International Journal of Cardiology 196 (2015) 7–13
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Early repolarization and positive T-wave alternans as risk markers for life-threatening arrhythmias in patients with vasospastic angina☆ Yukihiro Inamura a,f,⁎, Mitsuhiro Nishizaki a, Masato Shimizu a, Hiroyuki Fujii a, Noriyosi Yamawake a, Makoto Suzuki b, Harumizu Sakurada c, Masayasu Hiraoka d,e, Mitsuaki Isobe f a
Department of Cardiology, Yokohama Minami Kyosai Hospital, Yokohama, Japan Department of Cardiology, Kameda Medical Center, Chiba, Japan Division of Cardiology, Tokyo Metropolitan Health and Medical Treatment Corporation Ohkubo Hospital, Tokyo, Japan d Department of Health Examination, Toride Kitasoma Medical Center Hospital, Ibaraki, Japan e Tokyo Medical and Dental University, Tokyo, Japan f Department of Cardiology, Tokyo Medical and Dental University, Tokyo, Japan b c
a r t i c l e
i n f o
Article history: Received 15 March 2015 Received in revised form 21 May 2015 Accepted 26 May 2015 Available online 29 May 2015 Keywords: Vasospastic angina J wave T wave alternans Multivessel vasospasm Ventricular fibrillation
a b s t r a c t Background: Several arrhythmogenic markers have been suggested as predictors for risk of life-threatening arrhythmias during symptom-free periods in vasospastic angina (VSA), but no definite conclusion has been drawn. Objective: To investigate prevalence of fatal ventricular tachyarrhythmia in VSA and its relation to appearance of early repolarization (ER) and positive T wave alternans (p-TWA) in patients with VSA during symptom-free periods. Methods: We studied 116 consecutive patients with chest pain who underwent an acetylcholine provocation test for VSA diagnosis. Patients were divided into two groups with positive (VSA group; 66 cases) and negative (control group; 50 cases) provocation test results. The presence of ER on electrocardiogram and the modified moving average analysis of TWA during symptom-free periods were explored. Results: The incidences of ER and p-TWA were higher in the VSA than in the control group (P = 0.001 and P = 0.006, respectively). Multivariate analysis revealed that ER and p-TWA were independent predictors of VSA (odds ratio, 5.65 and 4.94; 95% confidence interval: 1.11–28.9 and 1.22–19.9, respectively). The incidence of coexisting baseline ER and p-TWA was significantly higher in VSA patients with life-threatening arrhythmic events (3/3 vs. 6/38; P b 0.001) than in those without. Conclusions: VSA patients with arrhythmic events showed a high incidence of ER and p-TWA during symptom-free periods. Therefore, baseline ER and p-TWA may help to identify VSA patients at high risk for life-threatening arrhythmias. © 2015 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Vasospastic angina (VSA) is caused by coronary artery vasospasm resulting in severe chest pain and transient ST-segment elevation on electrocardiogram (ECG). VSA episodes are generally not provoked by
Abbreviations: Ach, acetylcholine;CI, confidence interval;ECG,electrocardiography; ER, early repolarization; LAD, left anterior descending artery; LCX, left circumflex artery; MMATWA, modified moving average analysis of T-wave alternans; OR, odds ratio; p-TWA, positive T wave alternans; PVT, polymorphic ventricular tachycardia; RCA, right coronary artery; TWA, T wave alternans; VF, ventricular fibrillation; VT, ventricular tachycardia; VSA, vasospastic angina. ☆ This paper was presented at the 78th Annual Scientific Meeting of the Japanese Circulation Society. ⁎ Corresponding author at: Yokohama Minami Kyosai Hospital, 1-21-1 Mutsuurahigashi, Kanazawa-ku, Yokohama 236-0037, Japan. E-mail address: [email protected] (Y. Inamura).
http://dx.doi.org/10.1016/j.ijcard.2015.05.147 0167-5273/© 2015 Elsevier Ireland Ltd. All rights reserved.
physical activity or emotional stress, but occur at rest without specific warning signs. VSA can be complicated by life-threatening ventricular arrhythmias and atrioventricular conduction block, or, if prolonged spastic events, by acute myocardial infarction. Life-threatening ventricular arrhythmia is a serious complication that can occur during attacks of VSA. While the incidence of life-threatening arrhythmias is not high (b10%), the events are nonetheless clinically important due to an increased risk for sudden cardiac death in subjects without significant coronary stenosis [1,2]. Our previous studies indicated that patients with VSA had potential substrates for malignant ventricular tachyarrhythmia with increased vulnerability and repolarization abnormalities [3,4]. Patients with VSA experienced frequent episodes of polymorphic ventricular tachycardia (PVT), which was inducible by programmed ventricular stimulation [3,4]. Even during asymptomatic periods, the patients showed increased QT dispersion, an indicator of inhomogeneous ventricular repolarization [5,6]. The modified moving average
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analysis of T-wave alternans (MMA-TWA) was shown to be superior to the measurement of QT dispersion for assessing the inhomogeneity of ventricular repolarization and predicting risk for life-threatening tachyarrhythmia and sudden cardiac death [7–10]. Our studies using the MMA-TWA also indicated that patients with VSA had high T wave alternans (TWA) values during event-free periods [11,12]. Early repolarization (ER) had been regarded as a benign ECG sign for many years because of its frequent association with healthy, young individuals and athletes without overt heart disease [13]. Recent clinical reports, however, have indicated that an ER pattern in the inferolateral leads is associated with the development of ventricular fibrillation (VF) in patients with idiopathic VF [14–17], and similar ER patterns with horizontal/descending ST segment have been associated with increased cardiac mortality in general populations [18,19]. Further, the presence of an ER pattern has also been shown to indicate a high risk for fatal ventricular arrhythmias in patients with Brugada syndrome [20], acute myocardial infarction [21,22], and Takotsubo cardiomyopathy [23]. Therefore, ER plays a critical role in the pathogenesis of malignant ventricular arrhythmias in certain clinical settings, while the genesis of the ER is controversial as to whether it is caused by repolarization or by depolarization abnormality [24–26]. Oh et al. reported that ER could predict cardiac death and fatal arrhythmias in patients with VSA [27]. It was not known, however, whether the presence of ER could predict life-threatening arrhythmic risk due to repolarization or depolarization abnormalities. The aim of the present study was to investigate prevalence of fatal ventricular tachyarrhythmia in VSA and its relation to appearance of early repolarization (ER) and positive T wave alternans (p-TWA) as a measure of inhomogeneous repolarization, in VSA patients during the asymptomatic period. 2. Methods 2.1. Patient population The study included 116 consecutive patients who had chest pain at rest and underwent coronary angiography with an acetylcholine (ACh) provocation test for the diagnosis of VSA between July 2010 and April 2014 at the Yokohama Minami Kyosai Hospital (71 men and 45 women; mean age, 63.1 ± 11.2 years). Patients were divided into two groups according to the results of the Ach provocation test: the VSA group (n = 66) with ACh-induced vasospasm and the control group (n = 50) without ACh-induced vasospasm. All patients in the VSA group were given vasodilator drugs and/or calcium antagonists after the coronary angiography and followed at our outpatient clinic until October 2014 or their last visit. Patients with bundle branch block, intra-ventricular conduction disturbances, or Wolff–Parkinson– White syndrome were excluded from analysis. In this study, patients taking calcium channel blockers during Holter monitoring were included. The study protocol was approved by the ethics committee of Yokohama Minami Kyosai Hospital. Written informed consent was obtained from all subjects before enrollment in the study.
