Statistical analysis of clinical risk factors for coronary artery spasm: Identification of the most important determinant

Statistical analysis of clinical risk factors for coronary artery spasm: Identification of the most important determinant Coronary artery spasm plays an important role in acute ischemic events, and it has a close relationship with coronary atherosclerosis. Thus we attempted to determine the most significant risk factor for coronary artery spasm. Among 3000 consecutive patients who underwent coronary cineangiography with ergonovine maleate testing, 330 with typical angina pectoris (group 1) and 294 with old myocardial infarction (group 2) were studied. We divided each group into three or four subgroups according to the presence of fixed organic stenosis (FOS+) or a positive reaction to ergonovine maleate (coronary artery spasm [CAS]+). We examined the relationship between coronary artery spasm and eight coronary risk factors: age, sex, hypertension, diabetes mellitus, smoking, and serum cholesterol, uric acid, and high-density lipoprotein cholesterol levels. The proportion of smokers in the subgroups with CAS( +) was significantly higher than in the subgroups with CAS(-)(p < 0.01). There was no correlation between smoking and fixed organic stenosis. According to the results of multiple regression analysis, there was a positive correlation between smoking and CAS( +) and between serum high-density lipoprotein cholesterol levels and CAS(+)(p < 0.01). Thus we concluded that smoking is the most significant risk factor in discriminating between patients with and without coronary artery spasm. (AM HEART J 1992;124:32.)

Masakiyo Nobuyoshi, MD, Masayuki Abe, MD, Hideyuki Nosaka, MD, Takeshi Kimura, MD, Hiroatsu Yokoi, MD, Naoya Hamasaki, MD, Takashi Shindo, MD, Kazuo Kimura, MD, Toshika Nakamura, MD, Yoshihisa Nakagawa, MD, Nobuo Shiode, MD, Akira Sakamoto, MD, Hideaki Kakura, MD, Yoshihiro Iwasaki, MD, Kotaku Kim, MD, and Shouji Kitaguchi,

MD. Kitakyushu,

Japan

It is generally believed that, there is a close correlation between coronary vasospasm and coronary at,herogenesis and between coronary vasospasm and the progression of coronary atherosclerosis.‘-” Coronary artery spasm and coronary vasoconstriction play an important role in acute ischemic events, that is, acute myocardial infarction and exertional angina.4-6 Possible mechanisms have been proposed in which coronary art,erial thrombosis or coronary artery disease might provoke coronary vasospasm. Marzille et a1.5 and MacAlpins recently stated that coronary spasm might cause coronary atherosclero-

From Received

the Department

Reprint requests: KokuraMemorial tm, Japan. 4/l/3734

32

of Cardiolugg,

for publication Masakiyo Hospital,

,July 2, 1991;

Kokura accepted

Nobuyoshi, MD, l-l Kihune-machi,

Memorial

Hospital.

DEC :i~. 1991. Department Kokurakita-ku.

of Cardiology. Kitakyushu

sis. Other reports have hypothesized that individual risk factors themselves act to develop and accelerate coronary atherosclerosis and that coronary vasospasm is provoked by such atherosclerotic lesions 01 the coronary artery.g Thus the exact relationship between coronary vasospasm and coronary atherosclerosis is still controversial. For coronary vasospasm neither the pathophysiologic mechanisms nor the risk factors have yet been clearly elucidated. The purpose of this study was to determine the primary risk fact,ors for coronary vasospasm among the many risk factors that, have already been established.1°‘14 We attempted to evaluate these risk factors retrospectively by means multivariate analysis. METHODS Patients.

