- Email: [email protected]
Reflex heart rate and blood pressure changes during ST segment elevation in patients with variant angina
Volume Number
108 5
Ca++ antagonist/nitrate
9. Goldberg S, Reichek N, Wilson J, Hirshfeld JW Jr, Muller J, Kastor JA: Nifedinine in the treatment of Prinzmetal’s (variant) angina. Ai J Cardiol44:804, 1979. 10. Schroeder JS, Lamb IH, Ginsburg R, Bristow MR, Hung J: Diltiazem for long-term therapy of coronary arterial spasm. Am J Cardiol49:533, 1982. 11. Stone PH, Antman EM, Muller JE, Braunwald E: Calcium channel blocking agents in the treatment of cardiovascular disorders. Part II. Hemodynamic effects‘ and clinical applications. Ann Intern Med 93:886, 1980. 12. Anderson R: Cyclic AMP as a mediator of the relaxing action of papaverine, nitroglycerin, d&oxide, and hydralazine in intestinal and vascular smooth muscle. Acta Pharmacol Toxic01 32:321, 1973.
therapy for variant angina
13. Muller JE, Gunther SJ: Nifedipine therapy for Prinzmetal’s angina. Circulation 57:137, 1978. 14. Johnson SM, Mauritson DR, Willerson JT, Hillis LD: A controlled trial of verapamil for Prinzmetal’s variant angina. N Engl J Med 304:862, 1981. 15. Noether GE: Introduction to statistics: A nonparametric approach. Boston, 1971, Houghton-Mifflin Company, pp 147-9. 16. Zar JH: Biostatistical analysis. Englewood Cliffs, N.J., 1974, Prentice-Hall, Inc, pp 173-7. 17. Walker WS, Winniford MD, Mauritson DR, Johnson SM, Hillis LD: Atrioventricular junctional rhythm in patients receiving oral verapamil therapy. JAMA 249:389, 1983.
Reflex heart rate and blood pressure changes during ST segment elevation in patients with variant angina Responses of heart rate and blood pressure to transient myocardial ischemia were analyzed in patients with variant angina. Heart rate changes during ST segment elevation were examined by means of a Holter ECG monitoring system. All 27 ST segment elevations from 10 patients with anterior ischemia were accompanied by an increase in heart rate by 12 -+ 2 bpm (mean +- SEM, p < 0.001) at peak ST segment elevation. With inferior ischemia in nine patients, heart rate decreased significantly by 4 5 1 bpm (n = 28, p < 0.001). However, 9 of these 28 ST segment elevations showed a biphasic response of heart rate, that is, an initial increase and subsequent decrease. Such heart rate changes were not different between ST segment elevations with and without chest pain. With chest pain systolic blood pressure rose in anterior ischemla by 42 + 5 mm Hg (n = 10, p < 0.001) but fell in inferior ischemia by 22 + 8 mm Hg (n = 7, p < 0.05). We conclude that a different cardiovascular reflex occurs in response to inferior versus anterior ischemia and it is independent of chest pain. (AM HEART J 108:1273, 1984.)
Haruo Araki, M.D., Tsuyoshi Anan, M.D., Yasushi Koiwaya, M.D., Osamu Nakagaki, M.D., Akira Takeshita, M.D., and Motoomi Nakamura,
M.D.
Fukuoka, Japan.
Inhibitory cardiac receptors with vagal afferenta are known to be distributed predominantly in the inferoposterior wall of the left ventricle in dogs.le3 In patients with acute myocardial infarction, bradycar-
From the Research Institute Faculty Received accepted
of Medicine,
Kyushu
for publication April 10, 1984.
of Angiocardiology University.
Dec.
1, 1983;
revision
and Cardiovascular received
March
Clinic, 8, 1984;
Reprint requests: Haruo Araki, M.D., Research Institute of Angiocardiology and Cardiovascular Clinic, Faculty of Medicine, Kyushu University, 3-l-l Maidashi, Higashi-ku, Fukuoka 812, Japan.
dia and hypotension occur more frequently in inferior than in anterior infarction.” 5 Injection of contrast medium into the coronary artery supplying the inferior left ventricle also results in bradycardia and hypotension.6 It has recently been reported that reperfusion of the inferior ischemic area by means of thrombolysis may cause an inhibitory cardiovascular response.’ These results suggest the preferential distribution of inhibitory cardiac receptors in the inferoposterior wall of the left ventricle in humans. Perez-Gomez et al? reported that the heart rate 1273
November,
1274
Araki et al.
American
Heart
1984 Journal
1. Trendgrams of heart rate (HR) and ST segment,and real-time tracings of ECGs of two patients with anterior (upper panel) and inferior ischemia(lower panel). The patient in the upper panel wasasleep and did not have chest pain when ST segmentelevation developed.The patient in the lower panel woke up with chest pain on ST segmentelevation. Note that the heart rate increasedin anterior ischemia and decreasedin inferior ischemia during ST segmentelevation. Fig.
decreased with inferior ischemia but increased with anterior ischemia in patients with variant angina. They measured the sinus rate at only two points; before and during chest pain in their own patients, and also analyzed R-R intervals of the ECG at control and during ST segment elevation in many patients, which had been published by other investigators. In order to evaluate the exact manner of cardiovascular reflex in variant angina, however, it will be important to monitor the heart rate continuously during the attack. Furthermore, it will be interesting to examine the difference in the cardiovascular reflex during painful and painless myocardial ischemia in variant angina, since pain may evoke various cardiovascular reflexes.g We employed a Holter ECG monitoring system and examined the time course of heart rate changes in relation to ST segment elevation. In addition, we examined changes in blood pressure during ST segment elevation with anterior or inferior ischemia and also the effect of chest pain on changes in heart rate. METHODS Patients.
