Long-term prognostic significance of right bundle-branch morphology ventricular ectopy induced during stress test in patients with intermediate to high probability of coronary artery disease

Long-term prognostic significance of right bundle-branch morphology ventricular ectopy induced... Abstract Aims Stress-induced right bundle-branch block morphology ventricular ectopy (SI-RBVE) may be caused by left ventricular myocardial anomalies. While frequent ventricular ectopy (FVE) has been linked to poor outcomes, the prognostic value of SI-RBVE has not been established. The study aims to determine whether SI-RBVE is associated with increased mortality. Methods and results Three hundred forty-three patients with an intermediate to high probability of coronary artery disease were prospectively included. Patients were referred for a single-photon emission computed tomography and underwent a stress test according to standard protocols. Stress-induced right bundle-branch block morphology ventricular ectopy (VE) was defined as one or more induced premature beats with positive predominance in V1. Frequent VE was defined as the presence of seven or more ventricular premature beats per minute or any organized ventricular arrhythmia. During a mean follow-up of 4.5 ± 1.3 years, 59 deaths occurred. The death rate was higher in the SI-RBVE group (23.4% vs. 14.0%, P = 0.021). Age [odds ratio (OR) = 1.09 (95% CI: 1.06–1.13), P < 0.001] and peripheral artery disease [OR = 2.47 (95% CI: 1.35–4.50) P = 0.003] were independent factors of mortality, but single-photon emission computed tomography findings were not. There was an interaction between SI-RBVE and left ventricular ejection fraction (LVEF). In patients with LVEF > 50%, SI-RBVE was an incremental risk factor for mortality [OR = 2.83 (95% CI: 1.40–5.74), P = 0.004]. Stress-induced right bundle-branch block morphology VE patients also presented higher rates of known coronary artery disease, ischaemia, scar, and ST-segment changes. Frequent VE was not related to mortality. Conclusion Stress-induced right bundle-branch block morphology VE is associated with an increased mortality in patients with preserved LVEF. Coronary artery disease, Right bundle-branch morphology ventricular ectopy, Exercise testing, SPECT Introduction Exercise-induced ventricular ectopy (VE) has been related to mortality in large cohorts of patients principally when abundant.1–3 VE is usually caused by focal ectopy and re-entry. Electrode mapping studies locate a large amount of ventricular arrhythmia as originating near ischaemic border zones,4,5 and origins can be grossly determined by a routine electrocardiogram (ECG).6 While stress-induced left bundle-branch block morphology VE (SI-LBVE) is commonly benign and catecholamine mediated, right bundle-branch block morphology may notably be caused by left ventricular (LV) myocardial anomalies, either transient (ischaemia) or permanent (scar or LV injury). Supporting this thought, increased mortality was specifically associated with complex arrhythmia featuring right bundle-branch block morphology, presumably originating in the LV.7 Notwithstanding the controversial link between VE and coronary artery disease (CAD),8 the evaluation and management of CAD is currently mainly driven by the use of non-invasive imaging, notably in patients with intermediate risk.9,10 We sought to determine whether infrequent stress-induced right bundle-branch block morphology VE (SI-RBVE) provided any incremental prognostic information beyond that obtained from resting LV function, stress, and single-photon emission computed tomography (SPECT) findings. Methods Study population We prospectively included 343 patients referred for SPECT between April 2008 and April 2010 in the laboratory of Nuclear Cardiology (University Hospital of Angers, France). All patients underwent a detailed assessment of their medical history and a clinical evaluation, including cardiovascular history, symptomatic status and treatment administered, indication and characteristics of the SPECT, LV ejection fraction (LVEF), and LV hypertrophy. The protocol was approved by the Institutional Ethics Committee, and the study was conducted in accordance with the Declaration of Helsinki and French regulatory requirements. Stress test Exercise was symptom limited and performed on a treadmill according to the standard Bruce protocol. Tracer was administered at near maximal exercise. A 2-min cool down walk was then observed. If symptom-limited exercise testing was considered as infeasible, dipyridamole was infused at 0.56 mg/kg for 4 min at rest in patients instructed not to consume caffeine products for 24 h before. Tracer was injected 4 min later. Patients may have undergone joint stress with dipyridamole as an adjunct to symptom-limited exercise. SPECT was initiated a few minutes later. Whatever the stress used, a standard 12-lead ECG was continuously recorded (Case, General Electric, USA). During each stage of stress and recovery, data relating to symptoms, heart rate, blood pressure, ST-segment changes, and exercise capacity (given in metabolic equivalents) were prospectively collected and recorded until 6 min of recovery being complete. In case of dipyridamole test, ECG was monitored for a minimum 4 min after tracer infusion. Every single ventricular arrhythmia was recorded including single VE. Repolarization abnormalities were defined as the following ST-segment changes: horizontal or down sloping ST depression ≥0.1 mV at 0.08 s from J point, in two or more leads except aVR, ST elevation ≥ 0.2 mV. SPECT acquisition protocol and analysis SPECT (Ventri, General Electric, Milwaukee, USA) was performed using 180-degree acquisition for 64 projections at 20 s per projection using standard energy windows for Thallium 201 and Tc99m sestamibi. No attenuation or scatter correction was used. Patients were put in the prone or supine position as necessary. Stress and rest imaging was performed with about 1.5 MBq/kg and 0.5 MBq/kg of Thallium 201 after 4 h or 3.7 MBq/kg and 11.1 MBq/kg of Tc99m sestamibi, respectively. As patient management decisions were based on the clinically reported interpretations, analyses of patient outcomes were based on the reported site interpretation. Briefly, SPECT findings were assessed semi-quantitatively and visually using the recommended 17-segment scoring system. Segmental scoring was performed by site readers. SPECT scans were considered abnormal based on the presence of ischaemia or scar. Ischaemia and scar were defined by the presence of reversible (at least three segments) or permanent perfusion defects, respectively.9,10 Analysis of VE Data regarding VE were collected prospectively by recording continuous 12-lead ECGs. The analysis of the ECG pattern was performed subsequently by the consensus of two blinded investigators and focused on the following characteristics: (i) the bundle-branch block pattern (ii) the QRS morphology of the VE in all 12 leads, (iii) the width of the QRS complex, and (iv) the number and timing of VE. Ventricular ectopy was defined as one or more induced ventricular ectopic beats (infrequent VE). We described stress-induced VE as SI-RBVE or left bundle-branch block morphology (SI-LBVE) assuming there was a positive or negative predominance in V1, respectively.11,12 SI-RBVE of apical origin was defined in cases of occurrence of negative concordance in precordial leads. Frequent VE (FVE) was defined as the presence of seven or more ventricular premature beats per minute, ventricular bigeminy or trigeminy, couplets, triplets, sustained, or non-sustained ventricular tachycardia or ventricular fibrillation.13 Ventricular ectopy and FVE were exclusively considered when recorded during stress and recovery. Follow-up Data relating to cardiovascular outcomes were collected and adjudicated after consultation of medical records and the computer database by two physicians (LB, THM) who were unaware of clinical data, SPECT, and VE results. When necessary, a referent cardiologist or general practitioner was called to complete the follow-up assessment. Four patients were lost to follow-up. We distinguished deaths resulting from cardiovascular causes from other types. Death, acute coronary syndrome (ACS) including myocardial infarction and major adverse cardiac events (associating CV death with ACS) were tabulated per subject. Statistical analysis The data have been presented as