Differential Incidence and Morphology of Spasm According to Coronary Arterial Location by Intracoronary Ergonovine Spasm Provocation Testing
論文ID: CJ-16-1046
この記事には本公開記事があります。
詳細
論文ID: CJ-16-1046
Background: We reported less provoked spasm in the left circumflex artery (LCX) by acetylcholine testing compared with the left anterior descending artery (LAD) and right coronary artery (RCA), so we investigated the clinical characteristics of provoked spasm in the LCX by ergonovine (ER) testing.
Methods and Results: We retrospectively analyzed 1,185 consecutive cases of intracoronary ER testing during 25 years. Maximal ER dose was 64 μg into the left coronary artery (LCA) and 40 μg into the RCA. Positive spasm was defined as a transient ≥90% narrowing and usual chest symptoms or ischemic ECG changes. Positive provoked spasm was recognized in 347 patients (29.3%), including 207 RCA spasms, 166 LAD spasms, and 79 LCX spasms. Spasm was provoked in the LCX significantly less than in the other vessels (P<0.001). LCX-provoked spasm was obtained in 79 patients consisting of 16 patients (20.3%) with triple-vessel spasm, 38 patients (48.1%) with double-vessel spasm and 25 patients (31.6%) with single-vessel spasm. Less than 70% patients with LCX-provoked spasm had multiple spasms, whereas approximately 60% patients had single-vessel spasm in the RCA (64.3%) or LAD (59.6%). In 25 patients with LCX single-vessel spasm, 18 patients (72.0%) had a focal spasm.
Conclusions: Under maximal ER dose of 64 μg into the LCA, LCX-provoked spasm occurred significantly less than spasm in the other vessels and less than 70% patients had multiple spasms.
Hackett et al reported the usefulness of intracoronary ergonovine (ER) testing in diagnosing patients with coronary spasm approximately 30 years ago.1 Since then, most cardiologists have used intracoronary administration of ER in the cardiac catheterization laboratory as well as an intravenous injection of ER.2–5 Compared with past intravenous ER tests, the incidence of provoked spasm by intracoronary ER testing was significantly higher in the clinic.6 We have already reported the differential incidence and type of spasm according to coronary arterial location by acetylcholine (ACh) testing.7 Compared with the right coronary artery (RCA) and left anterior descending artery (LAD), the incidence of provoked spasm in the left circumflex artery (LCX) was significantly lower. Moreover, more than 90% of patients had multiple spasms. It is controversial whether ER-provoked spasm in the LCX artery has the same results as ACh testing. Therefore, we retrospectively investigated the incidence and type of provoked spasm in each of the 3 coronary arteries and also examined the clinical characteristics of spasm in the LCX artery provoked by ER testing.
From January 1991 to March 2016, we performed ER spasm provocation tests in 1,185 patients (755 male patients, mean age 66.0±10.9 year). Significant organic stenosis was found in 294 patients (24.8%). History of smoking was observed in 672 patients (56.7%) and hypertension was recognized in 543 patients (45.8%). Dyslipidemia was also found in 504 patients (42.5%), and diabetes mellitus was observed in 256 patients (21.6%) (Table 1). Before performing the ER spasm provocation tests, calcium-channel antagonist or nitrate/nicorandil had been administered to 687 patients (58.1%) or 513 patients (43.3%), respectively, while β-blockers were given to 100 patients (8.4%). Angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker was taken by 201 patients (17.0%) and statins were taken by 232 patients (19.6%). As much as possible we attempted to perform selective spasm provocation tests to examine the incidence of provoked spasm in patients who had undergone coronary angiography. Subjects were excluded and the provocation test was not performed if patients had left main narrowing (>50%), 3-vessel disease, 2-vessel disease with total occlusion, heart failure (New York Heart Association functional class III or IV), renal failure (creatinine >2.0 mg/dL), if spontaneous spasm occurred or if isosorbide dinitrate was initially used to relieve spasm in the coronary artery tested.
