- Email: [email protected]
Effects of nitroglycerin and nifedipine on coronary and systemic hemodynamics during transient coronary artery occlusion
Jaffe et al.
American
Blood Substitutes, Kyoto. Amsterdam: Excerpta Medica, 1978285-93. 38. Nunn G, Dance G, Peters J, Cohn L. Effect of fluorocarbon exchange transfusion on myocardial infarction size in dogs. Am J Cardiol 1983;52:203-5. 39. Forman M, Bingham S, Kopelman H, et al. Reduction of infarct size with intracoronary perfluorochemical in a canine preparation of reperfusion. Circulation 1985;71:1060-8. 40. Faithful1 NS, Fennema M, Essed CE, et al. Collateral oxygenation of the ischemic myocardium: the effect of viscosity and oxygen carrying fluorocarbons. In: Advances in blood substitute research. New York: Alan R. Liss, Inc., 1983:229.
June 1988 Heart Journal
41. Tokioka H, Miyazaki A, Fung P, Rajagopalan RE, et al. Effects of intracoronary infusion of arterial blood or FluosolDA 20% on regional myocardial metabolism and function during brief coronary artery occlusions. Circulation 1987; 75:473-81. 42. Spears JR, Serur J, Bairn DS, Grossman W, Paulin S. Myocardial protection wiht Fluosol-DA 20% during prolonged coronary balloon occlusion in the dog [Abstract]. Circulation 1983;68(Suppl 111):317.
Effects of nitroglycerin and nifedipine coronary and systemic hemodynamics trawient coronary artery occlusion
on during
Nitroglycerin (NTG) and nifedipine (NIF) have the potential to augment coronary blood flow in addition to reducing peripheral determinants of myocardial oxygen demand as a synergistic protective mechanism during ischemia. To examine these effects, systemic and coronary hemodynamic responses were measured continuously before and during brief periods of myocardial ischemia induced by left anterior descending coronary balloon occlusion in 26 patients undergoing angioplasty (PTCA). Data were compared for two matched occlusion periods, one control and one “drug” occlusion. In 17 patients (NTG group), 200 pg of intracoronary NTG was given immediately before coronary occlusion. In nine patients (NIF group), 10 mg of sublingual NIF was given 15 minutes before the “drug” occlusion. NTG significantly b.ut transiently redqced ‘mean arterial pressure (91 ? 11 to 62 i 15 mm Hg, p < 0.05) and augmented basal coronary blood flow (95 + 36 to 127 * 54 ml/min, p < 0.05) but did not alter great vein blood flow (59 + 29 vs 61 + 29 ml/min) or coronary occlusion pressure (26 + 7 to 24 + 7 mm Hg) during ischemia. NIF sigtilflcantly reduced systolic, diastolic, and mean arterial pressure (119 + 21 to 95 2 6 mm Hg, p < 0.001) and heart rate-pressure product from control. NIF maintained basal great vein blood flow (125 f 41 to 106 + 57 ml/min) during reduced myocardial oxygen demand, but did not affect great vein blood flow (73 + 29 to 79 f 37 ml/min) or coronary occlusion pressures. during ischemia. Neither agent prolonged the time to ischemic. ST segment alteration after the 50 to 60 second coronary flow occlusion periods. These data suggest that during the initial minutes of myocardial ischemla due to coronary occlusion,. neither the coronary nor peripheral hemodynamic effects of the two vasodilators significantly improved regional coronary blood flow responses or ECG signs of myocardial ischemia. During PTCA, the beneficial effects of these agents most likely occur through mechanisms such as spasmolytic action, or indirectly by reduction of myocardlal oxygen demand, more than directly augmenting coronary blood flow or collateral supply. (AM HEART J 1988;115:1164.)
Morton J. Kern, M.D., Ubeydullah Deligonul, M.D., Arthur Labovitz, M.D., Gregory Gabliani, M.D., Michel Vandormael, M.D., and Harold L. Kennedy,
M.D.
St. Louis, MO.
From the Medicine. Received
Department for publication
Reprint requests: Morton tory, St. Louis University MO 63104.
1164
of Cardiology,
St.
Louis
Dec. 22, 1987; accepted J. Kern, Medical
University
School
of
Feb. 1, 1988.
M.D., Cardiac Catheterization Center, 1326 S. Grand Blvd.,
LaboraSt. Louis,
. A controlled model of transient myocardial ischemia in man with coronary balloon occlusion permits examination of systemic and coronary hemodynamic responses to drugs that are commonly used to reduce myocardial ischemia. Nitroglycerin (NTG)
Volume 115 Number 6
has a predominant mechanism of vasodilation acting to decrease peripheral determinants of myocardial oxygen demand more than to augment coronary perfusion.’ Intravenous NTG2 and propranolol,3 intracoronary nifedipineP intracoronary propranoloI,5 and nicardipine6 have been demonstrated to produce salutary effects on hemodynamic variables and changes in left ventricular function associated with ischemia induced during transient coronary artery balloon occlusion. Nifedipine, with potent coronary and peripheral vasodilating action, has been proposed4 as a regional cardioplegic agent permitting prolonged coronary occlusion while minimizing indices of myocardial ischemia. Few studies have provided information on regional coronary blood flow alterations with these agents during ischemia. Whether the transient, but marked, coronary vasodilation induced by intracoronary NTG or the combined systemic and coronary effects of nifedipine favorably alter regional coronary blood flow or reduce myocardial ischemia after transient reduction or cessation of coronary flow in man is unknown. Accordingly, the effects of NTG and nifedipine during transient coronary artery balloon occlusion were studied, examining the alterations in regional coronary blood flow, systemic hemodynamic responses, and ischemic ECG changes during the initial minutes of myocardial ischemia. METHODS Patient population. Patients were selected from those undergoing routine percutaneous transluminal coronary angioplasty (PTCA) with suitable left anterior descending stenoses (>60% stenosis by visual estimation of two experienced angiographers). Each patient demonstrated some objective evidence of myocardial ischemia despite medical therapy. The protocols were approved by the Human Subjects Committee of the Institutional Review Board of St. Louis University School of Medicine. All patients gave written informed consent. Patients with recent (
Nitrate
and nifedipine
effects during
PTCA
1165
through a left antecubital vein. The distal. thermistor was positioned close to the juncture with the anterior interventricular vein. The proximal thermistor in most cases was situated at least 2 cm from the coronary sinus ostia to avoid right atrial-coronary sinus reflux. The ECG was recorded with one or two simultaneously recorded leads (II and V, or V,) continuously during the study. Pulmonary artery pressure was recorded in 14 patients with a balloon-tipped flotation catheter introduced through the femoral vein. PTCA was performed in a routine fashion as previously reported,7 with the use of a No. 8 French femoral arterial sheath and No. 8 French left coronary guiding catheter. Appropriately sized (2.0 to 3.5 mm diameter) angioplasty balloon catheters (USC1 Division of C. R. Bard, Billerica, Mass., and Advanced Cardiovascular Systems, Inc., Temecula, Calif.) and steerable guidwires were used. The guiding and balloon catheters were cleared of contrast and were flushed with saline to record distal coronary and aortic guiding catheter pressures continuously with the ECGs and simultaneous regional and total coronary sinus blood flow. When stable thermodilution coronary signals had been obtained, the angioplasty balloon was inflated to between 6 and 8 atm of pressure and 45 to 60 seconds later deflated, recording data during the hyperemic period for another 60 to 90 seconds. Absolute coronary occlusion (wedge) pressure was recorded in those patients with satisfactory gradients to estimate the presence of recruitable or pot,ential collateral suppl~.~-*O Initial balloon dilatations (usually one or two) were performed for clinical purposes and to establish relatively stable baseline coronary flow and translesional gradients before any intervention. Subsequent coronary occlusions were matched, one for control and one for drug evaluation. At least a 3-minute equilibration period was observed between balloon occlusions to minimize residual ischemia. In patients with ECG changes, the time from coronary occlusion to 1.0 mm ST depression or elevation or new T wave inversion in either of the two ECG monitoring leads was recorded. Although patients were asked to grade the severity of chest pain, this late indicator of ischemia after premeditation was felt to be inconsistent and was therefore not analyzed. Study protocol. For the NTG occlusion (17 patients), while continuously recording hemodynamic, ECG, and coronary flow signals, 200 kg of NTG was given through the guiding catheter into the left coronary artery, and within 10 seconds balloon inflation was performed as in the preceding occlusions. For the nifedipine occlusion (nine patients), 10 mg of sublingual nifedipine was given after the control occlusion. After a l&minute equilibration period, the drug occlusion measurements were obtained. In seven patients, duplicate occlusions prior to drugs were performed to establish the reproducibility of repeated occlusions on coronary hemodynamic responses. Data analysis. Regional coronary thermodilution flow values were calculatd by the methods of Ganz et al.” and Pepine et a1.12The great cardiac vein efflux represents anterior left ventricular regional flow supplied predomi-
1166 Table
Kern
et al.