mean ± standard deviation or median (25th; 75th percentiles) in cases of abnormal distribution, with categorical data expressed as frequencies and percentages. Comparisons of variables were performed using unpaired Student’s t-test or the chi-squared test, as appropriate. For multivariate analysis assessing all-cause mortality during follow-up, clinical data, stress findings, and VE were tested by means of a Cox analysis, including variables with P values < 0.05 in univariate analysis. We applied several models to test, one after the other, every ventricular arrhythmia criterion (VE, SI-LBVE, SI-RBVE, and FVE). Specific interactions were tested between ventricular arrhythmia and LVEF, age, SPECT findings, and gender. Exercise capacity14,15 was not included in the multivariate analysis due to the heterogeneity of our cohort combining patients submitted to exercise, dipyridamole, and joint tests. Variables were included in multivariate models in forced entry mode, with the exception of the use of a backward stepwise analysis in the subgroup of patient with preserved LVEF and ischaemia, due to lower number of clinical events. The analyses were performed using the SPSS Version 17.0 for Windows (SPPS Inc., Chicago, IL). A P value < 0.05 was considered statistically significant. Results Population study Out of 343 patients, 235 patients (68.5%) were men with a mean age of 67.0 ± 11.7 years. The mean LVEF was 55.9 ± 10.5%. Ninety-two patients (26.8%) in the cohort presented a LVEF less than 50%. Table 1 lists patient characteristics at baseline. Table 1 Population characteristics   Global population  SI-RBVE  No SI-RBVE  P value  n = 343  n = 127  n = 216  Demographic characteristics   Age—years  67.0 ± 11.7  68.5 ± 10.6  66.1 ± 12.3  0.07   Male gender—no. (%)  235 (68.5)  92 (72.4)  143 (66.2)  0.14  Risk factors—no. (%)   Diabetes  102 (29.7)  44 (34.6)  58 (26.9)  0.08   Hypertension  190 (55.4)  72 (56.7)  118 (54.6)  0.39   Tobacco use  39 (11.8)  10 (7.9)  29 (13.4)  0.08   Dyslipidaemia  179 (52.2)  64 (50.4)  115 (53.2)  0.34   Heredity  15 (4.4)  4 (3.1)  11 (5.1)  0.28  Medical history—no. (%)   CAD  165 (48.1)  69 (54.3)  96 (44.4)  0.049   Prior coronary artery bypass grafting  23 (6.7)  7 (5.5)  16 (7.5)  0.32   Prior myocardial infarction  96 (28.2)  45 (35.4)  51 (23.9)  0.016   Prior percutaneous coronary intervention  103 (30.2)  43 (33.9)  60 (28.0)  0.15   Stroke  8 (2.3)  2 (1.6)  6 (2.8)  0.37   Peripheral artery disease  44 (12.8)  17 (13.4)  27 (12.5)  0.46   Dysrhythmia  4 (1.2)  3 (2.4)  1 (0.5)  0.14   LV hypertrophy  64 (18.7)  31 (24.4)  33 (15.3)  0.026   LVEF—%  55.9 ± 10.5  52.9 ± 12.4  57.6 ± 8.8  <0.001  Medication use—no. (%)   Aspirin  199 (60.7)  74 (60.7)  125 (60.7)  0.54   Clopidogrel  126 (38.4)  53 (43.4)  73 (35.4)  0.09   Calcium inhibitor  11 (3.2)  3 (2.4)  8 (3.7)  0.36   Ivabradine  6 (1.8)  3 (2.4)  3 (1.4)  0.39   Betablockers  198 (57.9)  81 (63.8)  117 (54.4)  0.06   Antiarrhythmic agent  33 (9.7)  11 (8.7)  22 (10.3)  0.39    Global population  SI-RBVE  No SI-RBVE  P value  n = 343  n = 127  n = 216  Demographic characteristics   Age—years  67.0 ± 11.7  68.5 ± 10.6  66.1 ± 12.3  0.07   Male gender—no. (%)  235 (68.5)  92 (72.4)  143 (66.2)  0.14  Risk factors—no. (%)   Diabetes  102 (29.7)  44 (34.6)  58 (26.9)  0.08   Hypertension  190 (55.4)  72 (56.7)  118 (54.6)  0.39   Tobacco use  39 (11.8)  10 (7.9)  29 (13.4)  0.08   Dyslipidaemia  179 (52.2)  64 (50.4)  115 (53.2)  0.34   Heredity  15 (4.4)  4 (3.1)  11 (5.1)  0.28  Medical history—no. (%)   CAD  165 (48.1)  69 (54.3)  96 (44.4)  0.049   Prior coronary artery bypass grafting  23 (6.7)  7 (5.5)  16 (7.5)  0.32   Prior myocardial infarction  96 (28.2)  45 (35.4)  51 (23.9)  0.016   Prior percutaneous coronary intervention  103 (30.2)  43 (33.9)  60 (28.0)  0.15   Stroke  8 (2.3)  2 (1.6)  6 (2.8)  0.37   Peripheral artery disease  44 (12.8)  17 (13.4)  27 (12.5)  0.46   Dysrhythmia  4 (1.2)  3 (2.4)  1 (0.5)  0.14   LV hypertrophy  64 (18.7)  31 (24.4)  33 (15.3)  0.026   LVEF—%  55.9 ± 10.5  52.9 ± 12.4  57.6 ± 8.8  <0.001  Medication use—no. (%)   Aspirin  199 (60.7)  74 (60.7)  125 (60.7)  0.54   Clopidogrel  126 (38.4)  53 (43.4)  73 (35.4)  0.09   Calcium inhibitor  11 (3.2)  3 (2.4)  8 (3.7)  0.36   Ivabradine  6 (1.8)  3 (2.4)  3 (1.4)  0.39   Betablockers  198 (57.9)  81 (63.8)  117 (54.4)  0.06   Antiarrhythmic agent  33 (9.7)  11 (8.7)  22 (10.3)  0.39  CAD, coronary artery disease; LV, left ventricle; LVEF, left ventricular ejection fraction; SI-RBVE, stress-induced right bundle-branch block VE. Ventricular ectopy One hundred and seventy-nine patients (52.2%) presented VE during the stress test, among which 107 patients (31.2%) had SI-LBVE and 127 patients (37.0%) had SI-RBVE. The groups were similar with regard to age and cardiovascular risk factors. Medical history of CAD, previous myocardial infarction, and LV hypertrophy were higher among patients with SI-RBVE. Left ventricular ejection fraction was lower among patients with SI-RBVE (52.9 ± 12.4% vs. 57.6 ± 8.8%, P < 0.001). Stress-induced right bundle-branch block morphology ventricular ectopy occurred only once in 43 patients (12.5%). Fifty patients (14.6%) presented FVE. Only seven patients presented at least one triplet during testing. Figure 1 shows the flowchart of the study. Mean QRS width of SI-RBVE was 156 ± 46 ms. Figure 1 View largeDownload slide Study flow chart. VE, ventricular ectopy, which occurred during stress or recovery; SI-LBVE, at least one stress-induced left bundle-branch VE; SI-RBVE, at least one stress-induced right bundle-branch VE; FVE, frequent VE, whatever the morphology13: seven or more ventricular premature beats per minute, ventricular bigeminy or trigeminy, couplets, triplets, sustained, or non-sustained ventricular tachycardia or ventricular fibrillation. Figure 1 View largeDownload slide Study flow chart. VE, ventricular ectopy, which occurred during stress or recovery; SI-LBVE, at least one stress-induced left bundle-branch VE; SI-RBVE, at least one stress-induced right bundle-branch VE; FVE, frequent VE, whatever the morphology13: seven or more ventricular premature beats per minute, ventricular bigeminy or trigeminy, couplets, triplets, sustained, or non-sustained ventricular tachycardia or ventricular fibrillation. Stress tests characteristics Stress tests were indicated for ischaemic evaluation in 228 patients (66.5%), including symptomatic angina in 66 patients (19.2%), atypical chest pain in 60 patients (17.5%), and 113 (32.9%) for the purpose of systematic follow-up (Table 2). Exercise was used more commonly (144 patients, 42.4%) than dipyridamole (131 patients, 38.2%) and joint stress (68 patients, 19.8%). Stress test types were distributed evenly among SI-RBVE and non SI-RBVE patients; and width and abundance of SI-RBVE were not influenced by stress type (Table 3). The most frequent reason for exercise termination was reaching maximum level of exertion (56.6%). Table 2 Distribution of induced VE according to stress type   Dipyridamole  Exercise  Join test  P  n = 131  n = 144  n = 68  Ventricular arrhythmia—no. (%)   VE  59 (45.7)  92 (63.9)  28 (41.2)  0.002   SI-RBVE  47 (36.4)  60 (41.7)  20 (29.4)  0.253   SI-LBVE  24 (18.6)  65 (45.1)  18 (26.0)  <0.001   FVE  16 (12.4)  29 (20.1)  5 (7.5)  0.037   Nonsustained ventricular tachycardia  0 (0)  1 (0.7)  1 (1.5)  0.132   Bigeminy  0 (0)  2 (1.4)  1 (1.5)  0.426  SI-RBVE duration, ms  158 ± 43  153 ± 41  160 ± 44  0.884  SI-RBVE number  2.3 ± 6  2.8 ± 7  1.5 ± 5  0.232    Dipyridamole  Exercise  Join test  P  n = 131  n = 144  n = 68  Ventricular arrhythmia—no. (%)   VE  59 (45.7)  92 (63.9)  28 (41.2)  0.002   SI-RBVE  47 (36.4)  60 (41.7)  20 (29.4)  0.253   SI-LBVE  24 (18.6)  65 (45.1)  18 (26.0)  <0.001   FVE  16 (12.4)  29 (20.1)  5 (7.5)  0.037   Nonsustained ventricular tachycardia  0 (0)  1 (0.7)  1 (1.5)  0.132   Bigeminy  0 (0)  2 (1.4)  1 (1.5)  0.426  SI-RBVE duration, ms  158 ± 43  153 ± 41  160 ± 44  0.884  SI-RBVE number  2.3 ± 6  2.8 ± 7  1.5 ± 5  0.232  SI-LBVE, stress-induced left bundle-branch block VE; SI-RBVE, stress-induced right bundle-branch block VE; FVE, frequent VE; VE, ventricular ectopy. Categorical and continuous data were compared by the means of Pearson Chi-Square and Kruskal–Wallis tests. Table 3 Stress test characteristics   Global population  SI-RBVE  No SI-RBVE  P value  Cardiovascular assessment and exercise