| n | 1,185 |
| Male (%) | 755 (63.7%) |
| Age (years) | 66.0±10.9 |
| Organic stenosis | 294 (24.8%) |
| Smoking | 672 (56.7%) |
| Hypertension | 543 (45.8%) |
| Dyslipidemia | 504 (42.5%) |
| Diabetes mellitus | 256 (21.6%) |
| Total cholesterol (mg/dL) | 192.3±36.51 |
| Triglyceride (mg/dL) | 131.0±86.3 |
| LDL-C (mg/dL) | 115.1±30.9 |
| HDL-C (mg/dL) | 49.3±13.0 |
| Fasting blood sugar (mg/dL) | 111.9±37.8 |
| Medications before ER spasm provocation testing | |
| Calcium-channel antagonist | 687 (58.0%) |
| Nitrate or nicorandil | 513 (43.3%) |
| ACEI or ARB | 201 (17.0%) |
| β-blocker | 100 (8.4%) |
| Statin | 232 (19.6%) |
| Aspirin | 497 (41.9%) |
| Antiplatelet drug | 201 (17.0%) |
ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin-receptor blocker; ER, ergonovine; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol.
During the 25-year study, we worked in 4 hospitals (Kita Medical Association Hospital from January 1991 to June 1995, Takanoko Hospital from July 1995 to June 1997, Saiseikai Saijo Hospital from July 1997 to March 2008, and Ehime Prefectural Niihama Hospital from April 2008 to March 2016). We investigated the cardiac events at each hospital only. The mean time period after the ER spasm provocation tests was 44±24 months. We defined major cardiac events as sudden cardiac death or acute coronary syndrome and all cardiac events were included in readmission for recurrence of angina pectoris.
Definition of Positive SpasmWe defined positive spasm as ≥90% transient stenosis and usual chest symptoms or ischemic ECG changes. The degree of ST-segment depression was measured at 80 ms after the J point. We considered a result to be positive when at least 1 of the following ischemic ECG changes was observed during and/or after the ER test: (1) ST-segment elevation ≥0.1 mV in at least 2 contiguous leads and (2) ST-segment depression of 0.1 mV in at least 2 contiguous leads. We also considered negative U wave as positive ischemic ECG change.
Spasm Provocation TestAll drugs except for nitroglycerine were discontinued for ≥24 h before the study and nitroglycerine was discontinued ≥4 h before the study. Cardiac catheterization was performed from 9:00 am to 4:00 pm in the fasting state, as previously reported.6,8–10 Moreover, we attempted to perform the ER spasm provocation tests in the morning whenever possible. Coronary arteriograms of the left coronary artery (LCA) in the right anterior oblique with caudal projection and of the RCA in the left anterior oblique with cranial projection were obtained by injection of 8–10 mL of contrast medium.
ER (ergometrine injection F, 0.2 mg/mL; Fuji Seiyaku, Tokyo, Japan) in 0.9% warm saline solution was injected in 10 μg/min for 4 min for a maximal dose of 40 μg into the RCA and 16 μg/min over 4 min for a total dose of 64 μg into the LCA, with at least a 5-min interval between each injection. Standard 12-lead ECG was recorded every 30 s. At 1 min after each intracoronary injection of ER or when usual chest pain or significant ischemic ST changes on the ECG appeared, we obtained a coronary arteriogram, while a standard 12-lead ECG was recorded every 30–60 s. We used the ECG findings when ER, saline and contrast medium were not injected into the responsible vessel for at least 60 s. After the spasm provocation tests were completed, an intracoronary injection of 5.0 mg isosorbide dinitrate was administered, and coronary arteriography was then performed in multiple projections. If systolic blood pressure was >190 mmHg prior to performing ER tests, we did not perform the tests in the patient.
During the study, arterial blood pressure and ECG were continuously monitored on an oscilloscope by Nihon-Kohden polygraphy (Tokyo, Japan). In the present study, coronary arteriograms were analyzed separately by 2 independent observers. The percent luminal diameter narrowing of the coronary arteries was measured using an automatic edge-counter detection computer analysis system. The size of the coronary catheter was used to calibrate the images in millimeters and the measurement was performed in the same projection of coronary angiography at each stage. Focal spasm was defined as a discrete transient vessel narrowing ≥90% localized in a major coronary artery, whereas diffuse spasm was diagnosed when transient vessel narrowing ≥90%, compared with baseline coronary angiography, was observed from the proximal to distal segments in all 3 major coronary arteries. Proximal spasm was defined as America College of Cardiology (ACC)/American Heart Association (AHA) classification of segments 1, 2, 5, 6, and 11 and distal spasm was also defined as that of segments 3, 4, 7, 8, 9, 12, 13, 14, and 15. Patients with catheter-induced spasm were excluded. Significant organic stenosis was defined as >75% luminal narrowing according to the ACC/AHA classification.11
The study protocol complied with the Declaration of Helsinki. Written informed consent was given by all patients before the study and the protocol of this study was in agreement with the guidelines of the institutional ethical committees.
