Small vessel pathology and coronary hemodynamics in patients with microvascular angina

FI SEWER SCIFNCI IRFLANI>

International

Journal

of Cardiolog)

42 ( 19041

13%

I50

Small vessel pathology and coronary hemodynamics in patients with microvascular angina Hiroshi

Suzuki*,

Youichi

(Received

Takeyama, Shinji Takashi Katagiri

Y July

1993;

revision

accepted

IJ October

iYY?)

Abstract We studied the ultrastructure of cardiac myocytes and small blood vessels obtained by endomyocardial biopsy from 21 patients with microvascular angina. lschemic ST segment depression during atrial pacing was recognised in all the patients who had normal coronary arteriograms and biopsy tissues were examined by light and electron microscopy. In patients with microvascular angina, insufficient increases in coronary sinus blood flow and in myocardial oxygen consumption measured with a Webster’s catheter were apparent during atrial pacing. Biopsy samples under the light microscope showed evidence of myocardial hypertrophy and sclerosis of small arteries and arterioles with perivascular fibrosis in I8 of I9 (95%) patients. Electron microscopy revealed that many endothelial nuclei in capillaries were swollen and that lumina of small arteries and arterioles were irregularly narrowed with proliferated and deformed medial smooth muscle cells. These findings suggest that disturbances in the coronary microcirculation in these patient5 is responsible for the ischemic changes in electrocardiograms. Kq, words: Microvascular angina; Coronary of small arteries; Arteriolosclerosis

microcirculation:

In 1967, Likoff et al. [I] described a group of patients, mainly women of about 40 years of age. who had angina-like episodes such as ST segment depression and T wave flattening or inversion. both at rest and after exertion despite normal coronary arteriograms as well as clear ischemic changes on their electrocardiograms (EC&).

Ol67-5273/Y41$07.00 SSDl

author.

G) 1994

0167-5273(93)01924-M

Elsevier

Science

Ireland

Ltd.

All

X: Vascular

ultrastructure:

Arteriosclerosis

These patients were diagnosed as having syndrome X by Kemp [2] in 1973 and the pathogenesis of this condition is still controversial. In recent years. abnormalities of the coronary microcirculation. such as small vessel disease [3] and impaired vasodilatol reserve [4] have been suggested as being involved in the etiology of this syndrome. Cannon and Epstein [4] called the syndrome microvasculal angina and, recently, this terminology has become widely accepted. We consider that the cause of this disease is arteriosclerosis of small arterial levels

1. Introduction

* Corresponding

Syndrome

rights

rescrvcd

H. Suzuki ei ul. /Int.

140

because many of our patients showed slow progression of dye and mild luminal narrowing from the mild to distal portion of the epicardial coronary arteries on coronary angiography. In order to investigate the pathogenesis of syndrome X, we measured coronary sinus blood flow, myocardial oxygen consumption and the myocardial lactate extraction rate during cardiac catheterization, while performing some provocations. Finally, myocardial samples were obtained by biopsy from both ventricles, and the myocytes, small arteries, arterioles and capillaries were examined in detail by light and electron microscopy. 2. Patients and methods 2. I. Patients Informed consent for the study was obtained from each patient and the study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a priori approval by the human research committee of our university. Patients with organic epicardial coronary artery disease, vasospastic angina, valvular heart disease, hypertensive heart disease, idiopathic cardiomyopathy, endocrine or metabolic disease and collagen disease were excluded from the study. Studies were carried out on 21 patients with microvascular angina who were admitted to our hospital during the period from January 1988 to December 1991. The criteria for inclusion in the study were the occurrence of ischemic ST segment depression (1 mm or more of horizontal or downsloping depression at 80 ms from the J point) in many ECG leads (mostly II, III, aVf and Vs-V,) either at rest or during treadmill exercise or right atria1 pacing. There were 3 males and 18 females, with a mean age of 56.9 + 9.0 years (range, 39-75 years). The demographic, clinical and morphologic data for the patients with microvascular angina are summarized in Table 1. The control group consisted of 10 patients with neurocirculatory asthenia, also called cardiac neurosis (5 males and 5 females with a mean age of 53.1 f 5.90 years; range, 41-59 years), who had chest pain but no ECG changes. 2.2. Methods Hemodynamic

