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ORIGINAL ARTICLE
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One of Six Patients with Non-Ischemic Heart Disease Exhibit Provoked Coronary Spasms: Non-Ischemic Heart Disease Associated with Ischemia? Shozo Sueda, Toru Miyoshi, Yasuhiro Sasaki, Tomoki Sakaue, Hirokazu Habara and Hiroaki Kohno
Abstract Objective The majority of cardiologists do not perform spasm provocation tests in patients with nonischemic heart disease (non-IHD) or non-obstructive coronary artery disease (non-ob-CAD). We herein examined the frequency of provoked spasms in non-IHD and non-ob-CAD patients, including those with atypical chest pain (Aty), valvular heart disease (Val), hypertrophic cardiomyopathy (HCM), congestive heart failure (CHF), and others (Oth). Methods & Results We performed acetylcholine (ACh) spasm provocation tests over a period of 22 years (1991-2012) among 1,440 patients, including 981 IHD and 459 non-IHD subjects. A total of 43 patients with significant organic stenosis were excluded, and the remaining 416 patients with non-IHD or non-ob-CAD disease were assessed. ACh was injected in incremental doses of 20/50/80 μg into the right coronary artery (RCA) and 20/50/100/(200) μg into the left coronary artery (LCA). Positive coronary spasms were defined as transient luminal narrowing of >99%. Positive coronary spasms were noted in 17.3% of the non-IHDs patients (72/416), compared to 11.4% (15/132), 19% (8/42), 16.7% (5/30), 23.9% (16/67), and 19.3% (28/145), in the patients in the Aty, Val, HCM, CHF, and Oth groups, respectively. The rate of positive provoked spasms was higher in men than women, although not significantly [20.6% (46/223) vs. 13.4% (26/193), ns], and significantly higher in the late period (2001-2012) than in the early period (1991-2000) (36.8% vs. 7.0%, p50%), triple-vessel disease, two-vessel disease with total occlusion, heart failure (New York Heart Association class III or IV), renal failure (creatinine >2.0 mg/dL) or, spontaneous spasms, or if isosorbide dinitrate was initially used to relieve spasms in the tested coronary artery. Spasm provocation tests were also not performed in patients scheduled to undergo multiple coronary angioplasty procedures or bypass surgery. Positive coronary artery spasms were defined as transient luminal narrowing of >99%. The procedure was explained in detail to each patient, and informed consent was obtained from all participants. The study protocol was in agreement with the guidelines of the ethics committee at our institution. A diagnosis of typical angina was made in patients meeting all of the following criteria: (1) retrosternal burning or squeezing chest pain, (2) quick relief of pain (150 mg/dL. Diabetes mellitus was defined according to the World Health Organization criteria (17). Systemic hypertension was defined as either a systolic blood pressure of >140 mmHg or diastolic blood pressure of >90 mmHg and/or as the use of antihypertensive drugs (18). Smoking habits were assessed in all patients on admission. In this study, a history of habitual smoking for > five years was considered positive. Congestive heart failure was defined as an ejection fraction of < 40% on cardiac echocardiography. Angiographic analysis The coronary arteriograms were analyzed separately by two independent observers. The percent luminal diameter narrowing of the coronary arteries was measured using an automatic edge-contour detection computer analysis system (CARDIO 500, Kontron Instrument, Tokyo, Japan). The size of the coronary catheter was used to calibrate the image in millimeters, and the measurements were obtained on the same coronary angiography projection at each stage. Positive coronary artery spasms were defined as luminal narrowing of >99%. Patients with catheter-induced spasms were excluded from the study. Significant organic stenosis was defined as luminal narrowing of >75% according to the American Heart Association (AHA) classification (19). The
As shown in Table 1, more than half of the patients were men. Hypertension was observed in 144 patients (31.4%), with dyslipidemia in 97 patients (23.3%), diabetes mellitus in 62 patients (14.9%) and a history of smoking in 211 patients (50.7%). Atypical chest pain was recognized in 132 patients, Val in 42 patients, HCM in 30 patients, CHF in 67 patients, including 46 cases of dilated cardiomyopathy, and others in 145 patients, including 27 cases of sick sinus syndrome, 12 cases of atrioventricular block, 22 cases of arrhythmia (ventricular tachycardia: 13, paroxysmal supraventricular tachycardia: 5, paroxysmal and persistent atrial fibrillation: 4), nine cases of abnormal electrocardiography (ECG) changes, six cases of congenital heart disease, six cases of syncope, four cases of myopericarditis and 59 cases of other diseases. Prior to ACh spasm provocation tests, calcium-channel