Changes in heart rate (sinus rate) during coronary spasm were analyzed in patients with variant
angina by means of a Holter ECG monitoring system. Nineteen hospitalized patients with variant angina documented by chest pain at rest and transient ST segment elevation on 12-lead ECG were used for the study. There were 16 men and three women, ranging in age from 46 to 70 years (59 * 2 years, mean + SEM). During repeated attacks of variant angina, nine of them showed ST segment elevation in inferior leads (II, III, and aVr) and the remaining 10 in anterior leads(I, aVL, and V, to V,). None of them had a history of myocardial infarction. Coronary angiography was done in 15 patients. Five patients showednormal coronary angiograms.Eight had coronary narrowing of less than 50% and two had 51% to 74% narrowing. Blood pressurewas measuredby sphygmomanometer on chestpain at rest in the supineposition and 30 to 60 minutes after the relief of chest pain, while the patient remained in the supineposition. Twelve-lead ECG wasrecorded on chest pain and the transient ST segment elevation was confirmed on measurementof blood pressure. Halter ECG. A 24-hour continuous recording of precordial bipolar ECG wasperformed by a calibrated magnetic tape system (Avionics, model 445-B or 446). One of the two leads was selected to mimic the ECG lead which showed the highest ST segmentelevation observed on a 12-leadECG during anginal attack, and another lead was placed on the opposite site to record the reciprocal ST
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108
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Cardiovascular reflexes in variant angina 1275
segment depression. Precautions were taken to ensure that the electrodes were placed firmly to avoid motion artifacts. Patient activities and symptoms including the time of occurrence were entered in detail in the diary. Any drugs which might affect coronary spasm or the cardiovascular system had been discontinued for at least 2 days before the study. Analysis of the recorded magnetic tapes was done with the use of a dynamic electrocardioscanner (Avionics 660A). Trendgrams of ST segment and heart rate, averaging 15 beats, were obtained, where ST segmentdeviations were measuredat a point of 0.08 secondfrom the nadir of the S wave. These trendgrams were amplified and displayed on a pen oscillograph (San-Ei Instrument, type 8K 21). ST segmentelevation was consideredto be ischemic when the shift of the ST segmentwas transient, smooth, and was not accompanied by an abrupt change in QRS complex as previously reported.‘O All such ST segment elevations of 1 mm or greater were analyzed. Postural ST segment changes were excluded carefully. To evaluate changes in heart rate accurately during the attack of variant angina, we analyzed ST segment elevation only when the heart rate prior to the attack of coronary spasm was stable. ST segmentelevation with frequent extrasystoles or atrioventricular block of the second or third degreewas excluded. Statistics. Statistical analysis was done by means of Student’s t test for paired data. Values were expressedas mean of:SEM. RESULTS
Fig. 1 shows trendgrams of heart rate and ST segment in two patients who had ST segment elevation in the anterior leads of V3 through V, (upper panel) and the inferior leads of II, III, and aV, (lower panel) during the attack of variant angina. As shown in the upper panel, ST segment elevation occurred in a lead of CM, at 3:30 A.M. Mild depression of the ST segment followed the elevation. The heart rate increased rapidly from 60 to 88 bpm with ST segment elevation and returned to the control level after about 15 minutes when the ST segment was also reverted. This patient was asleep and did not have chest pain during the ST segment elevation. The patient in the lower panel, who had ST segment elevation in the inferior leads, woke up with chest pain at 4:40 A.M. The chest pain lasted for about 10 minutes and disappeared spontaneously. As shown in the trendgrams, heart rate decreased from 45 to 37 bpm during the ST segment elevation. The lowest heart rate was attained after the peak of ST segment elevation and then returned to the control level. The Heart
rate
changes
during
variant
angina.
real-time tracings of ECG are shown in the right panel.
Fig. 2 summarizes
changes in heart rate during ST
ANTERIOR
INFERIOR .-.
with pain
o--owithout
uain
PcO.OtN I CONTROL
I
ST ELEVATION
6
CoNrROL
I
ST EWATlON
2. Changesin heart rate during ST segment elevation in patients with anterior or inferior ischemia. The heart rate increasedin anterior ischemiaand decreasedin most patients with inferior ischemia.The sameresponses were observed during ST segment elevations with and without chest pain. Fig.
segment elevation in two groups having ST segment elevation in anterior or inferior leads during the attack of variant angina. The heart rate during the attack was measured at the peak of ST segment elevation. In anterior ischemia the heart rate increased during ST segment elevation in all 27 occasions and the difference was statistically significant (60 + 2 bpm at control and 72 + 3 at the peak ST segment elevation, p < 0.001). Among 28 ST segment elevations with inferior ischemia the heart rate decreased in 20, increased in four, and did not change in the remaining four. The difference was statistically significant (64 + 4 bpm at control, 60 + 3 at peak ST segment elevation, p < 0.001). Among 55 ST segment elevations, 32 were without chest pain. Changes in heart rate during painless ST segment elevations were similar to those in painful episodes. The heart rate increased with anterior ischemia but decreased in inferior ischemia even without chest pain (Fig. 2).