parameters

were initially

deter-

J. Curdiol. 43 (1994) 139-150

mined, and then left ventriculography and right and left coronary angiography as a control were performed. Right and left coronary angiography was repeated during atria1 pacing at a rate of 150 beatsimin for 5 min, after a stepwise intravenous injection of ergonovine maleate up to a dose of 0.4 mg, and the administration of 2.5 mg of isosorbide dinitrate into each coronary artery, as well as during atria1 pacing after the administration of isosorbide dinitrate. A Webster’s thermodilution catheter was placed in the coronary sinus to measure coronary sinus blood flow. Coronary sinus blood flow (mlimin) was measured during each procedure and myocardial oxygen consumption (mlimin) and the myocardial lactate extraction rate (%) were determined by simultaneous blood sampling from the aorta and from the coronary sinus. Coronary sinus blood flow was measured using a Webster’s coronary sinus flowmeter (CF300A; Webster Labs.. London, UK). Myocardial oxygen consumption was calculated using Eq. I, shown below, and the myocardial lactate extraction rate was calculated using Eq. 2 after the lactate level was measured by an enzymatic method using lactate oxidase. MVO: = (Ao-CSO?) x CSBF LER = Lac(Ao-CS)/Lac.Ao

x 100

(1) (2)

where MVOz (mlimin) is myocardial oxygen consumption; CSBF (mlimin) is coronary sinus blood flow; Ao-CSO? (ml/100 ml blood) is atrialcoronary sinus oxygen difference; LER (I%,) the myocardial oxygen consumption rate; Lac(Ao-CS) (mgidl) the lactate level between aorta and coronary sinus: and Lac.Ao (mgidl) the lactate level in aorta. Biopsy samples were obtained from several sites in both ventricles (3 from the right ventricle and 5 from the left ventricle on average) with a Machida bioptome. The tissue specimens for light microscopy were fixed in 10% formalin, dehydrated in a graded ethanol series, and embedded in paraffin. The tissue specimens were cut into 3-pm sections and stained with hematoxylin and eosin, azan, elastica van Gieson and periodic acid-Schiff before observation under light microscopy. The tissue specimens for electron microscopy were cut into lmm3 blocks and prefixed for 2 h in 2.5%

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et al. ,/Int.

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Table 1 Clinical and morphological Case

data in patients

139-150

141

with microvascular

angina

Initials

Age (years)

Sex

Gradingd

Diameterb

ST (mm)

EF

2 3 4 5 6

KK RK TT TS RA TA

45 56 50 59 58 39

F M F F F M

I 3 3 2 3 3

+ + + + ++ +

3.0 3.0 2.5 2.0 2.0 2.0

0.82 0.82 0.X6 0.6X 0.67 0.80

I

TK

70

F

2

++

2.5

0.52

8 9 10 II 12 I3 14

JS MU HS KS SH YY MH

51 63 58 56 50 49 56

F F F F M F F

7 3 3 3 3 3 2

+ + f + + ++ +

3.0 2.0 3.5 2.5 2.0 3.5 3.5

0.69 O.hS 0.63 O.YO 0.69 0.79 0.96

15 16 17 IX 19 20

TS .4K HA NM MY MT

46 65 63 67 75 53

F F F F F F

2 3 3 _ 2

+ +++ + if ++

3.0 2.0 3.0 3.0 5.0 2.5

0.70 0.x0 0.68 0.82 0.62 0.75

21

TK

66

F

2

+

2.0

0.70

1

Ahbresiutions:

F. female:

M. male; ST, maximum

ST segment

depression

during

right atrial

pacing;

EF. ejection

fraction

in left

0. none:

I. mild:

ventricle. “Quantitative assessment, O-3. of degree of wall thickening and luminal narrowing in small arteries 2. moderate; 3. severe. -. cases did not have small vessels that can be assessed. ‘Mean transverse diameter of cardimyocytes in left ventricle (pm). -, < 18; +. 19-23: ++. 24-28;

glutaraldehyde. They were then posttixed for 2 h in 1% osmium tetroxide. Specimens were dehydrated in a graded ethanol series and then embedded in Epon-Araldite. Ultrathin sections were made in the usual manner and double-stained with uranyl acetate and lead citrate, and then examined under a transmission electron microscope (H7000; Hitachi, Ibaragi). Small arteries and arterioles were examined by electron microscopy to assess changes in the intima, media, and adventitia. The presence of arteriosclerosis was determined in vessels of 50-150 pm in external diameter by light and electron microscopy, and only transversely sectioned vessels were examined. Thickening of walls of small arteries or arterioles and luminal narrowing were graded according to the modified classification of the Pathology Branch of the National

and arterioles. +++.