the maximum dose was given. Coronary vasospasm was defined as total or subtotal occlusion of single or multiple coronary arteries with delayed filling of their distal segments and was associated with chest pain and/or ischemic ST-T changes on ECG [28]. If coronary vasospasm was induced in the left coronary artery, we waited until coronary vasospasm recovered spontaneously and then performed the ACh provocation test for the right coronary artery as well as for the diagnosis of multi-vessel vasospasm. 2.3. ECG analysis ER was defined as a J point elevation ≥1 mm above baseline and slurring or notching of the terminal portion of QRS at ≥2 inferior (II, III, aVF) and/or lateral (I, aVL, V5–6) leads [15,24]. We analyzed ECG records obtained before and during the ACh provocation test for VSA. The presence and lead locations of ER as well as the amplitude of the J wave were evaluated. ER during the ACh provocation test was defined as positive if ER became apparent when coronary vasospasm was induced by coronary angiography regardless of the presence or absence of ST-T wave changes, and defined as negative if there was no ER 60 s after ACh provocation test. New ER was defined as an ER which newly appeared during the ACh provocation test. We categorized ST segment patterns after ER as either the horizontal/descending or the concave/rapidly ascending type. The horizontal/ descending type was defined as descending or ≤ 0.1 mV elevation of the ST segment at 100 ms after the J point. The concave/rapidly ascending ST segment type was defined as N 0.1 mV elevation of the ST segment at 100 ms after the J point or a persistently elevated ST segment of N 0.1 mV through the ST segment [19]. The QT interval and QRS duration were measured in all 12-leads of ECG recorded at a speed of 50 mm/s for 2 consecutive cycles. The QT interval was measured from the beginning of the QRS complex to the end of the T wave, which was defined as the return to the TP baseline (between the end of the T wave and the following P wave). And QT interval was rate-corrected with a modification of Bazett's formula as follow: QTc interval = QT / square root of the QT interval [5,29]. 2.4. MMA-TWA analysis The MMA-TWA was analyzed from two channel records (NASA and CM5) by ambulatory Holter monitoring using MARS PC version 7.03 (GE Healthcare, Milwaukee, WI) and identified periods of possible TWA by applying an MMA in 68 patients (41 in the VSA group and 27 in the control group). MMA is a time-domain-based method that bifurcates the beat stream and generates a separate moving average template (ABABABA) [8–10] Average values were updated by a weighting factor one-eighth of the difference between the ongoing average and the current pair of beats. A noise level of 20 μV was adopted in the system configuration. Manual editing was performed if the data were not eligible for analysis because of artifacts or noise. The maximum TWA value was defined as the highest value in either channel. Positive TWA (pTWA) was defined as a TWA value N 65 μV, in accordance with previous reports [30,31].
2.2. Coronary angiography and acetylcholine provocation test 2.5. Definition of arrhythmic events All vasodilator drugs and calcium antagonists were discontinued at least 3 days before coronary angiography. The coronary angiography began around 9 am on the morning of the study day. After confirming no significant stenotic lesions in both right and left coronary arteries, a bipolar electrode catheter was inserted into the right ventricular apex through the right femoral vein and connected to a temporary pacemaker. The pacing rate was set at 50 bpm. Incremental doses of acetylcholine were injected into the left coronary artery (20, 50, and 100 μg) and the right coronary artery (20, 50, and 70 μg) until acetylcholineinduced coronary vasospasm was detected angiographically or until
We defined arrhythmic events as spontaneous PVT/VF documented before the ACh provocation test and during follow-up period of 26.1 ± 14.0 months. We excluded syncope without documentation of PVT/VF from arrhythmic events, even if syncope occurred with chest pain. Syncope without documentation of PVT/VF might be caused by other conditions such as hemodynamic deterioration, complete atrioventricularblock, or sinus arrest due to ischemic events. None of the VSA group in this study developed complete atrioventricular block or acute myocardial infarction throughout the follow-up period.
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Table 1 Clinical data of the patients in the 2 groups.
Male (n) Age (years) LVEF (%) QRS width (ms) QTc (ms) Presence of PVT/VF (n) Before ACh provocation test During follow-up periods Presence of syncope without PVT/VF documented Number of vessels with induced spasm 1 vessel (LAD/LCX/RCA) 2 vessels (LAD–LCX/LAD–RCA/LCX–RCA) 3 vessels Baseline ER (n) ST segment, rapidly ascending ST segment, horizontal/descending Inferior leads Lateral leads Inferolateral leads J-point amplitude (mV) Max TWA (μV) TWA N65 μV (n) Baseline ER + TWA N65 μV (n) During ACh provocation test New ER (n) Inferior leads (n) Lateral leads (n) Inferolateral leads (n) J-point amplitude (mV) Polymorphic PVT/VF induction (n)
VSA group n = 66
Control group n = 50
P
46 (70%) 63.9 ± 11.4 64.9 ± 9.9 79.8 ± 12.0 384.6 ± 35.3 3 (5%) 2 1 4 (6%)
25 (50%) 60.4 ± 12.1 65.2 ± 7.1 77.8 ± 15.5 386.1 ± 33.5 0 (0%)
0.031⁎ 0.115 0.912 0.144 0.893 0.127
0 (0%)
0.076
23 (10/0/13) 31 (3/23/5) 12 24 (36%) 16 8 15 (63%) 6 (25%) 3 (13%) 0.60 ± 0.80 60.6 ± 16.9 18/41 (44%) 9 (22%)
6 (12%) 6 0 4 (67%) 2 (33%) 0 (0%) 0.18 ± 0.54 50.5 ± 9.7 3/27 (11%) 0 (0%)
0.001⁎ 0.096 0.011⁎ 0.454 0.68 0.361 0.002⁎ 0.007⁎ 0.006⁎ 0.009⁎
7 7 0 0 1.01 ± 1.22 2
0 0 0 0 0.20 ± 0.66 0
0.018⁎ 0.018⁎
b0.0001⁎ 0.214
Values are expressed as mean ± standard deviation. LVEF, left ventricular ejection fraction; QTc, QT interval corrected for heart rate. ⁎P b 0.05
2.6. Statistical analysis Data were expressed as mean ± standard deviation The Welch t test was used for comparisons between group means expressed as continuous variables. The chi-square test was used to evaluate differences in categorical variables between the two groups. Univariate logistic regression analysis was done for the existence of VSA in all patients and multivessel vasospasm in VSA group. Multivariate logistic regression analysis was used for defining independent predictors of vasospasm. A P b 0.05 was considered statistically significant.
