Incidence, Predictors, and Outcome Associated With Ventricular Tachycardia or Fibrillation in Patients Undergoing Primary Percutaneous Coronary Intervention for Acute Myocardial Infarction

Abstract

Background: The characteristics and clinical outcomes associated with sustained ventricular tachycardia and fibrillation (VT/VF) in Japanese acute myocardial infarction (AMI) patients remain unknown.

Methods and Results: Consecutive AMI patients (n=1,941) transferred to the Hirosaki University Hospital and treated with primary percutaneous coronary intervention (PCI) within 12 h of onset were retrospectively studied. The incidence of VT/VF during hospitalization was 8.3%, and 75% of cases occurred by the end of PCI. Independent predictors associated with VT/VF occurrence by the end of PCI and after PCI, respectively, were identified. Additionally, the differences between patients with VT and VF were examined, which revealed that the characteristics of patients and predictors for VT and VF were clearly different. Additionally, the QRS duration during VT was measured, which demonstrated the possible involvement of Purkinje fibers for VT in the acute phase of AMI. Of the patients with VT/VF, 12% required ECMO support due to refractory VT/VF despite intravenous antiarrhythmic agents such as β-blockers, amiodarone, and nifekalant. Among the patients discharged alive, 1,690 were followed up for a mean of 3.7 years. VT/VF occurrence during hospitalization did not affect the mid-term clinical outcomes even in patients with VT.

Conclusions: The results clearly indicated that VT/VF is still a serious complications of AMI. We need to identify patients at high risk of developing VT/VF for careful observation and appropriate intervention.

Life-threatening ventricular tachyarrhythmias such as sustained ventricular tachycardia and fibrillation (VT/VF) occur suddenly and unpredictably in the setting of acute myocardial infarction (AMI), particularly within the first few hours after onset,¹ followed by rapid collapse of systemic hemodynamics. Electrical cardioversion/defibrillation is effective for the return of spontaneous circulation in most cases, but VT/VF is sometimes resistant and requires extracorporeal membrane oxygenation (ECMO) support for hemodynamic stabilization.² In addition, VT/VF can occur even in the late period of the hospitalization when ECG monitoring is not routinely performed. Although the reperfusion strategy including primary percutaneous coronary intervention (PCI) has been well-established,^3,4 and has dramatically improved AMI patients’ outcomes,⁵ as well as leading to a decline in the incidence of VT/VF over the past 2 decades,⁶ clinical studies have demonstrated that VT/VF still occurs in ≈5% of AMI patients, resulting in worse in-hospital outcomes.^7–11 Thus, VT/VF remains a serious complication of AMI even in current clinical practice, because the incidence, predictors, and outcomes associated with VT/VF have not been fully elucidated.

Therefore, we examined the incidence and predictors of VT/VF in AMI patients treated with primary PCI to identify high-risk patients, focusing on the timing of VT/VF occurrence (i.e., by the end of primary PCI vs. after PCI). Additionally, the effect of VT/VF on both in-hospital and mid-term clinical outcomes after hospital discharge was also evaluated to validate the current understanding of the prognosis of VT/VF.

Methods

Study Patients

The study population included 1,941 consecutive AMI patients transferred to the Hirosaki University Hospital within 12 h of onset and treated with primary PCI between April 2000 and March 2019. Among the patients discharged from the hospital, a total of 1,691 (117 with VT/VF during hospitalization and 1,574 without) were followed for a mean period of 3.7 years. Transthoracic echocardiography was performed routinely in all patients to detect mechanical complications before emergency coronary angiography, and patients who received thrombolytic therapy at any time were excluded from this study. We used the Killip classification to assess the severity of AMI at hospital admission.¹² The study was based on the ethical guidelines for medical research on humans in the Declaration of Helsinki, and approved by the Ethical Committee of the Hirosaki University Graduate School of Medicine (approval no. 2020-070).

Diagnosis and Definitions

The clinical definition of AMI is described in the Supplementary Methods. VT was defined as a regular, wide complex tachycardia of ventricular origin and sustained for >30 s or was accompanied by hemodynamic compromise requiring electrical cardioversion/defibrillation or the use of intravenous antiarrhythmic agents. VF was defined as irregular undulations, varying in amplitude and contour without distinct QRS complexes or T waves.¹³ Cardiac death was defined as death due to AMI, congestive heart failure, or sudden cardiac death (SCD). SCD was defined as (1) sudden and unexpected death within 1 h of cardiac symptoms without progressive cardiac deterioration; (2) unexpected death during sleep; and (3) unexpected death within 24 h of last being seen alive.

