The paradox of nitrates in patients with angina pectoris and angiographically normal coronary arteries

BRIEF REPORTS

The Paradox of Nitrates in Patients with Angina Pectoris and Angiographically Normal Coronary Arteries Raffaele Bugiardini, MD, Alberico Borghi, MD, Andrea Pozzati, MD, Filippo Ottani, MD, Gian Luigi Morgagni, MD, and Paolo Puddu, MD atients with angina pectoris found to have angioP graphically normal coronary arteries and no evidenceof coronary spasmor ventricular hypertrophy present a managementdilemma to all physicians. Most of these patients have an inadequate vasodilatory capacity of the coronary microcirculation, which may result in ischemia during increases in myocardial oxygen demand; accordingly, they could benefit from either vasodilator agentsor drugs that reduce myocardial oxygen demand. Nitrates are among the oldest, effective antianginal pharmacologic agents;their mechanismsof action are capableof affecting both the supply and demand side of the metabolic equation of the heart,* which appeared promising in regard to treatment of this syndrome. Therefore, the present study was performed to investigate the effectsof isosorbide dir&rate on coronary hemodynamics and anginal threshold in a group of patients with the aforementionedset of tindings, as well as reversible thallium abnormalities during exercise. Sixteen patients (I3 women and 3 men; mean age 47 f 6 years, range 34 to 58) presenting with angina pectoris and angiographically normal epicardial coronary arteries (as assessed independently by 2 obFrom the Institute of Patologia SpecialeMedica e Metodologia Clinica, University of Bologna, Bologna, Italy. Dr. Bugiardini’s current address is: Istituto di Patologia Medica III, Policlinico S. Orsola, Via Massarenti, 9, 40138, Bologna, Italy. Manuscript received June 22, 1992; revised manuscript received and acceptedMarch 1, 1993.

servers) were considered eligible for participation in this study (Table I). Patients fulfilled the following criteria: (1) positive exercise response (angina1 pain and 20.1 mV horizontal or downsloping ST depression); (2) no significant electrocardiographic changes during ergonovine testing (total dose 0.65 mg intravenously); and (3) objective evidence of myocardial ischemia in the anterior wall obtained by radionuclide studies during exercise stress testing. No patient had systemic hypertension, primary cardiomyopathy, valvular heart diseases or diabetes mellitus. All patients showed dt@use abnormal epicardial coronary artery constriction (225% diameter reduction) during hyperventilation andlor ergonovine testing. Each patient gave written informed consent for the study. All cardiovascular medications were withdrawn 48 hours before the study. Long-acting /3-adrenergic blockers were discontinued 21 week before the study. All patients underwent diagnostic and research sessions of the study simultaneously. Diagnostic left-sided cardiac catheterization and coronary angiography were performed by a standard percutaneous approach. At least 15 minutes after completion of diagnostic catheterization, patient classtfication was obtained, and those eligible for the study were selected by consensus. The catheter used for coronary angiography was positioned in the aorta to measure pressure with a Statham P25 transducer. A thermodilution catheter with pacing elec-

TABLE I Clinical Features of Patients

Pt.

Age (yr) &Sex

Hypertension

Total Cholesterol (mg/dl)

Smoking

Diabetes Mellitus

ST 1 at EST

Perfusion Defect at TI-201 SC.

Patients Treated with Sublingual ISDN (group A)

1 2 3 4 5 6 7 8 9

10 11 12

34F 40F 40M 42F 43F 47F 47F 48F 50M 50F

0 0 0 0 0 0 0 0 0 0

186 210

0 0

0 0

v3-V6

193

+

0

V4-Ve, Dr-aVL

248 176 208 220 215 222 180

0 0 + + 0 0 0

0 0 0 0 0 0 0

v4-V6

v3-v6,

52F 58F

0 0

175 225

+ 0

0 0

V4-V6, Dr-aVL

vZ--v5

v4--v6 v3--v6 v2-v6 v4--v6 v3--v5 DIII, aVF v4--v6

Septal + apical Anterior Apical + anterolateral Anterior Anterior + apical Septal + anterior Septal + apical Anterolateral Apical Anterior, lateral, inferoseptal Anterior Apical + anterolateral

Patients Treated with lntracoronary ISDN (group B) 13 14 15 16

44F 50F 51M 56F

0 0 0 0

203 224 218

0 0 +

0 0 0

195

0

0

EST = exercise stress testing; ISDN = isosorbide dinitrate;

V@e,

DII, Din, aVF VZ--v5 vZ--v6 v3--v6

ST 1 = ST-segment

depression;

Anterior + apical Septal + anterolateral Septal + apical Anterior + apical TI-201

SC. = thallium-201

exercise scintigraphy.