>29.

Heart, Lung and Blood Institute, National Institutes of Health [5] using the following scale of O-3: 0, none (Fig. la); 1, mild change (Fig. I b): 7. moderate change (Fig. lc); and 3, severe change (Fig. Id). Patients with small arterial or arteriolar disease of grades 2 or 3 on the scale were considered to have arteriosclerosis. Endothelial cytoplasmic, nuclear. and other ultrastructural changes of the blood capillaries were examined by electron microscopy. Transverse views of five blood capillaries of 5- 10 pm in external diameter, including endothelial cell nuclei. were selected at random from each patient, and the area of the whole capillary (C), the area of the endothelial cell (E), and the area of the endothelial cell nucleus (N) were measured with a digitizer (Graphtec Inc.). Then the ratio of E/c’ and the ratio of N/C were calculated [6]. The data were

H. Suzulii ri ul. /Inr.

142

Fig. I. The grading of thickening hematoxylin

small arterial

or arteriolar

J. Car&l.

43 (1994)

139-150

walls and luminal narrowing

and eosin; bar, 50 pm: (b) I. mild; hematoxylin

on a scale of O-3 is shown. (a) 0. none: and eosin; bar. 50 pm; (c) 2. moderate: hematoxylin and eosin; bar.

50 pm: (d) 3. severe; azan: bar. 50 pm.

analysed statistically using Student’s t-test to determine the significance of differences between the control group and the microvascular angina group. A P value of less than 0.05 was considered to indicate statistical significance. Changes in myocardial cells and organelles were also carefully examined. 3. Results A representative case of microvascular angina is illustrated in Fig. 2. In almost all patients in the microvascular angina group, left ventriculography did not reveal any abnormality in wall motion. Coronary angiography was normal in the basal state, but the velocity of coronary arterial blood Ilow was reduced, as shown by the slow progres-

sion of dye from the mid to the distal portion of the coronary arteries, which was associated with mild narrowing. 3. I. ECG changes after various provocation tests During right atria1 pacing, the control group only revealed evidence of J-type ST segment depression of less than 2.0 mm, whereas all patients in the MVA group had 1.0 mm or more of horizontal or downsloping ischemic ST segment depression in several leads (mostly II, III, aVf, and V3-V6). When J-type ST segment depression was found soon after the start of pacing, it advanced to horizontal or downsloping depression within a few minutes. The mean maximal ST segment depression was 2.69 f 0.77 mm in leads V3 or V4 on average. ST segment depression was noted as soon

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LVG RAO 30”

LAO 60”

Enddiastole

Endsystole

Hemodynamic

parameters

Fig. 2. Left ventriculography and hemodynamic parameters in a representative case of a patient with microvascular angina. Case 8: 51 years, F. Left ventriculography did not show any abnormalities in wall motion and coronary hemodynamic parameters

were normal.

as right atria1 pacing was started at a rate of 150 beats/min, and the time to maximum ST segment depression was shorter than it was in patients with epicardial vessel coronary artery disease. Furthermore, recovery to the baseline of the depressed ST segment after the cessation of pacing tended to be protracted. Intravenous ergonovine maleate, at doses up to 0.4 mg, was used to examine epicardial coronary artery spasm, but at this dose the drug failed to provoke vasospasm, although slight contraction was seen on coronary angiography without any ECG changes. Then 2.5 mg of isosorbide dinitrate was injected into each coronary artery to confirm that they were entirely non-