VSA group than the control group at baseline. In the VSA group, the amplitude of J points increased from 0.60 ± 0.80 mV at baseline to 1.01 ± 1.22 mV (P = 0.024) after the Ach test, whereas the amplitude was not changed by the Ach test in the control group (0.18 ± 0.54 mV before and 0.20 ± 0.66 mV after the Ach test; P = 0.841) (Fig. 1). ER appeared and/or its amplitude was augmented in the leads associated with vasospastic areas revealed by angiography. ST-T wave changes followed the appearance and/or augmentation of J wave. ECG records and coronary angiograms from a typical case are shown in Fig. 2.
3. Results 3.1. Clinical and electrophysiological characteristics of the VSA and control groups Table 1 shows clinical and electrophysiological profiles of patients in the VSA and control groups. The VSA group had higher male predominance than the control group (P = 0.031). The VSA group showed ER at baseline ECG in 24 (36%) patients, and the control group in 6 (12%) cases. Types of ST-segment elevation in the VSA group included 16 cases of the concave/rapidly ascending type and 8 of the horizontal/ descending type, whereas 6 patients presented the concave/rapidly ascending type but no horizontal/descending type in the control group (P = 0.001). The VSA group had a higher incidence of p-TWA than the control group (18/41 patients [44%] vs. 3/27 patients [11%], respectively; P = 0.006). Nine patients in the VSA group exhibited both positive ER at baseline and p-TWA, but none in the control group had positive signs of both parameters. During the ACh provocation test, 7 patients had new ER in the VSA group and none in the control group (P = 0.018). New ER appeared exclusively at the inferior leads. The amplitude of J wave was higher in the
Fig. 1. Change in J point amplitude by the acetylcholine (ACh) provocation test in the control and VSA group.
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Fig. 2. ECG records and coronary angiograms before and during ACh provocation test from a representative case. A 59-year-old man (Case 1) without past history of ventricular fibrillation (VF) or syncope experienced sudden chest pain at around 7:00 am when he was at rest in the spine position. Then, he suddenly groaned and lost consciousness with spontaneous recovery after 1 min. On arrival at the hospital, J wave was observed in the inferior leads (baseline ECG). No stenotic lesion was observed in the coronary angiogram (baseline). During the acetylcholine (ACh) provocation test, amplitudes of J wave were augmented and diffuse coronary vasospasms were provoked in 3 vessels. A value of T wave alternans (TWA) was 68 μV. Only right coronary angiograms (baseline and Ach provocation) are shown.
On univariate analysis, sex, presence of ER at baseline, horizontal/ descending ST-segment elevation, and p-TWA were significant predictors of VSA. On multivariate logistic regression analysis, presence of ER at baseline and p-TWA revealed independent predictors of VSA (odds ratio [OR], 5.65 and 4.94; 95% confidence interval [CI]: 1.11–28.9 and 1.22–19.9; P = 0.037 and P = 0.025, respectively) (Table 2).
3.2. Predictors for single-vessel or multi-vessel vasospasm Multi-vessel vasospasm might cause severe ischemic injury compared to single-vessel vasospasm. We sought to explore predictive values of the presence of ER and p-TWA for single-vessel versus multivessel vasospasm. In the VSA group, 23 patients developed singlevessel vasospasm; left anterior descending artery (LAD; n = 10), right coronary artery (RCA; n = 13) and left circumflex artery (LCX; n = 0). Two-vessel vasospasm was observed in 31 patients: RCA–LAD (n = 23), RCA–LCX (n = 5) and LAD–LCX (n = 3). Three-vessel vasospasm was seen in 12 patients. The presence of baseline ER alone was a significant predictor for multi-vessel (two- and three-vessels) over
Table 2 Results of the univariate and multivariate analyses for vasospasm. Univariate
Age (years) Male LVEF (%) QRS width QTc Baseline J wave Horizontal/descending TWA N 65 μV
single-vessel vasospasm (Fig. 3; OR, 4.13; 95% CI: 1.20–14.2; P = 0.024). The presence of p-TWA could not predict multi-vessel or single-vessel vasospasm (P = 0.923). 3.3. Parameters discriminating the VSA patients with and without arrhythmic events Of 116 patients, 3 had documented PVT/VF. Two patients who did not take vasodilator drugs developed spontaneous VF before the ACh test, and one patient who exhibited documented VF during the follow-up period was on vasodilator drugs and forgot to take them on the day of event. Among the three patients with PVT/VF, two developed non-sustained VT and one showed PVT during the ACh provocation test with multi-vessel spasm. They showed both ER at baseline and p-TWA (Table 3). A representative case (no. 3) who developed VF during the follow-up period is shown in Fig. 4. This patient showed p-TWA throughout the follow-up period. Table 4 shows a comparison of the parameters between the patients with PVT/VF and those without arrhythmic events. While the incidence of both baseline ER and p-TWA were higher in the patients with arrhythmic events than those without, there were no significant differences between the two groups for the presence of horizontal/descending STsegment elevation. 4. Discussion
Multivariate
OR (95% CI)
P value
1.03 (0.99–1.06) 2.30 (1.07–4.94) 1.00 (0.93–1.07) 1.01 (0.98–1.04) 1.00 (0.99–1.01) 4.19 (1.56–11.3) 11.7 (1.52–90.9) 5.91 (1.53–22.9)
0.116 0.033 0.910 0.466 0.840 0.005 0.018 0.010
OR (95% CI)
P value
0.82 (0.28–2.44)
0.724
5.65 (1.11–28.9)
0.037
4.94 (1.22–19.9)
0.025
Logistic regression analysis was done for the existence of VSA in all patients (n = 116). OR, odds ratio; 95% CI, 95% confidence interval.