American
June 1999 Heart Journal
1. Clinical, angiographic, and hemodynamic data LAD %
NTG
Sex
L VEF
66 32 45 58 51 63 74 67 57 75 64 56 67 45 56 48
M M F M M M M F M F M F M M M M M
76 87 70 78 69 52 70 59 64 N 61 82 56 N 49
LVWM
Pre
Post
95
43 36 15 25 15 29 20 20 15 20 20 20 40 15 24 20
group
2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 M k SD NIF
Age
group 1 2 3 4 5 6 8 9
M + SD
41 57 + 12
59 54 63 63 60 57 51 63 63 59 + 4
M M M M M M M M M
N
63 67 ii 11
N 76 59 N 77 76 54 N 62 67 -r- 10
AH NL NL NL IH NL AH IH NL NL NL NL NL IH NL AH AH
AH NL NL NL NL NL AH NL NL
AH = anterior hypokinesia; F = female; IA = inferior akinesis; IH = inferior hypokinesis; LAD % = percent artery pre- and post-PTCA; LVEF = left ventricular ejection fraction (N = ectopy precluded precise NIF = nifedipine; NL = normal; NTG = nitroglycerin; M = SD = mean ? 1 standard deviation.
nantly by the left anterior descending coronary artery. Coronary resistance was calculated as mean arterial pressure divided by great cardiac vein flow. The coronary hyperemic response was calculated as percent of basal flow increases [(peak flow - basal flow)/basal flow) X 1001. Data were analyzed by one-way analysis of variance. When significant differences were indicated, comparisons of the study section means were made with Duncan’s multiple range F statistic for multiple comparisons.*3 Comparisons between groups were made with nonpaired t test. Probability (p) values <0.05 were considered significant. RESULTS
Clinical and angiographic data are summarized on Table I. Mean left ventricular ejection fraction was similar for both NTG and nifedipine groups (67 f 11% , 67 + 10%). In the NTG and nifedipine groups, respectively, 11 and 5 patients were receiv-
75 80 80 95 70 85 70 80 65 80 95 93 80 83 90 80 82 L 9
25 24 f
9
80 83 86 80 87 95 78 66
10 17 19 18 36 50 29 15
77 81 L 8
24 24 of- 12
narrowing of left anterior descending coronary %); LVWM = left ventricular wall motion;
ing beta blockers at the time of study; 16 and 7 patients were receiving a calcium channel blocker prior to study. Four patients in the NTG group and two patients in the nifedipine group had prior myocardial infarction with anterior left ventricular wall motion abnormalities. There were no clinical or hemodynamic differences between the patients with anterior left ventricular wall motion abnormalities compared to those with normal left ventricular wall motion who were included in the analysis. No patient had angiographically visible collateral supply to the left anterior descending coronary artery. Significant ECG changes during coronary occlusion occurred in 13 patients in the NTG group and in six patients in the nifedipine group. Satisfactory translesional pressure measurements could be obtained in 11 patients in the NTG group and in nine patients in the nifedipine group. The durations of coronary
Volume 115 Number 6
Table
Nitrate
and
nifedipine
II. Systemic and coronary hemodynamics during coronary occlusion Control No.
Group
Base
1
1
Hyperemia
1
Base
2
during
--_~-Drug
occlusion occ
effects
1167
PTCA
- --
occlusion
NTG*
occ
2
Hyperemia
2 -
.GVF GVR MAP SYS DIA PAS PAD HR HR*SYS
17 9 17 9 17 9 17 9 17 9 7 7 7 7 17 9 17 9
NTG NIF NTG NIF NTG NIF NTG NIF NTG NIF NTG NIF NTG NIF NTG NIF NTG NIF
90 125 1.13 1.05 90 119 115 161 70 84 26 28 10 10 74 62 8744 10137
* ct * -t 2 k If: k ++ t + + k k k rf+
31 41” 0.47 0.39 10 21b 21 28b 10 13b 11 7 5 2 16 9 2508 2700
59 73 1.70 1.86 86 112 107 143 71 90 33 36 18 16 76 67 8164 9697
+ 29 f 29 f 0.66 k 1.07 + 13 -+ 18b * 22 +- 25b k 11 +- 17b k 14 rt 11 k 10 +- 7 + 17 + 7 k 2634 f 2532
121 160 0.81 0.85 89 120 118 160 71 84 30 33 12 14 73 65 8685 10450
+ + f f
40’ 63 0.24’ 0.33
+ 11
-c +!c +_ f k + k -c c k k +
21b 23 28b 11 14 12 8 7 3 17 8 2951 2699
95 106 1.12 1.07
k f + iY
91 *
95 121 128 67 72 27 28 12 12 72 67 8799 8474
k ++ f 3~ c f +k I r k k
38 57 0.54 0.40 11
8d 18 21d 13 10 10 8 5 6 16 7 2401 1368d
127 I 45' 0.79 i 0.28 88 I13 117 c 17 67 + 17 29 i 11 12 k 6 71 !I 13 8463 k 2282 -
61 79 1.59 1.52 82 93 104 119 67 77 30 32 15 15 79
AZ 29 + 37 t 0.69 t 1.07 L 15. + 11'9 * 20 + 190 t 15 2 7 iI 17 -e 9 t- 13 -t 6 3: 17
71 t
8264 8393
6
t 2808 i 141fid
114 134 0.82 0.84 87 98 112 131 66 75 25 31 12 13 76 68 8538 8876
z t t +
35 55 0.26' 0.33
r 13
" t t t t t r I i i t + +-
9" 15 21d,” 13 a 12 8 7 4 16 8 2436 1543’
-.--._-_-~~ --.-__ Base = baseline value; DIA = diastolic pressure (mm Hg); GVF = great cardiac vein blood flow (mUmin); GVR = great cardiac vein resistance (units); HR = heart rate (beats/min); HY*SYS = heart rate-pressure product (mm Hg X beats/mm-I); hyperemia = values taken at peak blood flow responses after release of occlusion; MAP = mean arterial pressure (mm Hg); NIF = nifedipine; NTG = intracoronary nitroglycerin; Occ = end coronary occlusion values; PAD = pulmonary artery diastolic pressure (mm Hg); PAS = pulmonary artery systolic pressure (mm Hg); SYS = systolic pressure (mm Hgl. a = p < 0.05 vs NTG group; b = p < 0.01 vs NTC group; C= p < 0.05 vs baseline; d = p < 0.01 YS control. ‘NTG = nitroglycerin was given via intracoronary route after new baseline; nifedipine was given 15 minutes before baseline 2
occlusions were matched (55 + 15 and 54 f. 18 seconds) and similar for both groups for both the control and drug occlusions. Systemic hemodynamics (Table II). Intracoronary NTG reduced mean arterial pressure (91 f 11 to 82 + 15 mm Hg, p < 0.05) without significant alterations in heart rate, heart rate-systolic blood pressure product, or pulmonary artery pressures. In contrast, the nifedipine group had high control occlusion period mean arterial, systolic, and diastolic pressures, which were significantly reduced after drug administration. Heart rate-pressure products were also significantly reduced by nifedipine administration. Coronary hemodynamic responses (Table II). Basal great vein flow increased 36% (95 + 38 ml/min to 127 + 54 ml/min, p < 0.05) in response to intracoronary NTG. However, NTG did not alter great vein flow (59 + 29 vs 61 * 29 ml/min) during transient ischemia. For patients receiving nifedipine, there were no significant differences in great vein flow at baseline (in Table II; Base 1 before drug 125 + 41 to Base 2 after drug 106 + 57 ml/min), indicating that despite a significant decline in determinants of myocardial oxygen demand, nifedipine-induced vasodilation maintained basal coronary blood flow. Great vein
flow was similar for both the control and drug occlusions (73 + 29 vs 79 f 37 ml/min) for nifedipine patients during transient myocardial ischemia. The time to ST segment change was similar for the control and drug occlusions for both NTG (27 + 12 vs 26 + 7 seconds) and nifedipine (24 t- 14 vs 33 & 10 seconds) groups (Table III). The initial translesional gradients for the NTG group were slightly higher for the control occlusion. The absolute coronary occlusion pressures for both control and drug periods were similar (25 k ‘7, 24 rt 7 mm Hg). The translesional gradients were higher for the nifedipine group than for the NTG group, and in some patients, gradients persisted despite adequate angiographic results after PTCA. Patient No. 8 had no residual gradient after the clinical inflations. Dilations were performed to improve the angiographic appearance of the lesion. One patient (No. 7) had a persistent large gradient due to dissection that would not be ameliorated after repeated dilations, and he went to elective coronary bypass surgery in the following week. Elevated (>30 mm Hg) coronary occlusion (wedge) pressures suggested recruitable collateral supply in three patients in each group. The control coronary occlusion pressures were 25 ? 7 and 24 + 7 mm Hg for the two
June 1998
1168
Kern
et al.