BRIEFREPORTS 343

trodes (Wilton Webster Laboratories) was inserted percutaneously using the left subclavian approach and positioned in the great cardiac vein to measure coronary blood flow. The thermodilution technique for determining coronary sinus and great vein blood flow was previously described? Great cardiac vein instead of coronary sinus blood flow measurement was selected

for the following 2 reasons: (I) It represents the flow from the left anterior descending region, and (2) it is not altered by the right atria1 reflex into the coronary sinus that occurs during pacing.4 Anterior coronary vascular resistance was calculated as mean aortic pressure divided by great cardiac vein flow. Pacing was performed with heart rate increments of IO beatslmin, each

TABLE II Effects of lsosorbide Dinitrate (ISDN) on Resting Systemic and Coronary Hemodynamics Three Minutes After Administration Heart Rate (beatslmin) Patient

RPP (beats/min . mm Hg x 103)

MAP

(mm Hg)

Control

ISDN

Control

ISDN

80 84 70

88 87 74

68 76 88 84 67 84

80 82 90 88 79 84

95 101 111 110

85 95 106 91 73 74 73 93

102

105

85 79 81 116 98 83

Control

ISDN

GCVBF (ml/min)

ACR (mm Hg/ml/min)

Control

ISDN

Control

195

64 48 67 83 57

137 190 108 93 72 49 46 40 64 45

0.49 0.48 0.73 0.92 0.84 1.23

160

121

93

64

95

122

ISDN

Patients Treated with Sublingual ISDN (group A) 1 2 3 4 5 6 7 8 9 10

7.6 8.5 7.8 7.5 6.5 6.9 6.8 7.7 8.2 8.5

91 75

7.4 8.3 7.8 7.3 6.0 6.6 6.4 7.3 7.6 7.9

212 152 120

101

0.62 0.50 0.98 0.98

1.01 1.51

1.69

1.59

1.74 1.18

2.32 1.42

1.46

1.67

0.58 0.95 0.88

0.60

Patients Treated with lntracoronary ISDN (group B) 11 12 13 14 15 16 Mean& SD

82 97 78 67 62 84 80

90

105 88 70 63 89 86*

11

11

93 88 85 93 132

73 79 73 90 128

100 97 15

87* 15

7.6 8.5 6.6 6.3 8.3 8.4 7.6 0.8

91

6.6 8.3 6.4 6.3 8.2 8.1 7.3* 0.8

1.23 0.63

65

78

1.43

1.15

150

0.88

0.80 0.83

110

160 109 94t

50

44

0.39

98

1.02 1.03

1.11 0.49

l p
TABLE Ill

Effects of lsosorbide Dinitrate WDN) on Systemic and Coronary Hemodynamics at Peak Pacing MAP (mm Hg)

Heart Rate (beats/min) Patient

Control

ISDN

Control

RPP (beats/min . mm Hg x 103)

ISDN

Control

ISDN

GCVBF (ml/min) Control

ACR (mm Hg/ml/min)

ISDN

Control

ISDN

Patients Treated with Sublingual ISDN (group A) 2 3 4 5 6 7 8 9 10

1

140 150 120 140 150

130 140 110 140 140

102 104 111 121

94 102 105 97

14.3 15.6 13.3 16.9

150 140 140 160 130

83 79 83 102 94 88

73 65 82 94 114 74

12.5

150 130 130 150 130

11

150

150

83

12

80

130 140 130

100

93

14

130 150 140

15 16

130 150

130 150

Mean-t SD

142

136*

11.9 11.6 14.3 15.0 11.4

12.2 14.3 11.6 13.6 10.2 9.8 10.7 12.2 17.1 9.6

152

92

173

128

199

138

151 146 83

108 67 53 48

0.67 0.60 0.56 0.82 0.57 0.95

1.02 0.80 0.76 0.93

59 94

1.69 1.02 1.04

1.08 1.22 1.71 1.59 1.21

68

64

1.30

1.16

144

110

103 138 90 187 141 126 44

90

0.58 0.97 0.72 1.21 0.75 0.77 0.89 0.31

0.73 1.03 0.73 1.17 0.74 0.80

49 100 90

Patients Treated with lntracoronary ISDN (group B)

13

11

11

99

73

109 141 108 100 16

101 136 111 93* 18

12.5 13.0 14.9 15.3 18.3 16.2 14.2 2.0

12.0 12.1 10.2 13.1 17.7 16.7 12.7* 2.6

l p
344

THE AMERICAN JOURNAL OF CARDIOLOGY

VOLUME 72

AUGUST 1,1993

100 86 185 138 98* 37

1.04t 0.30

lasting 2 minutes, until development of angina1 pain and diagnostic ST-segment changes (10.15 mV) or achievement of the maximal tolerated level of heart rate (150 to 160 beatslmin). Great cardiac vein blood flow was measured at rest ana’ during pacing, both off drugs and after isosorbide dinitrate. The drug was administered sublingually (IO mg) in 10 patients (group A); the intracoronary route (2 mg) was used in the remaining 6 (group B). Coronary arteriograms were repeated at the end of the procedure (i.e., IO to 1.5 minutes afier isosorbide dinitrate). The electrocardiogram was monitored with 1 bipolar lead (CM5). All group data are presented as mean f SD. Data were analyzed using the Student t test for paired data. Statistical signtjicance was assumed at the 0.05 probability level. Hemodynamic data at rest are summarized in Table II. Heart rate was significantly (p
isosorbide din&rate caused a consistent (p
P