143

sclerotic, and much slower progression of the dye was observed. Right atria1 pacing after administration of isosorbide dinitrate produced similar ischemic ST segment depression in response to basal right atria1 pacing (Fig. 3). 3.2. Changes in coronary circulation As shown in Fig. 4a, basal coronary sinus blood flow (ml/min), measured with a Webster’s catheter, in the control and microvascular angina groups was 119 f 25 and 113 f 30, respectively. Coronary sinus blood flow increased to 342 f 81 in the control group with right atria1 pacing but rose only to 178 f 49 in the microvascular angina group. Thus, there was a marked difference between the two groups (P < 0.001). During similar pacing after administration of isosorbide dinitrate, coronary sinus blood flow increased to 251 f 34 in the control group, but to no more than 154 f 56 in the microvascular angina group, again showing a significant difference (P < 0.0 1). By contrast, myocardial oxygen consumption (ml/min) was 8.6 f 1.5 and 8.6 f 2.0 in the control and the microvascular angina group before pacing, respectively. During right atria1 pacing, myocardial oxygen consumption increased to 21.1 f 10.7 in the control group, but to only 12.2 f 4.0 in the microvascular angina group (P < 0.001). Myocardial oxygen consumption increased to 14.9 f 10.6 in the control group, but to no more than 10.0 f 1.8 in the microvascular angina group during similar pacing after administration of isosorbide dinitrate (P < 0.001; Fig. 4b). As for the myocardial lactate extraction rate (%), it barely changed in the control group throughout the study, while it decreased from 22 f 16 to 12 f 14 during pacing in the microvascular angina group (no significant difference; Fig. 4~). 3.3. Histological findings Light microscopy. Light microscopic examination of specimens from patients with microvascular angina revealed mild myocardial hypertrophy with a marked increase in lipofuscin granules in the perinuclear areas. The average transverse diameter of the myocytes in the left ventricle was significantly greater in the microvascular

H. Suzuki PI ul. /IN.

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I ii__

pi+&

I

J. Cardiol. 43 (1994) 139-150

.L-.___A

n

In 1”.

EIVR

n

-f-J---;-

11,

aVL

n

~T---Y-

aVF

VI

V2

V3

Vd

v5

VS

(a) Fig. 3. ECG changes

in a representative

(b)

(c)

case of a patient with microvascular

(d) angina.

(9)

Case 13: 49 years, F. (a) In the basal state, ECG

showed a normal sinus rhythm and no ST-T changes were found. (b.c) During atrial pacing at I50 beatsimin. horizontal or downsloping ischemic ST segment depression in several leads (mostly II. 111, aVf, and Vs-V,) was recognised and similar changes were apparently found just after pacing. (d,e) During right atrial pacing after administration of isosorbide dinitrate and just after pacing. similar ischemic ST segment depression was found.

angina group than in the control group (21 f 6 pm vs. 16 f 4 pm; P
evidence of interstitial fibrosis or endomyocardial hypertrophy. More detailed observations of the small vessels revealed that the luminal narrowing was mainly due to a medial component, but the intimal changes were generally less conspicuous than those seen in larger arteries with atherosclerosis (Figs. 5 and 6). Thickening of walls of small arteries and arterioles and luminal narrowing was

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I45

Fig. 4. Changes in (a) coronary sinus blood flow (mlimin); (b) myocardial oxygen consumption (ml/min): (c) lactate extraction rate (‘l/u)with various loadings in patients with microvascular angina and in controls. RA-pacing, right atrial pacing; ISDN, isosorbide dinitrate. The microvascular angina group (n = 21) is shown by solid symbols, the control group (n = IO) by open symbols. *P < 0.05: **P < 0.01; ***P < 0.001. (a) Coronary sinus blood flow (mUmin) increased to 342 f 81 in the control group with right atrial pacing and only rose to 178 f 49 in the microvascular angina group. giving rise to a marked difference between the two groups (P < 0.001). During similar pacing after administration of isosorbide dinitrate. coronary sinus blood flow increased to 251 + 34 in the control group, but to no more than I54 f 56 in the microvascular angina group, again showing a signifwant difference (P < 0.01). (b) During right atrial pacing, myocardial oxygen consumption (mUmin) increased to 21. I * 10.7 in the control group and only to 12.2 f 4.0 in the microvascular angina group (P < 0.001). Myocardial oxygen consumption increased to 14.9 f 10.6 m the control group. but to no more than 10.0 f I.8 in the microvascular angina group during similar pacing after administration of isosorbide dinitrate (P < 0.001). (c) Myocardial lactate extraction rate (‘X) barely changed in the control group throughout the study. while it decreased from 22 f I6 to 12 f I4 during pacing in the microvascular angina group (no significant difference).