Statistical Analysis

Variables are expressed as mean with standard deviation or number (percentage). Differences in the distribution of selected characteristics between patient groups were analyzed using the chi-square test for categorical variables (Fisher’s exact test when necessary) and Student’s t-test for comparisons between the mean of 2 independent groups. Odds ratios and 95% confidence intervals (CIs) for VT/VF at any time during hospitalization, by the end of PCI, and after PCI were calculated using the Cox proportional hazard model after adjustment of covariates for which the P value was <0.10 by univariate analysis. The survival curves after hospital discharge were estimated using the Kaplan-Meier method, and the differences between groups were compared using the log-rank test. Hazard ratios and 95% CIs for the incidence of SCD+VT/VF after hospital discharge were calculated using a Cox proportional hazards model after adjustment of covariates for which the P value was <0.10 by univariate analysis. JMP Pro statistical software version 13 (SAS Institute Inc., Cary, NC, USA) was used for all analyses, and a P<0.05 was considered significant.

Results

Baseline and Angiographic Characteristics, Intravenous Medications, and In-Hospital Outcomes

The baseline characteristics of patients with and without VT/VF during hospitalization are shown in Table 1. VT/VF occurred in 161 of 1,941 patients (8.3%) during hospitalization, comprising 99 patients with VF and 62 patients with VT. The 18 patients with both VT and VF were classified into the VT group. The patients with VT/VF during hospitalization were characterized by earlier hospital admission after onset, higher proportions of Killip classifications II–IV, atrial fibrillation on admission, and requiring ECMO or intra-aortic balloon pumping (IABP) support, higher incidence of VT/VF before hospital admission, lower left ventricular ejection fraction (LVEF) at hospital admission, larger infarction indicated as greater maximum creatine phosphokinase (CPK) and myocardial-specific isoenzyme of CPK fraction (CPK-MB) levels, and much higher in-hospital mortality rate than those without VT/VF. Analysis of the angiographic characteristics showed that patients with VT/VF were more likely to have a culprit artery with left main trunk (LMT) or right coronary artery (RCA), and multivessel disease compared with those without VT/VF. The proportions of both Thrombolysis in Myocardial Infarction (TIMI) flow grade 0 before primary PCI and TIMI flow grade <3 after primary PCI were higher in patients with VT/VF than in those without VT/VF.

Table 1. Baseline and Angiographic Characteristics of, and Medications for, Patients With VT/VF

	VT/VF during hospitalization		P value	Timing of VT/VF		P value
	VT/VF (+) (n=161)	VT/VF (−) (n=1,780)		By the end of PCI (n=123)	After PCI (n=38)
Age, years	66.9±12.0	66.5±12.2	0.72	66.2±11.7	69.2±12.8	0.17
Male sex, n (%)	122 (76)	1,359 (76)	0.87	94 (76)	28 (74)	0.73
Body mass index, kg/m2	23.7±3.8	24.1±3.6	0.25	23.8±3.9	23.3±3.6	0.61
Maintenance hemodialysis, n (%)	4 (3)	34 (2)	0.63	2 (2)	2 (5)	0.25
Prior MI, n (%)	13 (8)	113 (6)	0.41	9 (7)	4 (11)	0.54
Prior PCI, n (%)	17 (11)	126 (7)	0.12	13 (11)	4 (11)	0.99
Prior CABG, n (%)	0 (0)	17 (1)	0.09	0 (0)	0 (0)	N/A
Comorbidities, n (%)
Hypertension	98 (61)	1,194 (67)	0.11	75 (61)	23 (61)	0.96
Diabetes	69 (43)	752 (42)	0.88	53 (43)	16 (42)	0.91
Dyslipidemia	84 (52)	960 (54)	0.67	70 (57)	14 (37)	0.03
Current smoker	69 (43)	750 (42)	0.86	53 (43)	16 (42)	0.91
VT/VF prior to hospital admission, n (%)	30 (19)	70 (4)	<0.01	24 (20)	6 (16)	0.60
Time from onset to hospital admission, min	184±128	250±156	<0.01	167±108	239±167	<0.01
AF on admission, n (%)	23 (14)	136 (8)	<0.01	15 (12)	8 (21)	0.19
Killip classification II–IV on admission, n (%)	69 (43)	284 (16)	<0.01	42 (34)	27 (71)	<0.01
LVEF on admission, %	41.1±13.6	45.5±9.8	<0.01	44.3±12.3	30.1±12.0	<0.01
Use of ECMO, n (%)	36 (22)	15 (1)	<0.01	23 (19)	13 (34)	0.052
Due to refractory VT/VF	20 (12.4)			14 (11.4)	6 (15.8)	0.48
Due to cardiogenic shock	16 (9.9)	3 (0.2)	<0.01	9 (7.3)	7 (18.4)	0.06
Use of IABP, n (%)	81 (50)	443 (25)	<0.01	56 (46)	25 (66)	0.03
VT/VF, n (%)
VF	99 (61.5)			93 (75.6)	6 (15.8)	<0.01
VT	62 (38.5)			30 (24.4)	32 (84.2)
Maximum CPK, IU/L	6,597±6,002	3,518±2,981	<0.01	5,615±5,180	9,722±7,320	<0.01
Maximum CPK-MB, IU/L	511±412	326±255	<0.01	448±356	713±510	<0.01
Angiographic characteristics
Culprit artery, n (%)
RCA	72 (45)	654 (37)	<0.01	65 (53)	7 (18)	<0.01
LAD	45 (28)	850 (48)	<0.01	30 (24)	15 (39)	0.08
LMT	28 (17)	40 (2)	<0.01	14 (11)	14 (37)	<0.01
LCX	14 (9)	236 (13)	0.10	12 (10)	2 (5)	0.37
No. of stenotic arteries, n (%)
Single vessel	62 (39)	838 (47)	0.04	48 (39)	9 (24)	0.08
Multivessel	99 (62)	942 (53)		75 (61)	29 (76)
TIMI flow grade 0 before PCI, n (%)	120 (75)	1,179 (66)	0.03	93 (76)	27 (71)	0.58
TIMI flow grade <3 after PCI, n (%)	41 (26)	251 (14)	<0.01	22 (18)	19 (52)	<0.01
Intravenous medications, n (%)
Amiodarone	61 (37.9)			38 (30.9)	23 (60.5)	0.001
Nifekalant	22 (13.7)			9 (7.3)	13 (34.2)	<0.0001
Lidocaine	22 (13.7)			17 (13.8)	5 (13.2)	0.92
β-blockers	5 (3.1)			1 (0.8)	4 (10.5)	0.007
In-hospital death, n (%)	36 (22)	59 (3)	<0.01	13 (11)	23 (61)	<0.01