American
Heart Journal
III. Coronary gradients, absolute coronary occlusion pressures, and time to ischemic ST segment change during transient coronary occlusion
Table
Initial gradient (mm Hd Pt no.
COFOnaFy occlusion wedge pressure (mm f&J
Final gradient (mm W
Time to ST (seconds)
Control
Drug
Control
Drug
Control
Drug
Control
Drug
36 30 32 36 20 32 12 18 18 36 30
22 18 32 28 20 10 0 12 0 22 22 -
30 20 32 28 20 0 0 12 0 22 22
20 16 32 28 18 10 0 0 0 22 20 -
30 20 20 32 28 -
25 20 20 35 22 -
25 18 20 20 38
20 20 18 20 38 -
20 25 NC 20 40 60 NC 20 20 20 20 15 35 30 25 NC
35 30 NC 20 25 20 NC 35 40 15 25 NC 25 20 25 NC
NTG 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 M + SD
-
17
17
L 25 f
18
7
NC 27 f
257
12
NC 26 + 7
NC 30 30 NC 25 NC NC 30 50 33 + 10
NIF 1 2 3 4 5 6 7 8 9 M f
40 25 40 30 42 40 86 0 SD
Gradient = aortic-coronary *p < 0.05 vs control.
51 39 f
23
balloon
45 24 30 30 22 32 71 0
38 32 40 50 40 42 100 0
43 33 F 19
43 43 k 26
pressures;
NC = no changes
observed;
groups, respectively, and were unchanged after drug administration. To assess reproducibility, repeated coronary occlusions without drug intervention in a subset of patients produced similar coronary and hemodynamic responses (Table IV). DISCUSSION
This study provides data on the systemic and coronary hemodynamic effects of two commonly used vasodilators during experimental human myocardial ischemia of complete, but transient, coronary occlusion. Both NTG and nifedipine have been proposed”, 7 as regional cardioprotective agents during coronary angioplasty occlusion. Nifedipine (0.2 mg), given into the left main coronary artery imme-
48 28 30 30 38 40 82 0 43 38 f (-)
22
13 30 24 24 34 15 20 31
15 29 16 14 29 16 12 27
NC 30 20 15 15 NC NC 15
23 24 ? 7
28 21 * 7
50 24 k 14
= no data; NTG
= nitroglycerin;
NIF
= nifedipine.
diately preceding coronary occlusion for 45 seconds, produced a regional cardioplegic effect, increasing poststenotic flow and suppressing lactate production. Our data indicate that neither sublingual nifedipine nor intracoronary NTG affected the regional coronary blood flow response or altered the times to ischemic ST segment changes during the initial minute of myocardial ischemia. These data, however, cannot be used to exclude a regional cardioprotective mechanism, since neither metabolic nor functional (e.g., anterior left ventricular wall motion or thickening) indices of ischemia were measured. Zalewski et al5 have reported that regional ,& Adrenergic blockade with intracoronary propranolol decreased myocardial ischemia during balloon
volume
115
Nitrate
Number 6
IV. Reproducibility
Table
Base
GVF GVR MAP
(7) (7) (7)
SYS
(7)
DIA HR
(7) (7)
1
112 + 52 1.09 f 0.48 101 f 15 146
78 70
+ 26
rfr 18 t 16
effects during
1169
PTCA
of systemic and coronary hemodynamics during PTCA Control occlusion
No.
and nifedipine
occ
Control occlusion
1 1
71 * 37 1.84 * 0.97 101 + 20
HYl 176 rt 87 0.70 ? 0.27
Base
2
110 2 54 1.17
z? 0.52
105 + 19
106 k 18
130 & 24
151
z!z 29
144
81 t 20 75 f 19
81 68
f 19 * 19
* 18 78 + 16
68
it 16
occ
2 2
67 -fr 39 1.92
-+ 0.89
99 t 16 129
* 15
83 I 22 73 t- 18
HY2 153
0.86
“I, .A HY
It 81
re 0.39
106 k 18 142 r 17 79 I
14
71 -+ 19
64 2 49 -32 ir 19 -4 -2 5 3i4 4&f? -3
R AHY2 43 t 51 -23 iz 23 1+7 -1
? 3 1t5
+ Ii
Values are mean -t 1 standard deviation. Con = control; DIA = diastolic pressure (mm Hg); GVF = diastolic pressure (mm Hg); GVF = great cardiac vein blood flow (units); vein resistance (units); HR = heart rate (beats/min); HY = peak hyperemic flow response; MAP = mean arterial pressure (mm occlusion; SYS = systolic pressure (mm Hg); % A HY = percent change during hyperemia [(peak flow - control)/controlj x 100.