In inferior ischemia, 11 of 28 ST segment elevations were accompanied only by the decrease in heart rate. However, in nine ST segment elevations, the heart rate increased initially and then started to decline before the peak of ST segment elevation, showing the biphasic pattern of heart rate change.
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1984 Journal
at control and 160 + 5 during angina, n = 10, p < 0.001). In inferior ischemia five attacks from
five patients were accompanied by a fall in blood pressure, one attack from one patient by a rise, and the other one from the same patient by no change (128 + 7 at control and 106 + 7 during angina, n = 7, p < 0.05). Heart rate always increased during the ST segment elevations, which accompanied a rise in the blood pressure. Heart rate decreased in the ST segment elevations, which accompanied a fall in blood pressure. DISCUSSION
I
I
I
I
A
B
C
D
3. Initial increase in heart rate on ST segment elevation in patients with inferior ischemia.Abbreviations in abscissaare as follows: A = heart. rate at control or before ST segmentelevation; B = highest heart rate during ST segment elevation; C = lowest heart rate; D = heart rate when elevated ST segmentreturned to its control level. Peak ST segmentelevation is betweenB and C in all cases. Fig.
Fig. 3 summarizes changes in heart rate during these nine ST segment elevations. The lowest heart rate was observed after the peak ST segment elevation but before it returned to the control level in all patients. Again, even without chest pain, the initial increase in the heart rate was observed. Blood pressure changes during variant angina. Fig. 4 shows changes in systolic blood pressure, which were measured during chest pain with ST segment elevations with anterior or inferior ischemia. Blood pressure measured at 30 to 60 minutes after the relief of chest pain was used as control, which was not different from the average blood pressure of each patient measured at rest on days without angina. Blood pressure rose significantly during the attack in patients with anterior &hernia (117 + 3 mm Hg
Inferior versus anterior lschamia. The present study confirmed that inferior ischemia was accompanied by a decrease but anterior ischemia by an increase in heart rate in patients with variant angina. In addition to heart rate changes, we measured changes in blood pressure during attacks of variant angina in some patients and found that blood pressure fell with inferior ischemia and rose with anterior ischemia. These results indicate that changes in heart rate during variant angina were not elicited by arterial baroreceptors, since arterial baroreceptors would decrease heart rate in response to a rise in blood pressure or vice versa. Thus, these changes in heart rate during variant angina are likely to be elicited by activation of cardiac receptors. Initial heart rata increase. We recorded and analyzed changes in heart rate continuously throughout ST segment elevation. The results showed that nine ST segment elevations with inferior ischemia had an initial increase in heart rate before the decline. This initial increase in heart rate was observed during painless ST segment elevations as well as painful ones. These results suggest that the initial cardiac acceleration was not caused by chest pain but by some other reflexes. Coronary pathoanatomy. A difference in the coronary artery supplying the inferoposterior wall of the left ventricle, either the right or the left circumflex coronary artery, might influence the response of heart rate to ischemia. However, all seven patients with inferior ischemia in whom coronary angiography was performed had a prominent right coronary artery, which supplied the inferior left ventricle, but some of them had an initial increase in heart rate during ischemia. None of these patients with inferior ischemia had significant coronary lesions of more than 50% of luminal narrowing. Thus it appears that neither coronary lesions nor coronary anatomy affect heart rate or blood pressure responses to inferior &hernia. Cheat pain. It is well known that the somatic
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Cardiovascular ANTERIOR
reflexes in variant angina
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INFERIOR l
: :b bb 0 b
? 0 $
l
p’o.!M
p-=0.05
I
I
I
I
CONTROL
CHESTPAIN
CONTROL
CHEST PAIN
Fig. 4. Changesin systolic blood pressure during chest pain attack with ST segment elevation. The systolic blood pressuredropped in five of sevenepisodesof inferior ischemiaand rosein all of the anterior ones.
sensation of pain occurring for many reasons alters heart rate and blood pressure.s In the present study, however, changes in heart rate during myocardial ischemia were independent of the existence of chest pain. This suggests that the cardiovascular responses occurring in variant angina are not elicited by somatic reflex caused by chest pain but by the activation of cardiac receptors themselves. However, more study will be needed to evaluate whether the cardiovascular reflex through the cardiac receptors is modified, to any extent, by chest pain. Coronary reperfusion. Recently, Wei et al.7 reported the cardiovascular reflex changes upon reperfusion of occluded coronary artery by means of thrombolysis in patients with acute myocardial infarction. They reported that the cardioinhibitory response occurred when the reperfused coronary artery supplied the inferior myocardium, and cardioacceleratwhen the anterior ing response occurred myocardium was reperfused. They postulated that the cardioinhibitory receptors were distributed mainly in the inferior myocardium and were activated by the reperfusion. Our results showed that heart rate decreased further after the elevated ST segment started to decline, and the lowest heart rate was attained between the peak ST segment elevation and the time when the ST segment returned to control level. From these results, it is possible to postulate that the cardioinhibitory reflex in variant
angina is activated not only by myocardial ischemia but also by its reperfusion. Clinical implications. Variant angina is known to accompany various kinds of arrhythmias such as ventricular tachyarrhythmias and atrioventricular block.1°-13 Preferential occurrence of atrioventricular block in inferior ischemia has been observed frequently.** lo,11,14Its underlying mechanism may be the cardioinhibitory reflex caused by the activation of cardiac receptors in inferior myocardium as evidenced by heart rate changes in our study. Variant angina seems to activate the sympathetic nervous system especially in patients with anterior ischemia. It will be important to know whether this sympathetic activation had any roles in the pathogenesis of ventricular tachyarrhytyhmias during the attack of variant angina.