AF, atrial fibrillation; CABG, coronary artery bypass grafting; CPK, creatinine phosphokinase; CPK-MB, myocardial-specific isoenzyme of CPK; ECMO, extracorporeal membrane oxygenation; IABP, intra-aortic balloon pumping; LAD, left anterior descending artery; LCX, left circumflex artery; LMT, left main trunk; LVEF, left ventricular ejection fraction; MI, myocardial infarction; PCI, percutaneous coronary intervention; RCA, right coronary artery; TIMI, Thrombolysis in Myocardial Infarction; VF, ventricular fibrillation; VT, ventricular tachycardia.

Next, we divided the patients with VT/VF during hospitalization into 2 groups: VF/VF occurring by the end of primary PCI (n=123) and VT/VF after primary PCI (n=38) to analyze the differences in the patients’ characteristics and in-hospital clinical outcomes. The 9 patients who had VT/VF both by the end of primary PCI and after primary PCI were classified into the group with VT/VF after primary PCI. The patients with VT/VF occurring after primary PCI were characterized by delayed hospital admission after onset, higher proportions of Killip classifications II–IV and requiring IABP support, lower LVEF at hospital admission, larger infarction indicated as greater maximum CPK and CPK-MB levels, and much higher in-hospital mortality rate compared with those with VT/VF occurring by the end of primary PCI. On angiography, patients with VT/VF occurring after primary PCI were characterized by a higher proportion of LMT and TIMI culprit artery with flow grade <3 after primary PCI than those with VT/VF occurring by the end of PCI. Although 94% of VF cases occurred by the end of PCI, VT occurred with the same frequency by the end of PCI and after PCI. We used amiodarone for 37.9%, nifekalant for 13.7%, β-blockers for 3.1%, and lidocaine for 13.7% of patients with VT/VF, and 12.4% of patients with VT/VF required ECMO support due to refractory VT/VF (Table 1).

The Supplementary Figure shows the detailed trends of VT/VF occurrence during hospitalization: 123 patients (76%) developed VT/VF by the end of primary PCI, and the remaining 38 patients (24%) developed VT/VF after PCI. Of the patients with VT/VF after PCI, 16 (42%) developed VT/VF by 24 h after PCI, and 24 patients (63%) developed VT/VF by 48 h after PCI. The remaining 14 patients (37%) developed VT/VF over 48 h after PCI and up to 8 days. The in-hospital deaths of patients with and without VT/VF during hospitalization are shown in Supplementary Table 1. Among the patients without VT/VF during hospitalization, cardiogenic shock was the leading cause of death (44%) followed by cardiac rupture (22%). However, 64% of in-hospital deaths were due to cardiogenic shock followed by hypoxic encephalopathy (19%) in patients with VT/VF during hospitalization.