occlusion. The time to development of ST segment elevation was prolonged and the magnitude of ST segment elevation was significantly diminished during myocardial ischemia after administration of intracoronary propranolol. Unlike propranolol, intracoronary NTG and systemic nifedipine in our patients had different hemodynamic, and potentially, metabolic effects, suggesting alternative myocardial protective mechanisms during ischemia. Comparison to systemic vasodilation. Salutary effects of systemic NTG can be observed when the drug is administered immediately before coronary occlusion.2 A smaller increase in left ventricular end-diastolic pressure and time constant of relaxation, as well as delayed time to onset of angina and time to 1 mm ST segment depression occurred, coincident with a reduction of mean arterial pressure and an improvement in left ventricular wall motion in some regions. In our study, intracoronary NTG did not produce such striking systemic effects and did not augment regional myocardial blood flow nor attenuate time to ischemic ST segment changes. It may be postulated that intravenous NTG reduced myocardial oxygen demand so that the limited coronary supply during occlusion was better tolerated, with a prolongation of time to ischemia. Similar responses would be anticipated with nifedipine. This speculation has support in recent experimental studies14 examining effects of calcium channel blockade (nifedipine) and a vasodilator (sodium nitroprusside) on diastolic function during ischemia produced by 30 to 60 seconds of bilateral coronary artery occlusion in dogs. Systemic calcium channel blockade failed to attenuate the ischemic changes. However, preload reduction mediated through peripheral vasodilation of sodium nitroprusside improved isovolumetric relaxation and ameliorated
I
324
GVR = great cardiac Hg); Occ = coronary
early diastolic dysfunction, suggesting a predominant beneficial result through systemic hemodynamic effects.14 The small number of patients with suitable ECG changes in the nifedipine group may preclude statistically significant observations of reduced time to ST change, but the regional blood flow responses also support a systemic, more than a coronary, hemodynamic mechanism of action. Effects on collateral supply. NTG has been reportedl5 to decrease the coronary collateral resistance index and pressure determinants of myocardial oxygen demand during acute balloon occlusion. Augmentation of postcoronary occlusive flow or increase in coronary occlusion wedge pressure following balloon inflation was not observed with either vasodilator despite the potentially extensive precapillary vasodilatation that could be anticipated. The NTGin.duced augmentation of basal coronary flow in the current study appeared insufficient to improve myocardial oxygen supply in these patients without angiographic collaterals. However, acute collateral recruitment during coronary balloon occlusion has been demonstrated in some patients>g and may explain why several of the patients in both groups had only minimal ischemic ECG responses during coronary occlusion. Probst et a1.g and Meier et al.s indicate that visible collaterals are usually associated with coronary occlusion pressures of 41 k 12 mm Hg, with recruitable collaterals identified with occlusion pressures of 36 + 12 mm Hg. Elevated (>30 mm Hg) distal coronary pressures during balloon occlusion were present in three patients in each group before vasodilator administration without significant changes in coronary occlusive pressure after vasodilator administration, indicating minimal additional acute collateral recruitment. Limitations.
This study examined
the systemic and
1170
Kern
et al.
regional coronary hemodynamic responses during brief periods of controlled ischemia in man produced by coronary balloon occlusion. Several limitations in clinical studies of this type must be emphasized. First, the coronary sinus thermodilution method approximates antegrade coronary flow by assessing great cardiac vein efflux and may be widely variable depending on the individual venous return patterns. In most cases, however, the great cardiac vein efflux is a relatively stable indicator of anterior left ventricular blood flow changes. This technique, like other coronary flow techniques in man, cannot measure subendocardial/subepicardial flow alterations. NTG or nifedipine may have promoted a favorable transmural redistribution in flow ratios without a net change in regional coronary sinus efflux. Second, using only one or two leads to capture all ischemic ECG changes may lack the sensitivity required to establish the therapeutic effects of our interventions. However, with the use of the anterior chest lead, Vs, most anterior ST changes during occlusion should be detected. Third, the doses of NTG and nifedipine were selected based on current clinical practice. Intracoronary nifedipine was not approved for our use at the time of this study. Previous studies on the dose responses to intracoronary NTG16 indicate that 200 pg produces a maximal coronary vasodilatory response with only minimal systemic effects. The administration of nifedipine assumes peak effect by 15 minutes, with marked changes in systemic hemodynamics. The time course of changes in coronary blood flow may be different. However, as used clinically, the effects of nifedipine and timing of PTCA after drug administration should be adequate to observe most clinical benefits. Last, the complete reduction of intracoronary gradients was not achieved during the study occlusions. Although further dilations after drug administration were performed, the assessment of regional flow alterations should be comparable during coronary occlusion despite persistent or unrelieved transcoronary gradients. The relationship of hyperemic responses to the degree of ischemia may be influenced by the residual gradients and therefore may be a less reliable finding in these patients. Clinical significance. Although intracoronary NTG and sublingual nifedipine did not alter regional coronary blood flow responses or ECG signs of myocardial ischemia during brief coronary occlusions, clinical benefits of NTG and nifedipine during PTCA may be observed. Benefits with the use of these agents may therefore occur through mecha-
American
June 1988 Heart Journal
nisms such as spasmolytic action, or indirectly through reduction of preload and peripheral determinants of myocardial oxygen demand, more than by direct augmentation of coronary artery or collateral blood flow. The authors thank the Cardiac Catheterization Team of the Mudd Laboratory and Donna Sander for manuscript preparation. REFERENCES
1. Ganz W, Marcus HS. Failure of intracoronary nitroglycerin to alleviate pacing-induced angina. Circulation 1976;46:880-9. 2. Doorey AJ, Mehmel HC, Schwarz RX, Kubler W. Amelioration by nitroglycerin of left ventricular ischemia induced by percutaneous transluminal coronary angioplasty: assessment by hemodynamic variables and left ventriculography. J Am Co11 Cardiol 1985;6:267-74. 3. Feldman RL, Macdonald RG, Hill HA, Limacher MC, Conti R, Pepine CJ. Effect of propranolol on myocardial ischemia occurring during acute coronary occlusion. Circulation 1986;4:727-33. 4. Serruys PW, VanDenBrand M, Brower RW, Hugenholtz PG. Regional cardioplegia and cardioprotection during transluminal angioplasty; which role for nifedipine? Eur Heart J 1983;4:115-21. 5. Zalewski A. Goldberg S. Dervan JP. Slvsh S. Maroko PR. Myocardial’ protection ‘during transient coronary artery occlusion in man: beneficial effects of regional P-adrenergic blockade. Circulation 1986;4;734-9. 6. Rousseau MF, Renkin J, Lavenne-Pardonge E, Henet C, Pouleur H. Myocardial protection by intracoronary injection of nicardipine during transluminal coronary angioplasty [Abstract]. Circulation 1985;72(Suppl 111):400. 7. Vandormael MG, Chaitman BR, Ischinger T, Aker UT, Harper M, Hernandez J, Deligonul U, Kennedy HL. Immediate and short-term benefit of multilesion coronary angioplasty: influence of degree of revascularization. J Am Co11Cardiol 1985;6:983-91. 8. Meier B, Luethy P, Finci L, Steffenino GD, Rutishauser W. Coronary wedge pressure in relation to spontaneously visible and recruitable collaterals. Circulation 1987;75:906-13. 9. Probst P, Zangl W, Pachinger 0. Relation of coronary arterial occlusion pressure during percutaneous transluminal coronary angioplasty to presence of collaterals. Am J Cardiol 198$55:1264-g. 10. Simon R, Amende I, Lichtlen PR. Coronary blood flow and hemodynamics during prolonged balloon inflation in coronary angioplasty. J Am Co11 Cardiol 1984;3:507. 11. Ganz W. Tamura K. Marcus HS. Donoso R. Yoshida S. Swan HJC. Mkasurement’of coronary sinus blood flow by continuous thermodilution in man. Circulation 1971;44:181-95. 12. Pepine CJ, Mehta J, Webster WW, Nichols WW. In vivo validation of a thermodilution method to determine regional left ventricular blood flow in patients with coronary disease. Circulation 1978;58:795-802. 13. Duncan DB. Multiple range and multiple F tests. Biometrics 1955;11:1-42. 14. Applegate RJ, Walsh RA, O’Rourke RA. Effects of nifedipine on diastolic function during brief periods of flow-limiting ischemia in the conscious dog. Circulation 1987;76:1409-21. 15. Feldman RL, Joyal M, Conti CR, Pepine CJ. Effect of nitroglycerin on coronary collateral flow and pressure during acute coronary occlusion. Am J Cardiol 1984;54:958-63. 16. Kern MJ, Miller JT, Henry RL. Dose-related effects of intracoronary nitgroglycerin on systemic hemodynamics and coronary hyperemia in patients with coronary artery disease. AM HEART J 1986;111:845-52.
