Hemodynamic and angiographic effects of prostaglandin E1 in coronary artery disease

Hemodynamic Prostaglandin

and Angiographic Effects of El in Coronary Artery Disease

Robert L. Feldman, MD, Barry Rose, MD, and Kathleen M. Verbust, RN

The effects of prostaglandin El (PGEI) were assessed in 24 patients with coronary artery disease. Quantitative coronary angiography was performed in 15 patients. PGEl was found to produce dilation of coronary stenoses (6 f 12% to intravenous PGEI, difference not significant, 19 f 22% to intracoronary PGEI, p
From the Department of Medicine, Division of Cardiology, University of Florida, and the Veterans Administration Medical Center, Gainesville, Florida. Manuscript received March 16, 1988; revised manuscript received and accepted June 7, 1988. Address for reprints: Robert L. Feldman, MD, Cardiac Catheterization Laboratory, The Heart Center, Ocala, Florida 32671.

698

THE AMERICAN

JOURNAL

OF CARDIOLOGY

VOLUME

62

lthough the atherosclerotic plaque plays a central role in all coronary artery disease (CAD) syndromes, the importance of coronary vasomotion, platelets and thrombus has recently also been recognized.1-3 Coronary spasm, platelet vessel wall interactions and intracoronary thrombus are crucial participants in acute ischemic syndromes such as unstable angina, acute myocardial infarction and sudden cardiac death. Prostaglandin Et (PGEt) has vasodilating and platelet aggregation inhibiting properties.4-7 In current clinical practice, PGEt is principally used to maintain patency of the ductus arteriosus in certain newborn infants with cyanotic congenital heart disease. PGEt has shown promise in the treatment of patients with unstable angina.* Used recently in patients with evolving acute myocardial infarction, intracoronary PGEt combined with streptokinase was shown to lead to a higher rate of successful coronary thrombolysis.9J l Intracoronary administration of nitroglycerin in these and other studies has not been shown to facilitate thrombolysis. Additionally, in an in vitro testing system, clot lysis by either tissue plasminogen activator or urokinase were accelerated by PGEt.12J3 In an animal model of acute myocardial infarction, PGEt (but not prostacyclin) has shown cytoprotection and a decrease in infarct size.14J5 This study more thoroughly assessesthe clinical, coronary angiographic and hemodynamic, and systemic hemodynamic effects of PGEt in patients with CAD.

A

METHODS

We studied 24 patients (22 men and 2 women, ages 43 to 69 years) using 2 protocols. In 15 patients with CAD undergoing diagnostic catheterization we evaluated the effects of intravenous PGEt on heart rate, aortic and pulmonary artery pressures and coronary artery diameters (group 1). In 9 other patients who were undergoing angioplasty we assessed the effects of PGEt during transient coronary occlusion (group 2). In all patients, vasoactive medications (P-adrenergic blockers, calcium antagonists and long-acting nitrates) were discontinued at least 18 hours before the study. Sublingual nitroglycerin was permitted up to 2 hours before the study to relieve angina attacks. Cardiac catheterization was performed in the fasting state and patients were premeditated with benadryl, 50 mg orally. No vasoactive medications were administered during catheterization before intravenous PGEt. After baseline heart rate, pressure and angiographic measurements in group 1 patients were obtained, a coronary stenosis(es) was selected for study. We used a low

