Original article
Use of T-wave alternans in identifying patients with coronary artery disease Stefano Figliozzi, Alessandra Stazi, Gaetano Pinnacchio, Marianna Laurito, Rossella Parrinello, Angelo Villano, Giulio Russo, Maria Milo, Roberto Mollo, Gaetano A. Lanza and Filippo Crea Aims Microvolt T-wave alternans (MTWA) has been found to predict fatal events in patients with coronary artery disease (CAD). In a previous study, we found that MTWA values are higher in patients with CAD, compared with apparently healthy individuals. In this study, we assessed the relation between CAD and MTWA in patients with a diagnosis based on coronary angiography results. Methods We studied 98 consecutive patients undergoing coronary angiography for suspected CAD. All patients underwent a maximal exercise stress test (EST), and MTWA was measured in the precordial ECG leads. Patients were divided into three groups: 40 patients without any significant (>50%) stenosis (group 1); 47 patients with significant stenosis (group 2); and 11 patients with a previous percutaneous coronary intervention (PCI) who had no evidence of restenosis (group 3). EST was repeated after 1 month in 24 group 2 patients who underwent PCI and in 17 group 1 patients. Results MTWA was significantly higher in group 2 (58.7 W 24 mV) compared with group 1 (34.2 W 15 mV, P < 0.01) and group 3 (43.2 W 24 mV, P < 0.05). An MTWA greater than 60 mV had 95% specificity and 82% positive
Introduction The exercise stress test (EST) remains the first-line test for the diagnosis of coronary artery disease (CAD).1,2 EST-induced ST-segment depression is considered the most reliable ECG sign of CAD-related myocardial ischemia.3 The accuracy of this finding for the diagnosis of obstructive CAD is, however, less than optimal, with sensitivity and specificity of only 68 and 77%, respectively.4 Several other ECG variables and parameters have been proposed in an attempt to improve the diagnostic value of ECG-EST, including the ST/heart rate slope or index and the ST-heart rate recovery loop,5–7 but none has shown sufficient additional diagnostic value clinical practice. In recent years, microvolt T-wave alternans (MTWA) has been shown to predict arrhythmic events in some groups of patients, in particular those with documented CAD or heart failure.8–13 However, its relation with the induction of myocardial ischemia during EST remains substantially unknown, although even macroscopic T-wave alternans 1558-2027 Copyright ß 2016 Wolters Kluwer Health, Inc. All rights reserved.
predictive value for obstructive CAD. At 1-month follow-up, MTWA decreased significantly in patients treated with PCI (from 61.3 W 22 to 43.5 W 17 mV; P < 0.001), but not in group 1 patients (from 50.5 W 22 to 44.3 W 19 mV, P U 0.19). Conclusion MTWA is increased in patients with obstructive CAD and is reduced by coronary revascularization. An assessment of MTWA can be helpful in identifying which patients with suspected CAD are likely to show obstructive CAD on angiography. J Cardiovasc Med 2016, 17:20–25 Keywords: coronary artery disease, exercise stress test, myocardial ischemia, T wave alternans Department of cardiovascular medicine, Universita` Cattolica del Sacro Cuore, Roma, Italy Correspondence to Gaetano A. Lanza, MD, Istituto di Cardiologia, Universita` Cattolica del Sacro Cuore, Largo A. Gemelli, 8, 00168 Roma, Italy Tel: +39 06 3015 4126; fax: +39 06 30 55 535; e-mail: [email protected] Received 16 September 2013 Revised 20 November 2013 Accepted 1 December 2013
has sometimes been reported during severe, transmural myocardial ischemia.14,15 In a recent study, patients with a history of CAD were shown to have higher MTWA compared with apparently healthy individuals; the coronary angiographic picture of the latter group of individuals, however, was unknown.16 In this study, we prospectively investigated whether MTWA can be helpful in identifying patients who subsequently are found to have significant coronary stenosis on angiography, out of those with suspected obstructive CAD, based on the presence of chest pain on effort and evidence of myocardial ischemia on noninvasive stress tests. The relation of MTWA with the evidence of EST-induced myocardial ischemia was also evaluated.