capacity   Resting heart rate—beats/min  74 ± 15  76 ± 15  74 ± 15  0.51   Resting systolic blood pressure—mm Hg  132 ± 20  131 ± 22  133 ± 19  0.23   Peak exercise capacity—metabolic equivalents  8.8 ± 3.4  9.1 ± 3.3  8.7 ± 3.6  0.40   Age-predicted maximal heart rate—%  86 ± 14  89 ± 14  84 ± 13  0.013  Stress type—no. (%)   Exercise  144 (42.4)  60 (47.2)  86 (39.8)  0.09   Dipyridamole  131 (38.2)  47 (37.0)  82 (40.0)  0.50   Joint test  68 (19.8)  20 (15.7)  48 (22.2)  0.70  Exercise termination—no. (%)   Maximal effort  117 (56.6)  47 (58.7)  72 (55.0)  0.40   Lipothymia or hypotension  6 (2.8)  3 (3.8)  3 (2.3)  0.39   Chest pain  14 (6.7)  5 (6.2)  9 (6.9)  0.56   Dyspnoea  18 (8.6)  11 (13.7)  7 (5.3)  0.031   Other  60 (28.8)  14 (17.5)  45 (34.6)  0.011  Exercise result—no. (%)   Clinical symptoms  40 (11.7)  21 (26.2)  19 (14.2)  0.026   ST-segment changes  63 (18.4)  25 (31.2)  38 (28.4)  0.37  Medication used during stress test—no. (%)   Betablockers  146 (42.7)  57 (44.9)  89 (41.1)  0.30   Calcium inhibitor  7 (2.1)  3 (2.4)  4 (1.9)  0.51  SPECT findings—no. (%)   Scar  85 (24.8)  45 (35.4)  40 (18.5)  <0.001   Ischaemia  80 (23.3)  38 (29.9)  42 (19.4)  0.019   Any of ischaemia or scar  146 (42.6)  74 (58.3)  72 (33.3)  <0.001    Global population  SI-RBVE  No SI-RBVE  P value  Cardiovascular assessment and exercise capacity   Resting heart rate—beats/min  74 ± 15  76 ± 15  74 ± 15  0.51   Resting systolic blood pressure—mm Hg  132 ± 20  131 ± 22  133 ± 19  0.23   Peak exercise capacity—metabolic equivalents  8.8 ± 3.4  9.1 ± 3.3  8.7 ± 3.6  0.40   Age-predicted maximal heart rate—%  86 ± 14  89 ± 14  84 ± 13  0.013  Stress type—no. (%)   Exercise  144 (42.4)  60 (47.2)  86 (39.8)  0.09   Dipyridamole  131 (38.2)  47 (37.0)  82 (40.0)  0.50   Joint test  68 (19.8)  20 (15.7)  48 (22.2)  0.70  Exercise termination—no. (%)   Maximal effort  117 (56.6)  47 (58.7)  72 (55.0)  0.40   Lipothymia or hypotension  6 (2.8)  3 (3.8)  3 (2.3)  0.39   Chest pain  14 (6.7)  5 (6.2)  9 (6.9)  0.56   Dyspnoea  18 (8.6)  11 (13.7)  7 (5.3)  0.031   Other  60 (28.8)  14 (17.5)  45 (34.6)  0.011  Exercise result—no. (%)   Clinical symptoms  40 (11.7)  21 (26.2)  19 (14.2)  0.026   ST-segment changes  63 (18.4)  25 (31.2)  38 (28.4)  0.37  Medication used during stress test—no. (%)   Betablockers  146 (42.7)  57 (44.9)  89 (41.1)  0.30   Calcium inhibitor  7 (2.1)  3 (2.4)  4 (1.9)  0.51  SPECT findings—no. (%)   Scar  85 (24.8)  45 (35.4)  40 (18.5)  <0.001   Ischaemia  80 (23.3)  38 (29.9)  42 (19.4)  0.019   Any of ischaemia or scar  146 (42.6)  74 (58.3)  72 (33.3)  <0.001  SI-RBVE, stress-induced right bundle-branch block VE. SPECT results SPECT revealed ischaemia in 80 patients (23.3%), scar in 85 patients (24.8%), and none of these findings in 146 patients (42.6%). SPECT findings were frequent among patients with SI-RBVE but not among SI-LBVE, FVE, or VE patients. SI-RBVE patients presented 38 cases (29.9%, P < 0.019) of ischaemia, 45 cases (35.4%, P < 0.001) of scar, and 74 cases (58.3%, P < 0.001) of ischaemia or scar (Table 3). Thirty-three patients with SI-RBVE had normal SPECT. Among them, 12 had ventricular hypertrophy and 4 had a history of heart failure. Moreover, SPECT findings were more frequent in subjects with LVEF inferior to 50% (77.2% vs. 29.8%, P < 0.001). Cardiovascular outcomes Fifty-nine (17.4%) deaths, including 23 (6.9%) cardiovascular deaths, 40 MACE (11.7%) including 20 ACS (6.0%) occurred during a mean follow-up of 4.5 ± 1.3 years (Table 4). All-cause mortality was high in patients with SI-RBVE (23.4% vs. 14.0%, P = 0.021) but not in VE, SI-LBVE, or FVE patients. All-cause mortality was higher in patients with LVEF ≤ 50% compared to patients with LVEF > 50% (28.3% vs. 13.4%, P = 0.002). We found no link between ventricular rhythmic disorders and MACE. Table 4 Cardiovascular events   Global population  SI-RBVE  No SI-RBVE  P value  All-cause mortality—no. (%)  59 (17.4)  29 (23.4)  30 (14.0)  0.027   Cardiovascular mortality  23 (6.9)  12 (9.8)  11 (5.2)  0.08   Non-cardiovascular mortality  36 (10.5)  17 (13.7)  19 (8.8)  0.11  ACS—no. (%)  20 (6.0)  8 (6.6)  12 (5.6)  0.72   Myocardial infarction  10 (3.0)  4 (3.3)  6 (2.8)  0.73  MACE—no. (%)  40 (11.7)  18 (14.2)  22 (10.2)  0.27    Global population  SI-RBVE  No SI-RBVE  P value  All-cause mortality—no. (%)  59 (17.4)  29 (23.4)  30 (14.0)  0.027   Cardiovascular mortality  23 (6.9)  12 (9.8)  11 (5.2)  0.08   Non-cardiovascular mortality  36 (10.5)  17 (13.7)  19 (8.8)  0.11  ACS—no. (%)  20 (6.0)  8 (6.6)  12 (5.6)  0.72   Myocardial infarction  10 (3.0)  4 (3.3)  6 (2.8)  0.73  MACE—no. (%)  40 (11.7)  18 (14.2)  22 (10.2)  0.27  SI-RBVE, stress-induced right bundle-branch block VE; ACS, acute coronary syndrome; MACE, major adverse cardiovascular events. VE or FVE were not independently related to mortality. We found an interaction between SI-RBVE and LVEF (P = 0.036); in patients with LVEF > 50%, SI-RBVE was an independent factor of mortality [OR = 2.17 (95% CI: 1.09–4.34), P = 0.028] (see Figure 2 and Table 5). The other independent determinants of all-cause mortality were age [OR = 1.10 (95% CI: 1.06–1.13), P < 0.001] and peripheral artery disease [OR = 2.33 (95% CI: 1.27–4.26), P = 0.006]. Age was the only independent factor for cardiovascular death [OR= 1.06 (95% CI: 1.03–1.10] P < 0.001). Medical history of CAD and ST segment changes were independent factors for MACE [OR= 2.64 (95% CI: 1.20–5.81), P = 0.015 and OR = 2.21 (95% CI: 1.11–4.39), P = 0.024]. If we exclude the subjects with FVE from the analysis, the results did not change significantly. Finally, the analysis was run after dichotomizing the population considering the presence or absence of ischaemia. Interactions between SI-RBVE and LVEF > 50% were still significant in both groups (P = 0.015 and 0.013, respectively), with OR of 5.89 (95% CI: 1.84–18.83) and 2.21 (95% CI: 1.02–4.82) after multivariate analyses, respectively. Table 5 Univariate and multivariate predictors for all-cause mortality   Univariate  Multivariate     P value  HR (95% CI)  P value  Age  <0.001  1.10 (1.06–1.13)  <0.001  Diabetes  0.08  —  —  Current smoker  0.07  —  —  Dyslipidaemia  0.24  —  —  Hypertension  0.10  —  —  History of heart failure  <0.001  1.80 (0.97–3.30)  0.06  History of stroke  0.09  —  —  Known CAD  0.40  —  —  Peripheral arterial disease  0.002  2.33 (1.27–4.26)  0.006  Scar  0.003  1.72 (0.98–3.04)  0.06  Ischaemia  0.97  —  —  LVEF < 50%  0.001  0.47 (0.21–1.03)  0.06  SI-RBVE  0.026      LVEF < 50% SI-RBVE +    0.71 (0.32–1.57)  0.40  LVEF ≥ 50% SI-RBVE +    2.17 (1.09–4.34)  0.028  VE  0.14  —  —  ST-segment changes  0.38  —  —    Univariate  Multivariate     P value  HR (95% CI)  P value  Age  <0.001  1.10 (1.06–1.13)  <0.001  Diabetes  0.08  —  —  Current smoker  0.07  —  —  Dyslipidaemia  0.24  —  —  Hypertension  0.10  —  —  History of heart failure  <0.001  1.80 (0.97–3.30)  0.06  History of stroke  0.09  —  —  Known CAD  0.40  —  —  Peripheral arterial disease  0.002  2.33 (1.27–4.26)  0.006  Scar  0.003  1.72 (0.98–3.04)  0.06  Ischaemia  0.97  —  —  LVEF < 50%  0.001  0.47 (0.21–1.03)  0.06  SI-RBVE  0.026      LVEF < 50% SI-RBVE +    0.71 (0.32–1.57)  0.40  LVEF ≥ 50% SI-RBVE +    2.17 (1.09–4.34)  0.028  VE  0.14  —  —  ST-segment changes  0.38  —  —  SI-RBVE, stress-induced right bundle-branch block VE. Figure 2 View largeDownload slide Survival in stress-induced right bundle-branch VE group with or without preserved LV ejection fraction. Figure 2 View largeDownload slide Survival in stress-induced right bundle-branch VE group with or without preserved LV ejection fraction. Discussion The major findings of this study were as follows: (i) patients with SI-RBVE presented higher all-cause mortality (23.4% vs. 14.0%, P = 0.021) and (ii) in case of LVEF > 50%, SI-RBVE was an independent predictor of mortality. Ventricular ectopies or arrhythmias are described as related to mortality when frequent,1 exercise-induced, or occurring during recovery.13,16–19 Data regarding ventricular arrhythmias are somewhat disparate among studies, notably with regard to prevalence, ranging from 2%13 to 42%,20 and also with regard to patient characteristics. Exercise-induced ventricular tachycardia was strongly predictive of mortality in patients with a LVEF inferior to 35%.21 In contrast to these results, we found an interaction between LVEF and SI-RBVE indicating that