Statistical AnalysisAll data are presented as mean±1SD. The clinical characteristics of patients with and without provoked spasm and differences among the 3 coronary arteries were analyzed by χ2-test with correction or analysis of variance test. P<0.05 was considered significant.
The clinical characteristics of the patients with positive- and negative-provoked spasms are shown in Table 2A. Positive-provoked spasm was identified in 347 patients (29.3%). Compared with patients with negative-provoked spasm, organic stenosis, male sex and a history of smoking were significantly higher in patients with positive-provoked spasm. Vasodilator administration, including calcium-channel antagonists or nitrate/nicorandil, was significantly higher in ER-positive patients than in ER-negative patients. However, other medications were not different between the 2 groups. We could perform intracoronary ER testing of both coronary arteries in 959 patients (80.9%) and in the remaining 226 patients (19.1%) only 1 coronary artery, consisting of 160 RCA tests and 66 LCA tests.
| A | Negative | Positive | P value |
|---|---|---|---|
| n | 838 (70.7%) | 347 (29.3%) | |
| Male (%) | 455 (61.9%) | 300 (86.5%) | <0.001 |
| Age (years) | 66.2±11.3 | 65.6±10.0 | NS |
| Organic stenosis | 180 (21.5%) | 114 (32.9%) | <0.001 |
| Smoking | 400 (47.7%) | 272 (78.4%) | <0.001 |
| Hypertension | 386 (46.1%) | 157 (45.2%) | NS |
| Dyslipidemia | 351 (41.9%) | 153 (44.1%) | NS |
| Diabetes mellitus | 179 (21.4%) | 77 (22.2%) | NS |
| Total cholesterol (mg/dL) | 193.4±36.7 | 189.8±35.7 | NS |
| Triglyceride (mg/dL) | 129.3±89.7 | 134.9±78.1 | NS |
| LDL-C (mg/dL) | 115.7±31.0 | 113.7±30.6 | NS |
| HDL-C (mg/dL) | 50.3±13.3 | 47.2±12.1 | NS |
| Fasting blood sugar (mg/dL) | 111.8±36.53 | 112.4±41.0 | NS |
| Glycohemoglobin (%) | 5.5±1.4 | 5.7±1.2 | NS |
| Calcium-channel antagonist | 440 (52.5%) | 247 (71.2%) | <0.001 |
| Nitrate or nicorandil | 302 (36.0%) | 211 (60.8%) | <0.001 |
| ACEI or ARB | 145 (17.2%) | 56 (16.1%) | NS |
| β-blocker | 64 (7.6%) | 36 (10.4%) | NS |
| Statin | 164 (19.6%) | 68 (19.6%) | NS |
| Aspirin | 341 (40.7%) | 156 (45.0%) | NS |
| Antiplatelet drug | 127 (15.2%) | 74 (21.3%) | NS |
| B | RCA | LAD | LCX |
| n | 207 | 166 | 79 |
| Male (%) | 181 (86.5%) | 145 (87.3%) | 70 (88.6%) |
| Age (years) | 66.0±9.8 | 64.4±10.2 | 67.9±8.9 |
| Organic stenosis | 59 (28.5%) | 62 (37.3%) | 28 (35.4%) |
| Smoking | 168 (81.2%) | 127 (76.5%) | 68 (86.1%) |
| Hypertension | 95 (45.9%) | 70 (42.1%) | 41 (51.9%) |
| Dyslipidemia | 89 (43.0%) | 80 (48.2%) | 32 (40.5%) |
| Diabetes mellitus | 44 (21.3%) | 36 (21.7%) | 16 (20.3%) |
| Total cholesterol (mg/dL) | 187.1±34.4 | 190.6±37.2 | 188.0±31.2 |
| Triglyceride (mg/dL) | 138.6±84.9 | 134.3±64.8 | 129.0±73.4 |
| LDL-C (mg/dL) | 112.9±30.6 | 113.4±32.3 | 111.5±24.1 |
| HDL-C (mg/dL) | 45.6±11.6 | 48.3±11.8 | 48.7±12.1 |
| Fasting blood sugar (mg/dL) | 112.4±42.9 | 111.8±41.7 | 111.8±38.9 |
| Glycohemoglobin (%) | 5.6±1.3 | 5.6±1.1 | 5.7±1.3 |