Methods Population
We studied 98 consecutive patients referred to our hospital to undergo an elective coronary angiography DOI:10.2459/JCM.0000000000000080
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Microvolt T-wave alternans and myocardial ischemia Figliozzi et al. 21
with suspected myocardial ischemia, as suggested by typical chest pain induced by effort or documentation of myocardial ischemia from noninvasive imaging stress tests. Only patients who also fulfilled the following inclusion criteria were eligible for the study: no history or ECG evidence of previous myocardial infarction and no conditions that could interfere with ST-segment analysis or assessment of MTWA during EST, including atrial fibrillation, pacemaker rhythm and intraventricular conduction defects. Exercise stress test
After obtaining written informed consent to participate in the study, patients underwent symptom/sign-limited EST the day before undergoing coronary angiography. A treadmill EST (Cardiosoft GE Healthcare system, version 4.14, Milan, Italy) was carried out according to a standard Bruce protocol. Leads II, V2 and V5 were monitored continuously; a 12-lead ECG was printed at the end of each stage, or when clinically indicated, and at 1-min intervals in the recovery phase. Blood pressure was measured at baseline, at peak exercise and during the last minute of each stage. ST-segment depression was considered significant if it was horizontal or downsloping and at least 1 mm at 0.06 s from the J-point in any lead apart from aVR. The EST was stopped in cases of physical exhaustion, progressive angina, ST-segment depression of at least 4 mm or relevant clinical events (e.g. dyspnea, hypotension and arrhythmias). Microvolt T-wave alternans
MTWA was assessed with the time-domain modified moving average method, using the software provided by the EST system manufacturer. As described in detail elsewhere,17 in this method a sequence of beats is separated into odd and even beats. Along the entire J–T segment, separated average morphologies of both the odd and even beats are calculated separately and continuously and updated by each new incoming beat using a weighting factor of one of eight in order to minimize the influence of noise on the MTWA measurement and, therefore, obtain a higher degree of reliability. MTWA is calculated as the maximal difference between the averages of odd and even beats along one of the J–Tsegment sampled points in any lead. MTWA is analyzed continuously during the entire stress test up to a heart rate of 125 bpm. Periods with elevated noise level (>25 mV) are automatically excluded from the analysis. Two measures of MTWA were initially obtained: one from all ECG leads apart from aVR, and one from the six precordial ECG leads only. In our previous study, we found that precordial MTWA was slightly better in discriminating between CAD patients and apparently healthy controls.16 The results of the present study confirmed this finding. Indeed, similar results were observed with MTWA values obtained from all ECG
leads or from precordial leads only, but the latter showed slightly better differences between groups (data not shown). Accordingly, only precordial MTWA values are reported in this study. Coronary angiography
Coronary angiography was performed the day after the EST using standard methods and through a percutaneous femoral or radial approach. Significant stenoses in the epicardial coronary artery vessels were diagnosed in cases of obstruction of at least 50% of the internal coronary artery diameter. Patient groups
Patients were divided into three groups according to clinical history and the results of coronary angiography: 40 patients (group 1) without any previous evidence of CAD and showing no significant coronary stenosis; 47 patients (group 2) without any previous evidence of CAD and showing significant coronary stenosis in one or more coronary arteries; and 11 patients who had previously undergone a percutaneous coronary intervention (PCI) and who were found to have no evidence of restenosis (group 3). No patient with previous PCI showing restenosis was found in this consecutive series of patients undergoing elective coronary angiography as a result of recurrence of chest pain. Follow-up assessment