The major findings of the present study were as follow: 1) incidences of baseline ER and p-TWA were higher in the VSA patients than in the control subjects with chest pain alone; 2) presence of baseline ER and p-TWA was an independent predictor of VSA; 3) baseline ER was a significant indicator of multi-vessel vasoconstriction; and 4) the presence of both baseline ER and p-TWA was a strong risk factor for PVT/VF in VSA. There have been very few clinical studies exploring the incidence of ER and p-TWA in patients with chest pain divided into two groups with and without VSA proved by ACh provocation test. Oh et al. reported that
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Fig. 3. Predictors of multi-vessel vasospasm in VSA group by logistic regression analysis. Logistic regression analysis of various parameters was performed in VSA group (n = 66). In the right side of the graph, it is superior in multi-vessel vasospasm, and in the left side of the graph, it is superior in single-vessel vasospasm. Abbreviation: OR; odds ratio, CI; confidence interval, LVEF; left ventricular ejection fraction, ER; early repolarization, ACh; acetylcholine.
any type of ER in the inferior and/or lateral leads was persistently observed in 21.4% of patients with VSA [27], but their study population consisted only of VSA patients. Our study compared the incidences of ER and p-TWA during asymptomatic periods in 2 groups of patients complaining chest pain with and without VSA as revealed by ACh provocation test. The incidence of ER was relatively higher in our study (36%) than the report of Oh et al. [27]. Further the patients with VSA had significantly higher incidences of ER and p-TWA than the subjects showing chest pain without vasospasm during the ACh provocation test. On multivariate analysis, the presences of baseline ER and p-TWA were independent predictors of VSA. While the positive predictive values were less than 90% in either cases of ER alone or p-TWA alone, the value for VSA was 100% in patients with chest pain, baseline ER and p-TWA. Therefore, two parameters of these non-invasive evaluations were helpful in differential diagnosis of chest pain resulted from VSA or other cause. In the VSA group, ER appeared and/or was augmented in the leads associated with ischemic areas, caused by ACh-induced vasospasm (Figs. 2 and 4). By contrast, the ER pattern was virtually unchanged during ACh provocation test in the control group that showed chest pain without VSA. The results suggested that the J-point elevation during ACh provocation test was not due to a direct action of ACh but might be related to ischemic events. While the presence of baseline ER was a significant predictor for multi-vessel (two- and three-vessels) over single-vessel vasospasm, the substrate of ER appeared to be sensitive to the severity of ischemic insults. The exact genesis of ER is not known, and various factors contributing to depolarization and repolarization
phases of action potentials are supposed. From the experimental studies, the genesis of ER, especially J wave, was proposed to be produced by transmural voltage gradient during the early phase of ventricular repolarization between the epicardium and endocardium [24]. The MMA-TWA has been shown as a useful tool for evaluating the inhomogeneity of ventricular repolarization and predicting risk for life-threatening tachyarrhythmia and sudden cardiac death [7–10]. Our previous study demonstrated high values and incidences of positive MMA-TWA in VSA patients with ventricular tachycardia, but the incidence decreased in patients taking calcium channel blockers [11]. In the present study, all patients with VF had p-TWA, and patient no. 3 (Fig. 4) maintained high TWA values during the follow-up period. Our study also showed that p-TWA together with baseline ER was the predictive factor of ventricular tachyarrhythmia, but p-TWA alone did not predict which patients would develop multi-vessel vasospasm. There are multiple factors that are supposed to cause ER, such as cardiac ischemia [32], depolarization [26] and/or repolarization [33] abnormalities, and the effect of autonomic nerves [34]. The present results might suggest that ER had additional contributors different from inhomogeneity of ventricular repolarization that could be detected by p-TWA. Only a few clinical studies have investigated the relationship between ER and TWA in patients with VSA; thus, actual contribution and their mechanisms for risk stratification remain unclear. However, we demonstrated that 3/9 patients with both baseline ER and p-TWA experienced PVT/VF associated with VSA event. These results may indicate that the coexistence of ER and TWA is a strong risk factor for PVT/VF in patients with VSA.
Table 3 Characteristics of the patients with PVT/VF. Case no.
Age
Sex
VF
VT/VF during
ER after ACh test
Ach provocation
Site of coronary spasm
TWA
Baseline ER
ER pattern
1
59
M
Before diagnosis
Non-sustained VT
3 vessels
68 μV
III aVF
Horizontal
2
39
M
Before diagnosis
Non-sustained VT
Total occlusion of 3 vessels
85 μV
II III aVF V5
Upslope
3
53
M
Follow-up period
Pulseless polymorphic VT
3 vessels
77 μV
aVL V6
Upslope
Increased amplitude (IIIIIaVF) Increased amplitude (V5) Increased amplitude (IIIIIaVF)
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Fig. 4. ECGs and coronary angiograms from a case who developed PVT during ACh provocation test and VF during follow-up period. A 53-year-old man (Case 3) without past history of VF or syncope experienced recurring chest pain episodes. Despite taking a calcium channel blocker, he lost consciousness and transferred to the hospital. On arrival, J wave was observed in aVL and V6 leads (baseline). Coronary angiography showed no stenotic lesion at baseline, but diffuse coronary vasoconstriction was provoked in 3 vessels (ACh provocation at the top right corner) by Ach injection. At the same time, augmentation of ST elevation and new J wave was observed in I, II, aVF and V6 leads. Then, pulse-less PVT developed (bottom left). Coronary vasoconstriction was relieved by isosorbide dinitrate (ISDN) injection (middle right corner). During follow-up periods, VF occurred even though he was taking vasodilator drugs and calcium channel blockers (bottom right). TWA was positive at baseline (77 μV) and during follow-up period (73 μV). Right coronary angiograms during Ach provocation test and after ISDN injection are shown.
Oh et al. reported that VSA patients with the horizontal/descending ST-segment variant had a higher incidence of arrhythmic events [27], similar results to increased mortality in general population [18,19] and acute coronary event [22]. In our study, all 3 patients with VF had positive ER, but only one case had the horizontal/descending type. It was difficult to conclude the relationship between baseline ER of the horizontal/descending type and development of PVT/VF because of small numbers of cases.
4.1. Study limitations The present study included a relatively small number of patients, especially cases with VT/VF, and it was a retrospective, single-center study. We could not perform MMA analysis of TWA in all the patients. The shortage of numbers of PVT/VF cases did not allow us to perform multivariate analysis, and a significant difference in types of STsegment elevation after J wave. The clinical implications of the presence of ER and p-TWA need to be further investigated in large-scale prospective studies.
Table 4 Results of the VSA patients with cardiac event.
Male (n) Age (years) LVEF (%) QRS width (ms) QTc (ms) Baseline ER (n) Horizontal/descending (n) TWA N 65 μV (n) Baseline ER + TWA N 65 μV (n) Multivessels (n)
VSA with PVT/VF (n = 3)
VSA without PVT/VF (n = 63)
3 50.3 ± 10.3 61.0 ± 1.0 72.7 ± 15.3 357.7 ± 42.9 3 1 3 (/3) 3 (/3)
43 65.8 ± 9.9 65.3 ± 10.6 78.0 ± 11.6 385.8 ± 35.6 21 7 15 (/38) 6 (/38)
3
40
5. Conclusions
P
0.031 0.581 0.301 0.192 0.019 1.000 0.042 b0.001 0.195
The VSA patients in this study exhibited a high incidence of baseline ER and p-TWA, and the presence of both parameters could be a predictor of VSA. Baseline ER was a significant indicator of multi-vessel vasospasm. The presence of both baseline ER and p-TWA is an independent predictor of VT/VF in VSA patients.
Conflict of interest All authors have no conflicts of interest to declare.