Among 3000consecutive patients admitted to the cardiovascular center at Kokura Memorial Hospital from ,July 1979 to September 1982, who had undergone

Volume Number

124 1

coronary arteriography with ergonovine maleate provocation testing, 330 with typical angina pectoris (group 1) and 274 with old myocardial infarction (group 2) were retrospectively reviewed (Tables I and II). Patientzs with more than 75cc segmental narrowing in the coronary artery’” were considered to have fixed organic stenosis (FOS+). In the ergonovine maleate provocation t,est a transient total or subtotal occlusion accompanied by chest pain and ECG evidence of transmural (ST segment elevation) or subendocardial (ST segment depression) &hernia is provoked in the coronary artery. Test results were considered positive for coronary artery spasm (CA%) when the occlusion was immediately relieved by the administration of isosorbide dinitrate or relieved spontaneously. All of the patients with CAS+ had chest pain and ST segment. alterations during the time of angiographic narrowing. Group 1 was divided into three subgroups: group A with FOS+ and CAS+, group B wit,h FOS+ and CAS-, and group C with FOS- and CA%; there were 103 patients in group A, 121 in group B, and 106 in group C. Patients who did not have both fixed organic stenosis and a positive reaction to ergonovine maleate were excluded because they might not have had ischemic heart disease. Group 2 was divided into four subgroups: group D with FOS+ and CAS+, group E with FOS+ and CAS-, group F with FOSand CA%, and group G with FOS- and CAS-; there were 87 patients in group D, 174 in group E, 10 in group F, and 23 in group G. None of the patients had undergone percutaneous transluminal coronary angioplasty before their first admIssion to our hospital. Coronary risk factors analysis. The risk factors used for statistical analysis in this study were hypertension, diabetes mellitus, hypercholesterolemia, smoking, age, sex, hyperuricemia, and plasma high-density lipoprotein (HDL) cholesterol level. Patients were considered to have hypertension if they met the criteria of the World Health Organization s or if they were already being treated for this condition. Diabetes mellitus was considered to be present in patients if they were already being treated for this condition or if fast,ing or 2-hour blood sugar levels after administration of 75 gm of glucose exceeded 120 mg/dl and 130 mg/dl, respectively.” If fasting serum cholesterol levels exceeded 250 mg/dl, the pakent was considered to have hypercholesterolemia. but for statistical analysis serum cholesterol levels were used. Iiormal serum HDL cholesterol levels range from 51 to 83 mg/dl in women and from 39 to 70 mg/dl in men. Normal serum uric acid levels range from 2.6 to 6.6 mg/dl in women and from 3.7 to 8.6 mg/dl in men. Patients who smoked at least 10 cigarettes/day for more than 1 year or had done so until less than 6 months before the onset of symptoms were considered smokers. Ergonovine provocation testing during coronary arteriography. Selective coronary angiography and ventriculography were performed by means of the Sones technique” as follows: First, cineangiograms of the left coronary artery were obtained in the 30-degree right anterior oblique projection and the right coronary artery in the

33

Risk factors for coronary spasm

Table

1. Patient

population

of group

Group A

FoSi+)

I

Group B -___

-

Group (’

C.4Sr+) (N = 1twi

P’X’C+J CASf-J (AI’ = 121 J

FOSf-i c’,4sc+j (A’ = 1061

S8.0 iI 8.6

59.9 * 9.6

ST.:, f 9.7

-

A,ve (yr) Sex Male

89 14 83 44 15

Female

(86.4’ i ) (13.6’r) (80.6’1 ) (42.7’, ) (14.6’, I

Smoking Hypertension Diabetes mellitus Coronary artery disease 68 (66.1”, 1VD

) 30 (39.1 (‘I ) s ( 4.8’, )

2VD 3w Ft)S, Fixed ~1 discahe;

organic stenosis; PVU, double-\wsel

87 34 71 69 26

(S1.9’r (%8.1’, (58,S’, 157.0’< (XS’,

1 i 1 1 i

53 (4X8’, ) 44 (X.4’, ) “4 (19.X’ #.1

x7 (82.1’1) 19

(17.11’,)

82 (77.4”< 37 (34.Y’i 8 I 7.5’, 0 / I) ( 0 (

) ) I

0’ ; k I)‘, ) O’, i

(‘AS. coronary arteryspasm: I VD. single-vesdisease; .PVD. triple-vessel diseae.