REFERENCES
Jarisch A, Zotterman Y: Depressor reflexes from the heart. Acta Physiol Stand 16:31, 1948. Thames MD. Klonhenstein HS. Ahboud FM. Mark AL. Walker JL: Prefeiential distribution of inhibitory cardiac receptors with vagal afferents to inferoposterior wall of the left ventricle activated during coronary occlusion in the dog. Circ Res 43512, 1978. Zucker IH, Cornish KG: The Bezold-Jarisch reflex in the conscious dog. Circ Res 49:940, 1981. Webb SW, Adgey AAJ, Pantridge JF: Autonomic disturbance at onset of acute myocardial infarction. Br Med J 3:89, 1972.
Araki
et al.
American
5. Scheinman MM, Thorburn D, Abbott JA: Use of atropine in patients with acute myocardial infarction and sinus bradycardia. Circulation 52:627, 1975. 6. Eckberg DL, White CW, Kioschos JM, Abboud FM: Mechanisms mediating bradycardia during coronary arteriography. J Clin Invest 54:1455, 1974. 7. Wei JY, Markis JE, Malagold M, Braunwald E: Cardiovascular reflexes stimulated by reperfusion of ischemic myocardiurn in acute myocardial infarction. Circulation 67:796, 1983. 8. Perez-Gomez F, Martin DeDios R, Rey J, Garcia Aguado A: Prinzmetal’s angina: Reflex cardiovascular responses during episodes of pain. Br Heart J 42:81, 1979. 9. Brown AM: Cardiac reflexes. In Bern RM, Sperelakis N, Geiger SR, editors: Handbook of physiology, Section 2, The cardiovascular system, vol 1, The heart. Bethesda, 1979, Waverly Press, Inc, p 667. 10. Araki H, Koiwaya Y, Nakagaki 0, Nakamura M: Diurnal
function patients
11. 12.
13.
14.
November, 1984 Heart Journal
distribution of ST-segment elevation and related arrhythmias in patients with variant angina: A study by ambulatory ECG monitoring. Circulation 67:995, 1983. Prinzmetal M, Kennamer R, Merliss R, Wada T, Bor N: Angina pectoris I A variant form of angina pectoris. Am J Med 27:375, 1959. Maseri A, Severi S, DeNes M, L’abbate A, Chierchia S, Marzilli M, Ballestra AM, Parodi 0, Biagini A, Distante A: “Variant angina: One aspect of a continuous spectrum of vasospastic myocardial ischemia. Am J Cardiol 42:1019, 1978. Kerin NZ, Rubenfire M, Naini M, Wajszczuk WJ, Pamatmat A, Cascade PN: Arrhythmias in variant angina pectoris: Relationship of arrhythmias to ST-segment elevation and R-wave changes. Circulation 60:1343, 1979. Botti RE: A variant form of angina pectoris with recurrent transient complete heart block. Am J Cardiol 17:443, 1966.
17,043 in
f with severe cEwo@c
To evaluate the mechanisms for improved left ventricular function with MDL 17,043 in patients with severe chronic heart failure, 24 patients were evaluated by simultaneous determlnat(on of hemodynamics by right heart catheterization and ejection fraction by computerized nuclear probe before and following intravenous administration of MDL 17,043 (mean cumulative dose 3.6 mg/kg). Following MDL 17,043, there was an increase in cardiac index (+62%), stroke volume index (+42%), and stroke work index (+66%), together with a decrease in pulmonary capillary wedge pressure (-46%), indicating improved left ventricular pump function. There was a marked reduction in systemic vascular resistance (-40%) and a modest reduction in arterial pressure, indicating decreased left ventricular outflow resistance. The ratio of peak systolic blood pressure to calculated left ventricular end-systolic volume tended to increase, but the change was not statistically significant. Despite a marked increment In stroke volume Index, ieft ventricular ejection time corrected for heart rate was shortened, suggestrng enhanced contractility. In the group as a whole, the calculated left ventricular end-diastolic volume remained unchanged, but it increased in 14 patients. Since pulmonary capillary wedge pressure fell in each patient, this suggests improved overall left ventricular distensibility. Thus, decreased left ventricular outflow resistance, and possibly increased contractlie function, and improved left ventricular diastolic compliance may all contribute to improved left ventricular pump function with MDL 17,043 in patients with severe heart failure. (AM HEART J 106~1278, 1964.)
Dean J. Kereiakes, M.D., Christian Viquerat, M.D., Peter Lamer, M.D., Elias H. Botvinick, M.D., Robert Spangenberg, M.D., Ph.D., Michael Buckingham, R.N., B.S., William W. Parmley, M.D., and Kanu Chatterjee, M.B., F.R.C.P. Sun Francisco, Calif.
From the Cardiovascular Division of the Department of Medicine, Nuclear Medicine Division of the Department of Radiology, and Cardiovascular Research Institute of the University of California, Francisco. This work was supported in part by a Grant-in-Aid Susan Schleicher Cardiology Research Fund; by
1276
an
the the San
from the Don and American Heart
Association D. Smith Received
Reprint Hospital, 94143.
Established Investigator Award (Dr. Botvinick); Fund, Inc.; and by the Fanny Ripple Foundation. for publication requests: University
June
4, 1984;
Kanu Chatterjee, of California,
accepted
July
by the George
10, 1984.