+ 40 -

2 P 2

+ so-

<0.05,

i! s

+ 20,

g 2 0 8 1

+lO-

z I P 8

--

---------

0 -.---

- lo-

z B P

- 20 -

I 0 8.

- 30 -

- 40

I BASELINE

1 ISOSORBIDE DINITRATE

BRIEFREPORTS 345

on the systemic and coronary circulation. Therapeutic dosessublingually administeredhave large effectson the conductive arteries and veins throughout the body; they may also causemoderateperipheral arterial dilation with a resultant slight decreasein blood pres~ure.~Higher doses may also a&& coronary arteriolar vessels, but may induce a larger decreasein arterial blood pressure with concomitant adverseside effects.Thus, a better solution to assessthe effectsof nitrates on small coronary resistancevessels is to administer lower doses through the intracoronary route. In the present study, isosorbide dir&rate was admiuistered sublingually in 10 patients

underwent atria1 pacing. In all patients in group B, the net increment in great cardiac vein blood flow at peak pacing was ~50% which was comparable to that in group A. There are so many possible mechanismsby which nitrates may benefit myocardial ischemia that they are usually administeredas drugs of first choice in the overall anginal population, including patients who have chest pain despiteangiographically normal appearingcoronary arteries. A source of confusion in studies designed to test which actions of nitrates are important is the inability to recognize the different effects of these drugs

. ISDN 8.1. 0 ISDN i.c.

TIME TO ANGINA (SW

600

[,

:

.

“’

*

ISDN

BASELINE

CHEST

CHEST

ai.]

FiauRE2.Timetotlccu-of~M duhlgamalpachgt-dhRmte (l6DR)lNMl~~-of Jmglnaluwshaul.c.=inbacoronary; 8.1.= sll#inIpld.

l oo

l oe

2”

CHEST

2

FlGURE2lIbl2VldWl~dS (wmof-af --(=I athlnl~byMry (I&) route. Measure mentsof~cadlacveh bloalRow(6cvF)wereob tdndatsadal-corr

4”

60 110 -I

-(cl~w-lm

3

3

=g

346

0.9

$

0.7

5

0.6 0.6 1 0.5

12 I PEAK AP

, ”

,

0 I c3

2 I C4

5

7 I c5

10 I C6

ISDN 2 mQ l.c.

THE AMERICANJOURNALOF CARDIOLOGY VOLUME72

AUGUST1,1993

18 I PEAK AP Tlma (mln)

I

-P=w(Ap).bldodhlbateuulsedtrarr sientlnaea8elnbioodnow @Idand-paln.Pahmdchmgesln bloodflowdlmweadln fewmlnutes(c.).Tlmeto m-v%Rwn1Olllht6SWlUlOUt thgeto8minuteswlth nbates.ACR=aktiorco~ -MA?= maatkprmwro.

and by the intracoronary rate in the remaining 6. Both protocols involved pacing patients at increasing rates until they had angina and ST depression. The results showed that both sublingual and intracoronary administration of nitrates could reduce the ischemic threshold, causing a concurrent decrease in aortic pressure and coronary flow at peak pacing. Individual analysis of the response to nitrates before pacing showed that sublingual isosorbide dir&rate could diminish flow soon after its administration, whereas its intracoronary administration caused a transient increase in flow in 4 of 6 patients, which was often associatedwith the development of chest pain and ST depression. Symptoms and increasedblood flow persistedfor a few minutes, and then disappearedspontaneously. The decreasein blood flow after systemicadministration of isosorbide dinitrate was parallel to changes in aortic pressure, and was probably due to the combination of decreasedcoronary perfusion pressure and myocardial oxygen demand.(jNormally, the effects of decreasedarterial blood pressureon coronary flow reserve are minimal or absent,becauseof compensatorydilation of downstream resistancevesselsdue to autoregulation. If autoregulation is impaired so that an appropriate compensatory dilation of resistance vessels can not occur, as in the present patients, then reduction of arterial pressuredue to administration of nitrates will cause coronary flow reserve to decrease.This may influence the level of anginal threshold at peak pacing and explain the paradoxical effects of these drugs. In this study, it was also shown that a relatively high local dose of isosorbide dir&rate administered by the intracoronary mute may cause a transient increase in flow at rest, which should result from coronary arteriolar vasodilation. Becausethe subendocardialareaswould have been fully vasodilated, further drug-induced vasodilation of small coronary arteries should only have occurred in the subepicardialareasof the muscle. This may have caused transmural myocardial blood flow steal. The pathogenesisof angina with normal appearing coronary arteries remains unkn~wn.~~~ The cause of the implied coronary microcirculation dysfunction does not have to be the same in all patients. The present study examined a subset of patients in whom chest pain was ischemic, as shown by the occurrenceof regional perfu-