Y. Inamura et al. / International Journal of Cardiology 196 (2015) 7–13
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International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Early repolarization and positive T-wave alternans as risk markers for life-threatening arrhythmias in patients with vasospastic angina☆ Yukihiro Inamura a,f,⁎, Mitsuhiro Nishizaki a, Masato Shimizu a, Hiroyuki Fujii a, Noriyosi Yamawake a, Makoto Suzuki b, Harumizu Sakurada c, Masayasu Hiraoka d,e, Mitsuaki Isobe f a
Department of Cardiology, Yokohama Minami Kyosai Hospital, Yokohama, Japan Department of Cardiology, Kameda Medical Center, Chiba, Japan Division of Cardiology, Tokyo Metropolitan Health and Medical Treatment Corporation Ohkubo Hospital, Tokyo, Japan d Department of Health Examination, Toride Kitasoma Medical Center Hospital, Ibaraki, Japan e Tokyo Medical and Dental University, Tokyo, Japan f Department of Cardiology, Tokyo Medical and Dental University, Tokyo, Japan b c
a r t i c l e
i n f o
Article history: Received 15 March 2015 Received in revised form 21 May 2015 Accepted 26 May 2015 Available online 29 May 2015 Keywords: Vasospastic angina J wave T wave alternans Multivessel vasospasm Ventricular fibrillation
a b s t r a c t Background: Several arrhythmogenic markers have been suggested as predictors for risk of life-threatening arrhythmias during symptom-free periods in vasospastic angina (VSA), but no definite conclusion has been drawn. Objective: To investigate prevalence of fatal ventricular tachyarrhythmia in VSA and its relation to appearance of early repolarization (ER) and positive T wave alternans (p-TWA) in patients with VSA during symptom-free periods. Methods: We studied 116 consecutive patients with chest pain who underwent an acetylcholine provocation test for VSA diagnosis. Patients were divided into two groups with positive (VSA group; 66 cases) and negative (control group; 50 cases) provocation test results. The presence of ER on electrocardiogram and the modified moving average analysis of TWA during symptom-free periods were explored. Results: The incidences of ER and p-TWA were higher in the VSA than in the control group (P = 0.001 and P = 0.006, respectively). Multivariate analysis revealed that ER and p-TWA were independent predictors of VSA (odds ratio, 5.65 and 4.94; 95% confidence interval: 1.11–28.9 and 1.22–19.9, respectively). The incidence of coexisting baseline ER and p-TWA was significantly higher in VSA patients with life-threatening arrhythmic events (3/3 vs. 6/38; P b 0.001) than in those without. Conclusions: VSA patients with arrhythmic events showed a high incidence of ER and p-TWA during symptom-free periods. Therefore, baseline ER and p-TWA may help to identify VSA patients at high risk for life-threatening arrhythmias. © 2015 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Vasospastic angina (VSA) is caused by coronary artery vasospasm resulting in severe chest pain and transient ST-segment elevation on electrocardiogram (ECG). VSA episodes are generally not provoked by
Abbreviations: Ach, acetylcholine;CI, confidence interval;ECG,electrocardiography; ER, early repolarization; LAD, left anterior descending artery; LCX, left circumflex artery; MMATWA, modified moving average analysis of T-wave alternans; OR, odds ratio; p-TWA, positive T wave alternans; PVT, polymorphic ventricular tachycardia; RCA, right coronary artery; TWA, T wave alternans; VF, ventricular fibrillation; VT, ventricular tachycardia; VSA, vasospastic angina. ☆ This paper was presented at the 78th Annual Scientific Meeting of the Japanese Circulation Society. ⁎ Corresponding author at: Yokohama Minami Kyosai Hospital, 1-21-1 Mutsuurahigashi, Kanazawa-ku, Yokohama 236-0037, Japan. E-mail address: [email protected] (Y. Inamura).
http://dx.doi.org/10.1016/j.ijcard.2015.05.147 0167-5273/© 2015 Elsevier Ireland Ltd. All rights reserved.
physical activity or emotional stress, but occur at rest without specific warning signs. VSA can be complicated by life-threatening ventricular arrhythmias and atrioventricular conduction block, or, if prolonged spastic events, by acute myocardial infarction. Life-threatening ventricular arrhythmia is a serious complication that can occur during attacks of VSA. While the incidence of life-threatening arrhythmias is not high (b10%), the events are nonetheless clinically important due to an increased risk for sudden cardiac death in subjects without significant coronary stenosis [1,2]. Our previous studies indicated that patients with VSA had potential substrates for malignant ventricular tachyarrhythmia with increased vulnerability and repolarization abnormalities [3,4]. Patients with VSA experienced frequent episodes of polymorphic ventricular tachycardia (PVT), which was inducible by programmed ventricular stimulation [3,4]. Even during asymptomatic periods, the patients showed increased QT dispersion, an indicator of inhomogeneous ventricular repolarization [5,6]. The modified moving average
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analysis of T-wave alternans (MMA-TWA) was shown to be superior to the measurement of QT dispersion for assessing the inhomogeneity of ventricular repolarization and predicting risk for life-threatening tachyarrhythmia and sudden cardiac death [7–10]. Our studies using the MMA-TWA also indicated that patients with VSA had high T wave alternans (TWA) values during event-free periods [11,12]. Early repolarization (ER) had been regarded as a benign ECG sign for many years because of its frequent association with healthy, young individuals and athletes without overt heart disease [13]. Recent clinical reports, however, have indicated that an ER pattern in the inferolateral leads is associated with the development of ventricular fibrillation (VF) in patients with idiopathic VF [14–17], and similar ER patterns with horizontal/descending ST segment have been associated with increased cardiac mortality in general populations [18,19]. Further, the presence of an ER pattern has also been shown to indicate a high risk for fatal ventricular arrhythmias in patients with Brugada syndrome [20], acute myocardial infarction [21,22], and Takotsubo cardiomyopathy [23]. Therefore, ER plays a critical role in the pathogenesis of malignant ventricular arrhythmias in certain clinical settings, while the genesis of the ER is controversial as to whether it is caused by repolarization or by depolarization abnormality [24–26]. Oh et al. reported that ER could predict cardiac death and fatal arrhythmias in patients with VSA [27]. It was not known, however, whether the presence of ER could predict life-threatening arrhythmic risk due to repolarization or depolarization abnormalities. The aim of the present study was to investigate prevalence of fatal ventricular tachyarrhythmia in VSA and its relation to appearance of early repolarization (ER) and positive T wave alternans (p-TWA) as a measure of inhomogeneous repolarization, in VSA patients during the asymptomatic period. 2. Methods 2.1. Patient population The study included 116 consecutive patients who had chest pain at rest and underwent coronary angiography with an acetylcholine (ACh) provocation test for the diagnosis of VSA between July 2010 and April 2014 at the Yokohama Minami Kyosai Hospital (71 men and 45 women; mean age, 63.1 ± 11.2 years). Patients were divided into two groups according to the results of the Ach provocation test: the VSA group (n = 66) with ACh-induced vasospasm and the control group (n = 50) without ACh-induced vasospasm. All patients in the VSA group were given vasodilator drugs and/or calcium antagonists after the coronary angiography and followed at our outpatient clinic until October 2014 or their last visit. Patients with bundle branch block, intra-ventricular conduction disturbances, or Wolff–Parkinson– White syndrome were excluded from analysis. In this study, patients taking calcium channel blockers during Holter monitoring were included. The study protocol was approved by the ethics committee of Yokohama Minami Kyosai Hospital. Written informed consent was obtained from all subjects before enrollment in the study.