osmolar contrast to minimize contrast-induced hemodynamic effects. Orthogonally paired (10 patients) or single-plane (5 patients) views of the left (12 patients) or right (3 patients) coronary arteries were obtained. Views were chosen to select those which showed the stenosis(es) in the most severe view and which avoided overlap of adjacent segments. After these angiograms were obtained, control hemodynamic values of heart rate and mean aortic and pulmonary pressures were recorded. An intravenous infusion of PGEl (Upjohn) was begun at a rate of 0.05 pg/kg/min through a peripheral vein. Fifteen minutes later we repeated the recording of hemodynamic values. Coronary angiograms in the same projection were also repeated. While the intravenous PGE, infusion was continued, a 0.065-pg bolus of PGEl diluted in 5 ml of normal saline was given directly into the proximal coronary artery through the diagnostic catheter. One minute later, recordings of hemodynamic values were repeated and a third set of coronary angiograms obtained. As the intravenous PGE, infusion was continued, a lOO-pg bolus of nitroglycerin was given directly into the coronary artery. We chose this dose after finding that it produced maximal dilation of epicardial vessels.16One minute later we recorded again the hemodynamic values and obtained a fourth set of coronary angiograms. After the nitroglycerin angiograms were completed, the PGEl infusion was stopped and the catheterization procedure completed in a routine fashion. Quantitative coronary angiography was performed with hand held calipers and tine images magnified approximately 5 times. Briefly, the left coronary artery (right anterior oblique view) was divided into 7 segments (left main; proximal, middle and distal segments of the anterior descending; and proximal, middle and distal segments of the circumflex) and the right coronary artery into 3 segments (proximal, middle and distal thirds).16 Coronary stenoses were measured in 2 views when orthogonal views were available at their minimal diameter. In the 9 patients in group 2, balloon angioplasty was carried out in the anterior descending in 6 patients, in the circumflex in 2 and in the right in 1. In patients undergoing angioplasty of the anterior descending or circumflex, a catheter capable of measuring regional coronary flow (thermodilution) was positioned at the junction of the great cardiac vein and anterior interventricular vein as described previously.17-*I Angioplasty was performed in a routine fashion in all patients using over-the-wire balloon dilation systems (USCI) which allowed measurement of distal coronary pressure. After several initial inflations to diminish the initial transstenotic pressure gradient to a low value, repeated control balloon occlusions (up to 70 seconds) were performed to assessthe reproducibility of hemodynamic change and time to ischemia. Ischemia was assessed by quantitating changes in the ST segments and T waves of electrocardiographic leads I, II and V2 or V5.17-*’ Before and during these balloon occlusions, we

TABLE I Effect of Prostaglandin Coronary

El and Nitroglycerin

on

Diameter Percent

Change

Prostaglandin

from Control

El

Nitroglycerin*

Route of Administration

IV Only

Wand

Segment stenosis+ Left main Anterior descending Proximal Middle Distal Circumflex Proximal (%) Middle (%) Distal (“7) Right Proximal Middle Distal

6f 0

12

19 f 22* lf3

24f 21* 6f5

0 2flO 5f 11

255 4f 13 13f22

10zt7* 16 f 15’ 39 f 233

oi4 Of8 2f6

6f 11 4f12 lOf15

15+8~ 21 f 15* 35 f 17*

0 0 0

IC

0 0 0

IC

11 f3 10*3 19f8

*I Nitroglycerin was adminlstered after intravenous and intracoronary prostaglandin El and thus these effects are cumulative of the 3 Interventions; f mean f standard deviation; * p <0.05 YScontrol. IC = intracoronary; IV = intravenous.

recorded the aortic, distal coronary and pulmonary capillary wedge pressures and coronary sinus, great cardiac vein and indicator temperature signals. After obtaining the control recordings, we began an intravenous infusion of PGEl at 0.05 pg/kg/min using a peripheral vein. If after 10 minutes the systolic aortic pressure was >lOO mm Hg and had not fallen by at least 10 mm Hg, the infusion was sequentially increased to 0.1 and 0.2 pg/kg/min. Once this decrease in aortic pressure had occurred and stabilized (& 5%) for at least 5 minutes, the balloon coronary occlusions were repeated and electrocardiographic and hemodynamic variables recorded. After these recordings were finished, the PGEl infusion was stopped, intravenous nitroglycerin begun and angioplasty completed in the usual fashion. Statistical analysis: Means f standard deviations were calculated for all variables. In group 1 an analysis of variance and an appropriate multiple comparison procedure were used to assessdifferences between the 4 study intervals. In group 2, a paired t test was used to compare control with PGEl values. Hemodynamic vaPues from the last control period recording and the last recording after PGEl were used for comparison. A p value <0.05 was considered significant. An important difference in the time to ischemia during repeat coronary occlusions was considered to be >6 seconds. Calculations: We calculated the percent change in coronary segment size as compared with the control angiogram. Coronary flows were calculated from the respective temperature signals. Total coronary resistance was estimated as mean aortic pressure divided by coronary sinus flow. An index of anterior region collateral resistance was calculated during anterior descending occlusion as the difference between mean aortic and distal coronary pressures and residual great cardiac vein blood flow.

THE AMERICAN

JOURNAL

OF CARDIOLOGY

OCTOBER

1. 1988

699

PGEl

IN CORONARY

ARTERY

TABLE II Hemodynamic Diagnostic Catheterization

Heart rate (beats/min) Mean aortic pressure (mm Hg) Mean pulmonary artery pressure

DISEASE

Findings

in Patients

Undergoing

Control

IV Only

IV and IC

IC Nitroglycerin*

69f14

74f14+

76f16+

76%15+

98 f 14

89 f 15t

85 f 15+

84 f 15+

19f7

17*7+

17&7+

16&6+

(mm W All values are mean f standard deviation. * Nitroglycerin was administered after intravenous and intracoronary prostaglandin El and thus these effects are cumulative of the 3 interventions; t p <0.05 vs control. All abbreviations as in Table I.