M.B., F.R.C.P., Room 1188 Moffitt 505 Parnassus Ave., San Francisco, CA
108 5
Ca++ antagonist/nitrate
9. Goldberg S, Reichek N, Wilson J, Hirshfeld JW Jr, Muller J, Kastor JA: Nifedinine in the treatment of Prinzmetal’s (variant) angina. Ai J Cardiol44:804, 1979. 10. Schroeder JS, Lamb IH, Ginsburg R, Bristow MR, Hung J: Diltiazem for long-term therapy of coronary arterial spasm. Am J Cardiol49:533, 1982. 11. Stone PH, Antman EM, Muller JE, Braunwald E: Calcium channel blocking agents in the treatment of cardiovascular disorders. Part II. Hemodynamic effects‘ and clinical applications. Ann Intern Med 93:886, 1980. 12. Anderson R: Cyclic AMP as a mediator of the relaxing action of papaverine, nitroglycerin, d&oxide, and hydralazine in intestinal and vascular smooth muscle. Acta Pharmacol Toxic01 32:321, 1973.
therapy for variant angina
13. Muller JE, Gunther SJ: Nifedipine therapy for Prinzmetal’s angina. Circulation 57:137, 1978. 14. Johnson SM, Mauritson DR, Willerson JT, Hillis LD: A controlled trial of verapamil for Prinzmetal’s variant angina. N Engl J Med 304:862, 1981. 15. Noether GE: Introduction to statistics: A nonparametric approach. Boston, 1971, Houghton-Mifflin Company, pp 147-9. 16. Zar JH: Biostatistical analysis. Englewood Cliffs, N.J., 1974, Prentice-Hall, Inc, pp 173-7. 17. Walker WS, Winniford MD, Mauritson DR, Johnson SM, Hillis LD: Atrioventricular junctional rhythm in patients receiving oral verapamil therapy. JAMA 249:389, 1983.
Reflex heart rate and blood pressure changes during ST segment elevation in patients with variant angina Responses of heart rate and blood pressure to transient myocardial ischemia were analyzed in patients with variant angina. Heart rate changes during ST segment elevation were examined by means of a Holter ECG monitoring system. All 27 ST segment elevations from 10 patients with anterior ischemia were accompanied by an increase in heart rate by 12 -+ 2 bpm (mean +- SEM, p < 0.001) at peak ST segment elevation. With inferior ischemia in nine patients, heart rate decreased significantly by 4 5 1 bpm (n = 28, p < 0.001). However, 9 of these 28 ST segment elevations showed a biphasic response of heart rate, that is, an initial increase and subsequent decrease. Such heart rate changes were not different between ST segment elevations with and without chest pain. With chest pain systolic blood pressure rose in anterior ischemla by 42 + 5 mm Hg (n = 10, p < 0.001) but fell in inferior ischemia by 22 + 8 mm Hg (n = 7, p < 0.05). We conclude that a different cardiovascular reflex occurs in response to inferior versus anterior ischemia and it is independent of chest pain. (AM HEART J 108:1273, 1984.)
Haruo Araki, M.D., Tsuyoshi Anan, M.D., Yasushi Koiwaya, M.D., Osamu Nakagaki, M.D., Akira Takeshita, M.D., and Motoomi Nakamura,
M.D.
Fukuoka, Japan.
Inhibitory cardiac receptors with vagal afferenta are known to be distributed predominantly in the inferoposterior wall of the left ventricle in dogs.le3 In patients with acute myocardial infarction, bradycar-
From the Research Institute Faculty Received accepted
of Medicine,
Kyushu
for publication April 10, 1984.
of Angiocardiology University.
Dec.
1, 1983;
revision
and Cardiovascular received
March
Clinic, 8, 1984;
Reprint requests: Haruo Araki, M.D., Research Institute of Angiocardiology and Cardiovascular Clinic, Faculty of Medicine, Kyushu University, 3-l-l Maidashi, Higashi-ku, Fukuoka 812, Japan.
dia and hypotension occur more frequently in inferior than in anterior infarction.” 5 Injection of contrast medium into the coronary artery supplying the inferior left ventricle also results in bradycardia and hypotension.6 It has recently been reported that reperfusion of the inferior ischemic area by means of thrombolysis may cause an inhibitory cardiovascular response.’ These results suggest the preferential distribution of inhibitory cardiac receptors in the inferoposterior wall of the left ventricle in humans. Perez-Gomez et al? reported that the heart rate 1273
November,
1274
Araki et al.
American
Heart
1984 Journal
1. Trendgrams of heart rate (HR) and ST segment,and real-time tracings of ECGs of two patients with anterior (upper panel) and inferior ischemia(lower panel). The patient in the upper panel wasasleep and did not have chest pain when ST segmentelevation developed.The patient in the lower panel woke up with chest pain on ST segmentelevation. Note that the heart rate increasedin anterior ischemia and decreasedin inferior ischemia during ST segmentelevation. Fig.
decreased with inferior ischemia but increased with anterior ischemia in patients with variant angina. They measured the sinus rate at only two points; before and during chest pain in their own patients, and also analyzed R-R intervals of the ECG at control and during ST segment elevation in many patients, which had been published by other investigators. In order to evaluate the exact manner of cardiovascular reflex in variant angina, however, it will be important to monitor the heart rate continuously during the attack. Furthermore, it will be interesting to examine the difference in the cardiovascular reflex during painful and painless myocardial ischemia in variant angina, since pain may evoke various cardiovascular reflexes.g We employed a Holter ECG monitoring system and examined the time course of heart rate changes in relation to ST segment elevation. In addition, we examined changes in blood pressure during ST segment elevation with anterior or inferior ischemia and also the effect of chest pain on changes in heart rate. METHODS Patients.