SI-RBVE, when occurring in patients with preserved LVEF, was independently related to mortality. Stress-induced right bundle-branch block morphology ventricular ectopy may not be a problem in depressed LVEF due to the high prevalence of mortality inherent to LV dysfunction. Thus a significant amount of mortality may not be mediated by depressed LV systolic function22 but may be marked up by SI-RBVE to a certain extent. Frequent VE during exercise has been previously defined as either >7 VE/minute13 or >10% VE during 30 s.1 Nevertheless, a CAD-free unselected cohort revealed FVE occurrence to be very low, affecting only 4 out of 2885 individuals22 that convinced the authors to redefine their arrhythmia criteria as the median value of occurrence, which was about 1 VE for every 4.5 min of exercise. Such infrequent events were still predictive for mortality. Similarly, Califf et al.23 demonstrated a gradual prognosis among high-risk patients with respect to ventricular arrhythmia complexity (from single VE to couplet or more). The use of any threshold on VE frequency would appear subjective and arbitrary. We successfully gained interest in investigating infrequent VE as soon as a single event occurred, with the aim to assess both myocardial ischaemia and prognosis.20 Even if the link between exercise-induced VE and CAD has been demonstrated,13,17,20 the presence of SI-RBVE was not exclusive to ischaemic myocardium (SPECT abnormalities were found in only 58% of patients with SI-RBVE) and did also not determine ACS events during follow-up. It is noteworthy that the likelihood of CAD-related, exercise-induced VE may largely be associated with the pre-test probability.8,20 Our results suggest that SI-RBVE may be consecutive to very small areas of LV anomalies that are not stressed by symptoms, ST-segment changes, or SPECT findings during stress tests. Of note, the effect of SI-RBVE on mortality was found as well in patients with and without ischaemia, although patients with ischaemia commonly present higher rates of adverse outcomes.10 Myocarditis,24 LV hypertrophy, valvular heart disease, and ion channel diseases are other potential sources25 to rule out in the context of SI-RBVE. We deliberately compared SI-LBVE with SI-RBVE. The interest of distinguishing left and right bundle-branch block morphology arrhythmias has already been pointed out7 when considering couplets or more. In our study, however, we stressed the impact on mortality of infrequent SI-RBVE in patients with intermediate-to-high CV risk while questioning any potential role of SI-LBVE. Indeed, LBVE often originates from the right ventricular outflow tract and may be induced by benign adrenergic activation in healthy individuals. Interestingly, there were similar rates of VE, including SI-RBVE, irrespective of the stress test type performed. While ventricular arrhythmias are common physiology in the context of exercise and potential ischaemia, this is not clearly described in vasodilator uses. The largest registry available on dipyridamole use reported six cases of sustained ventricular arrhythmias requiring immediate cardioversion.26 Two mechanisms may be responsible for ventricular arrhythmias in vasodilator tests. First, an underestimated rate of authentic ischaemia induced by flow diversion may be suggested. Indeed, some wall motion abnormalities are observed during perfusion in magnetic resonance stress imaging.27 Second, targeting adenosine receptors may contribute to increased vagal activity and impaired neurovegetative balance.28 This is a prospective study centred on real-life activity in nuclear cardiology. As such, our patients notably presented a high prevalence of CAD (48.1% prior to test). Results may be specific to our dataset and no conclusions should be done on low risk patients with SI-RBVE, as their risk appeared to be very low.3 Our study is purely observational and no consequences should be done on therapeutics. Appropriate follow-up, aggressive control of CV risk factors and diagnosis of subclinical cardiac disease should be recommended. It has been shown that VE during recovery is a better predictor of an increased risk of death than VE occurring only during exercise.13 However, evidences were given in case of frequent VE,1,15,22 not infrequent VE. Ventricular ectopy occurrence in our study includes VE during stress and/or during recovery but the exact timing was not prospectively collected, so that its impact on prognosis should be examined in future studies. Conclusions In patients with intermediate to high risk of CAD, SI-RBVE is associated with an increased mortality and may refine prognostic assessment in patients with LVEF > 50%. What is more, SI-RBVE was often linked to ischaemia and scar, as assessed by SPECT. These results may be specific to our dataset and need further investigation, notably targeting low to intermediate risk patients. Conflict of interest: none declared. References 1 Jouven X, Zureik M, Desnos M, Courbon D, Ducimetiere P. Long-term outcome in asymptomatic men with exercise-induced premature ventricular depolarizations. N Engl J Med  2000; 343: 826– 33. Google Scholar CrossRef Search ADS PubMed  2 Schweikert RA, Pashkow FJ, Snader CE, Marwick TH, Lauer MS. Association of exercise-induced ventricular ectopic activity with thallium myocardial perfusion and angiographic coronary artery disease in stable, low-risk populations. Am J Cardiol  1999; 83: 530– 4. Google Scholar CrossRef Search ADS PubMed  3 Marine JE, Shetty V, Chow GV, Wright JG, Gerstenblith G, Najjar SS et al.   Prevalence and prognostic significance of exercise-induced nonsustained ventricular tachycardia in asymptomatic volunteers: BLSA (Baltimore Longitudinal Study of Aging). J Am Coll Cardiol  2010; 62: 595– 600. Google Scholar CrossRef Search ADS   4 Kay M, Swift L, Martell B, Arutunyan A, Sarvazyan N. Locations of ectopic beats coincide with spatial gradients of NADH in a regional model of low-flow reperfusion. Am J Physiol Heart Circ Physiol  2008; 294: H2400– 5. Google Scholar CrossRef Search ADS PubMed  5 Pogwizd SM, Hoyt RH, Saffitz JE, Corr PB, Cox JL, Cain ME. Reentrant and focal mechanisms underlying ventricular tachycardia in the human heart. Circulation  1992; 86: 1872– 87. Google Scholar CrossRef Search ADS PubMed  6 Josephson ME, Callans DJ. Using the twelve-lead electrocardiogram to localize the site of origin of ventricular tachycardia. Heart Rhythm  2005; 2: 443– 6. Google Scholar CrossRef Search ADS PubMed  7 Eckart RE, Field ME, Hruczkowski TW, Forman DE, Dorbala S, Di Carli MF et al.   Association of electrocardiographic morphology of exercise-induced ventricular arrhythmia with mortality. Ann Intern Med  2008; 149: 451– 60, W82. Google Scholar CrossRef Search ADS PubMed  8 Beckerman J, Wu T, Jones S, Froelicher VF. Exercise test-induced arrhythmias. Prog Cardiovasc Dis  2005; 47: 285– 305. Google Scholar CrossRef Search ADS PubMed  9 Hachamovitch R, Hayes SW, Friedman JD, Cohen I, Berman DS. Comparison of the short-term survival benefit associated with revascularization compared with medical therapy in patients with no prior coronary artery disease undergoing stress myocardial perfusion single photon emission computed tomography. Circulation  2003; 107: 2900– 7. Google Scholar CrossRef Search ADS PubMed  10 Shaw LJ, Berman DS, Maron DJ, Mancini GB, Hayes SW, Hartigan PM et al.   Optimal medical therapy with or without percutaneous coronary intervention to reduce ischemic burden: results from the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial nuclear substudy. Circulation  2008; 117: 1283– 91. Google Scholar CrossRef Search ADS PubMed  11 Josephson ME, Horowitz LN, Waxman HL, Cain ME, Spielman SR, Greenspan AM et al.   Sustained ventricular tachycardia: role of the 12-lead electrocardiogram in localizing site of origin. Circulation  1981; 64: 257– 72. Google Scholar CrossRef Search ADS PubMed  12 Miller JM, Marchlinski FE, Buxton AE, Josephson ME. Relationship between the 12-lead electrocardiogram during ventricular tachycardia and endocardial site of origin in patients with coronary artery disease. Circulation  1988; 77: 759– 66. Google Scholar CrossRef Search ADS PubMed  13 Frolkis JP, Pothier CE, Blackstone EH, Lauer MS. Frequent ventricular ectopy after exercise as a predictor of death. N Engl J Med  2003; 348: 781– 90. Google Scholar CrossRef Search ADS PubMed  14 Krone RJ, Gillespie JA, Weld FM, Miller JP, Moss AJ. Low-level exercise testing after myocardial infarction: usefulness in enhancing clinical risk stratification. Circulation  1985; 71: 80– 9. Google Scholar CrossRef Search ADS PubMed  15 Partington S, Myers J, Cho S, Froelicher V, Chun S. Prevalence and prognostic value of exercise-induced ventricular arrhythmias. Am Heart J  2003; 145: 139– 46. Google Scholar CrossRef Search ADS PubMed  16 Dewey FE, Kapoor JR, Williams RS, Lipinski MJ, Ashley EA, Hadley D et al.   