antagonists, nitrate/nicorandil, statins, betablockers, angiotensin-converting enzyme inhibitors and angiotensin receptor-blockers were administered in 29.3%, 23.8%, 10.6%, 8.7%, and 19.5% of all patients, respectively. Clinical background characteristics of the spasmpositive and -negative patients As shown in Table 2, positive spasms provoked by ACh were noted in 72 patients (17.3%). The age of the patents with positive spasms was significantly higher than of the patients with negative spasms. The coronary risk factors did not differ between the two groups. The rate of atypical chest pain was significantly higher among the spasm-negative patients than the spasm-positive patients, although no differences were observed in other diseases between the two groups. Meanwhile, the triglyceride levels were significantly higher in the spasm-positive patients than in the spasmnegative patients, whereas the high-density lipoprotein (HDL)-cholesterol levels were significantly lower in the spasm-positive patients than in the spasm-negative patients. Fig. 1 shows the incidence of positive provoked spasms according to the various cardiac disorders of non-IHD. The incidence of provoked spasms in the CHF patients was signifi-
283
Intern Med 54: 281-286, 2015
DOI: 10.2169/internalmedicine.54.2660
cantly higher than that observed in the subjects with atypical chest pain. However, no differences in medications administered prior to the ACh spasm provocation tests were found between the two groups. Comparisons of the data according to sex differences As shown in Table 3, positive spasms were observed in 46 men, compared to 26 women. The proportion of men was higher than that of women, although not significantly (20.6% vs. 13.4%, ns). Among the patients with positive spasms, the women were older than the men, while a history of smoking was observed significantly more frequently in men than in women. In contrast, no differences were noted between the men and women with positive spasms with respect to the frequency of multiple spasms, the configuration of the spasms, and the artery with provoked spasms. Among the patients with negative spasms, women were significantly older than men, and the frequency of a history of smoking was significantly higher in men in women. Furthermore, age was significantly higher in the spasm-positive group than in the spasm-negative group for both men and women.
(%)
50 40 30 20 10 0
19.0 11.4
Atypical
Val
23.9*
19.3
16.7
HCM
CHF
Others
17.3
All nonIHD
(*: p
ORIGINAL ARTICLE
□
One of Six Patients with Non-Ischemic Heart Disease Exhibit Provoked Coronary Spasms: Non-Ischemic Heart Disease Associated with Ischemia? Shozo Sueda, Toru Miyoshi, Yasuhiro Sasaki, Tomoki Sakaue, Hirokazu Habara and Hiroaki Kohno
Abstract Objective The majority of cardiologists do not perform spasm provocation tests in patients with nonischemic heart disease (non-IHD) or non-obstructive coronary artery disease (non-ob-CAD). We herein examined the frequency of provoked spasms in non-IHD and non-ob-CAD patients, including those with atypical chest pain (Aty), valvular heart disease (Val), hypertrophic cardiomyopathy (HCM), congestive heart failure (CHF), and others (Oth). Methods & Results We performed acetylcholine (ACh) spasm provocation tests over a period of 22 years (1991-2012) among 1,440 patients, including 981 IHD and 459 non-IHD subjects. A total of 43 patients with significant organic stenosis were excluded, and the remaining 416 patients with non-IHD or non-ob-CAD disease were assessed. ACh was injected in incremental doses of 20/50/80 μg into the right coronary artery (RCA) and 20/50/100/(200) μg into the left coronary artery (LCA). Positive coronary spasms were defined as transient luminal narrowing of >99%. Positive coronary spasms were noted in 17.3% of the non-IHDs patients (72/416), compared to 11.4% (15/132), 19% (8/42), 16.7% (5/30), 23.9% (16/67), and 19.3% (28/145), in the patients in the Aty, Val, HCM, CHF, and Oth groups, respectively. The rate of positive provoked spasms was higher in men than women, although not significantly [20.6% (46/223) vs. 13.4% (26/193), ns], and significantly higher in the late period (2001-2012) than in the early period (1991-2000) (36.8% vs. 7.0%, p50%), triple-vessel disease, two-vessel disease with total occlusion, heart failure (New York Heart Association class III or IV), renal failure (creatinine >2.0 mg/dL) or, spontaneous spasms, or if isosorbide dinitrate was initially used to relieve spasms in the tested coronary artery. Spasm provocation tests were also not performed in patients scheduled to undergo multiple coronary angioplasty procedures or bypass surgery. Positive coronary artery spasms were defined as transient luminal narrowing of >99%. The procedure was explained in detail to each patient, and informed consent was obtained from all participants. The study protocol was in