classified as grades 2 or 3 in 18 of 19 patients (95%) (grade 2, 12; grade 3, 15) in the microvascular angina group, while only one patient (5”/0) had changes classified as grades 0 or 1. Two patients in the microvascular angina group were excluded from this evaluation because of a lack of assessable small arteries or arterioles in their biopsy specimens. Although 4.8 pieces on average were obtained from the left ventricle, assessable small arteries or arterioles were found in only 1.6 pieces on average and diseased vessels (grades 2 and 3) were recognised in 1.3 pieces on average in the microvascular angina group. Similarly, although

2.6 pieces on average were obtained from the right ventricle, assessable small arteries or arterioles were found in only 1.0 pieces on average and diseased vessels were recognised in 0.6 pieces on average in the microvascular angina group. However, the control patients had small arterial or arteriolar changes classified as grades 0 or 1. Although the number of controls with grade 1 changes increased with age, none of the controls had changes classified as grades 2 or 3. Electron microscopy. Electron microscopy of the intima of the small arteries and arterioles revealed no signs of atherosclerosis (such as atheroma,

146

Fig. 5. A light micrograph of small arteries with marked perivascular fibrosis in a patient with microvascular angina, showing wall thickening and luminal narrowing that is mainly due to the medial component (hematoxylin and eosin; bar. 100 pm). Case 6: 39 years, M.

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Fig. 7. An electron micrograph of a small artery showing marked thickening and overlapping of the internal elastic lamina (IEL) in a patient with microvascular angina (bar, IO pm). Case 17: 63 years, F.

crystallization of cholesterin and the migration of smooth muscle cells) but the nuclei of the endothelial cells tended to be swollen and the chromatin was marginalized. The internal elastic lamina showed various changes, which included marked thickening and overlapping (Fig. 7). In the media, smooth muscle cells showed proliferation reflecting the pronounced and deformation, medial thickening (Fig. 8), as found also at the light microscopic level. The adventitia did not

show any appreciable changes, although the vessels were surrounded by fibrotic tissue. As shown in Fig. 9a, capillaries in the microvascular angina group also showed clear swelling of the endothelial cells that resulted in a significant increase of the E/C ratio from 0.20 f 0.057 to 0.35 f 0.086 in the control group (P < 0.001). Most of the nuclei of the capillary endothelial cells were also swollen and the electrondense chromatin was marginalized in many of them. Since the magnitude of N varied with each cross-section examined, it is difficult to define

Fig. 6. The lumen of a small artery is hardly visible as a result of medial thickening in a patient with microvascular angina. (hematoxylin and eosin; bar, 100 pm). Case 2: 56 years, M.

Fig. 8. Another electron micrograph of a small artery from a patient with microvascular angina, showing medial thickening and concomitant narrowing of the lumen (L) with proliferation and deformation of smooth muscle cells (SMC) (bar, 10 pm). Case 18: 67 years, F.

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100

70

P
60 50

C-J 40

s y

w

z

30

g

50

i

!

30

40

20

20

10

10 control

Mtcrovascular

controlMtcrovascular

a”gl”a

(b)

(a) Fig. 9. A bar graph

angIna

of results of ultrastructural

measurements

of capillaries in the control and microvascular angina groups. (a) Area of endothelial cytoplasm (E) divided by the transverse area of the capillary (B). Capillaries in the microvascular angina group revealed obvious swelling of the endothelial cells that resulted in a significant increase in the E/C ratio to 0.35 + 0.086 a compared with 0.20 f 0.057 in the control group (P < 0.001). (b) Area of endothelial nuclei (N) divided by B. Because most of the nuclei of the capillary endothelial cells were also swollen, the ratio of N/C was significantly increased to 0.54 f 0.20 in the microvascular angina group, as compared with the value of 0.29 f 0.12 for the control group (P < 0.001).

nuclear swelling on the basis of values of N. However, the N/C ratio was significantly increased to 0.54 f 0.20 in the MVA group, as compared with the control value of 0.29 f 0.12 (P c 0.001; Fig. Yb). The capillary lumina were irregularly narrowed, but perivascular fibrosis, observed around the small arteries and arterioles and lamination of the basal lamina, was rarely found in capillaries of the microvascular angina group (Fig. 10). As in the case of light microscopic observations, little myocardial degeneration was found and other changes, such as the thinning of myotilaments and mitochondrial swelling were only slight, although a marked increase in the number of lipofuscin granules was found in perinuclear areas (Fig. 11). 4. Discussion We consider that the cause of this disease, i.e. so-called syndrome X, is arteriosclerosis of small