60-degree left anterior oblique projection (control cineangiograms). Second, each patient initially received ergonovine maleate, 0.05 mg - 0.2 mg t.hrough a catheter positioned at the sinus of Valsalva; the ergonovine injected through the catheter was not injected directly into the coronary artery. Four minutes after the initial ergonovine injection, cineangiograms of the right and left coronary arteries were obtained in the same projections as the control cineangiograms. At that time if total or subtotal occlusion of the coronary artery was detected with chest pain and ECG changes, that is, ST segment elevation or depression. the ergonovine provocation t,est result,s were considered positive and this test was completed. If at that time the test results were negative, ergonovine maleate, 0.05 mg every 4 minutes, was administered and the preceding procedure was repeated until the cumulative dose reached 0.4 mg. If the test results were positive isosorbide dinitrate. 5 - 20 mg, was injected at the sinus of Valsalva, and the occlusion induced with ergonovine was promptly relieved. The 35 mm coronary cineangiograms were reviewed with a Tagarno projector on a 22 X 30 cm screen. The fixed organic stenosis of the coronary artery was estimated by three cardiologists according to the American Heart Association classification.‘” All drugs including long-acting nitrates and calcium channel blockers were discontinued at least 24 hours before coronary arteriography, with the exception of sublingual nitroglycerin for angina. Statistical analysis. Chi-square analysis and nonpaired Student’s t test were used for comparison of coronary risk factors among the three subgroups in group 1 and the four in group 2. Fur all 604 patients in groups A and B, we analyzed the relationship between each coronary risk facto] and coronary vasospasm by means of multivariate analysis especially multiple regression analysis. Coronary arteq spasm was used as a dependent variable and eight inde pendent variables were selected for multiple regressio: analysis. with cluster analysis used to explain the relation

34

riu,y 1992

i?obuyoshi et al.

American

Heart

Jourwl

FOS(t1 GAS(t)

FOS(t1 CASH

FOSH CAS(t1

Smokins

Diabetes Mellltus

Fig. 1. Group 1: Smoking, hypertension, and diabetes mellitus.

FOS(t) CASH)

82.1%&l

j N=W

,

-

P~l+Ol FEW CASI-I

N=174 P

FOSf-1 CA%+)

FOS(-1 CASH

N=lO

N=23

2T$ I

Smoking

N=23

I

Hxeftension

Diabetes Melliis

Fig. 2. Group 2: Smoking, hypertension, and diabetes mellitus.

ship to coronary artery spasm.These variables included age,sex, smoking,hypertension, diabetesmellitus, and serum cholesterol, HDL cholesterol, and uric acid levels. CAS+ findings were given a scoreof one, and CAS- findings were given a scoreof zero. Men were given a score of’ oneand women a scoreof zero. Smokerswere given a score of one and nonsmokers a score of zero. Patients with hypertension or diabetesmellitus were given a scoreof one. RESULTS Group 1 (Table

I). The mean age of each subgroup in group 1 is given in Table 1; the age differences were not statistically significant. With regard to sex, there was a significantly higher number of male patients in each subgroup (p < 0.01). Regarding smoking history (Fig. l), the incidence of smokers was significantly higher in group C(p < O.Ol), but there was no correlation between CAS+ and FOS+. Concerning hypertension (Fig. 1 j, there were 44 patients (42.7 “;, ) in group A, 69 (57.0”,) in group B, and 37 (34.9’; ) in group C. With regard to diabetes mellitus (Fig. l), the

incidence of diabetes was significantly higher in group B compared to group C(p < 0.01). Regarding the number of diseased vessels (Table I), the proportion of pat.ients with single-vessel disease was significantly lower in group C compared t,o group A (p < 0.01). Group 2 (Table SD. The mean age of each subgroup in group 2 is shown in Table II; the mean ages in groups D and E were significantly higher than in group G(p < 0.01). As shown in Table II, the proportion of male patients was significantly higher in each subgroup. There was no significant difference among the four subgroups in terms of the percent,age of male patients. With regard to smoking history (Fig. 2), the percentage of smokers in groups D and F were signif-

icantly higher than in groups E and G(p < 0.01). Concerning hypertension (Fig. 21, the proportion of patients with hypertension in group E was signifi-

cantIy higher than in group F(p < 0.05). Regarding diabetes mellitus (Fig. 2), there were eight patients