In order to assess whether coronary revascularization had any effect on MTWA, patients in group 1 who underwent successful complete coronary revascularization by PCI and patients of group 2 (controls) were invited to undergo a follow-up EST 1 month after PCI. However, only 24 patients from group 1 and 17 patients from group 2 gave their informed written consent to participate in this part of the study (see below). Statistical methods
Normal distribution of continuous variables was assessed by the Kolmogorov–Smirnov test. As all variables showed a distribution not significantly different from normal, means were compared by analysis of variance, whereas chi-square test was used to compare proportions. Repeated measure analysis of variance was applied to compare the changes in MTWA between groups at follow-up. The Bonferroni rule was applied to adjust statistical results for multiple between-group or withingroup comparisons. A generalized linear model was also applied to adjust the differences among groups in MTWA for potentially confounding clinical variables, specifically variables that showed a group difference of P < 0.1 on standard analysis. These variables included age, sex, BMI, smoking (yes/no) and use of b-blockers, angiotensin converting enzyme inhibitors, aspirin, statins and
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
22 Journal of Cardiovascular Medicine 2016, Vol 17 No 1
Table 1
Main clinical characteristics of the three groups of patients
Age (years) Sex (M/F) BMI (kg/m2) Angina Typical Atypical Absent Cardiovascular risk factors Family history of CAD Diabetes Hypertension Smoking Hypercholesterolemia Drug therapy b-Blockers Calcium-antagonists ACE-inhibitors ARBs Statins Antiaggregants Nitrates Antidiabetics
Group 1 (n ¼ 40)
Group 2 (n ¼ 47)
58.7 11 20/20 26.6 3.8
65.6 8 38/9 26.5 2.7
Group 3 (n ¼ 11) 64.7 10 11/0 29.0 3.1
P 0.005 0.001 0.07
15 (37%) 8 (20%) 17 (43%)
21 (45%) 1 (2%) 25 (53%)
3 (27%) 2 (18%) 6 (55%)
0.09
17 8 27 12 25
(42%) (20%) (68%) (30%) (63%)
21 18 36 27 35
(45%) (38%) (77%) (57%) (75%)
7 4 9 7 9
(64%) (36%) (82%) (64%) (82%)
0.45 0.17 0.51 0.02 0.32
20 7 5 14 15 20 3 5
(50%) (18%) (13%) (35%) (38%) (50%) (8%) (13%)
30 8 15 11 28 37 2 15
(64%) (17%) (32%) (23%) (60%) (79%) (4%) (32%)
10 2 5 4 9 11 0 3
(91%) (18%) (46%) (36%) (82%) (100%) (0%) (27%)
0.04 0.99 0.03 0.43 0.02 0.001 0.57 0.10
ACE, angiotensin-converting enzyme; ARBs, angiotensin-II receptor blockers; CAD, coronary artery disease; CCB, calcium channel blockers.
antidiabetic drugs (yes/no variables). Data were analyzed using the SPSS statistical package 20.0 (SPSS Italia, Florence, Italy). A P < 0.05 was always required for statistical significance.
Results Clinical characteristics
The main clinical characteristics of the three groups of patients are summarized in Table 1. Patients in group 1 showed a higher prevalence of women (P ¼ 0.001), a younger age (P ¼ 0.005) and a lower prevalence of cigarette smoking (P ¼ 0.02). Cardiovascular drugs were more frequently taken by group 3 patients (who had already undergone a previous PCI). Exercise stress test
The main EST results are shown in Table 2. ST-segment depression was induced during EST in 33 (82%), Table 2
42 (89%) and eight (73%) patients in group 1, 2 and 3, respectively (P ¼ 0.34). Typical angina was induced in 15 (37%), 21 (45%) and three (27%) patients in the three groups, respectively (P ¼ 0.09), with no patient developing angina without significant ST-segment depression. The three groups did not significantly differ for any EST parameter, except for time to 1 mm ST-segment depression, which was shorter in patients in group 2 (P ¼ 0.03). However, the duration of exercise and the hemodynamic parameters at peak EST were similar in the three groups.