agreement with the guidelines of the ethics committee at our institution. A diagnosis of typical angina was made in patients meeting all of the following criteria: (1) retrosternal burning or squeezing chest pain, (2) quick relief of pain (150 mg/dL. Diabetes mellitus was defined according to the World Health Organization criteria (17). Systemic hypertension was defined as either a systolic blood pressure of >140 mmHg or diastolic blood pressure of >90 mmHg and/or as the use of antihypertensive drugs (18). Smoking habits were assessed in all patients on admission. In this study, a history of habitual smoking for > five years was considered positive. Congestive heart failure was defined as an ejection fraction of < 40% on cardiac echocardiography. Angiographic analysis The coronary arteriograms were analyzed separately by two independent observers. The percent luminal diameter narrowing of the coronary arteries was measured using an automatic edge-contour detection computer analysis system (CARDIO 500, Kontron Instrument, Tokyo, Japan). The size of the coronary catheter was used to calibrate the image in millimeters, and the measurements were obtained on the same coronary angiography projection at each stage. Positive coronary artery spasms were defined as luminal narrowing of >99%. Patients with catheter-induced spasms were excluded from the study. Significant organic stenosis was defined as luminal narrowing of >75% according to the American Heart Association (AHA) classification (19). The
As shown in Table 1, more than half of the patients were men. Hypertension was observed in 144 patients (31.4%), with dyslipidemia in 97 patients (23.3%), diabetes mellitus in 62 patients (14.9%) and a history of smoking in 211 patients (50.7%). Atypical chest pain was recognized in 132 patients, Val in 42 patients, HCM in 30 patients, CHF in 67 patients, including 46 cases of dilated cardiomyopathy, and others in 145 patients, including 27 cases of sick sinus syndrome, 12 cases of atrioventricular block, 22 cases of arrhythmia (ventricular tachycardia: 13, paroxysmal supraventricular tachycardia: 5, paroxysmal and persistent atrial fibrillation: 4), nine cases of abnormal electrocardiography (ECG) changes, six cases of congenital heart disease, six cases of syncope, four cases of myopericarditis and 59 cases of other diseases. Prior to ACh spasm provocation tests, calcium-channel antagonists, nitrate/nicorandil, statins, betablockers, angiotensin-converting enzyme inhibitors and angiotensin receptor-blockers were administered in 29.3%, 23.8%, 10.6%, 8.7%, and 19.5% of all patients, respectively. Clinical background characteristics of the spasmpositive and -negative patients As shown in Table 2, positive spasms provoked by ACh were noted in 72 patients (17.3%). The age of the patents with positive spasms was significantly higher than of the patients with negative spasms. The coronary risk factors did not differ between the two groups. The rate of atypical chest pain was significantly higher among the spasm-negative patients than the spasm-positive patients, although no differences were observed in other diseases between the two groups. Meanwhile, the triglyceride levels were significantly higher in the spasm-positive patients than in the spasmnegative patients, whereas the high-density lipoprotein (HDL)-cholesterol levels were significantly lower in the spasm-positive patients than in the spasm-negative patients. Fig. 1 shows the incidence of positive provoked spasms according to the various cardiac disorders of non-IHD. The incidence of provoked spasms in the CHF patients was signifi-
283
Intern Med 54: 281-286, 2015
DOI: 10.2169/internalmedicine.54.2660
cantly higher than that observed in the subjects with atypical chest pain. However, no differences in medications administered prior to the ACh spasm provocation tests were found between the two groups. Comparisons of the data according to sex differences As shown in Table 3, positive spasms were observed in 46 men, compared to 26 women. The proportion of men was higher than that of women, although not significantly (20.6% vs. 13.4%, ns). Among the patients with positive spasms, the women were older than the men, while a history of smoking was observed significantly more frequently in men than in women. In contrast, no differences were noted between the men and women with positive spasms with respect to the frequency of multiple spasms, the configuration of the spasms, and the artery with provoked spasms. Among the patients with negative spasms, women were significantly older than men, and the frequency of a history of smoking was significantly higher in men in women. Furthermore, age was significantly higher in the spasm-positive group than in the spasm-negative group for both men and women.
(%)
50 40 30 20 10 0
19.0 11.4
Atypical
Val
23.9*
19.3
16.7
HCM
CHF
Others
17.3
All nonIHD
(*: p