Volume Number

Table

124 1

Risk factors

for coronary

35

spasm

II. Patient population of group B Group E

Group D FOS(+)

CAS(+)

iN=67) Age (yi-) Sex

57.9

Male Female Smoking

58 (86.6'c 9 (1X4', 55 (82.1", 28 (41.8',

flypertension IXabete; IVD ,VI) ::VD

mellitus

) ) ) )

8 ( 1.9”C ) 35 (5"."', 22 (3223°C

10 (14.Y’<‘)

PUS(+) CAS(-I (N = 17-1) 60.2

zt 8.6

) )

Group F

132

I’M’(-)

iz IO.'2

58.0

)

85 (48.9';') 33 (19.0',) 78 (44X', 63 (36."'<

) )

:x3 (19.0',

)

(1.9 ‘, ) in group D, 33 (19.O”c ) in group E, none in group F, and six (26.1“(.) in group G. There were no significant differences among them. Regarding the number of diseased vessels (Table II), there was no significant difference in the percentage of patients with single-vessel disease in each subgroup. Lipids and uric acid (Tables III and IV). The mean serum cholesterol levels in the three subgroups in group 1 are shown in Table III. The mean level in group C was significantly lower than that in group I3(p < 0.01). The mean serum HDL cholesterol levels in i-he subgroups in group 1 are shown in Table III. There were no significant differences among them. As shown in Table III, there were no significant differences in mean serum uric acid levels among the three subgroups. There were no significant differences in mean serum cholesterol, HDL cholesterol, and uric acid levels among the four subgroups in group 2. Multivariate analysis. The results of multiple regression analysis are shown in Table V. The variance ratio was 9.83 (p < 0.01). There were statistically significant correlations between coronary artery spasm and smoking and between coronary artery spasm and serum HDL cholesterol levels@ < 0.01). As shown in Table V, only smoking and serum HDL cholesterol levels are useful in distinguishing between patients tith and wit,hout coronary artery spasm.

Table

+ 11.5

9 (go’<) 1 (lo’, 1 9 (9OP, ) 1 (lo’,) 0 ( 0’ < ) O( 0’s) O( 0”;) 0 ( O’, 1

(752.')

42 (24.1" 84 (483,)

CAS(+) (N = 10)

19 4 10 7 6 0 (I 0

(8”.6’, (17.4’, (43.5’, (30.4’, (“6.1”, ( O’, ( O’, ( O’,

) ) ) ) ) 1 I i

III. Serum levels of lipid, blood sugar, and uric acid

Total cholesterol HDL cholesterol Uric acid

Group A

Group B

FoS(+)

FOS(+I

FoS(+)

CASf+) (N = 103)

CAS(+) (N= tL?t)

C/w(+) (N = 106j

195.6 _+ 47.2 41.4 i 11.2 6.1 + 1.5

209.1 + 43.2 41.5 + 11.8

FOS. Fixed organic stenosis: CAS, coronary

6.2

_t 1.7

artery

Group C

185.9 43.0 6.0

t 36.3 t

11.6

i

1.4

spasm.

the use of multivariable analysis there was a good correlation between coronary artery spasm and smoking. There was a higher percentage of patients with fixed organic stenosis who had hypert,ension and diabetes mellitus in both groups 1 and 2. However, we could not show a positive correlation between either hypertension or diabetes mellitus and coronary artery spasm. Regarding the number of diseased vessels in group 1, t.he proportion of patienm wit.h singlevessel disease was significantly higher in the subgroup with coronary artery spasm. This same tendency was seen in group 2. There was a positive correlation between serum cholesterol levels and coronary artery spasm. This is in agreement with the findings of Tasaki et al.is

DISCUSSION

Relationship between smoking and coronary vasoconstriction. It is generally suggested that smoking