Microvolt T-wave alternans
MTWA significantly differed between groups (P < 0.0001), with the highest value being observed in group 2 (58.7 24 vs. 34.2 15 and 43.2 24 mV in group 1 and group 3, respectively; Fig. 1). Subgroup analysis did
Exercise stress test parameters in the three groups of patients
Baseline SBP (mmHg) DBP (mmHg) HR (bpm) RPP (mmHg bpm) Peak SBP (mmHg) DBP (mmHg) HR (bpm) RPP (mmHg bpm) EST result Positive Negative Angina Time to 1 mm STD (s) Max ST (mm) Exercise duration (s)
Group 1 (n ¼ 40)
Group 2 (n ¼ 47)
Group 3 (n ¼ 11)
P
131 18 83 7 76 14 9933 2169
138 19 81 12 74 16 10313 2867
131 15 75 8 68 16 8865 2776
0.17 0.07 0.30 0.24
171 23 90 11 138 24 23793 5464
176 30 90 13 129 18 22863 5436
173 22 86 12 130 22 22275 4141
0.71 0.61 0.12 0.60
33 (82%) 7 (18%) 6 (15%) 365 151 1.3 0.7 466 151
42 (89%) 5 (11%) 6 (13%) 277 147 1.5 0.9 397 151
8 (73%) 3 (23%) 2 (18%) 335 172 1.1 0.8 462 199
0.34
EST, exercise stress test; HR, heart rate; RPP, rate pressure product; STD, ST depression.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
0.89 0.03 0.15 0.11
Microvolt T-wave alternans and myocardial ischemia Figliozzi et al. 23
The difference among groups in MTWA remained highly significant (P < 0.01) after adjustment for potentially confounding variables, including age, sex, BMI, smoking and use of b-blockers, angiotensin converting enzyme inhibitors, aspirin, statins and antidiabetic drugs. Subgroup analyses in coronary artery disease patients
No significant difference in MTWA was found among group 2 patients in relation to severity of CAD. MTWA was 55.2 24, 62.8 26 and 61.8 23 mV in patients with 1-vessel, 2-vessel and 3-vessel CAD, respectively (P ¼ 0.61). In order to assess the impact of myocardial ischemia on MTWA, group 2 patients were also divided into two subgroups according to whether a significant ST-segment depression was or was not induced during EST at a heart rate of less than 125 bpm (i.e. the maximal heart rate for MTWA detection). MTWA was 61.9 24 and 53.4 24 mV in patients with (n ¼ 29) or without (n ¼ 18) ST-segment depression at this cutoff heart rate during EST (P ¼ 0.25). Coronary revascularization and microvolt T-wave alternans values
As specified, only 24 patients of group 1 and 17 patients of group 2 agreed to participate in the follow-up part of the study. Clinical characteristics of these two groups were comparable. MTWA at basal EST was also similar in the two groups (Table 3). The change from baseline in MTWA at follow-up significantly differed between the two groups (group–variable interaction, P ¼ 0.039). The difference was explained by a significant reduction of MTWA in the PCI-treated group (61.3 22 vs. 43.5 17 mV; Fig. 1
100 P < 0.0001
MTWA (µV)
80
Table 3
Main clinical characteristics of the two follow-up groups Group PCI (n ¼ 24)
Age (years) Sex (M/F) BMI (kg/m2) Angina Typical Atypical Absent Cardiovascular risk factors Familiar history of CVD Diabetes Hypertension Smoking Hypercholesterolemia Drug therapy b-Blockers CCB ACE-inhibitors ARBs Statins Antiaggregants Nitrates Antidiabetics
66.5 8.7 19/5 26.2 2.2 13 (54%) 0 (0%) 11 (46%)
Controls (n ¼ 17)
P
64.9 7.3 10/7 27.3 4.8
0.55 0.18 0.34
9 (53%) 2 (12%) 6 (36%)
0.21
9 9 18 12 12
(38%) (40%) (75%) (50%) (70%)
8 5 10 6 17
(47%) (30%) (60%) (35%) (70%)
0.75 0.74 0.32 0.52 1.00
15 7 9 7 20 24 1 9
(63%) (29%) (38%) (29%) (83%) (100%) (4%) (38%)
12 3 2 10 12 9 3 5
(71%) (18%) (12%) (59%) (71%) (53%) (18%) (29%)
0.74 0.48 0.85 0.11 0.45