| Focal spasm | 127 (61.4%) | 95 (57.2%) | 44 (55.7%) |
| Diffuse spasm | 80 (38.6%) | 71 (42.8%) | 35 (44.3%) |
| Proximal spasm | 126 (60.9%)*,$ | 54 (32.5%) | 33 (41.8%) |
| Distal spasm | 81 (39.1%)*,$ | 112 (67.5%) | 46 (58.2%) |
| Calcium-channel antagonist | 149 (72.0%) | 114 (68.7%) | 50 (63.3%) |
| Nitrate or nicorandil | 127 (61.4%) | 109 (65.7%)# | 41 (51.9%) |
| ACEI or ARB | 36 (17.4%) | 23 (13.9%) | 16 (20.3%) |
| β-blocker | 25 (12.1%) | 12 (7.2%) | 8 (10.1%) |
| Statin | 40 (19.3%) | 34 (20.5%) | 15 (19.0%) |
| Aspirin | 89 (43.0%) | 76 (45.8%) | 36 (45.6%) |
| Antiplatelet drug | 47 (22.7%) | 37 (22.3%) | 18 (22.8%) |
| C | Negative | Positive | P value |
| SCD | 2 (0.2%) | 0 | NS |
| ACS death | 2 (0.2%) | 2 (0.6%) | NS |
| ACS alive | 6 (0.7%) | 3 (0.9%) | NS |
| Readmission for recurrence of AP | 18 (2.1%) | 17 (4.9%) | <0.05 |
| Major cardiac event (SCD or ACS) | 10 (1.2%) | 5 (1.4%) | NS |
| PCI performed | 11 (1.3%) | 7 (2.0%) | NS |
| Ventricular fibrillation | 1 (0.1%) | 1 (0.3%) | NS |
| All cardiac events | 28 (3.3%) | 22 (6.3%) | <0.05 |
*P<0.001 vs. LAD; $P<0.01 vs. LCX; #P<0.05 vs. LCX. ACS, acute coronary syndrome; AP, angina pectoris; LAD, left anterior descending artery; LCX, left circumflex artery; NS, not significant; PCI, percutaneous coronary intervention; RCA, right coronary artery; SCD, sudden cardiac death. Other abbreviations as in Table 1.
As shown in Figure 1A, the LCX artery (22.8%) had significantly less positive provoked spasms than the RCA (59.7%) and LAD (47.8%). However, as Table 2B shows, there was no difference in the patients’ clinical characteristics among the 3 coronary arteries. More than half of the provoked spasms in each of the 3 coronary arteries were the focal type. The occurrence of proximal provoked spasm in the RCA was significantly higher than in the other 2 arteries, while that of distal provoked spasm in the LAD and LCX was significantly higher than in the RCA. Medications before the ER spasm provocation tests, excepting nitrate/nicorandil, were not different among the 3 groups. Administration of nitrate/nicorandil was significantly higher in LAD-positive patients than in those who were LCX-positive. In 959 patients who underwent ER testing of both the RCA and LCA, the LCX artery (24.6% (65/264)) showed significantly less positive provoked spasm than the RCA (64% (169/264)) and LAD (48.9% (129/264)) and no difference in the patients’ clinical characteristics among the 3coronary arteries was found.
(A) Comparison of spasm provoked in the 3 coronary arteries. **P<0.001 vs. RCA & LAD; *P<0.01 vs. RCA. (B) Comparison of number of vessels with provoked spasm among the 3 coronary arteries. **P<0.001 vs. LCX; *P<0.01 vs. LCX; #P<0.05 vs. LCX. (C) Comparison of all cardiac events and major cardiac events among the 3 groups of coronary arteries with positive provoked spasm. LAD, left anterior descending (artery); LCX, left circumflex artery; RCA, right coronary artery.