Changes in heart rate (sinus rate) during coronary spasm were analyzed in patients with variant
angina by means of a Holter ECG monitoring system. Nineteen hospitalized patients with variant angina documented by chest pain at rest and transient ST segment elevation on 12-lead ECG were used for the study. There were 16 men and three women, ranging in age from 46 to 70 years (59 * 2 years, mean + SEM). During repeated attacks of variant angina, nine of them showed ST segment elevation in inferior leads (II, III, and aVr) and the remaining 10 in anterior leads(I, aVL, and V, to V,). None of them had a history of myocardial infarction. Coronary angiography was done in 15 patients. Five patients showednormal coronary angiograms.Eight had coronary narrowing of less than 50% and two had 51% to 74% narrowing. Blood pressurewas measuredby sphygmomanometer on chestpain at rest in the supineposition and 30 to 60 minutes after the relief of chest pain, while the patient remained in the supineposition. Twelve-lead ECG wasrecorded on chest pain and the transient ST segment elevation was confirmed on measurementof blood pressure. Halter ECG. A 24-hour continuous recording of precordial bipolar ECG wasperformed by a calibrated magnetic tape system (Avionics, model 445-B or 446). One of the two leads was selected to mimic the ECG lead which showed the highest ST segmentelevation observed on a 12-leadECG during anginal attack, and another lead was placed on the opposite site to record the reciprocal ST
Volume
108
Number
5
Cardiovascular reflexes in variant angina 1275
segment depression. Precautions were taken to ensure that the electrodes were placed firmly to avoid motion artifacts. Patient activities and symptoms including the time of occurrence were entered in detail in the diary. Any drugs which might affect coronary spasm or the cardiovascular system had been discontinued for at least 2 days before the study. Analysis of the recorded magnetic tapes was done with the use of a dynamic electrocardioscanner (Avionics 660A). Trendgrams of ST segment and heart rate, averaging 15 beats, were obtained, where ST segmentdeviations were measuredat a point of 0.08 secondfrom the nadir of the S wave. These trendgrams were amplified and displayed on a pen oscillograph (San-Ei Instrument, type 8K 21). ST segmentelevation was consideredto be ischemic when the shift of the ST segmentwas transient, smooth, and was not accompanied by an abrupt change in QRS complex as previously reported.‘O All such ST segment elevations of 1 mm or greater were analyzed. Postural ST segment changes were excluded carefully. To evaluate changes in heart rate accurately during the attack of variant angina, we analyzed ST segment elevation only when the heart rate prior to the attack of coronary spasm was stable. ST segmentelevation with frequent extrasystoles or atrioventricular block of the second or third degreewas excluded. Statistics. Statistical analysis was done by means of Student’s t test for paired data. Values were expressedas mean of:SEM. RESULTS
Fig. 1 shows trendgrams of heart rate and ST segment in two patients who had ST segment elevation in the anterior leads of V3 through V, (upper panel) and the inferior leads of II, III, and aV, (lower panel) during the attack of variant angina. As shown in the upper panel, ST segment elevation occurred in a lead of CM, at 3:30 A.M. Mild depression of the ST segment followed the elevation. The heart rate increased rapidly from 60 to 88 bpm with ST segment elevation and returned to the control level after about 15 minutes when the ST segment was also reverted. This patient was asleep and did not have chest pain during the ST segment elevation. The patient in the lower panel, who had ST segment elevation in the inferior leads, woke up with chest pain at 4:40 A.M. The chest pain lasted for about 10 minutes and disappeared spontaneously. As shown in the trendgrams, heart rate decreased from 45 to 37 bpm during the ST segment elevation. The lowest heart rate was attained after the peak of ST segment elevation and then returned to the control level. The Heart
rate
changes
during
variant
angina.
real-time tracings of ECG are shown in the right panel.
Fig. 2 summarizes
changes in heart rate during ST
ANTERIOR
INFERIOR .-.
with pain
o--owithout
uain
PcO.OtN I CONTROL
I
ST ELEVATION
6
CoNrROL
I
ST EWATlON
2. Changesin heart rate during ST segment elevation in patients with anterior or inferior ischemia. The heart rate increasedin anterior ischemiaand decreasedin most patients with inferior ischemia.The sameresponses were observed during ST segment elevations with and without chest pain. Fig.
segment elevation in two groups having ST segment elevation in anterior or inferior leads during the attack of variant angina. The heart rate during the attack was measured at the peak of ST segment elevation. In anterior ischemia the heart rate increased during ST segment elevation in all 27 occasions and the difference was statistically significant (60 + 2 bpm at control and 72 + 3 at the peak ST segment elevation, p < 0.001). Among 28 ST segment elevations with inferior ischemia the heart rate decreased in 20, increased in four, and did not change in the remaining four. The difference was statistically significant (64 + 4 bpm at control, 60 + 3 at peak ST segment elevation, p < 0.001). Among 55 ST segment elevations, 32 were without chest pain. Changes in heart rate during painless ST segment elevations were similar to those in painful episodes. The heart rate increased with anterior ischemia but decreased in inferior ischemia even without chest pain (Fig. 2).
In inferior ischemia, 11 of 28 ST segment elevations were accompanied only by the decrease in heart rate. However, in nine ST segment elevations, the heart rate increased initially and then started to decline before the peak of ST segment elevation, showing the biphasic pattern of heart rate change.