the maximum dose was given. Coronary vasospasm was defined as total or subtotal occlusion of single or multiple coronary arteries with delayed filling of their distal segments and was associated with chest pain and/or ischemic ST-T changes on ECG [28]. If coronary vasospasm was induced in the left coronary artery, we waited until coronary vasospasm recovered spontaneously and then performed the ACh provocation test for the right coronary artery as well as for the diagnosis of multi-vessel vasospasm. 2.3. ECG analysis ER was defined as a J point elevation ≥1 mm above baseline and slurring or notching of the terminal portion of QRS at ≥2 inferior (II, III, aVF) and/or lateral (I, aVL, V5–6) leads [15,24]. We analyzed ECG records obtained before and during the ACh provocation test for VSA. The presence and lead locations of ER as well as the amplitude of the J wave were evaluated. ER during the ACh provocation test was defined as positive if ER became apparent when coronary vasospasm was induced by coronary angiography regardless of the presence or absence of ST-T wave changes, and defined as negative if there was no ER 60 s after ACh provocation test. New ER was defined as an ER which newly appeared during the ACh provocation test. We categorized ST segment patterns after ER as either the horizontal/descending or the concave/rapidly ascending type. The horizontal/ descending type was defined as descending or ≤ 0.1 mV elevation of the ST segment at 100 ms after the J point. The concave/rapidly ascending ST segment type was defined as N 0.1 mV elevation of the ST segment at 100 ms after the J point or a persistently elevated ST segment of N 0.1 mV through the ST segment [19]. The QT interval and QRS duration were measured in all 12-leads of ECG recorded at a speed of 50 mm/s for 2 consecutive cycles. The QT interval was measured from the beginning of the QRS complex to the end of the T wave, which was defined as the return to the TP baseline (between the end of the T wave and the following P wave). And QT interval was rate-corrected with a modification of Bazett's formula as follow: QTc interval = QT / square root of the QT interval [5,29]. 2.4. MMA-TWA analysis The MMA-TWA was analyzed from two channel records (NASA and CM5) by ambulatory Holter monitoring using MARS PC version 7.03 (GE Healthcare, Milwaukee, WI) and identified periods of possible TWA by applying an MMA in 68 patients (41 in the VSA group and 27 in the control group). MMA is a time-domain-based method that bifurcates the beat stream and generates a separate moving average template (ABABABA) [8–10] Average values were updated by a weighting factor one-eighth of the difference between the ongoing average and the current pair of beats. A noise level of 20 μV was adopted in the system configuration. Manual editing was performed if the data were not eligible for analysis because of artifacts or noise. The maximum TWA value was defined as the highest value in either channel. Positive TWA (pTWA) was defined as a TWA value N 65 μV, in accordance with previous reports [30,31].
2.2. Coronary angiography and acetylcholine provocation test 2.5. Definition of arrhythmic events All vasodilator drugs and calcium antagonists were discontinued at least 3 days before coronary angiography. The coronary angiography began around 9 am on the morning of the study day. After confirming no significant stenotic lesions in both right and left coronary arteries, a bipolar electrode catheter was inserted into the right ventricular apex through the right femoral vein and connected to a temporary pacemaker. The pacing rate was set at 50 bpm. Incremental doses of acetylcholine were injected into the left coronary artery (20, 50, and 100 μg) and the right coronary artery (20, 50, and 70 μg) until acetylcholineinduced coronary vasospasm was detected angiographically or until
We defined arrhythmic events as spontaneous PVT/VF documented before the ACh provocation test and during follow-up period of 26.1 ± 14.0 months. We excluded syncope without documentation of PVT/VF from arrhythmic events, even if syncope occurred with chest pain. Syncope without documentation of PVT/VF might be caused by other conditions such as hemodynamic deterioration, complete atrioventricularblock, or sinus arrest due to ischemic events. None of the VSA group in this study developed complete atrioventricular block or acute myocardial infarction throughout the follow-up period.
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Table 1 Clinical data of the patients in the 2 groups.
Male (n) Age (years) LVEF (%) QRS width (ms) QTc (ms) Presence of PVT/VF (n) Before ACh provocation test During follow-up periods Presence of syncope without PVT/VF documented Number of vessels with induced spasm 1 vessel (LAD/LCX/RCA) 2 vessels (LAD–LCX/LAD–RCA/LCX–RCA) 3 vessels Baseline ER (n) ST segment, rapidly ascending ST segment, horizontal/descending Inferior leads Lateral leads Inferolateral leads J-point amplitude (mV) Max TWA (μV) TWA N65 μV (n) Baseline ER + TWA N65 μV (n) During ACh provocation test New ER (n) Inferior leads (n) Lateral leads (n) Inferolateral leads (n) J-point amplitude (mV) Polymorphic PVT/VF induction (n)
VSA group n = 66
Control group n = 50
P
46 (70%) 63.9 ± 11.4 64.9 ± 9.9 79.8 ± 12.0 384.6 ± 35.3 3 (5%) 2 1 4 (6%)
25 (50%) 60.4 ± 12.1 65.2 ± 7.1 77.8 ± 15.5 386.1 ± 33.5 0 (0%)
0.031⁎ 0.115 0.912 0.144 0.893 0.127
0 (0%)
0.076
23 (10/0/13) 31 (3/23/5) 12 24 (36%) 16 8 15 (63%) 6 (25%) 3 (13%) 0.60 ± 0.80 60.6 ± 16.9 18/41 (44%) 9 (22%)
6 (12%) 6 0 4 (67%) 2 (33%) 0 (0%) 0.18 ± 0.54 50.5 ± 9.7 3/27 (11%) 0 (0%)
0.001⁎ 0.096 0.011⁎ 0.454 0.68 0.361 0.002⁎ 0.007⁎ 0.006⁎ 0.009⁎
7 7 0 0 1.01 ± 1.22 2
0 0 0 0 0.20 ± 0.66 0
0.018⁎ 0.018⁎
b0.0001⁎ 0.214
Values are expressed as mean ± standard deviation. LVEF, left ventricular ejection fraction; QTc, QT interval corrected for heart rate. ⁎P b 0.05
2.6. Statistical analysis Data were expressed as mean ± standard deviation The Welch t test was used for comparisons between group means expressed as continuous variables. The chi-square test was used to evaluate differences in categorical variables between the two groups. Univariate logistic regression analysis was done for the existence of VSA in all patients and multivessel vasospasm in VSA group. Multivariate logistic regression analysis was used for defining independent predictors of vasospasm. A P b 0.05 was considered statistically significant.