Predictors of VT/VF During Hospitalization

In the multivariate analysis, predictors independently associated with VT/VF occurring at any time during hospitalization included the culprit artery with LMT, early hospital admission (within 6 h of onset), VT/VF before hospital admission, a maximum CPK-MB value ≥800 U/L, LVEF ≤30% on admission, and TIMI flow grade <3 after primary PCI (Table 2A). Predictors independently associated with VT/VF occurring by the end of PCI were early hospital admission (within 6 h of onset), culprit artery with LMT, and the occurrence of VT/VF before hospital admission (Table 2B). Predictors independently associated with VT/VF occurring after primary PCI were LVEF ≤30% on admission, TIMI flow grade <3 after primary PCI, the culprit artery with LMT, and Killip classification II–IV (Table 2C).

Table 2. Cox Proportional Hazard Models for VT/VF Occurrence

(A) At any time during hospitalization	Univariate analysis			Multivariate analysis
	OR	95% CI	P value	OR	95% CI	P value
TIMI flow grade 0 before PCI	1.49	1.03–2.16	0.03	1.44	0.91–2.27	0.12
TIMI flow grade <3 after PCI	2.06	1.41–3.02	0.0002	1.67	1.03–2.71	0.04
AF on admission	2.01	1.25–3.24	0.004	0.99	0.52–1.89	0.99
Maintenance hemodialysis	1.31	0.46–3.73	0.62
Prior MI	1.30	0.71–2.36	0.40
Prior PCI	1.55	0.91–2.64	0.11
VT/VF prior to hospital admission	5.59	3.52–8.89	<0.0001	3.00	1.66–5.45	0.0003
Killip classification II–IV on admission	3.95	2.82–5.53	<0.0001	1.55	0.93–2.58	0.09
Age ≥70 years	1.19	0.86–1.64	0.30
Male sex	0.97	0.66–1.41	0.87
LVEF ≤30% on admission	4.69	3.05–7.21	<0.0001	1.99	1.13–3.51	0.02
Early hospital admission (within 6 h of onset)	3.28	1.80–5.97	0.0001	3.78	1.79–8.00	0.0005
Hypertension	0.76	0.55–1.06	0.11
Diabetes	1.03	0.74–1.42	0.88
Dyslipidemia	0.93	0.67–1.29	0.67
Current smoker	1.03	0.74–1.43	0.86
Culprit artery with LMT	9.16	5.48–15.31	<0.0001	4.60	2.08–10.21	0.0002
Maximum CPK-MB ≥800 U/L	4.84	3.13–7.50	<0.0001	2.49	1.39–4.45	0.002
(B) By the end of PCI	Univariate analysis			Multivariate analysis
	OR	95% CI	P value	OR	95% CI	P value
TIMI flow grade 0 before PCI	1.57	1.03–2.40	0.04	1.60	0.99–2.59	0.06
AF on admission	1.61	0.92–2.84	0.09	1.00	0.50–2.00	0.99
Maintenance hemodialysis	0.82	0.19–3.44	0.71
Prior MI	1.45	0.57–2.32	0.30
Prior PCI	1.53	0.84–2.80	0.18
VT/VF prior to hospital admission	5.56	3.36–9.18	<0.0001	3.31	1.77–6.18	0.0002
Killip classification II–IV on admission	2.51	1.70–3.72	<0.0001	1.41	0.80–2.49	0.23
Age ≥70 years	1.08	0.75–1.58	0.68
Male sex	1.01	0.66–1.55	0.97
LVEF ≤30% on admission	2.16	1.24–3.75	0.006	1.17	0.59–2.32	0.64
Early hospital admission (within 6 h of onset)	4.34	2.00–9.37	<0.0001	4.66	1.87–11.61	0.001
Hypertension	0.77	0.53–1.12	0.18
Diabetes	1.04	0.72–1.50	0.85
Dyslipidemia	1.14	0.79–1.65	0.47
Current smoker	1.04	0.72–1.50	0.84
Culprit artery with LMT	4.20	2.26–7.79	<0.0001	3.50	1.43–8.44	0.006
(C) After PCI	Univariate analysis			Multivariate analysis
	OR	95% CI	P value	OR	95% CI	P value
TIMI flow grade 0 before PCI	1.22	0.60–2.47	0.59
TIMI flow grade <3 after PCI	6.40	3.16–12.96	<0.01	4.40	1.88–10.30	0.0006
AF on admission	3.11	1.33–7.28	<0.01	0.98	0.33–2.94	0.98
Maintenance hemodialysis	3.35	0.77–14.55	0.11
Prior MI	1.08	0.25–4.55	0.92
Prior PCI	1.26	0.38–4.19	0.70
VT/VF prior to hospital admission	3.41	1.29–9.22	0.01	1.67	0.52–5.28	0.39
Killip classification II–IV on admission	11.00	5.19–23.33	<0.01	2.83	1.04–7.72	0.04
Age ≥70 years	1.50	0.75–3.00	0.25
Male sex	1.16	0.50–2.01	0.73
LVEF ≤30% on admission	19.46	9.06–41.79	<0.0001	4.81	1.79–12.93	0.002
Early hospital admission (within 6 h of onset)	1.39	0.53–3.62	0.50
Hypertension	0.68	0.34–1.36	0.27
Diabetes	0.88	0.44–1.79	0.73
Dyslipidemia	0.55	0.27–1.12	0.099
Current smoker	1.14	0.57–2.28	0.70
Culprit artery with LMT	18.90	8.86–40.31	<0.01	4.31	1.44–12.93	0.009
Maximum CPK-MB ≥800 U/L	8.35	4.16–16.77	<0.0001	1.99	0.73–5.40	0.18