American
Blood Substitutes, Kyoto. Amsterdam: Excerpta Medica, 1978285-93. 38. Nunn G, Dance G, Peters J, Cohn L. Effect of fluorocarbon exchange transfusion on myocardial infarction size in dogs. Am J Cardiol 1983;52:203-5. 39. Forman M, Bingham S, Kopelman H, et al. Reduction of infarct size with intracoronary perfluorochemical in a canine preparation of reperfusion. Circulation 1985;71:1060-8. 40. Faithful1 NS, Fennema M, Essed CE, et al. Collateral oxygenation of the ischemic myocardium: the effect of viscosity and oxygen carrying fluorocarbons. In: Advances in blood substitute research. New York: Alan R. Liss, Inc., 1983:229.
June 1988 Heart Journal
41. Tokioka H, Miyazaki A, Fung P, Rajagopalan RE, et al. Effects of intracoronary infusion of arterial blood or FluosolDA 20% on regional myocardial metabolism and function during brief coronary artery occlusions. Circulation 1987; 75:473-81. 42. Spears JR, Serur J, Bairn DS, Grossman W, Paulin S. Myocardial protection wiht Fluosol-DA 20% during prolonged coronary balloon occlusion in the dog [Abstract]. Circulation 1983;68(Suppl 111):317.
Effects of nitroglycerin and nifedipine coronary and systemic hemodynamics trawient coronary artery occlusion
on during
Nitroglycerin (NTG) and nifedipine (NIF) have the potential to augment coronary blood flow in addition to reducing peripheral determinants of myocardial oxygen demand as a synergistic protective mechanism during ischemia. To examine these effects, systemic and coronary hemodynamic responses were measured continuously before and during brief periods of myocardial ischemia induced by left anterior descending coronary balloon occlusion in 26 patients undergoing angioplasty (PTCA). Data were compared for two matched occlusion periods, one control and one “drug” occlusion. In 17 patients (NTG group), 200 pg of intracoronary NTG was given immediately before coronary occlusion. In nine patients (NIF group), 10 mg of sublingual NIF was given 15 minutes before the “drug” occlusion. NTG significantly b.ut transiently redqced ‘mean arterial pressure (91 ? 11 to 62 i 15 mm Hg, p < 0.05) and augmented basal coronary blood flow (95 + 36 to 127 * 54 ml/min, p < 0.05) but did not alter great vein blood flow (59 + 29 vs 61 + 29 ml/min) or coronary occlusion pressure (26 + 7 to 24 + 7 mm Hg) during ischemia. NIF sigtilflcantly reduced systolic, diastolic, and mean arterial pressure (119 + 21 to 95 2 6 mm Hg, p < 0.001) and heart rate-pressure product from control. NIF maintained basal great vein blood flow (125 f 41 to 106 + 57 ml/min) during reduced myocardial oxygen demand, but did not affect great vein blood flow (73 + 29 to 79 f 37 ml/min) or coronary occlusion pressures. during ischemia. Neither agent prolonged the time to ischemic. ST segment alteration after the 50 to 60 second coronary flow occlusion periods. These data suggest that during the initial minutes of myocardial ischemla due to coronary occlusion,. neither the coronary nor peripheral hemodynamic effects of the two vasodilators significantly improved regional coronary blood flow responses or ECG signs of myocardial ischemia. During PTCA, the beneficial effects of these agents most likely occur through mechanisms such as spasmolytic action, or indirectly by reduction of myocardlal oxygen demand, more than directly augmenting coronary blood flow or collateral supply. (AM HEART J 1988;115:1164.)
Morton J. Kern, M.D., Ubeydullah Deligonul, M.D., Arthur Labovitz, M.D., Gregory Gabliani, M.D., Michel Vandormael, M.D., and Harold L. Kennedy,
M.D.
St. Louis, MO.
From the Medicine. Received
Department for publication
Reprint requests: Morton tory, St. Louis University MO 63104.
1164
of Cardiology,
St.
Louis
Dec. 22, 1987; accepted J. Kern, Medical
University
School
of
Feb. 1, 1988.
M.D., Cardiac Catheterization Center, 1326 S. Grand Blvd.,
LaboraSt. Louis,
. A controlled model of transient myocardial ischemia in man with coronary balloon occlusion permits examination of systemic and coronary hemodynamic responses to drugs that are commonly used to reduce myocardial ischemia. Nitroglycerin (NTG)
Volume 115 Number 6
has a predominant mechanism of vasodilation acting to decrease peripheral determinants of myocardial oxygen demand more than to augment coronary perfusion.’ Intravenous NTG2 and propranolol,3 intracoronary nifedipineP intracoronary propranoloI,5 and nicardipine6 have been demonstrated to produce salutary effects on hemodynamic variables and changes in left ventricular function associated with ischemia induced during transient coronary artery balloon occlusion. Nifedipine, with potent coronary and peripheral vasodilating action, has been proposed4 as a regional cardioplegic agent permitting prolonged coronary occlusion while minimizing indices of myocardial ischemia. Few studies have provided information on regional coronary blood flow alterations with these agents during ischemia. Whether the transient, but marked, coronary vasodilation induced by intracoronary NTG or the combined systemic and coronary effects of nifedipine favorably alter regional coronary blood flow or reduce myocardial ischemia after transient reduction or cessation of coronary flow in man is unknown. Accordingly, the effects of NTG and nifedipine during transient coronary artery balloon occlusion were studied, examining the alterations in regional coronary blood flow, systemic hemodynamic responses, and ischemic ECG changes during the initial minutes of myocardial ischemia. METHODS Patient population. Patients were selected from those undergoing routine percutaneous transluminal coronary angioplasty (PTCA) with suitable left anterior descending stenoses (>60% stenosis by visual estimation of two experienced angiographers). Each patient demonstrated some objective evidence of myocardial ischemia despite medical therapy. The protocols were approved by the Human Subjects Committee of the Institutional Review Board of St. Louis University School of Medicine. All patients gave written informed consent. Patients with recent (
Nitrate
and nifedipine
effects during
PTCA
1165
through a left antecubital vein. The distal. thermistor was positioned close to the juncture with the anterior interventricular vein. The proximal thermistor in most cases was situated at least 2 cm from the coronary sinus ostia to avoid right atrial-coronary sinus reflux. The ECG was recorded with one or two simultaneously recorded leads (II and V, or V,) continuously during the study. Pulmonary artery pressure was recorded in 14 patients with a balloon-tipped flotation catheter introduced through the femoral vein. PTCA was performed in a routine fashion as previously reported,7 with the use of a No. 8 French femoral arterial sheath and No. 8 French left coronary guiding catheter. Appropriately sized (2.0 to 3.5 mm diameter) angioplasty balloon catheters (USC1 Division of C. R. Bard, Billerica, Mass., and Advanced Cardiovascular Systems, Inc., Temecula, Calif.) and steerable guidwires were used. The guiding and balloon catheters were cleared of contrast and were flushed with saline to record distal coronary and aortic guiding catheter pressures continuously with the ECGs and simultaneous regional and total coronary sinus blood flow. When stable thermodilution coronary signals had been obtained, the angioplasty balloon was inflated to between 6 and 8 atm of pressure and 45 to 60 seconds later deflated, recording data during the hyperemic period for another 60 to 90 seconds. Absolute coronary occlusion (wedge) pressure was recorded in those patients with satisfactory gradients to estimate the presence of recruitable or pot,ential collateral suppl~.~-*O Initial balloon dilatations (usually one or two) were performed for clinical purposes and to establish relatively stable baseline coronary flow and translesional gradients before any intervention. Subsequent coronary occlusions were matched, one for control and one for drug evaluation. At least a 3-minute equilibration period was observed between balloon occlusions to minimize residual ischemia. In patients with ECG changes, the time from coronary occlusion to 1.0 mm ST depression or elevation or new T wave inversion in either of the two ECG monitoring leads was recorded. Although patients were asked to grade the severity of chest pain, this late indicator of ischemia after premeditation was felt to be inconsistent and was therefore not analyzed. Study protocol. For the NTG occlusion (17 patients), while continuously recording hemodynamic, ECG, and coronary flow signals, 200 kg of NTG was given through the guiding catheter into the left coronary artery, and within 10 seconds balloon inflation was performed as in the preceding occlusions. For the nifedipine occlusion (nine patients), 10 mg of sublingual nifedipine was given after the control occlusion. After a l&minute equilibration period, the drug occlusion measurements were obtained. In seven patients, duplicate occlusions prior to drugs were performed to establish the reproducibility of repeated occlusions on coronary hemodynamic responses. Data analysis. Regional coronary thermodilution flow values were calculatd by the methods of Ganz et al.” and Pepine et a1.12The great cardiac vein efflux represents anterior left ventricular regional flow supplied predomi-
1166 Table
Kern
et al.