Ventricular arrhythmias during clinical treadmill testing and prognosis. Arch Int Med  2008; 168: 225– 34. Google Scholar CrossRef Search ADS   17 Meine TJ, Patel MR, Shaw LK, Borges-Neto S. Relation of ventricular premature complexes during recovery from a myocardial perfusion exercise stress test to myocardial ischemia. Am J Cardiol  2006; 97: 1570– 2. Google Scholar CrossRef Search ADS PubMed  18 Lerma C, Gorelick A, Ghanem RN, Glass L, Huikuri HV. Patterns of ectopy leading to increased risk of fatal or near-fatal cardiac arrhythmia in patients with depressed left ventricular function after an acute myocardial infarction. Europace  2013; 15: 1304– 12. Google Scholar CrossRef Search ADS PubMed  19 Bastiaenen R, Batchvarov V, Gallagher MM. Ventricular automaticity as a predictor of sudden death in ischaemic heart disease. Europace  2012; 14: 795– 803. Google Scholar CrossRef Search ADS PubMed  20 Marieb MA, Beller GA, Gibson RS, Lerman BB, Kaul S. Clinical relevance of exercise-induced ventricular arrhythmias in suspected coronary artery disease. Am J Cardiol  1990; 66: 172– 8. Google Scholar CrossRef Search ADS PubMed  21 O'Neill JO, Young JB, Pothier CE, Lauer MS. Severe frequent ventricular ectopy after exercise as a predictor of death in patients with heart failure. J Am Coll Cardiol  2004; 44: 820– 6. Google Scholar CrossRef Search ADS PubMed  22 Morshedi-Meibodi A, Evans JC, Levy D, Larson MG, Vasan RS. Clinical correlates and prognostic significance of exercise-induced ventricular premature beats in the community: the Framingham Heart Study. Circulation  2004; 109: 2417– 22. Google Scholar CrossRef Search ADS PubMed  23 Califf RM, McKinnis RA, McNeer JF, Harrell FEJr, Lee KL, Pryor DB et al.   Prognostic value of ventricular arrhythmias associated with treadmill exercise testing in patients studied with cardiac catheterization for suspected ischemic heart disease. J Am Coll Cardiol  1983; 2: 1060– 7. Google Scholar CrossRef Search ADS PubMed  24 Jeserich M, Friedrich MG, Olschewski M, Kirchberger J, Kimmel S, Bode C et al.   Evidence for non-ischemic scarring in patients with ventricular ectopy. Int J Cardiol  2011; 147: 482– 4. 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Pacing Clin Electrophysiol  1994; 17: 417– 27. Google Scholar CrossRef Search ADS PubMed  Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Europace Oxford University Press

Long-term prognostic significance of right bundle-branch morphology ventricular ectopy induced during stress test in patients with intermediate to high probability of coronary artery disease

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Abstract

Abstract Aims Stress-induced right bundle-branch block morphology ventricular ectopy (SI-RBVE) may be caused by left ventricular myocardial anomalies. While frequent ventricular ectopy (FVE) has been linked to poor outcomes, the prognostic value of SI-RBVE has not been established. The study aims to determine whether SI-RBVE is associated with increased mortality. Methods and results Three hundred forty-three patients with an intermediate to high probability of coronary artery disease were prospectively included. Patients were referred for a single-photon emission computed tomography and underwent a stress test according to standard protocols. Stress-induced right bundle-branch block morphology ventricular ectopy (VE) was defined as one or more induced premature beats with positive predominance in V1. Frequent VE was defined as the presence of seven or more ventricular premature beats per minute or any organized ventricular arrhythmia. During a mean follow-up of 4.5 ± 1.3 years, 59 deaths occurred. The death rate was higher in the SI-RBVE group (23.4% vs. 14.0%, P = 0.021). Age [odds ratio (OR) = 1.09 (95% CI: 1.06–1.13), P < 0.001] and peripheral artery disease [OR = 2.47 (95% CI: 1.35–4.50) P = 0.003] were independent factors of mortality, but single-photon emission computed tomography findings were not. There was an interaction between SI-RBVE and left ventricular ejection fraction (LVEF). In patients with LVEF > 50%, SI-RBVE was an incremental risk factor for mortality [OR = 2.83 (95% CI: 1.40–5.74), P = 0.004]. Stress-induced right bundle-branch block morphology VE patients also presented higher rates of known coronary artery disease, ischaemia, scar, and ST-segment changes. Frequent VE was not related to mortality. Conclusion Stress-induced right bundle-branch block morphology VE is associated with an increased mortality in patients with preserved LVEF. Coronary artery disease, Right bundle-branch morphology ventricular ectopy, Exercise testing, SPECT Introduction Exercise-induced ventricular ectopy (VE) has been related to mortality in large cohorts of patients principally when abundant.1–3 VE is usually caused by focal ectopy and re-entry. Electrode mapping studies locate a large amount of ventricular arrhythmia as originating near ischaemic border zones,4,5 and origins can be grossly determined by a routine electrocardiogram (ECG).6 While stress-induced left bundle-branch block morphology VE (SI-LBVE) is commonly benign and catecholamine mediated, right bundle-branch block morphology may notably be caused by left ventricular (LV) myocardial anomalies, either transient (ischaemia) or permanent (scar or LV injury). Supporting this thought, increased mortality was specifically associated with complex arrhythmia featuring right bundle-branch block morphology, presumably originating in the LV.7 Notwithstanding the controversial link between VE and coronary artery disease (CAD),8 the evaluation and management of CAD is currently mainly driven by the use of non-invasive imaging, notably in patients with intermediate risk.9,10 We sought to determine whether infrequent stress-induced right bundle-branch block morphology VE (SI-RBVE) provided any incremental prognostic information beyond that obtained from resting LV function, stress, and single-photon emission computed tomography (SPECT) findings. Methods Study population We prospectively included 343 patients referred for SPECT between April 2008 and April 2010 in the laboratory of Nuclear Cardiology (University Hospital of Angers, France). All patients underwent a detailed assessment of their medical history and a clinical evaluation, including cardiovascular history, symptomatic status and treatment administered, indication and characteristics of the SPECT, LV ejection fraction (LVEF), and LV hypertrophy. The protocol was approved by the Institutional Ethics Committee, and the study was conducted in accordance with the Declaration of Helsinki and French regulatory requirements. Stress test Exercise was symptom limited and performed on a treadmill according to the standard Bruce protocol. Tracer was administered at near maximal exercise. A 2-min cool down walk was then observed. If symptom-limited exercise testing was considered as infeasible, dipyridamole was infused at 0.56 mg/kg for 4 min at rest in patients instructed not to consume caffeine products for 24 h before. Tracer was injected 4 min later. Patients may have undergone joint stress with dipyridamole as an adjunct to symptom-limited exercise. SPECT was initiated a few minutes later. Whatever the stress used, a standard 12-lead ECG was continuously recorded (Case, General Electric, USA). During each stage of stress and recovery, data relating to symptoms, heart rate, blood pressure, ST-segment changes, and exercise capacity (given in metabolic equivalents) were prospectively collected and recorded until 6 min of recovery being complete. In case of dipyridamole test, ECG was monitored for a minimum 4 min after tracer infusion. Every single ventricular arrhythmia was recorded including single VE. Repolarization abnormalities were defined as the following ST-segment changes: horizontal or down sloping ST depression ≥0.1 mV at 0.08 s from J point, in two or more leads except aVR, ST elevation ≥ 0.2 mV. SPECT acquisition protocol