Important new electrocardiographic changes indicative of transient ischemia during coronary occlusion were defined as: (1) I1 mm of ST-segment elevation or depression; (2) new T-wave inversion; (3) normalization of previously inverted T waves. RESULTS Coronary angiographic findings: A summary of the percent change in coronary artery diameters of the various left coronary segments is listed in Table I. Seventeen different coronary stenoses were measured at their minimal diameter. Four of these stenoses dilated to intravenous PGEi, 12 after intracoronary PGEi (p <0.05 TIME

TO

COMPARABLE

REPEATED

10

20

30

FIRST

FIGURE (doflned

ISCHEMIA

CORONARY

40

OCCLUSION

1. Time to onset of transient by changes in the ST segment

DURING

OCCLUSION

50

60

>60

(SEC.)

myocardial ischemia and T wave) &ring

during the prostaglandin El period. The time to ischemia during the first control period occlusion was compared with values during subsequent occlusions. The time to ischemia was reproducible during the control period and was usually longer in only 3 of the 8 patients who developed ischemia.

700

THE AMERICAN

JOURNAL

OF CARDIOLOGY

VOLUME

62

compared with control or intravenous PGEi) and 13 after intracoronary nitroglycerin (p -CO.05 compared with control intravenous PGEi, difference not significant when compared with intracoronary PGEi). Dilation of coronary stenoses was maximal after intravenous PGEt alone in 1 stenosis, after addition of intracoronary PGEt in 6 stenoses and after nitroglycerin in 8 stenoses. Two stenoses showed no dilation at any time. Regarding the angiographically normal segments of the left and right coronary artery, usually greater and more consistent dilation was seen in segments located further from the left or right ostium, as has been reported previously.16 In the left main segment, intravenous PGEi did not dilate any of the 12 segments. Addition of intracoronary PGEi led to dilation of 3 segments (difference not significant) and intracoronary nitroglycerin to further dilation of 6 segments (p <0.05 compared with control or intravenous PGEi, (difference not significant when compared with intracoronary PGEt). In the proximal anterior descending, 2 of 11 segments dilated and 1 narrowed slightly after intravenous PGEi (difference not significant). Addition of intracoronary PGEi led to further dilation in 2 segments (difference not significant), whereas intracoronary nitroglycerin led to further dilation of 8 segments (p <0.05) compared with either intravenous or intracoronary PGEt or control). In the middle anterior descending, 3 of 12 segments dilated and 1 narrowed (difference not significant) after intravenous PGEi. Addition of intracoronary PGEt led to further dilation of 1 segment (difference not significant), whereas intracoronary nitroglycerin led to further dilation of 10 segments (p -CO.05 compared with control and intravenous and intracoronary PGEt). In the distal anterior descending, 2 of 10 segments dilated to intravenous PGEi (difference not significant). Addition of intracoronary PGEi led to further dilation in 3 segments (difference not significant) and intracoronary nitroglycerin dilated all 10 segments as compared with control (p <0.05). In 1 segment this dilation was maximal after intracoronary PGEi and in the other 9 it was maximal after nitroglycerin (p <0.05 compared with either intravenous or intracoronary PGEi). Specific changes in coronary diameters of the 3 circumflex artery and 3 right artery segments after intravenous (all differences not significant) and intracoronary (all differences not significant) PGEt and intracoronary nitroglycerin (all p <0.5) were similar to changes in the left main and anterior descending artery segments. Clinical and hemodynamic findings: The hemodynamic findings from the 15 patients in group 1 are listed in Table II. Intravenous PGEi (0.05 pg/kg/min) led to vasodilation as both mean aortic and pulmonary pressures declined slightly (both p (0.05). This was accompanied by a reflex-mediated increase in heart rate (p <0.05). No further significant hemodynamic changes occurred after intracoronary PGEi (0.65 fig) or intracoronary nitroglycerin (100 pg). In the patients undergoing coronary angioplasty (group 2), the time to comparable ischemia (Figure 1)