American
June 1999 Heart Journal
1. Clinical, angiographic, and hemodynamic data LAD %
NTG
Sex
L VEF
66 32 45 58 51 63 74 67 57 75 64 56 67 45 56 48
M M F M M M M F M F M F M M M M M
76 87 70 78 69 52 70 59 64 N 61 82 56 N 49
LVWM
Pre
Post
95
43 36 15 25 15 29 20 20 15 20 20 20 40 15 24 20
group
2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 M k SD NIF
Age
group 1 2 3 4 5 6 8 9
M + SD
41 57 + 12
59 54 63 63 60 57 51 63 63 59 + 4
M M M M M M M M M
N
63 67 ii 11
N 76 59 N 77 76 54 N 62 67 -r- 10
AH NL NL NL IH NL AH IH NL NL NL NL NL IH NL AH AH
AH NL NL NL NL NL AH NL NL
AH = anterior hypokinesia; F = female; IA = inferior akinesis; IH = inferior hypokinesis; LAD % = percent artery pre- and post-PTCA; LVEF = left ventricular ejection fraction (N = ectopy precluded precise NIF = nifedipine; NL = normal; NTG = nitroglycerin; M = SD = mean ? 1 standard deviation.
nantly by the left anterior descending coronary artery. Coronary resistance was calculated as mean arterial pressure divided by great cardiac vein flow. The coronary hyperemic response was calculated as percent of basal flow increases [(peak flow - basal flow)/basal flow) X 1001. Data were analyzed by one-way analysis of variance. When significant differences were indicated, comparisons of the study section means were made with Duncan’s multiple range F statistic for multiple comparisons.*3 Comparisons between groups were made with nonpaired t test. Probability (p) values <0.05 were considered significant. RESULTS
Clinical and angiographic data are summarized on Table I. Mean left ventricular ejection fraction was similar for both NTG and nifedipine groups (67 f 11% , 67 + 10%). In the NTG and nifedipine groups, respectively, 11 and 5 patients were receiv-
75 80 80 95 70 85 70 80 65 80 95 93 80 83 90 80 82 L 9
25 24 f
9
80 83 86 80 87 95 78 66
10 17 19 18 36 50 29 15
77 81 L 8
24 24 of- 12
narrowing of left anterior descending coronary %); LVWM = left ventricular wall motion;
ing beta blockers at the time of study; 16 and 7 patients were receiving a calcium channel blocker prior to study. Four patients in the NTG group and two patients in the nifedipine group had prior myocardial infarction with anterior left ventricular wall motion abnormalities. There were no clinical or hemodynamic differences between the patients with anterior left ventricular wall motion abnormalities compared to those with normal left ventricular wall motion who were included in the analysis. No patient had angiographically visible collateral supply to the left anterior descending coronary artery. Significant ECG changes during coronary occlusion occurred in 13 patients in the NTG group and in six patients in the nifedipine group. Satisfactory translesional pressure measurements could be obtained in 11 patients in the NTG group and in nine patients in the nifedipine group. The durations of coronary
Volume 115 Number 6
Table
Nitrate
and
nifedipine
II. Systemic and coronary hemodynamics during coronary occlusion Control No.
Group
Base
1
1
Hyperemia
1
Base
2
during
--_~-Drug
occlusion occ
effects
1167
PTCA
- --
occlusion
NTG*
occ
2
Hyperemia
2 -
.GVF GVR MAP SYS DIA PAS PAD HR HR*SYS
17 9 17 9 17 9 17 9 17 9 7 7 7 7 17 9 17 9
NTG NIF NTG NIF NTG NIF NTG NIF NTG NIF NTG NIF NTG NIF NTG NIF NTG NIF
90 125 1.13 1.05 90 119 115 161 70 84 26 28 10 10 74 62 8744 10137
* ct * -t 2 k If: k ++ t + + k k k rf+
31 41” 0.47 0.39 10 21b 21 28b 10 13b 11 7 5 2 16 9 2508 2700
59 73 1.70 1.86 86 112 107 143 71 90 33 36 18 16 76 67 8164 9697
+ 29 f 29 f 0.66 k 1.07 + 13 -+ 18b * 22 +- 25b k 11 +- 17b k 14 rt 11 k 10 +- 7 + 17 + 7 k 2634 f 2532
121 160 0.81 0.85 89 120 118 160 71 84 30 33 12 14 73 65 8685 10450
+ + f f
40’ 63 0.24’ 0.33
+ 11
-c +!c +_ f k + k -c c k k +
21b 23 28b 11 14 12 8 7 3 17 8 2951 2699
95 106 1.12 1.07
k f + iY
91 *
95 121 128 67 72 27 28 12 12 72 67 8799 8474
k ++ f 3~ c f +k I r k k
38 57 0.54 0.40 11
8d 18 21d 13 10 10 8 5 6 16 7 2401 1368d
127 I 45' 0.79 i 0.28 88 I13 117 c 17 67 + 17 29 i 11 12 k 6 71 !I 13 8463 k 2282 -
61 79 1.59 1.52 82 93 104 119 67 77 30 32 15 15 79
AZ 29 + 37 t 0.69 t 1.07 L 15. + 11'9 * 20 + 190 t 15 2 7 iI 17 -e 9 t- 13 -t 6 3: 17
71 t
8264 8393
6
t 2808 i 141fid
114 134 0.82 0.84 87 98 112 131 66 75 25 31 12 13 76 68 8538 8876
z t t +
35 55 0.26' 0.33
r 13
" t t t t t r I i i t + +-
9" 15 21d,” 13 a 12 8 7 4 16 8 2436 1543’
-.--._-_-~~ --.-__ Base = baseline value; DIA = diastolic pressure (mm Hg); GVF = great cardiac vein blood flow (mUmin); GVR = great cardiac vein resistance (units); HR = heart rate (beats/min); HY*SYS = heart rate-pressure product (mm Hg X beats/mm-I); hyperemia = values taken at peak blood flow responses after release of occlusion; MAP = mean arterial pressure (mm Hg); NIF = nifedipine; NTG = intracoronary nitroglycerin; Occ = end coronary occlusion values; PAD = pulmonary artery diastolic pressure (mm Hg); PAS = pulmonary artery systolic pressure (mm Hg); SYS = systolic pressure (mm Hgl. a = p < 0.05 vs NTG group; b = p < 0.01 vs NTC group; C= p < 0.05 vs baseline; d = p < 0.01 YS control. ‘NTG = nitroglycerin was given via intracoronary route after new baseline; nifedipine was given 15 minutes before baseline 2
occlusions were matched (55 + 15 and 54 f. 18 seconds) and similar for both groups for both the control and drug occlusions. Systemic hemodynamics (Table II). Intracoronary NTG reduced mean arterial pressure (91 f 11 to 82 + 15 mm Hg, p < 0.05) without significant alterations in heart rate, heart rate-systolic blood pressure product, or pulmonary artery pressures. In contrast, the nifedipine group had high control occlusion period mean arterial, systolic, and diastolic pressures, which were significantly reduced after drug administration. Heart rate-pressure products were also significantly reduced by nifedipine administration. Coronary hemodynamic responses (Table II). Basal great vein flow increased 36% (95 + 38 ml/min to 127 + 54 ml/min, p < 0.05) in response to intracoronary NTG. However, NTG did not alter great vein flow (59 + 29 vs 61 * 29 ml/min) during transient ischemia. For patients receiving nifedipine, there were no significant differences in great vein flow at baseline (in Table II; Base 1 before drug 125 + 41 to Base 2 after drug 106 + 57 ml/min), indicating that despite a significant decline in determinants of myocardial oxygen demand, nifedipine-induced vasodilation maintained basal coronary blood flow. Great vein
flow was similar for both the control and drug occlusions (73 + 29 vs 79 f 37 ml/min) for nifedipine patients during transient myocardial ischemia. The time to ST segment change was similar for the control and drug occlusions for both NTG (27 + 12 vs 26 + 7 seconds) and nifedipine (24 t- 14 vs 33 & 10 seconds) groups (Table III). The initial translesional gradients for the NTG group were slightly higher for the control occlusion. The absolute coronary occlusion pressures for both control and drug periods were similar (25 k ‘7, 24 rt 7 mm Hg). The translesional gradients were higher for the nifedipine group than for the NTG group, and in some patients, gradients persisted despite adequate angiographic results after PTCA. Patient No. 8 had no residual gradient after the clinical inflations. Dilations were performed to improve the angiographic appearance of the lesion. One patient (No. 7) had a persistent large gradient due to dissection that would not be ameliorated after repeated dilations, and he went to elective coronary bypass surgery in the following week. Elevated (>30 mm Hg) coronary occlusion (wedge) pressures suggested recruitable collateral supply in three patients in each group. The control coronary occlusion pressures were 25 ? 7 and 24 + 7 mm Hg for the two
June 1998
1168
Kern
et al.