and analysis SPECT (Ventri, General Electric, Milwaukee, USA) was performed using 180-degree acquisition for 64 projections at 20 s per projection using standard energy windows for Thallium 201 and Tc99m sestamibi. No attenuation or scatter correction was used. Patients were put in the prone or supine position as necessary. Stress and rest imaging was performed with about 1.5 MBq/kg and 0.5 MBq/kg of Thallium 201 after 4 h or 3.7 MBq/kg and 11.1 MBq/kg of Tc99m sestamibi, respectively. As patient management decisions were based on the clinically reported interpretations, analyses of patient outcomes were based on the reported site interpretation. Briefly, SPECT findings were assessed semi-quantitatively and visually using the recommended 17-segment scoring system. Segmental scoring was performed by site readers. SPECT scans were considered abnormal based on the presence of ischaemia or scar. Ischaemia and scar were defined by the presence of reversible (at least three segments) or permanent perfusion defects, respectively.9,10 Analysis of VE Data regarding VE were collected prospectively by recording continuous 12-lead ECGs. The analysis of the ECG pattern was performed subsequently by the consensus of two blinded investigators and focused on the following characteristics: (i) the bundle-branch block pattern (ii) the QRS morphology of the VE in all 12 leads, (iii) the width of the QRS complex, and (iv) the number and timing of VE. Ventricular ectopy was defined as one or more induced ventricular ectopic beats (infrequent VE). We described stress-induced VE as SI-RBVE or left bundle-branch block morphology (SI-LBVE) assuming there was a positive or negative predominance in V1, respectively.11,12 SI-RBVE of apical origin was defined in cases of occurrence of negative concordance in precordial leads. Frequent VE (FVE) was defined as the presence of seven or more ventricular premature beats per minute, ventricular bigeminy or trigeminy, couplets, triplets, sustained, or non-sustained ventricular tachycardia or ventricular fibrillation.13 Ventricular ectopy and FVE were exclusively considered when recorded during stress and recovery. Follow-up Data relating to cardiovascular outcomes were collected and adjudicated after consultation of medical records and the computer database by two physicians (LB, THM) who were unaware of clinical data, SPECT, and VE results. When necessary, a referent cardiologist or general practitioner was called to complete the follow-up assessment. Four patients were lost to follow-up. We distinguished deaths resulting from cardiovascular causes from other types. Death, acute coronary syndrome (ACS) including myocardial infarction and major adverse cardiac events (associating CV death with ACS) were tabulated per subject. Statistical analysis The data have been presented as mean ± standard deviation or median (25th; 75th percentiles) in cases of abnormal distribution, with categorical data expressed as frequencies and percentages. Comparisons of variables were performed using unpaired Student’s t-test or the chi-squared test, as appropriate. For multivariate analysis assessing all-cause mortality during follow-up, clinical data, stress findings, and VE were tested by means of a Cox analysis, including variables with P values < 0.05 in univariate analysis. We applied several models to test, one after the other, every ventricular arrhythmia criterion (VE, SI-LBVE, SI-RBVE, and FVE). Specific interactions were tested between ventricular arrhythmia and LVEF, age, SPECT findings, and gender. Exercise capacity14,15 was not included in the multivariate analysis due to the heterogeneity of our cohort combining patients submitted to exercise, dipyridamole, and joint tests. Variables were included in multivariate models in forced entry mode, with the exception of the use of a backward stepwise analysis in the subgroup of patient with preserved LVEF and ischaemia, due to lower number of clinical events. The analyses were performed using the SPSS Version 17.0 for Windows (SPPS Inc., Chicago, IL). A P value < 0.05 was considered statistically significant. Results Population study Out of 343 patients, 235 patients (68.5%) were men with a mean age of 67.0 ± 11.7 years. The mean LVEF was 55.9 ± 10.5%. Ninety-two patients (26.8%) in the cohort presented a LVEF less than 50%. Table 1 lists patient characteristics at baseline. Table 1 Population characteristics   Global population  SI-RBVE  No SI-RBVE  P value  n = 343  n = 127  n = 216  Demographic characteristics   Age—years  67.0 ± 11.7  68.5 ± 10.6  66.1 ± 12.3  0.07   Male gender—no. (%)  235 (68.5)  92 (72.4)  143 (66.2)  0.14  Risk factors—no. (%)   Diabetes  102 (29.7)  44 (34.6)  58 (26.9)  0.08   Hypertension  190 (55.4)  72 (56.7)  118 (54.6)  0.39   Tobacco use  39 (11.8)  10 (7.9)  29 (13.4)  0.08   Dyslipidaemia  179 (52.2)  64 (50.4)  115 (53.2)  0.34   Heredity  15 (4.4)  4 (3.1)  11 (5.1)  0.28  Medical history—no. (%)   CAD  165 (48.1)  69 (54.3)  96 (44.4)  0.049   Prior coronary artery bypass grafting  23 (6.7)  7 (5.5)  16 (7.5)  0.32   Prior myocardial infarction  96 (28.2)  45 (35.4)  51 (23.9)  0.016   Prior percutaneous coronary intervention  103 (30.2)  43 (33.9)  60 (28.0)  0.15   Stroke  8 (2.3)  2 (1.6)  6 (2.8)  0.37   Peripheral artery disease  44 (12.8)  17 (13.4)  27 (12.5)  0.46   Dysrhythmia  4 (1.2)  3 (2.4)  1 (0.5)  0.14   LV hypertrophy  64 (18.7)  31 (24.4)  33 (15.3)  0.026   LVEF—%  55.9 ± 10.5  52.9 ± 12.4  57.6 ± 8.8  <0.001  Medication use—no. (%)   Aspirin  199 (60.7)  74 (60.7)  125 (60.7)  0.54   Clopidogrel  126 (38.4)  53 (43.4)  73 (35.4)  0.09   Calcium inhibitor  11 (3.2)  3 (2.4)  8 (3.7)  0.36   Ivabradine  6 (1.8)  3 (2.4)  3 (1.4)  0.39   Betablockers  198 (57.9)  81 (63.8)  117 (54.4)  0.06   Antiarrhythmic agent  33 (9.7)  11 (8.7)  22 (10.3)  0.39    Global population  SI-RBVE  No SI-RBVE  P value  n = 343  n = 127  n = 216  Demographic characteristics   Age—years  67.0 ± 11.7  68.5 ± 10.6  66.1 ± 12.3  0.07   Male gender—no. (%)  235 (68.5)  92 (72.4)  143 (66.2)  0.14  Risk factors—no. (%)   Diabetes  102 (29.7)  44 (34.6)  58 (26.9)  0.08   Hypertension  190 (55.4)  72 (56.7)  118 (54.6)  0.39   Tobacco use  39 (11.8)  10 (7.9)  29 (13.4)  0.08   Dyslipidaemia  179 (52.2)  64 (50.4)  115 (53.2)  0.34   Heredity  15 (4.4)  4 (3.1)  11 (5.1)  0.28  Medical history—no. (%)   CAD  165 (48.1)  69 (54.3)  96 (44.4)  0.049   Prior coronary artery bypass grafting  23 (6.7)  7 (5.5)  16 (7.5)  0.32   Prior myocardial infarction  96 (28.2)  45 (35.4)  51 (23.9)  0.016   Prior percutaneous coronary intervention  103 (30.2)  43 (33.9)  60 (28.0)  0.15   Stroke  8 (2.3)  2 (1.6)  6 (2.8)  0.37   Peripheral artery disease  44 (12.8)  17 (13.4)  27 (12.5)  0.46   Dysrhythmia  4 (1.2)  3 (2.4)  1 (0.5)  0.14   LV hypertrophy  64 (18.7)  31 (24.4)  33 (15.3)  0.026   LVEF—%  55.9 ± 10.5  52.9 ± 12.4  57.6 ± 8.8  <0.001  Medication use—no. (%)   Aspirin  199 (60.7)  74 (60.7)  125 (60.7)  0.54   Clopidogrel  126 (38.4)  53 (43.4)  73 (35.4)  0.09   Calcium inhibitor  11 (3.2)  3 (2.4)  8 (3.7)  0.36   Ivabradine  6 (1.8)  3 (2.4)  3 (1.4)  0.39   Betablockers  198 (57.9)  81 (63.8)  117 (54.4)  0.06   Antiarrhythmic agent  33 (9.7)  11 (8.7)  22 (10.3)  0.39  CAD, coronary artery disease; LV, left ventricle; LVEF, left ventricular ejection fraction; SI-RBVE, stress-induced right bundle-branch block VE. Ventricular ectopy One hundred and seventy-nine patients (52.2%) presented VE during the stress test, among which 107 patients (31.2%) had SI-LBVE and 127 patients (37.0%) had SI-RBVE. The groups were similar with regard to age and cardiovascular risk factors. Medical history of CAD, previous myocardial infarction, and LV hypertrophy were higher among patients with SI-RBVE. Left ventricular ejection fraction was lower among patients with SI-RBVE (52.9 ± 12.4% vs. 57.6 ± 8.8%, P < 0.001). Stress-induced right bundle-branch block morphology ventricular ectopy occurred only once in 43 patients (12.5%). Fifty patients (14.6%) presented FVE. Only seven patients presented at least one triplet during testing. Figure 1 shows the flowchart of the study. Mean QRS width of SI-RBVE was 156 ± 46 ms. Figure 1 View largeDownload slide Study flow chart. VE, ventricular ectopy, which occurred during stress or recovery; SI-LBVE, at least one stress-induced left bundle-branch VE; SI-RBVE, at least one stress-induced right bundle-branch