It is generally recognized that the incidence of ischemic heart disease is higher in men than in women. This was confirmed in our study. With regard to smoking history, the proportion of smokers in groups 1 and 2 was significantly high in the subgroups of patients with a positive reaction to ergonovine maleate whether or not they had fixed organic stenosis. With

has a sympathomimetic actionzO and causes an increase in the release of catecholamines.“l-‘” Thus smoking causes increases in heart rate, blood pressure, cardiac output, and oxygen consumption of the myocardium and influences lipid metabolism and platelet function.” ‘, “5 In laboratory investigations the mechanisms of smoking-induced vasoconstrict

36

Nobuyoshi

Table

et al.

IV. Serum levels of lipid,

blood sugar. and uric acid Group

11

-

Group

I,’

(:roup

/<.

---__ FOSI+J fN

Total cholesterol HDL cholesterol Uric acid

I’AS(-t,

Nls(+/

= h‘il

201.9 -C-ll.fi 38.7 i X.8 fi.”

(‘As(+J

lN

r,.9

4

V. Dependent

variable:

Independent clariablrs

Age (VT) Sex Smoking Hypertension Diabetes mellitus Total cholesterol level HDL Cholesterol level Cric acid level

(“3.‘;1+

iN

i

__.

I_--

i;.:i ___-

,F”).s! .L’

= 10;

f;

+, , ‘!l
-.---.-.

192.0 c ‘Ifi. 41.8 i 12.1

I.,?

__-__

Table

Fo.s(+)

= 17.1, __I-

195.9 + 41.X ?A.6 + 10.4

Yk 1.f;

(/ ‘Y,U,i .~.-

+ 2.:)

,SCi.fi_ 44.X !I ii L ix.0 (iI)

:

I.:!

~~~.~ ._...__

artery spasm

Coronary Partial

Standard

regrrssivn cafffiicien

regressf coeficient

t

-0.0010820; 0.020:37 0.‘845:1 -0.07910 -0.10747 -0.00075819 0.00494106 0.0071618~~

on

-0.02 1.5 0.0164 0.511 -0.0788 -0.0787 -0.0610 0.1096

.--___

0.W~‘~ I--~ -

E’ r>alut,

(I.-“771 0.1371 -41.70:34* :3.8969* X989412.5047* 7.38‘44” (),“9”” I I-

7’ Llaiuc

O. .i“64 0.33835 6.4578 1.9711 1.997:i

1.5826 I!.7171 0.540.

“p < 0.01 (variance ratio 9.82972). tp < 0.09

ing effects have been studied, mainly tu-adrenergitally mediated catecholamine release, increased platelet aggregation, and shortening of platelet survival with the possible release of the vasoconstrictor thromboxane Az.“6, “7 Tada et al.“s noted an increase in the thromboxane B level in patients with variant angina pectoris during an attack. This suggests that smoking activates platelet function and that activated platelet function has an effect on coronary artery spasm. However, findings in recent studies have shown that smoking does not induce platelet activation but rather causes increased secretion of hormones with vasoconstrictor properties, for example, vasopressin. 3g* - ” Cigarette smoking has been shown t.o trigger arginine-vasopressin release in humans,“l-‘J’i although the mechanisms responsible remain to be elucidated.“” Elevation of plasma arginine-vasopressin levels after smoking exerts profound hemodynamic effects. 2g.3”However,smoking-inducedarginine-vasopressin effects on platelet function are also possible but have not yet been proved. Inasmuch as both vascular smooth muscle cells and platelets are activated by arginine-vasopressin through stimulation of vasopressin receptors, resulting in vasoconstriction” and platelet aggregation,“j it is likely that elevated arginine-vasopressin levels may cause an additional proaggregatory stimulus for platelets.

Martin et. aI.“” noted that smoking in patients with coronary heart disease has vasospastic effects on the coronary arteries. Manoud et al.“‘, “s reported core nary artery spasm during cigarette smoking during angiography in patients with resting angina and angiographically normal coronary arteries.“‘, 38Winniford et al.“” measured changes in coronary blood flow during phentolamine and propranolol injections hefore and after smoking in patients with coronary heart disease. They concluded that the smoking-induced coronary vasospasm was mediated by an increase in coronary artery resistance, which was due to cu-adrenergically mediated catecholamine release. These facts suggest that coronary artery spasm is induced in the small coronary arteries and that smoking is its direct risk factor. In our study smoking was the greatest risk factor for coronary artery spasm. and other previously mentioned reports have suggested the same. Relationship atherogenesis.

between

coronary

vasoconstriction

and

There are many reports concerning the relationship between coronary artery spasm and coronary atherogenesis. Shimokawa et al.“” in a swine model were able to visualize the early stages of’ coronary arteriosclerosis in lesions in which coronar?’ vasospasm had occurred. Maseri et a1.l and MacAlpin6 also noted that most coronary artery spasmsoccurred at the site ot’ organic stenosis in pa-

Volume

124

Number

1

tients with coexisting organic coronary artery disease, although coronary artery spasm involved vessels with extreme variability in the extent of coronary atherosclerosis. ranging from angiographically normal to severely obstructed coronary arteries. Marzilli et aLi reported a case in which coronary artery spasm occurred in an angiographically normal coronary artery, and 8 months later a fixed organic stenosis was seen in the lesion in which the coronary vasospasm had occurred. They proposed that an abnormality of coronary smooth muscle manifests its disordered function as a reactive vasospasm, which then progresses to the development of atherosclerotic plaques and finally to fixed coronary stenosis.’ We also reported a case in which an angiographically normal coronary artery had a positive reaction to ergonovine maleate, and 18 months later coronary arteriography showed rapid progression of coronary atherosclerosis at the site where coronary vasospasm was provoked.40 The relationship between coronary artery spasm and the progression of coronary atherosclerosis has not been clearly elucidated, but the conceivable mechanisms are as follows: (1 Jcoronary artery spasms cause a transient reduction of coronary blood flow, increasing platelet aggregation, releasing plateletderived growth factors, and developing intracoronary thrombus; (2) hypoxia of coronary artery caused by coronary artery spasm induces dysfunction of the endothelium and dissection of the surface of the atheroma, thus causing progression of the invasion of serum lipids into the coronary artery wall and finally coronary atherosclerosis.‘, i On the other hand, an enhanced vasoconstrictive responsiveness to ergonovine maleate was demonstrated experimentally in the atherosclerot,ic canine coronary artery, characterized by regional intimal thickening with fibrous proliferation but little lipid deposition, which was produced by endothelial denudation and a long-term high-cholesterol diet.“’ These previously noted facts suggest a link between coronary artery spasm and atherosclerotic changes in the coronary artery wall, even at a stage so early that angiography shows a normal coronary artery. In our study there was a significant number of patients with single-vessel disease. Our results suggest that coronary vasospasm occurs at an early stage of coronary atherosclerosis. Others have noted the same reSUkS.“~ 1) Recently the role of macrophages in atherogenesis has been emphasized. Macrophages migrate to and accumulate in the subendothelial spaces and are subsequently transformed into lipid-laden foam cells. These lipid-laden foam cells have been suggested to

Risk factors for coroncq

spasm

37

represent the earliest stage of atheroma.4z-4” Yokode et a1.47also noted that cigarette smoke extract alters low-density lipoprotein into a form recognized and incorporated by macrophages. Therefore cigarett,e smoking influences lipid metabolism, leading to the early stages of atherosclerotic changes in the coronary arterial wall, which appears angiographically normal and influences sympathicus and platelet function leading to coronary artery spasm in the early stage of coronary atherosclerosis. From this viewpoint it is conceivable that smoking is the greatest risk factor for coronary vasospasm. Additional follow-up of the patients in this study to determine the relationship between continuation of smoking and reinducibility of coronary artery spasm and to estimate t.he progression of coronary atherosclerosis will provide us with important information. From this information we will be able to infer the relationship between smoking and both coronary artery spasm and coronary atherosclerosis. REFERENCES

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