sion defects during exercise.It has been speculatedthat a possible cause of impaired microvascular activity could be due to the endothelium-derived relaxing factor.9 This substancemay be nitric oxide or a closely related molecule.*oThe fact that isosorbide dir&rate was found to be ineffective in improving symptoms and STsegment changes during atrial pacing does not support the hypothesis that an impaired releaseof endotheliumderived relaxing factor may have a role in causing abnormal arteriolar constriction, at least in the present series of patients. In conclusion, this study was performed in a cohort of patients with angina pectoris and normal coronary angiograms showing a reduced coronary flow response to pacing and reversible thallium abnormalities during exercise.The results of this investigation show that isosorbide din&ate may further reduce coronary flow response to pacing, thus increasing the discrepancy between myocardial oxygen demand and supply. An inability of the autoregulatory mechanismsto adequately maintain coronary blood flow during decreasedaortic pressure is probably the reason for this unexpected effect. 1. Cannon RO, Leon RM, Rosing DR. Epstein SE. Angina causedby reduced vasodilator reserve of the. small coronary arteries. J Am CON Cardiol 1983;l: 1359-1373. 2. Brown GB, Bolsoo E, PetersenRB, PierceCD, Dodge HT. The mechanismof nitroglycerinaction:stenosisvasodilationasa majorcomponentof thedrugresponse. Circularion 1981;&1:1089-1096. 3. Ganz W, TamuraK. Marcus HS, Donoso R, Yoshida S. Swan HJC. Measurement of coronary sinusblood flow by continuousthermodilutionin man. Circuladon 1971;44:181-195. 4. Mathey DG, ChatterjeeK, Tyberg JV, Lekven J, BmndageB, Parmley WW. Coronary sinus mflux: a sourceof emx in measurementof themmdilutioncommy sims flow. Circulation 1978;57:778-786. 5. Badger RS, Brown BG, Gallery CA, Bolson EL, Dodge HT. Coronary artery dilatation and hemodyoamicresponseafter isosorbidedinitmte therapy in patients with coronary artery disease.Am J Car&l 1985:56:390-395. 6. Cohn PF, Maddox D, Hohnan LB, Ma&is JE, Adams JE, See JR. Effects of sublinguallyadministeredoitroglywin on regionalmyowdial blood flow in patients with coronary artery disease..I Am Co11Cardiol 1!977;39:672-678. 7. Maseri A, Crea F, Kaski JK, Crake T. Mechanismsof anginapectoris in syndrome X. J Am CONCardiol 1991;17:499-506. 8. CannonRO, EpsteinSE. “Microvascular angina” as a causeof chestpain with aogiogmphicallynormal coronary arteries.Am J Cardiol 1988;61:13311343. 9. V&s CJM, Bolt H, Hitter E, HermaoAG, SnoeckJF’.Impairedendotheliumdependentcholioergic coronary wsodilation in patients with angina and normal coromwyarteriogmms.J Am CONCardiol 1992;19:21-31. 10. palmer RMJ, Fenige AG, Moncada S. Nitric oxide releaseaccountsfor the biological activity of endotheliumderivedrelaxingfactor.Nature 1987;327:524526.

Serum Ferritin is Not a Risk Factor for Coronary Artery Disease in Men and Women Aged 262 Years Wilbert S. Aronow. MD in middle-aged EasternFinnish men. Therefore, we performed a study to correlate serum ferritin levels with the prevalence of CAD in elderly men and women. Serumferritin levels were obtained after a 14-hour showed that increasedserum ferritin levels were associated with an excessrisk of acute myocardial infarction overnight fast in I71 unselected elderly men and 406 unselectedelderly women in a long-term health carefaFrom Hebrew Hospital Home, 801 Co-op City Boulevard, Bronx, New cility. Blood was also obtained at the same time for York 10475;and the Departmentof Geriatrics and Adult Development, Mount Sinai School of Medicine, New York, New York. Manuscript hemoglobin and hematocrit determinations. The mean age of women with CALI was 82 + 8 years (range 62 received January 19, 1993; revised manuscript received and accepted to 100) and without CAD 81 f 8 years (range 62 to March 3, 1993.

ulli~at$~~hypothesizedthat iron overload is a major cause of the greater occurrence of coronary artery S disease (CAD) in men than in women. Salonen et al3

BRIEFREPORTS 347