CI, confidence interval; OR, odds ratio. Other abbreviations as in Table 1.

Effect of VT/VF on Mid-Term Clinical Outcomes

The patients’ characteristics at hospital discharge are shown in Supplementary Table 2. An implantable cardioverter-defibrillator (ICD) was used to treat 7.7% of patients with VT/VF, and the proportion of the prescription amiodarone was significantly higher in patients with VT/VF than in those without. The Kaplan-Meier survival analysis after hospital discharge revealed that the occurrence of VT/VF during hospitalization was not associated with the risk of all-cause death (Figure 1A), cardiac death (Figure 1B), SCD (Figure 1C), or SCD+VT/VF (Figure 1D) during the follow-up period. LVEF was followed up at a mean of 6.2±1.7 months after AMI onset in 1,293 patients, and was 49.1±10.6%, which was significantly greater than at hospital discharge (47.3±10.5%, P<0.0001). Of the 9 patients with VT/VF who received an ICD before hospital discharge, 4 had VT/VF over 48 h after AMI onset. In 2 patients, VT was induced by programmed stimulation at 600-270-230-250 ms at the right ventricle during electrophysiology study (EPS) before hospital discharge accompanied by LVEF ≤40%. One of the patients had LVEF 25% at 3 months after AMI onset during hospitalization. In 1 patient, VT was induced by EPS before hospital discharge, and the other patient had VF after primary PCI within 48 h after onset. Both of these patients were considered as high risk for VT/VF recurrence and received an ICD; of them, appropriate ICD therapy was delivered for VT at 12 months after hospital discharge in the patient with LVEF 24% at hospital discharge. Table 3 shows the Cox proportional hazard model for SCD+VT/VF during follow-up. LVEF ≤35% at hospital discharge and delayed hospital admission (>6 h after onset) were independent factors associated with SCD+VT/VF, whereas VT/VF during hospitalization was not a significant factor associated with SCD+VT/VF.

Figure 1.

Kaplan-Meier survival analysis for all-cause death (A), cardiac death (B), SCD (C), and SCD+VT/VF (D) during follow-up of patients with and without VT/VF occurring during hospitalization who were alive and discharged. SCD, sudden cardiac death; VF, ventricular fibrillation; VT, ventricular tachycardia.

Table 3. Cox Proportional Hazards Model for SCD+VT/VF After Hospital Discharge

	Univariate analysis			Multivariate analysis
	HR	95% CI	P value	HR	95% CI	P value
LVEF ≤35% at hospital discharge	5.96	2.04–17.42	0.002	5.78	1.98–16.90	0.002
TIMI flow grade <3 after PCI	1.86	0.52–5.34	0.31
AF during hospitalization	2.03	0.57–5.81	0.22
Age ≥75 years	1.78	0.60–4.78	0.27
Hospital admission >6 h after onset	4.12	1.52–11.21	0.006	4.18	1.43–12.24	0.01
VT/VF during hospitalization	0.88	0.05–4.35	0.90
Diabetes	2.36	0.87–6.92	0.09	2.64	0.91–8.60	0.07

CI, confidence interval; HR, hazard ratio; SCD, sudden cardiac death. Other abbreviations as in Table 1.