American
Heart Journal
III. Coronary gradients, absolute coronary occlusion pressures, and time to ischemic ST segment change during transient coronary occlusion
Table
Initial gradient (mm Hd Pt no.
COFOnaFy occlusion wedge pressure (mm f&J
Final gradient (mm W
Time to ST (seconds)
Control
Drug
Control
Drug
Control
Drug
Control
Drug
36 30 32 36 20 32 12 18 18 36 30
22 18 32 28 20 10 0 12 0 22 22 -
30 20 32 28 20 0 0 12 0 22 22
20 16 32 28 18 10 0 0 0 22 20 -
30 20 20 32 28 -
25 20 20 35 22 -
25 18 20 20 38
20 20 18 20 38 -
20 25 NC 20 40 60 NC 20 20 20 20 15 35 30 25 NC
35 30 NC 20 25 20 NC 35 40 15 25 NC 25 20 25 NC
NTG 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 M + SD
-
17
17
L 25 f
18
7
NC 27 f
257
12
NC 26 + 7
NC 30 30 NC 25 NC NC 30 50 33 + 10
NIF 1 2 3 4 5 6 7 8 9 M f
40 25 40 30 42 40 86 0 SD
Gradient = aortic-coronary *p < 0.05 vs control.
51 39 f
23
balloon
45 24 30 30 22 32 71 0
38 32 40 50 40 42 100 0
43 33 F 19
43 43 k 26
pressures;
NC = no changes
observed;
groups, respectively, and were unchanged after drug administration. To assess reproducibility, repeated coronary occlusions without drug intervention in a subset of patients produced similar coronary and hemodynamic responses (Table IV). DISCUSSION
This study provides data on the systemic and coronary hemodynamic effects of two commonly used vasodilators during experimental human myocardial ischemia of complete, but transient, coronary occlusion. Both NTG and nifedipine have been proposed”, 7 as regional cardioprotective agents during coronary angioplasty occlusion. Nifedipine (0.2 mg), given into the left main coronary artery imme-
48 28 30 30 38 40 82 0 43 38 f (-)
22
13 30 24 24 34 15 20 31
15 29 16 14 29 16 12 27
NC 30 20 15 15 NC NC 15
23 24 ? 7
28 21 * 7
50 24 k 14
= no data; NTG
= nitroglycerin;
NIF
= nifedipine.
diately preceding coronary occlusion for 45 seconds, produced a regional cardioplegic effect, increasing poststenotic flow and suppressing lactate production. Our data indicate that neither sublingual nifedipine nor intracoronary NTG affected the regional coronary blood flow response or altered the times to ischemic ST segment changes during the initial minute of myocardial ischemia. These data, however, cannot be used to exclude a regional cardioprotective mechanism, since neither metabolic nor functional (e.g., anterior left ventricular wall motion or thickening) indices of ischemia were measured. Zalewski et al5 have reported that regional ,& Adrenergic blockade with intracoronary propranolol decreased myocardial ischemia during balloon
volume
115
Nitrate
Number 6
IV. Reproducibility
Table
Base
GVF GVR MAP
(7) (7) (7)
SYS
(7)
DIA HR
(7) (7)
1
112 + 52 1.09 f 0.48 101 f 15 146
78 70
+ 26
rfr 18 t 16
effects during
1169
PTCA
of systemic and coronary hemodynamics during PTCA Control occlusion
No.
and nifedipine
occ
Control occlusion
1 1
71 * 37 1.84 * 0.97 101 + 20
HYl 176 rt 87 0.70 ? 0.27
Base
2
110 2 54 1.17
z? 0.52
105 + 19
106 k 18
130 & 24
151
z!z 29
144
81 t 20 75 f 19
81 68
f 19 * 19
* 18 78 + 16
68
it 16
occ
2 2
67 -fr 39 1.92
-+ 0.89
99 t 16 129
* 15
83 I 22 73 t- 18
HY2 153
0.86
“I, .A HY
It 81
re 0.39
106 k 18 142 r 17 79 I
14
71 -+ 19
64 2 49 -32 ir 19 -4 -2 5 3i4 4&f? -3
R AHY2 43 t 51 -23 iz 23 1+7 -1
? 3 1t5
+ Ii
Values are mean -t 1 standard deviation. Con = control; DIA = diastolic pressure (mm Hg); GVF = diastolic pressure (mm Hg); GVF = great cardiac vein blood flow (units); vein resistance (units); HR = heart rate (beats/min); HY = peak hyperemic flow response; MAP = mean arterial pressure (mm occlusion; SYS = systolic pressure (mm Hg); % A HY = percent change during hyperemia [(peak flow - control)/controlj x 100.
