, occurred after administration of atropine in type B patients (Fig. 2B). The observed firing rate of the junctional pacemaker in most clinical situations is reported to be between 40 to 60 beats/min2s and is often referred to as the “inherent” firing rate of the atrioventricular junctional pacer. Our work suggests that the inherent firing rate of this pacemaker, free from vagal influence, may be faster than 40 to 60 beats/min. The evidence also implicates vagal efferent connections in relation to pacemaker dominance.
References I. MacAlpln RN, Weidner WA, Kattus, AA Jr, et al: Electrocardiographic changes during selective coronary cineangiography. Circulation 34:627-637, 1966 2. Benchimol A, McNally EM: Hemodynamic and electrocardiographic effects of selective coronary angiography in man. N Engl J Med 274:1217-1224, 1966 3. Coskey RL, Magldson 0: Electrocardiographic response to selective coronary arteriography. Br Heart J 29512-519, 1987 4. Carson RP, Lazzara R: Hemodynamic responses initiated by coronary stretch receptors with special reference to coronary arteriography. Am J Cardiol 25571-578, 1970 5. DeMaria A, Amsterdam EA, Zelis I?, et al: Cardiac rhythm and QRS axis changes during coronary angiography. Relation to coronary anatomy and to the divisions of the left bundle (abstr). Clin Res 20:204, 1972 6. Massumi RA, DeMaria A, Amsterdam EA, et al: Electrocardiographic (ECG) and His bundle studies during coronary angiography (CA) (abstr). Clin Res 20:396, 1972 7. Benchimol A, McNally EM: Atrial pacing during selective coronary angiography. Br Heart J 29:767-769, 1967 8. White CW, Eckberg DL, Abboud FM: Influence of contrast media on the sinus node (abstr). Circulation 48: Suppl ll:ll-38, 1972 9. James TN: Pulse and impulse in the sinus node. Henry Ford Hosp Med J 15275-299, 1967 10. Meek WJ, Eyster JAE: Experiments on the origin and propagation of the impulse in the heart. IV. The effect of vagal stimulation and of cooling on the location of the pacemaker within the sino-auricular nod& Am J Physiol34:368-383, 1914 Il. Hoffman BF: The genesis of cardiac arrhythmias. Prog Cardiovast Dis 8:319-329, 1986 12. James TN, Nadeau RA: Sinus bradycardia during injection directly into the sinus node artery. Am J Physiol 204:9-15, 1963 13. James TN; Cardiac innervation: anatomic and pharmacologic
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relations. Bull NY Acad Med 43:1041-1086, 1967 14. James TN, Spence CA: Distribution of cholinesterase within the sinus node and AV node of the human heart. Anat Ret 155: 151-162, 1966 15. Colerldge HM, Coleridge JCG, Kidd C: Cardiac receptors in the dog with particular reference to two types of afferent ending in the ventricular wall. J Physiol 174:323-339, 1964 16. Brown AM: Mechanoreceptors in or near the coronary arteries. J Physiol 177:203-214, 1965 17. Sleight P, Wlddicombe JG: Action potentials in fibers from receptors in the epicardium and myocardium of the dog’s left ventricle. J Physiol 181:235-258, 1965 18. Dawes GS: Studies on veratrum alkaloid. VII. Receptor areas in the coronary arteries and elsewhere as revealed by the use of veratridine. J Pharmacol Exp Ther 89:325-342, 1947 19. Sleight P: A cardiovascular depressor reflex from the epicardium of the left ventricle in the dog. J Physiol 173:321-343, 1964 20. Frink RJ, James TN: Intracardiac route of the Bezold-Jarisch reflex. Am J Physiol 221:1464-1469, 197 1 21. Shepherd JT: lntrathoracic baroreflexes. Mayo Clin Proc 48: 426-437, 1973 22. Linden RJ: Function of cardiac receptors Circulation 48:463479, 1973 23. James TN; Anatomy of the Coronary Arteries. New York, Hoeber, 1961, p 93 24. Adams DF, Paulin S: Effect of radiographic contrast media in selective injections into the sinus node artery. Radiology 91: 719-724, 1968 25. James TN, Bear ES, Frink RJ, et al: Selective stimulation, suppression, or blockade of the atrioventricular node and His bundle. J Lab Clin Med 76:240-256, 1970 28. Stock JPP: Diagnosis and Treatment of Cardiac Arrhythmias. New York, Appleton-Century-Crofts, 1970, p 38
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