Fig. IO. An electron micrograph of a capillary from a patient with microvascular angina, indicating clear swelling of the cytoplasm (Ej and the swollen nucleus (M) of an endothetial cell (bar, I pm). Case 3: 50 years. F.

arterial levels because many of our patients showed slow progression of dye and mild luminal narrowing from the mid to distal portions of the epicardial arteries on coronary coronary angiography, and a myocardial biopsy is required for the diagnosis of this disease. However, there were no detailed reports about the small vessel pathology of this disease. Therefore, in this study, we used myocardial biopsy to examine the vascular tissues from both ventricles of patients and controls and we found arteriosclerosis of small

Fig. I I Limited myocardial degeneration with marked increases in numbers of lipofuscin granules (arrow) is seen in an electron micrograph of a patient with microvascular angrna (bar. I pm). Case 5: 58 years. F.

148

arteries and arterioles that was mainly due to medial thickening in patients with this disease. Various causes of syndrome X have been proposed [7-l 11. Recently, Cannon and Epstein [4] and co-workers [ 12,131 made detailed studies of the coronary microcirculation and cardiac metabolism in patients with microvascular angina and reported that the etiology involved a decrease in the coronary vasodilatory reserve and an increase in coronary vascular resistance. They designated the syndrome as microvascular angina, and this term has recently become more widely accepted. They stated that these patients had a more generalised abnormality of vascular and nonvascular smooth muscle function [12], which was suggested to be a generalised sensitivity to vasoconstrictor stimuli, neural or humoral, or a generalized abnormality of myogenic tone, perhps related to disordered regulation of intracellular calcium levels [4]. Consistent with the results reported by Cannon and Epstein [4], the increase in coronary sinus blood flow and myocardial oxygen consumption during pacing was significantly smaller and the myocardial lactate extraction rate was also diminished in the microvascular angina group when compared with the control group. However, the myocardial lactate extraction rate was reduced to a lesser extent in the microvascular angina group than it was in a group of patients with organic stenosis of the epicardial coronary arteries, suggesting that microvascular angina patients have less serious myocardial ischemia than patients with epicardial coronary artery disease. Cannon and Epstein [4] also stated that their microvascular angina group showed smaller increases in coronary sinus blood flow than their control group after the intravenous injection of dipyridamole, which causes vasodilation, in particular of the coronary resistance vessels. These hemodynamic studies on coronary circulation suggest that some disturbance in coronary microcirculation occurs in vessels of less than 100 pm in external diameter, or a level that is beyond the resolution of coronary angiography. However, Cannon and Epstein did not perform myocardial biopsies to examine the cardiac microvasculature. In a morphologic study of biopsied cardiac samples, Mosseri and co-workers [3,14] reported

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libromuscular hyperplasia, hypertrophy of the media, myointimal proliferation, and endothelial degeneration in small arteries in patients with angina pectoris and large patent coronary arteries. However, there were some reports [15-171 that there were no findings of significant small vessel disease. On the other hand, in myocardial biopsies, only the small arteries and arterioles near the endocardium can be examined. It has been demonstrated at autopsy in cases of hypertrophic cardiomyopathy [5] that the distribution of abnormal arteries throughout a tissue section shows no particular predilection for the subendocardial or subepicardial regions. This observation suggests that endocardial tissue is sufficient for an assessment of the extent of vascular sclerosis. In only 1 of 19 (5%) of our patients, all the small arteries and arterioles in the biopsy samples showed grade 0 or grade 1 changes. It is also possible that abnormal small arteries and arterioles are distributed unevenly [18]. Therefore, it is necessary to obtain biopsies from several sites. The arteriosclerosis of small arteries and arteriolosclerosis of the coronary vessels differed from the so-called intimal atherosclerosis that is seen in epicardial coronary arteries and larger arteries. Similar arteriosclerosis of small arteries or arteriolosclerosis that is mainly due to medial changes has been reported in patients with hypertrophic cardiomyopathy [5,19], but the cause of such changes is not yet clear. Capillary endothelial cells are vulnerable to hypoxia. Endothelial swelling in the capillaries was noted in our previous experimental study of myocardial ischemia [20]. These findings led us to postulate that capillary endothelial swelling in the microvascular acgina group may have arisen from an insufficient supply of oxygen due to arteriosclerosis of small arteries and arterioles. Furthermore, fibrosis was observed around the sclerotic small arteries and arterioles but was inconspicuous in the other areas of the myocardium. Thus, this change also seems to be secondary to arteriosclerosis of small arteries and arterioles. Our study indicates that medial thickening of small arteries and arterioles leads to luminal narrowing in patients with microvascular angina, with resultant disturbances of the coronary microcir-