was consistently increased by intravenous PGEi (0.13 f 0.05 pg/kg/min, mean f standard deviation) in only 3 of the 8 patients who developed ischemia during coronary occlusion (difference not significant). Intravenous PGEi did not lead to earlier development of ischemia in any patient. Changes in mean aortic, distal coronary and pulmonary capillary wedge pressures in these 9 patients were similar to those in group 1 and are listed in Table III. All pressures decreased and were accompanied by a reflex-mediated increase in heart rate (all p <0.05). Coronary sinus blood flow usually was not changed prior to coronary occlusion (difference not significant); thus, the calculated coronary vascular resistance decreased (6 of 7 patients, p <0.05). During coronary occlusion flow in the affected region usually was also preserved (p 0.05 pg/ kg/min) or after a longer duration of infusion at the dose we assessed (0.05 pg/kg/min) is unknown. Large doses of systemically administered PGEi would probably not be tolerated by many patients because of hypotension. The hemodynamic changes of a decrease in aortic, pulmonary artery and pulmonary arterial wedge pressures and the reflex-mediated increase in heart rate confirm observations of other studies.8,9J4J5 Dilation of the coronary microcirculation was observed as coronary sinus flow was preserved as aortic pressure fell. Thus, total coronary resistance declined. Additionally, during coronary occlusion the residual flow was usually preserved while the estimated collateral resistance decreased. Overall duration to ischemia during acute, transient coronary occlusion was not altered despite these potentially beneficial hemodynamic effects. However, 3 of the 8 patients did take longer to redevelop

TABLE Undergoing

III

Hemodynamic Findings Coronary Angioplasty

in the

Nine Patients

Control

IV PGEl 79f

71 f 14”

Heart rate (beats/min) Mean aortic pressure

lolfll*

(mm W Mean distal coronary pressure (mm Hg) Mean pulmonary capillary wedge pressure (mm Hg) Great cardiac vein flow (ml/min)+ Coronary collateral resistance (mm Hg/ml/min)+ Coronary sinus flow (ml/min)* Total coronary vascular resistance (mm Hg/ml/min)*

13

88f12

30 f IO’

25f5

26 f 7*

19f5

37 f 20’

36f25

3.2 f 2.9*

2.9 f 2.6

130 f 41

126f42

0.9 f 0.3*

0.8 f 0.3

* p <0.05 control YSintravenous PGE1;i values only from the 6 patients undergoing proximal anterior descending artery angioplasty; *values before transwt balloon occlusion, other values in this table are during coronary occlusion. All abbreviations as in Table I.

ischemia after intravenous PGEi. Because the indexes of global myocardial oxygen demand were reduced and residual total regional flow was preserved, we expected in most patients clinical improvement in time to ischemia similar to our prior observations after propranolol and nicardipine.*9,2c Perhaps PGEi led to a lower portion of flow to the endocardium in some of them. To our knowledge, no other vasoactive medication has a similar angiographic or hemodynamic profile. The angiographic effects were opposite to those reported after intracoronary acetylcholine-which dilates angiographically normal segments but constricts narrowed ones.22 Perhaps high local concentrations of PGEi lead to an increase in cyclic AMP and endothelial-dependent relaxant factor at the stenosis (where concentrations of these vasodilators are usually low) but to no change in coronary segments (where their concentrations are normal) . One limitation of this study was that cardiac output was not measured. However, the decline in aortic, pulmonary arterial, distal coronary and pulmonary arterial wedge pressures, the small increase in heart rate and the declines in total coronary and estimated collateral resistances suggest generalized, nonselective vasodilation. A second limitation was that the order of drug administration was fixed. If intracoronary PGEi or nitroglycerin was administered alone, the effects on coronary diameters might have differed. Nitroglycerin was administered in this study to document the potential that normal and narrowed segments have to dilate and to produce maximal dilation. It is possible (but unlikely), that PGEi plus nitroglycerin led to further dilation as compared with that produced by nitroglycerin alone. In addition, electrograms measured from the angioplasty wire may be more sensitive to regional ischemia and thus could have been used to complement the surface electrocardiogram. These data show that PGEi can be given safely to patients with CAD. PGEi had no detrimental effect