Patients’ Characteristics and Predictors of VT and VF, and the Effect of VT and VF on In-Hospital and Mid-Term Outcomes

We divided the 161 patients with VT/VF during hospitalization into VT (n=62) and VF (n=99) groups to examine the differences in patients’ characteristics and predictors. Patients with VT were characterized by older age, lower LVEF on admission, greater maximum CPK and CPK-MB levels, higher proportions of Killip classification II–IV on admission, use of ECMO due to cardiogenic shock and IABP, and much higher in-hospital mortality rate compared with those with VF. Angiography showed that patients with VT more likely to have culprit artery with LMT and multivessel disease, and less likely to have culprit artery with RCA compared with those with VF (Table 4). The Cox proportional hazard models revealed that a CPK-MB value ≥800 U/L was a common independent predictor associated with VT and VF occurrence. Killip classification II–IV on admission, age ≥70 years, LVEF ≤30% on admission, and culprit artery with LMT were independent predictors associated with VT occurrence (Table 5A), whereas VT/VF prior to hospital admission, early hospital admission within 6 h of onset, and culprit artery with RCA were independent predictors associated with VF occurrence (Table 5B). We performed additional survival analysis to examine the effect of the 2 types of life-threatening ventricular tachyarrhythmia for mid-term clinical outcomes after hospital discharge. Supplementary Table 3 shows the characteristics of the patients with VT or VF at hospital discharge. The patients with VT were characterized by lower LVEF at discharge, higher proportions of diabetes, Killip II–IV at hospital admission, ICD treatment during hospitalization, culprit artery with LMT, prescriptions of diuretics and amiodarone, and greater maximum CPK, CPK-MB, and B-type natriuretic peptide levels at discharge compared with those with VF. Kaplan-Meyer survival analysis revealed that no difference in the incidence of all-cause death (Figure 2A), cardiac death (Figure 2B), SCD (Figure 2C), or SCD+VT/VF (Figure 2D) between the groups.

Table 4. Baseline and Angiographic Characteristics of Patients With VT or VF

	VT (n=62)	VF (n=99)	P value
Age, years	69.6±12.0	65.1±11.7	0.02
Male sex, n (%)	47 (76)	75 (76)	0.99
Body mass index, kg/m2	23.0±3.9	24.1±3.8	0.16
Maintenance hemodialysis, n (%)	2 (3)	2 (2)	0.64
Prior MI, n (%)	5 (8)	8 (8)	0.99
Prior PCI, n (%)	5 (8)	12 (12)	0.41
Prior CABG, n (%)	0 (0)	0 (0)	N/A
Comorbidities, n (%)
Hypertension	38 (61)	60 (61)	0.93
Diabetes	31 (50)	38 (38)	0.15
Dyslipidemia	30 (48)	54 (55)	0.45
Current smoker	28 (45)	41 (41)	0.64
VT/VF prior to hospital admission, n (%)	8 (13)	22 (22)	0.13
Time from onset to hospital admission, min	196±116	177±135	0.35
AF on admission, n (%)	11 (18)	12 (12)	0.33
Killip classification II–IV on admission, n (%)	42 (68)	27 (27)	<0.01
LVEF on admission, %	34.3±13.3	45.3±12.0	<0.01
Use of ECMO, n (%)	17 (27)	19 (19)	0.23
Due to refractory VT/VF	7 (11)	13 (13)	0.73
Due to cardiogenic shock	10 (16)	6 (6)	0.04
Use of IABP, n (%)	38 (61)	43 (43)	0.03
Maximum CPK, IU/L	8,852±6,348	5,192±5,393	<0.01
Maximum CPK-MB, IU/L	677±484	408±322	<0.01
Angiographic characteristics
Culprit artery, n (%)
RCA	16 (26)	56 (57)	<0.01
LAD	16 (26)	29 (29)	0.63
LMT	22 (35)	6 (6)	<0.01
LCX	7 (11)	7 (7)	0.36
No. of stenotic arteries, n (%)
Single vessel	12 (19)	45 (44)	<0.01
Multivessel	50 (81)	54 (55)
TIMI flow grade 0 before PCI, n (%)	47 (76)	73 (74)	0.78
TIMI flow grade <3 after PCI, n (%)	39 (66)	76 (78)	0.09
In-hospital mortality, n (%)	24 (39)	12 (12)	<0.01

Abbreviations as in Table 1.