Use of T-wave alternans in identifying patients with coronary artery disease Stefano Figliozzi, Alessandra Stazi, Gaetano Pinnacchio, Marianna Laurito, Rossella Parrinello, Angelo Villano, Giulio Russo, Maria Milo, Roberto Mollo, Gaetano A. Lanza and Filippo Crea Aims Microvolt T-wave alternans (MTWA) has been found to predict fatal events in patients with coronary artery disease (CAD). In a previous study, we found that MTWA values are higher in patients with CAD, compared with apparently healthy individuals. In this study, we assessed the relation between CAD and MTWA in patients with a diagnosis based on coronary angiography results. Methods We studied 98 consecutive patients undergoing coronary angiography for suspected CAD. All patients underwent a maximal exercise stress test (EST), and MTWA was measured in the precordial ECG leads. Patients were divided into three groups: 40 patients without any significant (>50%) stenosis (group 1); 47 patients with significant stenosis (group 2); and 11 patients with a previous percutaneous coronary intervention (PCI) who had no evidence of restenosis (group 3). EST was repeated after 1 month in 24 group 2 patients who underwent PCI and in 17 group 1 patients. Results MTWA was significantly higher in group 2 (58.7 W 24 mV) compared with group 1 (34.2 W 15 mV, P < 0.01) and group 3 (43.2 W 24 mV, P < 0.05). An MTWA greater than 60 mV had 95% specificity and 82% positive
Introduction The exercise stress test (EST) remains the first-line test for the diagnosis of coronary artery disease (CAD).1,2 EST-induced ST-segment depression is considered the most reliable ECG sign of CAD-related myocardial ischemia.3 The accuracy of this finding for the diagnosis of obstructive CAD is, however, less than optimal, with sensitivity and specificity of only 68 and 77%, respectively.4 Several other ECG variables and parameters have been proposed in an attempt to improve the diagnostic value of ECG-EST, including the ST/heart rate slope or index and the ST-heart rate recovery loop,5–7 but none has shown sufficient additional diagnostic value clinical practice. In recent years, microvolt T-wave alternans (MTWA) has been shown to predict arrhythmic events in some groups of patients, in particular those with documented CAD or heart failure.8–13 However, its relation with the induction of myocardial ischemia during EST remains substantially unknown, although even macroscopic T-wave alternans 1558-2027 Copyright ß 2016 Wolters Kluwer Health, Inc. All rights reserved.
predictive value for obstructive CAD. At 1-month follow-up, MTWA decreased significantly in patients treated with PCI (from 61.3 W 22 to 43.5 W 17 mV; P < 0.001), but not in group 1 patients (from 50.5 W 22 to 44.3 W 19 mV, P U 0.19). Conclusion MTWA is increased in patients with obstructive CAD and is reduced by coronary revascularization. An assessment of MTWA can be helpful in identifying which patients with suspected CAD are likely to show obstructive CAD on angiography. J Cardiovasc Med 2016, 17:20–25 Keywords: coronary artery disease, exercise stress test, myocardial ischemia, T wave alternans Department of cardiovascular medicine, Universita` Cattolica del Sacro Cuore, Roma, Italy Correspondence to Gaetano A. Lanza, MD, Istituto di Cardiologia, Universita` Cattolica del Sacro Cuore, Largo A. Gemelli, 8, 00168 Roma, Italy Tel: +39 06 3015 4126; fax: +39 06 30 55 535; e-mail: [email protected] Received 16 September 2013 Revised 20 November 2013 Accepted 1 December 2013
has sometimes been reported during severe, transmural myocardial ischemia.14,15 In a recent study, patients with a history of CAD were shown to have higher MTWA compared with apparently healthy individuals; the coronary angiographic picture of the latter group of individuals, however, was unknown.16 In this study, we prospectively investigated whether MTWA can be helpful in identifying patients who subsequently are found to have significant coronary stenosis on angiography, out of those with suspected obstructive CAD, based on the presence of chest pain on effort and evidence of myocardial ischemia on noninvasive stress tests. The relation of MTWA with the evidence of EST-induced myocardial ischemia was also evaluated.