VE; FVE, frequent VE, whatever the morphology13: seven or more ventricular premature beats per minute, ventricular bigeminy or trigeminy, couplets, triplets, sustained, or non-sustained ventricular tachycardia or ventricular fibrillation. Figure 1 View largeDownload slide Study flow chart. VE, ventricular ectopy, which occurred during stress or recovery; SI-LBVE, at least one stress-induced left bundle-branch VE; SI-RBVE, at least one stress-induced right bundle-branch VE; FVE, frequent VE, whatever the morphology13: seven or more ventricular premature beats per minute, ventricular bigeminy or trigeminy, couplets, triplets, sustained, or non-sustained ventricular tachycardia or ventricular fibrillation. Stress tests characteristics Stress tests were indicated for ischaemic evaluation in 228 patients (66.5%), including symptomatic angina in 66 patients (19.2%), atypical chest pain in 60 patients (17.5%), and 113 (32.9%) for the purpose of systematic follow-up (Table 2). Exercise was used more commonly (144 patients, 42.4%) than dipyridamole (131 patients, 38.2%) and joint stress (68 patients, 19.8%). Stress test types were distributed evenly among SI-RBVE and non SI-RBVE patients; and width and abundance of SI-RBVE were not influenced by stress type (Table 3). The most frequent reason for exercise termination was reaching maximum level of exertion (56.6%). Table 2 Distribution of induced VE according to stress type   Dipyridamole  Exercise  Join test  P  n = 131  n = 144  n = 68  Ventricular arrhythmia—no. (%)   VE  59 (45.7)  92 (63.9)  28 (41.2)  0.002   SI-RBVE  47 (36.4)  60 (41.7)  20 (29.4)  0.253   SI-LBVE  24 (18.6)  65 (45.1)  18 (26.0)  <0.001   FVE  16 (12.4)  29 (20.1)  5 (7.5)  0.037   Nonsustained ventricular tachycardia  0 (0)  1 (0.7)  1 (1.5)  0.132   Bigeminy  0 (0)  2 (1.4)  1 (1.5)  0.426  SI-RBVE duration, ms  158 ± 43  153 ± 41  160 ± 44  0.884  SI-RBVE number  2.3 ± 6  2.8 ± 7  1.5 ± 5  0.232    Dipyridamole  Exercise  Join test  P  n = 131  n = 144  n = 68  Ventricular arrhythmia—no. (%)   VE  59 (45.7)  92 (63.9)  28 (41.2)  0.002   SI-RBVE  47 (36.4)  60 (41.7)  20 (29.4)  0.253   SI-LBVE  24 (18.6)  65 (45.1)  18 (26.0)  <0.001   FVE  16 (12.4)  29 (20.1)  5 (7.5)  0.037   Nonsustained ventricular tachycardia  0 (0)  1 (0.7)  1 (1.5)  0.132   Bigeminy  0 (0)  2 (1.4)  1 (1.5)  0.426  SI-RBVE duration, ms  158 ± 43  153 ± 41  160 ± 44  0.884  SI-RBVE number  2.3 ± 6  2.8 ± 7  1.5 ± 5  0.232  SI-LBVE, stress-induced left bundle-branch block VE; SI-RBVE, stress-induced right bundle-branch block VE; FVE, frequent VE; VE, ventricular ectopy. Categorical and continuous data were compared by the means of Pearson Chi-Square and Kruskal–Wallis tests. Table 3 Stress test characteristics   Global population  SI-RBVE  No SI-RBVE  P value  Cardiovascular assessment and exercise capacity   Resting heart rate—beats/min  74 ± 15  76 ± 15  74 ± 15  0.51   Resting systolic blood pressure—mm Hg  132 ± 20  131 ± 22  133 ± 19  0.23   Peak exercise capacity—metabolic equivalents  8.8 ± 3.4  9.1 ± 3.3  8.7 ± 3.6  0.40   Age-predicted maximal heart rate—%  86 ± 14  89 ± 14  84 ± 13  0.013  Stress type—no. (%)   Exercise  144 (42.4)  60 (47.2)  86 (39.8)  0.09   Dipyridamole  131 (38.2)  47 (37.0)  82 (40.0)  0.50   Joint test  68 (19.8)  20 (15.7)  48 (22.2)  0.70  Exercise termination—no. (%)   Maximal effort  117 (56.6)  47 (58.7)  72 (55.0)  0.40   Lipothymia or hypotension  6 (2.8)  3 (3.8)  3 (2.3)  0.39   Chest pain  14 (6.7)  5 (6.2)  9 (6.9)  0.56   Dyspnoea  18 (8.6)  11 (13.7)  7 (5.3)  0.031   Other  60 (28.8)  14 (17.5)  45 (34.6)  0.011  Exercise result—no. (%)   Clinical symptoms  40 (11.7)  21 (26.2)  19 (14.2)  0.026   ST-segment changes  63 (18.4)  25 (31.2)  38 (28.4)  0.37  Medication used during stress test—no. (%)   Betablockers  146 (42.7)  57 (44.9)  89 (41.1)  0.30   Calcium inhibitor  7 (2.1)  3 (2.4)  4 (1.9)  0.51  SPECT findings—no. (%)   Scar  85 (24.8)  45 (35.4)  40 (18.5)  <0.001   Ischaemia  80 (23.3)  38 (29.9)  42 (19.4)  0.019   Any of ischaemia or scar  146 (42.6)  74 (58.3)  72 (33.3)  <0.001    Global population  SI-RBVE  No SI-RBVE  P value  Cardiovascular assessment and exercise capacity   Resting heart rate—beats/min  74 ± 15  76 ± 15  74 ± 15  0.51   Resting systolic blood pressure—mm Hg  132 ± 20  131 ± 22  133 ± 19  0.23   Peak exercise capacity—metabolic equivalents  8.8 ± 3.4  9.1 ± 3.3  8.7 ± 3.6  0.40   Age-predicted maximal heart rate—%  86 ± 14  89 ± 14  84 ± 13  0.013  Stress type—no. (%)   Exercise  144 (42.4)  60 (47.2)  86 (39.8)  0.09   Dipyridamole  131 (38.2)  47 (37.0)  82 (40.0)  0.50   Joint test  68 (19.8)  20 (15.7)  48 (22.2)  0.70  Exercise termination—no. (%)   Maximal effort  117 (56.6)  47 (58.7)  72 (55.0)  0.40   Lipothymia or hypotension  6 (2.8)  3 (3.8)  3 (2.3)  0.39   Chest pain  14 (6.7)  5 (6.2)  9 (6.9)  0.56   Dyspnoea  18 (8.6)  11 (13.7)  7 (5.3)  0.031   Other  60 (28.8)  14 (17.5)  45 (34.6)  0.011  Exercise result—no. (%)   Clinical symptoms  40 (11.7)  21 (26.2)  19 (14.2)  0.026   ST-segment changes  63 (18.4)  25 (31.2)  38 (28.4)  0.37  Medication used during stress test—no. (%)   Betablockers  146 (42.7)  57 (44.9)  89 (41.1)  0.30   Calcium inhibitor  7 (2.1)  3 (2.4)  4 (1.9)  0.51  SPECT findings—no. (%)   Scar  85 (24.8)  45 (35.4)  40 (18.5)  <0.001   Ischaemia  80 (23.3)  38 (29.9)  42 (19.4)  0.019   Any of ischaemia or scar  146 (42.6)  74 (58.3)  72 (33.3)  <0.001  SI-RBVE, stress-induced right bundle-branch block VE. SPECT results SPECT revealed ischaemia in 80 patients (23.3%), scar in 85 patients (24.8%), and none of these findings in 146 patients (42.6%). SPECT findings were frequent among patients with SI-RBVE but not among SI-LBVE, FVE, or VE patients. SI-RBVE patients presented 38 cases (29.9%, P < 0.019) of ischaemia, 45 cases (35.4%, P < 0.001) of scar, and 74 cases (58.3%, P < 0.001) of ischaemia or scar (Table 3). Thirty-three patients with SI-RBVE had normal SPECT. Among them, 12 had ventricular hypertrophy and 4 had a history of heart failure. Moreover, SPECT findings were more frequent in subjects with LVEF inferior to 50% (77.2% vs. 29.8%, P < 0.001). Cardiovascular outcomes Fifty-nine (17.4%) deaths, including 23 (6.9%) cardiovascular deaths, 40 MACE (11.7%) including 20 ACS (6.0%) occurred during a mean follow-up of 4.5 ± 1.3 years (Table 4). All-cause mortality was high in patients with SI-RBVE (23.4% vs. 14.0%, P = 0.021) but not in VE, SI-LBVE, or FVE patients. All-cause mortality was higher in patients with LVEF ≤ 50% compared to patients with LVEF > 50% (28.3% vs. 13.4%, P = 0.002). We found no link between ventricular rhythmic disorders and MACE. Table 4 Cardiovascular events   Global population  SI-RBVE  No SI-RBVE  P value  All-cause mortality—no. (%)  59 (17.4)  29 (23.4)  30 (14.0)  0.027   Cardiovascular mortality  23 (6.9)  12 (9.8)  11 (5.2)  0.08   Non-cardiovascular mortality  36 (10.5)  17 (13.7)  19 (8.8)  0.11  ACS—no. (%)  20 (6.0)  8 (6.6)  12 (5.6)  0.72   Myocardial infarction  10 (3.0)  4 (3.3)  6 (2.8)  0.73  MACE—no. (%)  40 (11.7)  18 (14.2)  22 (10.2)  0.27    Global population  SI-RBVE  No SI-RBVE  P value  All-cause mortality—no. (%)  59 (17.4)  29 (23.4)  30 (14.0)  0.027   Cardiovascular mortality  23 (6.9)  12 (9.8)  11 (5.2)  0.08   Non-cardiovascular mortality  36 (10.5)  17 (13.7)  19 (8.8)  0.11  ACS—no. (%)  20 (6.0)  8 (6.6)  12 (5.6)  0.72   Myocardial infarction  10 (3.0)  4 (3.3)  6 (2.8)  0.73  MACE—no. (%)  40 (11.7)  18 (14.2)  22 (10.2)  0.27  SI-RBVE, stress-induced right bundle-branch block VE; ACS, acute coronary syndrome; MACE, major adverse cardiovascular events. VE or FVE were not independently related to mortality. We found an interaction between SI-RBVE and LVEF (P = 0.036); in patients with LVEF > 50%, SI-RBVE was an independent factor of mortality [OR = 2.17 (95% CI: 1.09–4.34), P = 0.028] (see Figure 2 and Table 5). The other independent determinants of all-cause mortality were age [OR = 1.10 (95% CI: 1.06–1.13), P < 0.001] and peripheral artery disease [OR = 2.33 (95% CI: 1.27–4.26), P = 0.006]. Age was the only independent factor for cardiovascular death [OR= 1.06 (95% CI: 1.03–1.10] P < 0.001). Medical history of CAD and ST segment changes were independent factors for MACE [OR= 2.64 (95% CI: 1.20–5.81), P = 0.015 and OR = 2.21 (95% CI: 1.11–4.39), P = 0.024]. If we exclude the subjects with FVE from the analysis, the results did not