Table 5. Cox Proportional Hazard Models for VT or VF Occurrence

(A) VT at any time during hospitalization	Univariate analysis			Multivariate analysis
	OR	95% CI	P value	OR	95% CI	P value
TIMI flow grade 0 before PCI	1.57	0.87–2.83	0.14
TIMI flow grade <3 after PCI	2.88	1.66–5.01	0.0002	1.94	0.92–4.07	0.08
AF on admission	2.52	1.29–4.94	0.007	0.68	0.25–1.89	0.46
Maintenance hemodialysis	1.71	0.40–7.25	0.47
Prior MI	1.27	0.50–3.24	0.61
Prior PCI	1.11	0.44–2.81	0.83
VT/VF prior to hospital admission	2.88	1.33–6.22	0.007	1.36	0.49–3.78	0.56
Killip classification II–IV on admission	10.59	6.13–18.28	<0.0001	3.11	1.42–6.82	0.005
Age ≥70 years	1.88	1.12–3.15	0.02	2.08	1.05–4.13	0.04
Male sex	0.97	0.54–1.76	0.93
LVEF ≤30% on admission	10.71	5.97–19.21	<0.0001	2.71	1.21–6.09	0.02
Early hospital admission (within 6 h of onset)	2.88	1.15–7.24	0.02	2.84	0.93–8.61	0.07
Hypertension	0.79	0.47–1.33	0.37
Diabetes	1.38	0.83–2.29	0.21
Dyslipidemia	0.80	0.48–1.33	0.39
Current smoker	1.13	0.68–1.88	0.63
Culprit artery with LMT	21.92	12.07–39.81	<0.0001	5.44	2.15–13.75	0.0003
Maximum CPK-MB ≥800 U/L	8.29	4.69–14.66	<0.0001	3.38	1.54–7.43	0.002
(B) VF at any time during hospitalization	Univariate analysis			Multivariate analysis
	OR	95% CI	P value	OR	95% CI	P value
TIMI flow grade 0 before PCI	1.41	0.89–2.23	0.13
TIMI flow grade <3 after PCI	1.52	0.92–2.51	0.11
AF on admission	1.59	0.85–2.98	0.17
Maintenance hemodialysis	1.03	0.25–4.36	0.96
Prior MI	1.30	0.71–2.36	0.40
Prior PCI	1.55	0.91–2.64	0.11
VT/VF prior to hospital admission	6.46	3.82–10.93	<0.0001	4.11	2.11–7.99	<0.0001
Killip classification II–IV on admission	1.74	1.10–2.76	0.02	1.09	0.55–2.14	0.81
Age ≥70 years	0.87	0.58–1.32	0.52
Male sex	0.97	0.60–1.55	0.90
LVEF ≤30% on admission	4.69	3.05–7.21	<0.0001	1.87	0.87–4.04	0.11
Early hospital admission (within 6 h of onset)	3.28	1.80–5.97	0.0001	4.52	1.62–12.59	0.004
Hypertension	0.76	0.50–1.15	0.20
Diabetes	0.84	0.56–1.28	0.42
Dyslipidemia	1.03	0.69–1.55	0.88
Current smoker	0.97	0.64–1.46	0.87
Culprit artery with RCA	2.28	1.51–3.43	<0.0001	3.35	2.02–5.55	<0.0001
Maximum CPK-MB ≥800 U/L	2.37	1.28–4.39	0.01	2.39	1.09–5.24	0.03

CI, confidence interval; HR, hazard ratio; SCD, sudden cardiac death. Other abbreviations as in Table 1.

Figure 2.

Kaplan-Meier survival analysis for all-cause death (A), cardiac death (B), SCD (C), and SCD+VT/VF (D) during the follow-up period in patients with VT or VF occurring during hospitalization who were alive and discharged. SCD, sudden cardiac death; VF, ventricular fibrillation; VT, ventricular tachycardia.

Possible Involvement of Purkinje Fibers in VT Occurrence

The possible involvement of Purkinje fibers in the development of VT/VF in the acute phase of AMI has been reported.^14–18 Therefore, we measured the QRS duration during VT. Among 62 patients with VT during hospitalization, we identified 24 ECGs during VT (9 ECGs occurring by the end of PCI and 15 ECGs occurring after PCI), and all were analyzed by a board-certified member of the Japanese Heart Rhythm Society. The mean QRS duration of VT was 143±36 ms (Figure 3), which was comparable to that of VT originating from Purkinje fibers in one of the previous studies.¹⁸ No difference was found in mean QRS duration between VT occurring by the end of PCI and after PCI (152±42 and 137±32 ms, respectively).

Figure 3.

Mean QRS duration of ventricular tachycardia (VT).