Methods Population
We studied 98 consecutive patients referred to our hospital to undergo an elective coronary angiography DOI:10.2459/JCM.0000000000000080
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Microvolt T-wave alternans and myocardial ischemia Figliozzi et al. 21
with suspected myocardial ischemia, as suggested by typical chest pain induced by effort or documentation of myocardial ischemia from noninvasive imaging stress tests. Only patients who also fulfilled the following inclusion criteria were eligible for the study: no history or ECG evidence of previous myocardial infarction and no conditions that could interfere with ST-segment analysis or assessment of MTWA during EST, including atrial fibrillation, pacemaker rhythm and intraventricular conduction defects. Exercise stress test
After obtaining written informed consent to participate in the study, patients underwent symptom/sign-limited EST the day before undergoing coronary angiography. A treadmill EST (Cardiosoft GE Healthcare system, version 4.14, Milan, Italy) was carried out according to a standard Bruce protocol. Leads II, V2 and V5 were monitored continuously; a 12-lead ECG was printed at the end of each stage, or when clinically indicated, and at 1-min intervals in the recovery phase. Blood pressure was measured at baseline, at peak exercise and during the last minute of each stage. ST-segment depression was considered significant if it was horizontal or downsloping and at least 1 mm at 0.06 s from the J-point in any lead apart from aVR. The EST was stopped in cases of physical exhaustion, progressive angina, ST-segment depression of at least 4 mm or relevant clinical events (e.g. dyspnea, hypotension and arrhythmias). Microvolt T-wave alternans
MTWA was assessed with the time-domain modified moving average method, using the software provided by the EST system manufacturer. As described in detail elsewhere,17 in this method a sequence of beats is separated into odd and even beats. Along the entire J–T segment, separated average morphologies of both the odd and even beats are calculated separately and continuously and updated by each new incoming beat using a weighting factor of one of eight in order to minimize the influence of noise on the MTWA measurement and, therefore, obtain a higher degree of reliability. MTWA is calculated as the maximal difference between the averages of odd and even beats along one of the J–Tsegment sampled points in any lead. MTWA is analyzed continuously during the entire stress test up to a heart rate of 125 bpm. Periods with elevated noise level (>25 mV) are automatically excluded from the analysis. Two measures of MTWA were initially obtained: one from all ECG leads apart from aVR, and one from the six precordial ECG leads only. In our previous study, we found that precordial MTWA was slightly better in discriminating between CAD patients and apparently healthy controls.16 The results of the present study confirmed this finding. Indeed, similar results were observed with MTWA values obtained from all ECG
leads or from precordial leads only, but the latter showed slightly better differences between groups (data not shown). Accordingly, only precordial MTWA values are reported in this study. Coronary angiography
Coronary angiography was performed the day after the EST using standard methods and through a percutaneous femoral or radial approach. Significant stenoses in the epicardial coronary artery vessels were diagnosed in cases of obstruction of at least 50% of the internal coronary artery diameter. Patient groups
Patients were divided into three groups according to clinical history and the results of coronary angiography: 40 patients (group 1) without any previous evidence of CAD and showing no significant coronary stenosis; 47 patients (group 2) without any previous evidence of CAD and showing significant coronary stenosis in one or more coronary arteries; and 11 patients who had previously undergone a percutaneous coronary intervention (PCI) and who were found to have no evidence of restenosis (group 3). No patient with previous PCI showing restenosis was found in this consecutive series of patients undergoing elective coronary angiography as a result of recurrence of chest pain. Follow-up assessment