VSA group than the control group at baseline. In the VSA group, the amplitude of J points increased from 0.60 ± 0.80 mV at baseline to 1.01 ± 1.22 mV (P = 0.024) after the Ach test, whereas the amplitude was not changed by the Ach test in the control group (0.18 ± 0.54 mV before and 0.20 ± 0.66 mV after the Ach test; P = 0.841) (Fig. 1). ER appeared and/or its amplitude was augmented in the leads associated with vasospastic areas revealed by angiography. ST-T wave changes followed the appearance and/or augmentation of J wave. ECG records and coronary angiograms from a typical case are shown in Fig. 2.
3. Results 3.1. Clinical and electrophysiological characteristics of the VSA and control groups Table 1 shows clinical and electrophysiological profiles of patients in the VSA and control groups. The VSA group had higher male predominance than the control group (P = 0.031). The VSA group showed ER at baseline ECG in 24 (36%) patients, and the control group in 6 (12%) cases. Types of ST-segment elevation in the VSA group included 16 cases of the concave/rapidly ascending type and 8 of the horizontal/ descending type, whereas 6 patients presented the concave/rapidly ascending type but no horizontal/descending type in the control group (P = 0.001). The VSA group had a higher incidence of p-TWA than the control group (18/41 patients [44%] vs. 3/27 patients [11%], respectively; P = 0.006). Nine patients in the VSA group exhibited both positive ER at baseline and p-TWA, but none in the control group had positive signs of both parameters. During the ACh provocation test, 7 patients had new ER in the VSA group and none in the control group (P = 0.018). New ER appeared exclusively at the inferior leads. The amplitude of J wave was higher in the
Fig. 1. Change in J point amplitude by the acetylcholine (ACh) provocation test in the control and VSA group.
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Fig. 2. ECG records and coronary angiograms before and during ACh provocation test from a representative case. A 59-year-old man (Case 1) without past history of ventricular fibrillation (VF) or syncope experienced sudden chest pain at around 7:00 am when he was at rest in the spine position. Then, he suddenly groaned and lost consciousness with spontaneous recovery after 1 min. On arrival at the hospital, J wave was observed in the inferior leads (baseline ECG). No stenotic lesion was observed in the coronary angiogram (baseline). During the acetylcholine (ACh) provocation test, amplitudes of J wave were augmented and diffuse coronary vasospasms were provoked in 3 vessels. A value of T wave alternans (TWA) was 68 μV. Only right coronary angiograms (baseline and Ach provocation) are shown.
On univariate analysis, sex, presence of ER at baseline, horizontal/ descending ST-segment elevation, and p-TWA were significant predictors of VSA. On multivariate logistic regression analysis, presence of ER at baseline and p-TWA revealed independent predictors of VSA (odds ratio [OR], 5.65 and 4.94; 95% confidence interval [CI]: 1.11–28.9 and 1.22–19.9; P = 0.037 and P = 0.025, respectively) (Table 2).
3.2. Predictors for single-vessel or multi-vessel vasospasm Multi-vessel vasospasm might cause severe ischemic injury compared to single-vessel vasospasm. We sought to explore predictive values of the presence of ER and p-TWA for single-vessel versus multivessel vasospasm. In the VSA group, 23 patients developed singlevessel vasospasm; left anterior descending artery (LAD; n = 10), right coronary artery (RCA; n = 13) and left circumflex artery (LCX; n = 0). Two-vessel vasospasm was observed in 31 patients: RCA–LAD (n = 23), RCA–LCX (n = 5) and LAD–LCX (n = 3). Three-vessel vasospasm was seen in 12 patients. The presence of baseline ER alone was a significant predictor for multi-vessel (two- and three-vessels) over
Table 2 Results of the univariate and multivariate analyses for vasospasm. Univariate
Age (years) Male LVEF (%) QRS width QTc Baseline J wave Horizontal/descending TWA N 65 μV
single-vessel vasospasm (Fig. 3; OR, 4.13; 95% CI: 1.20–14.2; P = 0.024). The presence of p-TWA could not predict multi-vessel or single-vessel vasospasm (P = 0.923). 3.3. Parameters discriminating the VSA patients with and without arrhythmic events Of 116 patients, 3 had documented PVT/VF. Two patients who did not take vasodilator drugs developed spontaneous VF before the ACh test, and one patient who exhibited documented VF during the follow-up period was on vasodilator drugs and forgot to take them on the day of event. Among the three patients with PVT/VF, two developed non-sustained VT and one showed PVT during the ACh provocation test with multi-vessel spasm. They showed both ER at baseline and p-TWA (Table 3). A representative case (no. 3) who developed VF during the follow-up period is shown in Fig. 4. This patient showed p-TWA throughout the follow-up period. Table 4 shows a comparison of the parameters between the patients with PVT/VF and those without arrhythmic events. While the incidence of both baseline ER and p-TWA were higher in the patients with arrhythmic events than those without, there were no significant differences between the two groups for the presence of horizontal/descending STsegment elevation. 4. Discussion
Multivariate
OR (95% CI)
P value
1.03 (0.99–1.06) 2.30 (1.07–4.94) 1.00 (0.93–1.07) 1.01 (0.98–1.04) 1.00 (0.99–1.01) 4.19 (1.56–11.3) 11.7 (1.52–90.9) 5.91 (1.53–22.9)
0.116 0.033 0.910 0.466 0.840 0.005 0.018 0.010
OR (95% CI)
P value
0.82 (0.28–2.44)
0.724
5.65 (1.11–28.9)
0.037
4.94 (1.22–19.9)
0.025
Logistic regression analysis was done for the existence of VSA in all patients (n = 116). OR, odds ratio; 95% CI, 95% confidence interval.