As shown in Figure 1B, the distribution of the number of vessels with provoked spasms did not differ between the RCA and the LAD. In contrast, 1-vessel spasm occurred significantly less in the LCX than in the other coronary arteries, whereas the incidence of 2- and 3-vessel spasm was significantly higher for the LCX artery than for the RCA and LAD. Focal spasm occurred in 72% (18/25), 67.7% (67/99) and 61.6% (82/133) of patients with a single provoked spasm in the LCX, LAD and RCA artery, respectively.
In-Hospital Cardiac EventsAs shown in Table 2C, major cardiac events including sudden cardiac death or acute coronary syndrome did not differ between the 2 ER groups, whereas readmission for recurrence of angina pectoris in patients with ER-provoked positive spasm was significantly higher than in those without ER-provoked spasm. Figure 1C shows that there was no difference in all cardiac events or major cardiac events among the 3 coronary artery groups.
Here we report the differential incidence and morphology of spasm according to coronary arterial location by ER testing. The occurrence of provoked spasm by ER test was significantly lower in the LCX artery than in the other 2 coronary arteries and the incidence of 2- or 3-vessel spasm was significantly higher in the LCX artery than the other 2 coronary arteries. Under a maximal ER dose of 64 μg injected into the LCA, the incidence of LCX-provoked spasm was significantly lower than in the other vessels and less than 70% of patients had multiple spasms. These results were similar to those obtained with ACh testing. The distribution of serotogenic receptors, as well as muscarinic receptors, may also be lower in the LCX than in the other 2 vessels. Major cardiac events during the first 44±24 months did not different between the ER-positive and ER-negative patients. Moreover, neither all cardiac events nor major cardiac events differed among the 3 groups of positive-provoked spasm of coronary arteries.
Clinical ImplicationsThe occurrence of 1-vessel spasm was significantly lower in the LCX artery than in the other 2 coronary arteries, but multivessel spasm involving the LCX artery was significantly higher than for the other 2 coronary arteries. The sensitivity of the LCX to ER may be less than the other coronary arteries. Less than 70% of patients with spasm provoked in the LCX artery had multiple coronary artery spasms. Only 31.6% of patients with spasm provoked in the LCX artery had 1-vessel spasm. In contrast, the RCA and LAD may have the same sensitivity to ER because they had a similar tendency towards vasoconstriction after the administration of ER. The LCX may be less sensitive to ER as well as ACh compared with the other 2 vessels.
Comparison With ACh TestingFor both ACh and ER testing, the distribution of the number of vessels with provoked spasm involving the LAD was almost similar to that for the RCA (Figure 2). However, the LCX artery was remarkably different from these 2 coronary arteries. Multivessel spasm was significantly higher in the LCX for both agents: 2-vessel spasm was significantly higher in the ER tests, and 3-vessel spasm was remarkably higher in the ACh tests. The LCX had different responses to these pharmacological agents.
Comparison of number of vessels with spasm provoked by ergonovine (ER) or acetylcholine (ACh) among the 3 coronary arteries. *P<0.001 vs. another. Abbreviations as in Figure 1.
This was a retrospective study and has several limitations. The first limitation was the maximal ER dose injected into the LCA. We used a maximum of 64 μg ER but a higher does might have achieved different results. The second limitation was that we could not perform ER testing of both coronary arteries in all patients. We performed one-sided ER testing in 226 patients and we could perform ER testing of both coronary arteries in 80.9% of patients. The third limitation was that we might have missed ischemic findings of positive provoked LCX spasm in the 12-lead ECG. The fourth limitation was the short duration of cardiac events monitoring. We could not analyze all cardiac events among the 25 years, because of working at several hospitals not just 1 institution. Further study is necessary to investigate the clinical characteristics of LCX-provoked spasm by ER test in the real world.
We thank Professor Yuji Shigematsu, MD, Professor Mareomi Hamada, MD, Professor Jitsuo Higaki, MD and Professor Kunio Hiwada, MD for their helpful comments.
None.
The authors declare that they have no conflicts of interest.