November,
1276
Araki et al.
American
o-o o-o
with pain without pain
l
a
‘\
.A’
Heart
1984 Journal
at control and 160 + 5 during angina, n = 10, p < 0.001). In inferior ischemia five attacks from
five patients were accompanied by a fall in blood pressure, one attack from one patient by a rise, and the other one from the same patient by no change (128 + 7 at control and 106 + 7 during angina, n = 7, p < 0.05). Heart rate always increased during the ST segment elevations, which accompanied a rise in the blood pressure. Heart rate decreased in the ST segment elevations, which accompanied a fall in blood pressure. DISCUSSION
I
I
I
I
A
B
C
D
3. Initial increase in heart rate on ST segment elevation in patients with inferior ischemia.Abbreviations in abscissaare as follows: A = heart. rate at control or before ST segmentelevation; B = highest heart rate during ST segment elevation; C = lowest heart rate; D = heart rate when elevated ST segmentreturned to its control level. Peak ST segmentelevation is betweenB and C in all cases. Fig.
Fig. 3 summarizes changes in heart rate during these nine ST segment elevations. The lowest heart rate was observed after the peak ST segment elevation but before it returned to the control level in all patients. Again, even without chest pain, the initial increase in the heart rate was observed. Blood pressure changes during variant angina. Fig. 4 shows changes in systolic blood pressure, which were measured during chest pain with ST segment elevations with anterior or inferior ischemia. Blood pressure measured at 30 to 60 minutes after the relief of chest pain was used as control, which was not different from the average blood pressure of each patient measured at rest on days without angina. Blood pressure rose significantly during the attack in patients with anterior &hernia (117 + 3 mm Hg
Inferior versus anterior lschamia. The present study confirmed that inferior ischemia was accompanied by a decrease but anterior ischemia by an increase in heart rate in patients with variant angina. In addition to heart rate changes, we measured changes in blood pressure during attacks of variant angina in some patients and found that blood pressure fell with inferior ischemia and rose with anterior ischemia. These results indicate that changes in heart rate during variant angina were not elicited by arterial baroreceptors, since arterial baroreceptors would decrease heart rate in response to a rise in blood pressure or vice versa. Thus, these changes in heart rate during variant angina are likely to be elicited by activation of cardiac receptors. Initial heart rata increase. We recorded and analyzed changes in heart rate continuously throughout ST segment elevation. The results showed that nine ST segment elevations with inferior ischemia had an initial increase in heart rate before the decline. This initial increase in heart rate was observed during painless ST segment elevations as well as painful ones. These results suggest that the initial cardiac acceleration was not caused by chest pain but by some other reflexes. Coronary pathoanatomy. A difference in the coronary artery supplying the inferoposterior wall of the left ventricle, either the right or the left circumflex coronary artery, might influence the response of heart rate to ischemia. However, all seven patients with inferior ischemia in whom coronary angiography was performed had a prominent right coronary artery, which supplied the inferior left ventricle, but some of them had an initial increase in heart rate during ischemia. None of these patients with inferior ischemia had significant coronary lesions of more than 50% of luminal narrowing. Thus it appears that neither coronary lesions nor coronary anatomy affect heart rate or blood pressure responses to inferior &hernia. Cheat pain. It is well known that the somatic
Volume Number
108 5
Cardiovascular ANTERIOR
reflexes in variant angina
1277
INFERIOR l
: :b bb 0 b
? 0 $
l
p’o.!M
p-=0.05
I
I
I
I
CONTROL
CHESTPAIN
CONTROL
CHEST PAIN
Fig. 4. Changesin systolic blood pressure during chest pain attack with ST segment elevation. The systolic blood pressuredropped in five of sevenepisodesof inferior ischemiaand rosein all of the anterior ones.
sensation of pain occurring for many reasons alters heart rate and blood pressure.s In the present study, however, changes in heart rate during myocardial ischemia were independent of the existence of chest pain. This suggests that the cardiovascular responses occurring in variant angina are not elicited by somatic reflex caused by chest pain but by the activation of cardiac receptors themselves. However, more study will be needed to evaluate whether the cardiovascular reflex through the cardiac receptors is modified, to any extent, by chest pain. Coronary reperfusion. Recently, Wei et al.7 reported the cardiovascular reflex changes upon reperfusion of occluded coronary artery by means of thrombolysis in patients with acute myocardial infarction. They reported that the cardioinhibitory response occurred when the reperfused coronary artery supplied the inferior myocardium, and cardioacceleratwhen the anterior ing response occurred myocardium was reperfused. They postulated that the cardioinhibitory receptors were distributed mainly in the inferior myocardium and were activated by the reperfusion. Our results showed that heart rate decreased further after the elevated ST segment started to decline, and the lowest heart rate was attained between the peak ST segment elevation and the time when the ST segment returned to control level. From these results, it is possible to postulate that the cardioinhibitory reflex in variant
angina is activated not only by myocardial ischemia but also by its reperfusion. Clinical implications. Variant angina is known to accompany various kinds of arrhythmias such as ventricular tachyarrhythmias and atrioventricular block.1°-13 Preferential occurrence of atrioventricular block in inferior ischemia has been observed frequently.** lo,11,14Its underlying mechanism may be the cardioinhibitory reflex caused by the activation of cardiac receptors in inferior myocardium as evidenced by heart rate changes in our study. Variant angina seems to activate the sympathetic nervous system especially in patients with anterior ischemia. It will be important to know whether this sympathetic activation had any roles in the pathogenesis of ventricular tachyarrhytyhmias during the attack of variant angina.