In order to assess whether coronary revascularization had any effect on MTWA, patients in group 1 who underwent successful complete coronary revascularization by PCI and patients of group 2 (controls) were invited to undergo a follow-up EST 1 month after PCI. However, only 24 patients from group 1 and 17 patients from group 2 gave their informed written consent to participate in this part of the study (see below). Statistical methods
Normal distribution of continuous variables was assessed by the Kolmogorov–Smirnov test. As all variables showed a distribution not significantly different from normal, means were compared by analysis of variance, whereas chi-square test was used to compare proportions. Repeated measure analysis of variance was applied to compare the changes in MTWA between groups at follow-up. The Bonferroni rule was applied to adjust statistical results for multiple between-group or withingroup comparisons. A generalized linear model was also applied to adjust the differences among groups in MTWA for potentially confounding clinical variables, specifically variables that showed a group difference of P < 0.1 on standard analysis. These variables included age, sex, BMI, smoking (yes/no) and use of b-blockers, angiotensin converting enzyme inhibitors, aspirin, statins and
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
22 Journal of Cardiovascular Medicine 2016, Vol 17 No 1
Table 1
Main clinical characteristics of the three groups of patients
Age (years) Sex (M/F) BMI (kg/m2) Angina Typical Atypical Absent Cardiovascular risk factors Family history of CAD Diabetes Hypertension Smoking Hypercholesterolemia Drug therapy b-Blockers Calcium-antagonists ACE-inhibitors ARBs Statins Antiaggregants Nitrates Antidiabetics
Group 1 (n ¼ 40)
Group 2 (n ¼ 47)
58.7 11 20/20 26.6 3.8
65.6 8 38/9 26.5 2.7
Group 3 (n ¼ 11) 64.7 10 11/0 29.0 3.1
P 0.005 0.001 0.07
15 (37%) 8 (20%) 17 (43%)
21 (45%) 1 (2%) 25 (53%)
3 (27%) 2 (18%) 6 (55%)
0.09
17 8 27 12 25
(42%) (20%) (68%) (30%) (63%)
21 18 36 27 35
(45%) (38%) (77%) (57%) (75%)
7 4 9 7 9
(64%) (36%) (82%) (64%) (82%)
0.45 0.17 0.51 0.02 0.32
20 7 5 14 15 20 3 5
(50%) (18%) (13%) (35%) (38%) (50%) (8%) (13%)
30 8 15 11 28 37 2 15
(64%) (17%) (32%) (23%) (60%) (79%) (4%) (32%)
10 2 5 4 9 11 0 3
(91%) (18%) (46%) (36%) (82%) (100%) (0%) (27%)
0.04 0.99 0.03 0.43 0.02 0.001 0.57 0.10
ACE, angiotensin-converting enzyme; ARBs, angiotensin-II receptor blockers; CAD, coronary artery disease; CCB, calcium channel blockers.
antidiabetic drugs (yes/no variables). Data were analyzed using the SPSS statistical package 20.0 (SPSS Italia, Florence, Italy). A P < 0.05 was always required for statistical significance.
Results Clinical characteristics
The main clinical characteristics of the three groups of patients are summarized in Table 1. Patients in group 1 showed a higher prevalence of women (P ¼ 0.001), a younger age (P ¼ 0.005) and a lower prevalence of cigarette smoking (P ¼ 0.02). Cardiovascular drugs were more frequently taken by group 3 patients (who had already undergone a previous PCI). Exercise stress test
The main EST results are shown in Table 2. ST-segment depression was induced during EST in 33 (82%), Table 2
42 (89%) and eight (73%) patients in group 1, 2 and 3, respectively (P ¼ 0.34). Typical angina was induced in 15 (37%), 21 (45%) and three (27%) patients in the three groups, respectively (P ¼ 0.09), with no patient developing angina without significant ST-segment depression. The three groups did not significantly differ for any EST parameter, except for time to 1 mm ST-segment depression, which was shorter in patients in group 2 (P ¼ 0.03). However, the duration of exercise and the hemodynamic parameters at peak EST were similar in the three groups.