THE AMERICAN

JOURNAL

OF CARDIOLOGY

OCTOBER

1, 1988

701

PGEi

IN CORONARY

ARTERY

DISEASE

during myocardial ischemia induced by repeated, temporary balloon coronary occlusion. BeCause other studies have suggested that PGE, may facilitate thrombolysis, this prostaglandin may become an important medication in patients with ischemic heart disease. We believe that further studies of adjunctive therapy with PGEl in patients with acute myocardial infarction or unstable angina who receive a lytic agent are appropriate. Our studies suggest that PGEl should be safe in such patients. RtFERENCES 1. Feldman RL. Coroi~ary thrombosis, coronary spasm and coronary atheroscle rosis and speculation on the link between unstable angina and acute myocardial infarction. Am J Cardiol 1987;59:1187-1190. 2. Hirsh PD, Campbell WB, Willerson jT, Hillis LD. Prostaglandins and ischemic heart disease. Am J Cardiol 1981;71:1009-1026. 3. Pitt B, Shea M, Romson JL, Lucchesi B. Prostaglandins and prostaglaridin inhibitors in ischemic heart disease. Ann Intern Med 1983,99:83-92. 4. Popat KD, Pitt B. hemodynamic effects of prostaglandin El infusion in patients with ricute myocardial infarction and left ventricular failurti. Am Heart J 1982;103:485-489. 5. Nakano J, McCurdy JR. Cardiovascular effects of prostaglandin El. J Pharmacol Exp Ther 1967;156:538-547. 6. Nutter DO, Crumly HJ. Canine coronary vascular and cardiac responses to the prostaglandins. Cardiouasc Res 1972,6:217-225. 7. Bloor CM, White FC, Sobel BE. Coronary and systemic haemodynamic effects of prostaglandins in the unanaesthetized dog. Cardiovasc Res 1973;7:156-166. 8. Siegel RJ, Shah PK, Nathan M, Rodriguez L, Shell WE. Prostaglandin E, infusion in unstable angina: effects of angina1 frequency and cardiac function. Am Heart J 1984:108:863-868. 9. Sharma B, Wyeth RP, Gimenez HJ, Franciosa JA. Intracoronary prostaglandin El plus streptokinase in acute myocardial infarction. Am J Cardiol 1986:58:1161-1166.

702

THE AMERICAN

JOUPNAL

OF CARDIOLOGY

VOLUME

62

10. Sharma B, Wyeth RP, Heinemann FA, Kolath G. Adjunctive use of intracoronary prostaglandin El with streptokinase enhances intracoronary thrombolysis (abstr). Circulation 1987:76:IV-181. 11. Sharma B, Wyeth RP, Heinemann F, Bissett JK. Addition of intracoronary prostaglandin El to streptokinase improves thrombolysis and left ventricular funo tion in acute myocardial infarction (abstr). JACC 11:104A. 12. Vaughan D, Plavin S, Schafer A, Loscalzo J. Prostaglandin El markedly accelerates thrombolysis by tissue plasminogen activator (abstr). Circulation 1987;76:IV-338. 13. Teires W, Beythien C, Kupper W, Bleifeld W. Thrombolysis with urokinase alone and in combination with PGE, in a model of combined platelet and fibrin thrombus formation (abstr). Circulation 1987;76:IV-104. 14. Jugdutt BI, Hutchins GM, BulkIey BH, Becher LC. Dissimilar effects of PGE, and PGE2 on myocardial infarct size after coronary occlusion in conscious dogs. In: Samuelssob B, Ramwell PW, Paoletti R, eds. Advances in Prostaglandin and Thromboxane Research. New York: Raven Press, 1980;675-677. 15. Jugdutt BI, Hutchins GM, Bulkley BH, Becher LC. Dissimilar effects of prostacyclin, prostaglandin El and prostaglandin E2 on myocardial infarct size after coronary occlusion in conscious dogs. Circ Res 1981;49:685-700. 16. Feldman RL, Marx JD, Pepine CJ, Conti CR. Analysis of coronary responses to various doses of intracoronary nitroglycerin. Circulation 1982;66:321&327. 17. Feldman RL, Pepihe CJ. Evaluation of coronary collateral circulation in conscious humans. Am J Cardiol 1984;53;1233-1238. 18. Macdonald RG, Hill JA, Feldman RL. ST segment response to acute coronary occlusion: coronary hemodynamic and angiographic determinants of direction of ST segment shift. Circulation 1986;74:973-979. 19. Feldman RL, Macdonald RG, Hill JA, Limacher MC, Conti CR, Pepine CJ. Effect of propranolol on myocardial ischemia occurring during acute coronary occlusion. Circulation 1986;73:727-733. 20. Feldman RL, Maedonald RG, Hill JA, Pepine CJ. Effect of nicardipine on determinants of myocardial ischemia occurring during acute coronary occlusion produced by percutaneous transluminal coronary angioplasty. Am J Cardiol 1987,60:267-270. 21. Feldman Ri, Joyal M, Conti CR, Pepine CJ. Effect of nitroglycerin on coronary collateral flow and pressure during acute coronary occlusion. Am J Cardiol 1984:54:958-963. 22. Ludmer PL, Selwyn AP, Shook TL, Wayne RR, Mudge GH, Alexander RW, Ganz P. Paradoxical vasoconstriction induced by acethylcholine in atherosclerotic coronary arteries. N Engl J Med 1986:315:1045-1051.