The major findings of the present study were as follow: 1) incidences of baseline ER and p-TWA were higher in the VSA patients than in the control subjects with chest pain alone; 2) presence of baseline ER and p-TWA was an independent predictor of VSA; 3) baseline ER was a significant indicator of multi-vessel vasoconstriction; and 4) the presence of both baseline ER and p-TWA was a strong risk factor for PVT/VF in VSA. There have been very few clinical studies exploring the incidence of ER and p-TWA in patients with chest pain divided into two groups with and without VSA proved by ACh provocation test. Oh et al. reported that
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Fig. 3. Predictors of multi-vessel vasospasm in VSA group by logistic regression analysis. Logistic regression analysis of various parameters was performed in VSA group (n = 66). In the right side of the graph, it is superior in multi-vessel vasospasm, and in the left side of the graph, it is superior in single-vessel vasospasm. Abbreviation: OR; odds ratio, CI; confidence interval, LVEF; left ventricular ejection fraction, ER; early repolarization, ACh; acetylcholine.
any type of ER in the inferior and/or lateral leads was persistently observed in 21.4% of patients with VSA [27], but their study population consisted only of VSA patients. Our study compared the incidences of ER and p-TWA during asymptomatic periods in 2 groups of patients complaining chest pain with and without VSA as revealed by ACh provocation test. The incidence of ER was relatively higher in our study (36%) than the report of Oh et al. [27]. Further the patients with VSA had significantly higher incidences of ER and p-TWA than the subjects showing chest pain without vasospasm during the ACh provocation test. On multivariate analysis, the presences of baseline ER and p-TWA were independent predictors of VSA. While the positive predictive values were less than 90% in either cases of ER alone or p-TWA alone, the value for VSA was 100% in patients with chest pain, baseline ER and p-TWA. Therefore, two parameters of these non-invasive evaluations were helpful in differential diagnosis of chest pain resulted from VSA or other cause. In the VSA group, ER appeared and/or was augmented in the leads associated with ischemic areas, caused by ACh-induced vasospasm (Figs. 2 and 4). By contrast, the ER pattern was virtually unchanged during ACh provocation test in the control group that showed chest pain without VSA. The results suggested that the J-point elevation during ACh provocation test was not due to a direct action of ACh but might be related to ischemic events. While the presence of baseline ER was a significant predictor for multi-vessel (two- and three-vessels) over single-vessel vasospasm, the substrate of ER appeared to be sensitive to the severity of ischemic insults. The exact genesis of ER is not known, and various factors contributing to depolarization and repolarization
phases of action potentials are supposed. From the experimental studies, the genesis of ER, especially J wave, was proposed to be produced by transmural voltage gradient during the early phase of ventricular repolarization between the epicardium and endocardium [24]. The MMA-TWA has been shown as a useful tool for evaluating the inhomogeneity of ventricular repolarization and predicting risk for life-threatening tachyarrhythmia and sudden cardiac death [7–10]. Our previous study demonstrated high values and incidences of positive MMA-TWA in VSA patients with ventricular tachycardia, but the incidence decreased in patients taking calcium channel blockers [11]. In the present study, all patients with VF had p-TWA, and patient no. 3 (Fig. 4) maintained high TWA values during the follow-up period. Our study also showed that p-TWA together with baseline ER was the predictive factor of ventricular tachyarrhythmia, but p-TWA alone did not predict which patients would develop multi-vessel vasospasm. There are multiple factors that are supposed to cause ER, such as cardiac ischemia [32], depolarization [26] and/or repolarization [33] abnormalities, and the effect of autonomic nerves [34]. The present results might suggest that ER had additional contributors different from inhomogeneity of ventricular repolarization that could be detected by p-TWA. Only a few clinical studies have investigated the relationship between ER and TWA in patients with VSA; thus, actual contribution and their mechanisms for risk stratification remain unclear. However, we demonstrated that 3/9 patients with both baseline ER and p-TWA experienced PVT/VF associated with VSA event. These results may indicate that the coexistence of ER and TWA is a strong risk factor for PVT/VF in patients with VSA.
Table 3 Characteristics of the patients with PVT/VF. Case no.
Age
Sex
VF
VT/VF during
ER after ACh test
Ach provocation
Site of coronary spasm
TWA
Baseline ER
ER pattern
1
59
M
Before diagnosis
Non-sustained VT
3 vessels
68 μV
III aVF
Horizontal
2
39
M
Before diagnosis
Non-sustained VT
Total occlusion of 3 vessels
85 μV
II III aVF V5
Upslope
3
53
M
Follow-up period
Pulseless polymorphic VT
3 vessels
77 μV
aVL V6
Upslope
Increased amplitude (IIIIIaVF) Increased amplitude (V5) Increased amplitude (IIIIIaVF)
12
Y. Inamura et al. / International Journal of Cardiology 196 (2015) 7–13
Fig. 4. ECGs and coronary angiograms from a case who developed PVT during ACh provocation test and VF during follow-up period. A 53-year-old man (Case 3) without past history of VF or syncope experienced recurring chest pain episodes. Despite taking a calcium channel blocker, he lost consciousness and transferred to the hospital. On arrival, J wave was observed in aVL and V6 leads (baseline). Coronary angiography showed no stenotic lesion at baseline, but diffuse coronary vasoconstriction was provoked in 3 vessels (ACh provocation at the top right corner) by Ach injection. At the same time, augmentation of ST elevation and new J wave was observed in I, II, aVF and V6 leads. Then, pulse-less PVT developed (bottom left). Coronary vasoconstriction was relieved by isosorbide dinitrate (ISDN) injection (middle right corner). During follow-up periods, VF occurred even though he was taking vasodilator drugs and calcium channel blockers (bottom right). TWA was positive at baseline (77 μV) and during follow-up period (73 μV). Right coronary angiograms during Ach provocation test and after ISDN injection are shown.
Oh et al. reported that VSA patients with the horizontal/descending ST-segment variant had a higher incidence of arrhythmic events [27], similar results to increased mortality in general population [18,19] and acute coronary event [22]. In our study, all 3 patients with VF had positive ER, but only one case had the horizontal/descending type. It was difficult to conclude the relationship between baseline ER of the horizontal/descending type and development of PVT/VF because of small numbers of cases.
4.1. Study limitations The present study included a relatively small number of patients, especially cases with VT/VF, and it was a retrospective, single-center study. We could not perform MMA analysis of TWA in all the patients. The shortage of numbers of PVT/VF cases did not allow us to perform multivariate analysis, and a significant difference in types of STsegment elevation after J wave. The clinical implications of the presence of ER and p-TWA need to be further investigated in large-scale prospective studies.
Table 4 Results of the VSA patients with cardiac event.
Male (n) Age (years) LVEF (%) QRS width (ms) QTc (ms) Baseline ER (n) Horizontal/descending (n) TWA N 65 μV (n) Baseline ER + TWA N 65 μV (n) Multivessels (n)
VSA with PVT/VF (n = 3)
VSA without PVT/VF (n = 63)
3 50.3 ± 10.3 61.0 ± 1.0 72.7 ± 15.3 357.7 ± 42.9 3 1 3 (/3) 3 (/3)
43 65.8 ± 9.9 65.3 ± 10.6 78.0 ± 11.6 385.8 ± 35.6 21 7 15 (/38) 6 (/38)
3
40
5. Conclusions
P
0.031 0.581 0.301 0.192 0.019 1.000 0.042 b0.001 0.195
The VSA patients in this study exhibited a high incidence of baseline ER and p-TWA, and the presence of both parameters could be a predictor of VSA. Baseline ER was a significant indicator of multi-vessel vasospasm. The presence of both baseline ER and p-TWA is an independent predictor of VT/VF in VSA patients.
Conflict of interest All authors have no conflicts of interest to declare.
Y. Inamura et al. / International Journal of Cardiology 196 (2015) 7–13
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