change significantly. Finally, the analysis was run after dichotomizing the population considering the presence or absence of ischaemia. Interactions between SI-RBVE and LVEF > 50% were still significant in both groups (P = 0.015 and 0.013, respectively), with OR of 5.89 (95% CI: 1.84–18.83) and 2.21 (95% CI: 1.02–4.82) after multivariate analyses, respectively. Table 5 Univariate and multivariate predictors for all-cause mortality   Univariate  Multivariate     P value  HR (95% CI)  P value  Age  <0.001  1.10 (1.06–1.13)  <0.001  Diabetes  0.08  —  —  Current smoker  0.07  —  —  Dyslipidaemia  0.24  —  —  Hypertension  0.10  —  —  History of heart failure  <0.001  1.80 (0.97–3.30)  0.06  History of stroke  0.09  —  —  Known CAD  0.40  —  —  Peripheral arterial disease  0.002  2.33 (1.27–4.26)  0.006  Scar  0.003  1.72 (0.98–3.04)  0.06  Ischaemia  0.97  —  —  LVEF < 50%  0.001  0.47 (0.21–1.03)  0.06  SI-RBVE  0.026      LVEF < 50% SI-RBVE +    0.71 (0.32–1.57)  0.40  LVEF ≥ 50% SI-RBVE +    2.17 (1.09–4.34)  0.028  VE  0.14  —  —  ST-segment changes  0.38  —  —    Univariate  Multivariate     P value  HR (95% CI)  P value  Age  <0.001  1.10 (1.06–1.13)  <0.001  Diabetes  0.08  —  —  Current smoker  0.07  —  —  Dyslipidaemia  0.24  —  —  Hypertension  0.10  —  —  History of heart failure  <0.001  1.80 (0.97–3.30)  0.06  History of stroke  0.09  —  —  Known CAD  0.40  —  —  Peripheral arterial disease  0.002  2.33 (1.27–4.26)  0.006  Scar  0.003  1.72 (0.98–3.04)  0.06  Ischaemia  0.97  —  —  LVEF < 50%  0.001  0.47 (0.21–1.03)  0.06  SI-RBVE  0.026      LVEF < 50% SI-RBVE +    0.71 (0.32–1.57)  0.40  LVEF ≥ 50% SI-RBVE +    2.17 (1.09–4.34)  0.028  VE  0.14  —  —  ST-segment changes  0.38  —  —  SI-RBVE, stress-induced right bundle-branch block VE. Figure 2 View largeDownload slide Survival in stress-induced right bundle-branch VE group with or without preserved LV ejection fraction. Figure 2 View largeDownload slide Survival in stress-induced right bundle-branch VE group with or without preserved LV ejection fraction. Discussion The major findings of this study were as follows: (i) patients with SI-RBVE presented higher all-cause mortality (23.4% vs. 14.0%, P = 0.021) and (ii) in case of LVEF > 50%, SI-RBVE was an independent predictor of mortality. Ventricular ectopies or arrhythmias are described as related to mortality when frequent,1 exercise-induced, or occurring during recovery.13,16–19 Data regarding ventricular arrhythmias are somewhat disparate among studies, notably with regard to prevalence, ranging from 2%13 to 42%,20 and also with regard to patient characteristics. Exercise-induced ventricular tachycardia was strongly predictive of mortality in patients with a LVEF inferior to 35%.21 In contrast to these results, we found an interaction between LVEF and SI-RBVE indicating that SI-RBVE, when occurring in patients with preserved LVEF, was independently related to mortality. Stress-induced right bundle-branch block morphology ventricular ectopy may not be a problem in depressed LVEF due to the high prevalence of mortality inherent to LV dysfunction. Thus a significant amount of mortality may not be mediated by depressed LV systolic function22 but may be marked up by SI-RBVE to a certain extent. Frequent VE during exercise has been previously defined as either >7 VE/minute13 or >10% VE during 30 s.1 Nevertheless, a CAD-free unselected cohort revealed FVE occurrence to be very low, affecting only 4 out of 2885 individuals22 that convinced the authors to redefine their arrhythmia criteria as the median value of occurrence, which was about 1 VE for every 4.5 min of exercise. Such infrequent events were still predictive for mortality. Similarly, Califf et al.23 demonstrated a gradual prognosis among high-risk patients with respect to ventricular arrhythmia complexity (from single VE to couplet or more). The use of any threshold on VE frequency would appear subjective and arbitrary. We successfully gained interest in investigating infrequent VE as soon as a single event occurred, with the aim to assess both myocardial ischaemia and prognosis.20 Even if the link between exercise-induced VE and CAD has been demonstrated,13,17,20 the presence of SI-RBVE was not exclusive to ischaemic myocardium (SPECT abnormalities were found in only 58% of patients with SI-RBVE) and did also not determine ACS events during follow-up. It is noteworthy that the likelihood of CAD-related, exercise-induced VE may largely be associated with the pre-test probability.8,20 Our results suggest that SI-RBVE may be consecutive to very small areas of LV anomalies that are not stressed by symptoms, ST-segment changes, or SPECT findings during stress tests. Of note, the effect of SI-RBVE on mortality was found as well in patients with and without ischaemia, although patients with ischaemia commonly present higher rates of adverse outcomes.10 Myocarditis,24 LV hypertrophy, valvular heart disease, and ion channel diseases are other potential sources25 to rule out in the context of SI-RBVE. We deliberately compared SI-LBVE with SI-RBVE. The interest of distinguishing left and right bundle-branch block morphology arrhythmias has already been pointed out7 when considering couplets or more. In our study, however, we stressed the impact on mortality of infrequent SI-RBVE in patients with intermediate-to-high CV risk while questioning any potential role of SI-LBVE. Indeed, LBVE often originates from the right ventricular outflow tract and may be induced by benign adrenergic activation in healthy individuals. Interestingly, there were similar rates of VE, including SI-RBVE, irrespective of the stress test type performed. While ventricular arrhythmias are common physiology in the context of exercise and potential ischaemia, this is not clearly described in vasodilator uses. The largest registry available on dipyridamole use reported six cases of sustained ventricular arrhythmias requiring immediate cardioversion.26 Two mechanisms may be responsible for ventricular arrhythmias in vasodilator tests. First, an underestimated rate of authentic ischaemia induced by flow diversion may be suggested. Indeed, some wall motion abnormalities are observed during perfusion in magnetic resonance stress imaging.27 Second, targeting adenosine receptors may contribute to increased vagal activity and impaired neurovegetative balance.28 This is a prospective study centred on real-life activity in nuclear cardiology. As such, our patients notably presented a high prevalence of CAD (48.1% prior to test). Results may be specific to our dataset and no conclusions should be done on low risk patients with SI-RBVE, as their risk appeared to be very low.3 Our study is purely observational and no consequences should be done on therapeutics. Appropriate follow-up, aggressive control of CV risk factors and diagnosis of subclinical cardiac disease should be recommended. It has been shown that VE during recovery is a better predictor of an increased risk of death than VE occurring only during exercise.13 However, evidences were given in case of frequent VE,1,15,22 not infrequent VE. Ventricular ectopy occurrence in our study includes VE during stress and/or during recovery but the exact timing was not prospectively collected, so that its impact on prognosis should be examined in future studies. Conclusions In patients with intermediate to high risk of CAD, SI-RBVE is associated with an increased mortality and may refine prognostic assessment in patients with LVEF > 50%. What is more, SI-RBVE was often linked to ischaemia and scar, as assessed by SPECT. These results may be specific to our dataset and need further investigation, notably targeting low to intermediate risk patients. Conflict of interest: none declared. References 1 Jouven X, Zureik M, Desnos M, Courbon D, Ducimetiere P. Long-term outcome in asymptomatic men with exercise-induced premature ventricular depolarizations. N Engl J Med  2000; 343: 826– 33. Google Scholar CrossRef Search ADS PubMed  2 Schweikert RA, Pashkow FJ, Snader CE, Marwick TH, Lauer MS. Association of exercise-induced ventricular ectopic activity with thallium myocardial perfusion and angiographic coronary artery disease in stable, low-risk populations. Am J Cardiol  1999; 83: 530– 4. 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EuropaceOxford University Press

Published: Mar 1, 2018

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