occlusion. The time to development of ST segment elevation was prolonged and the magnitude of ST segment elevation was significantly diminished during myocardial ischemia after administration of intracoronary propranolol. Unlike propranolol, intracoronary NTG and systemic nifedipine in our patients had different hemodynamic, and potentially, metabolic effects, suggesting alternative myocardial protective mechanisms during ischemia. Comparison to systemic vasodilation. Salutary effects of systemic NTG can be observed when the drug is administered immediately before coronary occlusion.2 A smaller increase in left ventricular end-diastolic pressure and time constant of relaxation, as well as delayed time to onset of angina and time to 1 mm ST segment depression occurred, coincident with a reduction of mean arterial pressure and an improvement in left ventricular wall motion in some regions. In our study, intracoronary NTG did not produce such striking systemic effects and did not augment regional myocardial blood flow nor attenuate time to ischemic ST segment changes. It may be postulated that intravenous NTG reduced myocardial oxygen demand so that the limited coronary supply during occlusion was better tolerated, with a prolongation of time to ischemia. Similar responses would be anticipated with nifedipine. This speculation has support in recent experimental studies14 examining effects of calcium channel blockade (nifedipine) and a vasodilator (sodium nitroprusside) on diastolic function during ischemia produced by 30 to 60 seconds of bilateral coronary artery occlusion in dogs. Systemic calcium channel blockade failed to attenuate the ischemic changes. However, preload reduction mediated through peripheral vasodilation of sodium nitroprusside improved isovolumetric relaxation and ameliorated
I
324
GVR = great cardiac Hg); Occ = coronary
early diastolic dysfunction, suggesting a predominant beneficial result through systemic hemodynamic effects.14 The small number of patients with suitable ECG changes in the nifedipine group may preclude statistically significant observations of reduced time to ST change, but the regional blood flow responses also support a systemic, more than a coronary, hemodynamic mechanism of action. Effects on collateral supply. NTG has been reportedl5 to decrease the coronary collateral resistance index and pressure determinants of myocardial oxygen demand during acute balloon occlusion. Augmentation of postcoronary occlusive flow or increase in coronary occlusion wedge pressure following balloon inflation was not observed with either vasodilator despite the potentially extensive precapillary vasodilatation that could be anticipated. The NTGin.duced augmentation of basal coronary flow in the current study appeared insufficient to improve myocardial oxygen supply in these patients without angiographic collaterals. However, acute collateral recruitment during coronary balloon occlusion has been demonstrated in some patients>g and may explain why several of the patients in both groups had only minimal ischemic ECG responses during coronary occlusion. Probst et a1.g and Meier et al.s indicate that visible collaterals are usually associated with coronary occlusion pressures of 41 k 12 mm Hg, with recruitable collaterals identified with occlusion pressures of 36 + 12 mm Hg. Elevated (>30 mm Hg) distal coronary pressures during balloon occlusion were present in three patients in each group before vasodilator administration without significant changes in coronary occlusive pressure after vasodilator administration, indicating minimal additional acute collateral recruitment. Limitations.
This study examined
the systemic and
1170
Kern
et al.
regional coronary hemodynamic responses during brief periods of controlled ischemia in man produced by coronary balloon occlusion. Several limitations in clinical studies of this type must be emphasized. First, the coronary sinus thermodilution method approximates antegrade coronary flow by assessing great cardiac vein efflux and may be widely variable depending on the individual venous return patterns. In most cases, however, the great cardiac vein efflux is a relatively stable indicator of anterior left ventricular blood flow changes. This technique, like other coronary flow techniques in man, cannot measure subendocardial/subepicardial flow alterations. NTG or nifedipine may have promoted a favorable transmural redistribution in flow ratios without a net change in regional coronary sinus efflux. Second, using only one or two leads to capture all ischemic ECG changes may lack the sensitivity required to establish the therapeutic effects of our interventions. However, with the use of the anterior chest lead, Vs, most anterior ST changes during occlusion should be detected. Third, the doses of NTG and nifedipine were selected based on current clinical practice. Intracoronary nifedipine was not approved for our use at the time of this study. Previous studies on the dose responses to intracoronary NTG16 indicate that 200 pg produces a maximal coronary vasodilatory response with only minimal systemic effects. The administration of nifedipine assumes peak effect by 15 minutes, with marked changes in systemic hemodynamics. The time course of changes in coronary blood flow may be different. However, as used clinically, the effects of nifedipine and timing of PTCA after drug administration should be adequate to observe most clinical benefits. Last, the complete reduction of intracoronary gradients was not achieved during the study occlusions. Although further dilations after drug administration were performed, the assessment of regional flow alterations should be comparable during coronary occlusion despite persistent or unrelieved transcoronary gradients. The relationship of hyperemic responses to the degree of ischemia may be influenced by the residual gradients and therefore may be a less reliable finding in these patients. Clinical significance. Although intracoronary NTG and sublingual nifedipine did not alter regional coronary blood flow responses or ECG signs of myocardial ischemia during brief coronary occlusions, clinical benefits of NTG and nifedipine during PTCA may be observed. Benefits with the use of these agents may therefore occur through mecha-
American
June 1988 Heart Journal
nisms such as spasmolytic action, or indirectly through reduction of preload and peripheral determinants of myocardial oxygen demand, more than by direct augmentation of coronary artery or collateral blood flow. The authors thank the Cardiac Catheterization Team of the Mudd Laboratory and Donna Sander for manuscript preparation. REFERENCES
1. Ganz W, Marcus HS. Failure of intracoronary nitroglycerin to alleviate pacing-induced angina. Circulation 1976;46:880-9. 2. Doorey AJ, Mehmel HC, Schwarz RX, Kubler W. Amelioration by nitroglycerin of left ventricular ischemia induced by percutaneous transluminal coronary angioplasty: assessment by hemodynamic variables and left ventriculography. J Am Co11 Cardiol 1985;6:267-74. 3. Feldman RL, Macdonald RG, Hill HA, Limacher MC, Conti R, Pepine CJ. Effect of propranolol on myocardial ischemia occurring during acute coronary occlusion. Circulation 1986;4:727-33. 4. Serruys PW, VanDenBrand M, Brower RW, Hugenholtz PG. Regional cardioplegia and cardioprotection during transluminal angioplasty; which role for nifedipine? Eur Heart J 1983;4:115-21. 5. Zalewski A. Goldberg S. Dervan JP. Slvsh S. Maroko PR. Myocardial’ protection ‘during transient coronary artery occlusion in man: beneficial effects of regional P-adrenergic blockade. Circulation 1986;4;734-9. 6. Rousseau MF, Renkin J, Lavenne-Pardonge E, Henet C, Pouleur H. Myocardial protection by intracoronary injection of nicardipine during transluminal coronary angioplasty [Abstract]. Circulation 1985;72(Suppl 111):400. 7. Vandormael MG, Chaitman BR, Ischinger T, Aker UT, Harper M, Hernandez J, Deligonul U, Kennedy HL. Immediate and short-term benefit of multilesion coronary angioplasty: influence of degree of revascularization. J Am Co11Cardiol 1985;6:983-91. 8. Meier B, Luethy P, Finci L, Steffenino GD, Rutishauser W. Coronary wedge pressure in relation to spontaneously visible and recruitable collaterals. Circulation 1987;75:906-13. 9. Probst P, Zangl W, Pachinger 0. Relation of coronary arterial occlusion pressure during percutaneous transluminal coronary angioplasty to presence of collaterals. Am J Cardiol 198$55:1264-g. 10. Simon R, Amende I, Lichtlen PR. Coronary blood flow and hemodynamics during prolonged balloon inflation in coronary angioplasty. J Am Co11 Cardiol 1984;3:507. 11. Ganz W. Tamura K. Marcus HS. Donoso R. Yoshida S. Swan HJC. Mkasurement’of coronary sinus blood flow by continuous thermodilution in man. Circulation 1971;44:181-95. 12. Pepine CJ, Mehta J, Webster WW, Nichols WW. In vivo validation of a thermodilution method to determine regional left ventricular blood flow in patients with coronary disease. Circulation 1978;58:795-802. 13. Duncan DB. Multiple range and multiple F tests. Biometrics 1955;11:1-42. 14. Applegate RJ, Walsh RA, O’Rourke RA. Effects of nifedipine on diastolic function during brief periods of flow-limiting ischemia in the conscious dog. Circulation 1987;76:1409-21. 15. Feldman RL, Joyal M, Conti CR, Pepine CJ. Effect of nitroglycerin on coronary collateral flow and pressure during acute coronary occlusion. Am J Cardiol 1984;54:958-63. 16. Kern MJ, Miller JT, Henry RL. Dose-related effects of intracoronary nitgroglycerin on systemic hemodynamics and coronary hyperemia in patients with coronary artery disease. AM HEART J 1986;111:845-52.