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culation. As a consequence, the capillary lumen also becomes narrower because of endothelial cell swelling, with further adverse effects on the coronary microcirculation. It is considered that these morphologic changes are intimately related to clinical manifestations such as ST segment depression and chest pain. It seems possible that a fairly large percentage of patients whose chest pain is now thought to be of non-cardiac origin or to be due to neurocirculatory asthenia may be diagnosed as microvascular angina by performing myocardial biopsy. We did not assess any abnormalities of coronary vasodilatory reserve [4] in the present study, although these are currently being investigated as a cause of microvascular angina. However, it is possible that arteriosclerosis of small arteries and arterioles and marked perivascular fibrosis could lead to disturbances in the dilation of the small vessels.

149

6

7

8

6. References Likoff W. Segal BL, Kasparian H. Paradox of normal selective coronary arteriograms in patients considered to have unmistakable coronary heart disease. N Engl J Med 1967; 276: 1063-1066. Kemp HG. Left ventricular function in patients with the angina1 syndrome and normal coronary arteriograms. Am J Cardiol 1973; 32: 375-376. Mosseri M. Yarom R, Gotsman MS, Hasin Y. Histologic evidence for small-vessel coronary artery disease in patients with angina pectoris and large patent coronary arteries. Circulation 1986; 74: 964-972. Cannon III RO, Epstein SE. ‘Microascular angina’ as a cause of chest pain with angiographically normal coronary arteries. Am J Cardiol 1988; 61: 1338-1343. Maron BJ, Wolfson JK, Epstein SE, Roberts WC. Intramural (‘small vessel’) coronary artery disease in hyper-

changes in blood capillaries among microvascular angina. and dilated carhypertrophic cardiomyopathy diomyopathy. J Clin Electron Microsc 1991; 24: 502-503. Kemp HG. Elliot WC. Gorlin R. The angina1 syndrome with normal coronary angiography. Tram Assoc Am Physicians 1967; 80: 59-70. Eliot RS, Bratt G. The paradox of myocardial ischemia and necrosis in young women with normal coronary

10

arteriograms. Am J Cardiol 1969: 23: 633-63X. Greenberg MA, Grose RM. Neubruger N. Silverman R. Strain JE. Cohen MV. Impaired coronary vasodilator responsiveness as a cause of lactate provocation during pacing-induced ischemia in patients with angina pectoris and normal coronary arteries. J Am Coil Cardiol 1987; 9: 743-75 I. Rubenfire M, Blevins RD. Barnhart M. Housholder S.

II

Selik N. Mammen EF. Platelet hyperaggregbility in patients with chest pain and angiographically normal coronary arteries. Am J Cardiol 1986: 57: 657-660. Bortone AS, Hess OM, Eberli FR, Nonogi H. Marolf AP,

9

5. Acknowledgements The authors express their sincere thanks to Professor Yasumitsu Nakai of the Showa University School of Medicine for his kind guidance and encouragement during this work, and also to Doctors Hitoshi Matsubara, Shigeo Hasegawa, Juichi Hiroshige, Mikitaka Murakami, Shin Inoue, ;Ind other fellow researchers at the Third Department of Internal Medicine, Showa University School of Medicine for their collaboration.

trophic cardiomyopathy. J Am Co11 Cardiol 1986: 8: 545-557. Suzuki H, Takeyama Y, Koba S. Suwa 1.. Matsubara H. Murakami M et al. Comparative studies on ultrstructural

12

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14

15

I6

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