REFERENCES
Jarisch A, Zotterman Y: Depressor reflexes from the heart. Acta Physiol Stand 16:31, 1948. Thames MD. Klonhenstein HS. Ahboud FM. Mark AL. Walker JL: Prefeiential distribution of inhibitory cardiac receptors with vagal afferents to inferoposterior wall of the left ventricle activated during coronary occlusion in the dog. Circ Res 43512, 1978. Zucker IH, Cornish KG: The Bezold-Jarisch reflex in the conscious dog. Circ Res 49:940, 1981. Webb SW, Adgey AAJ, Pantridge JF: Autonomic disturbance at onset of acute myocardial infarction. Br Med J 3:89, 1972.
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et al.
American
5. Scheinman MM, Thorburn D, Abbott JA: Use of atropine in patients with acute myocardial infarction and sinus bradycardia. Circulation 52:627, 1975. 6. Eckberg DL, White CW, Kioschos JM, Abboud FM: Mechanisms mediating bradycardia during coronary arteriography. J Clin Invest 54:1455, 1974. 7. Wei JY, Markis JE, Malagold M, Braunwald E: Cardiovascular reflexes stimulated by reperfusion of ischemic myocardiurn in acute myocardial infarction. Circulation 67:796, 1983. 8. Perez-Gomez F, Martin DeDios R, Rey J, Garcia Aguado A: Prinzmetal’s angina: Reflex cardiovascular responses during episodes of pain. Br Heart J 42:81, 1979. 9. Brown AM: Cardiac reflexes. In Bern RM, Sperelakis N, Geiger SR, editors: Handbook of physiology, Section 2, The cardiovascular system, vol 1, The heart. Bethesda, 1979, Waverly Press, Inc, p 667. 10. Araki H, Koiwaya Y, Nakagaki 0, Nakamura M: Diurnal
function patients
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14.
November, 1984 Heart Journal
distribution of ST-segment elevation and related arrhythmias in patients with variant angina: A study by ambulatory ECG monitoring. Circulation 67:995, 1983. Prinzmetal M, Kennamer R, Merliss R, Wada T, Bor N: Angina pectoris I A variant form of angina pectoris. Am J Med 27:375, 1959. Maseri A, Severi S, DeNes M, L’abbate A, Chierchia S, Marzilli M, Ballestra AM, Parodi 0, Biagini A, Distante A: “Variant angina: One aspect of a continuous spectrum of vasospastic myocardial ischemia. Am J Cardiol 42:1019, 1978. Kerin NZ, Rubenfire M, Naini M, Wajszczuk WJ, Pamatmat A, Cascade PN: Arrhythmias in variant angina pectoris: Relationship of arrhythmias to ST-segment elevation and R-wave changes. Circulation 60:1343, 1979. Botti RE: A variant form of angina pectoris with recurrent transient complete heart block. Am J Cardiol 17:443, 1966.
17,043 in
f with severe cEwo@c
To evaluate the mechanisms for improved left ventricular function with MDL 17,043 in patients with severe chronic heart failure, 24 patients were evaluated by simultaneous determlnat(on of hemodynamics by right heart catheterization and ejection fraction by computerized nuclear probe before and following intravenous administration of MDL 17,043 (mean cumulative dose 3.6 mg/kg). Following MDL 17,043, there was an increase in cardiac index (+62%), stroke volume index (+42%), and stroke work index (+66%), together with a decrease in pulmonary capillary wedge pressure (-46%), indicating improved left ventricular pump function. There was a marked reduction in systemic vascular resistance (-40%) and a modest reduction in arterial pressure, indicating decreased left ventricular outflow resistance. The ratio of peak systolic blood pressure to calculated left ventricular end-systolic volume tended to increase, but the change was not statistically significant. Despite a marked increment In stroke volume Index, ieft ventricular ejection time corrected for heart rate was shortened, suggestrng enhanced contractility. In the group as a whole, the calculated left ventricular end-diastolic volume remained unchanged, but it increased in 14 patients. Since pulmonary capillary wedge pressure fell in each patient, this suggests improved overall left ventricular distensibility. Thus, decreased left ventricular outflow resistance, and possibly increased contractlie function, and improved left ventricular diastolic compliance may all contribute to improved left ventricular pump function with MDL 17,043 in patients with severe heart failure. (AM HEART J 106~1278, 1964.)
Dean J. Kereiakes, M.D., Christian Viquerat, M.D., Peter Lamer, M.D., Elias H. Botvinick, M.D., Robert Spangenberg, M.D., Ph.D., Michael Buckingham, R.N., B.S., William W. Parmley, M.D., and Kanu Chatterjee, M.B., F.R.C.P. Sun Francisco, Calif.
From the Cardiovascular Division of the Department of Medicine, Nuclear Medicine Division of the Department of Radiology, and Cardiovascular Research Institute of the University of California, Francisco. This work was supported in part by a Grant-in-Aid Susan Schleicher Cardiology Research Fund; by
1276
an
the the San
from the Don and American Heart
Association D. Smith Received
Reprint Hospital, 94143.
Established Investigator Award (Dr. Botvinick); Fund, Inc.; and by the Fanny Ripple Foundation. for publication requests: University
June
4, 1984;
Kanu Chatterjee, of California,
accepted
July
by the George
10, 1984.
M.B., F.R.C.P., Room 1188 Moffitt 505 Parnassus Ave., San Francisco, CA