Microvolt T-wave alternans
MTWA significantly differed between groups (P < 0.0001), with the highest value being observed in group 2 (58.7 24 vs. 34.2 15 and 43.2 24 mV in group 1 and group 3, respectively; Fig. 1). Subgroup analysis did
Exercise stress test parameters in the three groups of patients
Baseline SBP (mmHg) DBP (mmHg) HR (bpm) RPP (mmHg bpm) Peak SBP (mmHg) DBP (mmHg) HR (bpm) RPP (mmHg bpm) EST result Positive Negative Angina Time to 1 mm STD (s) Max ST (mm) Exercise duration (s)
Group 1 (n ¼ 40)
Group 2 (n ¼ 47)
Group 3 (n ¼ 11)
P
131 18 83 7 76 14 9933 2169
138 19 81 12 74 16 10313 2867
131 15 75 8 68 16 8865 2776
0.17 0.07 0.30 0.24
171 23 90 11 138 24 23793 5464
176 30 90 13 129 18 22863 5436
173 22 86 12 130 22 22275 4141
0.71 0.61 0.12 0.60
33 (82%) 7 (18%) 6 (15%) 365 151 1.3 0.7 466 151
42 (89%) 5 (11%) 6 (13%) 277 147 1.5 0.9 397 151
8 (73%) 3 (23%) 2 (18%) 335 172 1.1 0.8 462 199
0.34
EST, exercise stress test; HR, heart rate; RPP, rate pressure product; STD, ST depression.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
0.89 0.03 0.15 0.11
Microvolt T-wave alternans and myocardial ischemia Figliozzi et al. 23
The difference among groups in MTWA remained highly significant (P < 0.01) after adjustment for potentially confounding variables, including age, sex, BMI, smoking and use of b-blockers, angiotensin converting enzyme inhibitors, aspirin, statins and antidiabetic drugs. Subgroup analyses in coronary artery disease patients
No significant difference in MTWA was found among group 2 patients in relation to severity of CAD. MTWA was 55.2 24, 62.8 26 and 61.8 23 mV in patients with 1-vessel, 2-vessel and 3-vessel CAD, respectively (P ¼ 0.61). In order to assess the impact of myocardial ischemia on MTWA, group 2 patients were also divided into two subgroups according to whether a significant ST-segment depression was or was not induced during EST at a heart rate of less than 125 bpm (i.e. the maximal heart rate for MTWA detection). MTWA was 61.9 24 and 53.4 24 mV in patients with (n ¼ 29) or without (n ¼ 18) ST-segment depression at this cutoff heart rate during EST (P ¼ 0.25). Coronary revascularization and microvolt T-wave alternans values
As specified, only 24 patients of group 1 and 17 patients of group 2 agreed to participate in the follow-up part of the study. Clinical characteristics of these two groups were comparable. MTWA at basal EST was also similar in the two groups (Table 3). The change from baseline in MTWA at follow-up significantly differed between the two groups (group–variable interaction, P ¼ 0.039). The difference was explained by a significant reduction of MTWA in the PCI-treated group (61.3 22 vs. 43.5 17 mV; Fig. 1
100 P < 0.0001
MTWA (µV)
80
Table 3
Main clinical characteristics of the two follow-up groups Group PCI (n ¼ 24)
Age (years) Sex (M/F) BMI (kg/m2) Angina Typical Atypical Absent Cardiovascular risk factors Familiar history of CVD Diabetes Hypertension Smoking Hypercholesterolemia Drug therapy b-Blockers CCB ACE-inhibitors ARBs Statins Antiaggregants Nitrates Antidiabetics
66.5 8.7 19/5 26.2 2.2 13 (54%) 0 (0%) 11 (46%)
Controls (n ¼ 17)
P
64.9 7.3 10/7 27.3 4.8
0.55 0.18 0.34
9 (53%) 2 (12%) 6 (36%)
0.21
9 9 18 12 12
(38%) (40%) (75%) (50%) (70%)
8 5 10 6 17
(47%) (30%) (60%) (35%) (70%)
0.75 0.74 0.32 0.52 1.00
15 7 9 7 20 24 1 9
(63%) (29%) (38%) (29%) (83%) (100%) (4%) (38%)
12 3 2 10 12 9 3 5
(71%) (18%) (12%) (59%) (71%) (53%) (18%) (29%)
0.74 0.48 0.85 0.11 0.45