Discussion

Incidence and Predictors of VT/VF

Previous studies have reported an incidence of VT/VF as 3.2–7.0% in the acute phase of AMI, and the following predictors: culprit artery with LMT or RCA, early hospital admission after onset, TIMI flow grade 0 before primary PCI, Killip classification II–IV, lower LVEF on admission, younger age, and a previous history of MI.^{8,10,13,19,20} The predictors associated with VT/VF in our study were comparable to those in the previous studies except for the occurrence of VT/VF before hospital admission. The incidence of VT/VF was higher in our study than in the previous studies, presumably due to differences in the inclusion and exclusion criteria. In the previous studies, patients with cardiogenic shock,⁷ isolated inferior MI,⁹ or VT/VF occurring after primary PCI were excluded,^7,8 and only the occurrence of VF was studied.^10,11

Regarding VT/VF occurring after primary PCI, previous studies reported that the incidence was 5.2% in ST-elevation MI patients, and Killip classification II–IV at hospital admission, TIMI flow grade 0 before primary PCI, and TIMI flow grade <3 after primary PCI were independent predictors associated with VT/VF.^9,21 Late VT/VF (occurring >2 days after admission) was characterized by longer time from onset to balloon, lower LVEF on admission, and greater CPK-MB value on admission compared with patients with VT/VF occurring within 2 days of hospital admission.²² LVEF on admission was an independent predictor of VT/VF occurrence >7 days after AMI onset.²³ The reason for the lower incidence of VT/VF occurrence after primary PCI in this study may be due to differences in the definition of VT. We defined VT as a wide complex tachycardia unrelated to bundle branch block at a rate >100 beats/min, which may include accelerated idiopathic ventricular rhythm.²¹ In the Assessment of Pexelizumab in Acute Myocardial Infarction (APEX-AMI) trial, the incidence of VT/VF occurrence after primary PCI was 2.0%,⁹ which was comparable to our study.

The current guideline recommends ECG monitoring for at least 24 h after symptom onset, and longer monitoring should be considered in patients with hemodynamic instability, presenting major arrhythmias, LVEF <40%, failed effective reperfusion, additional critical coronary stenosis of major vessels, or complications related to primary PCI.²⁴ Although the incidence of VT/VF occurring after primary PCI was low, our results indicated that longer ECG monitoring should be considered for high-risk patients such as those with LVEF ≤30% on admission, culprit artery with LMT, Killip classification II–IV on admission, and TIMI flow grade <3 after primary PCI.

Effect of VT/VF on In-Hospital and Mid-Term Clinical Outcomes

In the primary PCI era, the occurrence of VT/VF is associated with worse in-hospital mortality rates.^8,10,19,20 In fact, the occurrence of VT/VF is associated with a 4-fold increase in in-hospital deaths compared with patients without VT/VF,⁸ and the occurrence of VF is associated with 4–6-fold increase in in-hospital deaths, especially if VF occurred after primary PCI. Cardiogenic shock and refractory VT/VF are the major causes of in-hospital death of patients with VT/VF.²⁵ In the present study, the most common cause of in-hospital death was cardiogenic shock followed by hypoxic encephalopathy and refractory VT/VF, which suggests that the in-hospital outcome for patients with VT/VF depends on whether refractory VT/VF is complicated by cardiogenic shock or hypoxic encephalopathy under ECG monitoring and ECMO backup.

In contrast to the in-hospital outcomes, it is accepted that the occurrence of VT/VF during hospitalization does not affect clinical outcomes after hospital discharge,^7,9–11 and that VT/VF occurrence within 48 h of AMI onset is benign and patients do not require an ICD.^25,26 Indeed, in previous studies VT/VF occurrence in the catheterization laboratory did not affect the 1-year mortality rate,⁷ and VF occurrence did not affect either the 3- or 5-year mortality rate.¹⁰ VT/VF occurrence after primary PCI did not affect the 3-year mortality rate.²¹ The current guidelines do not recommend an ICD for patients within 40 days after AMI onset or 90 days after revascularization to allow for recovery from myocardial stunning even in patients with reduced LVEF or VT/VF occurrence within 48 h of AMI onset. After this period, ICD indication should be determined by the LVEF concomitantly with heart failure symptoms, presence of non-sustained VT, and VT/VF inducibility by EPS.^27–30 In our study, the incidence of SCD or VT/VF recurrence after hospital discharge was extremely low even in patients with VT/VF during hospitalization. Additionally, VT/VF occurrence during hospitalization was not significantly associated with SCD+VT/VF after hospital discharge, although reduced LVEF is considered an independent predictor associated with SCD+VT/VF. Our findings are consistent with the results of previous studies and guideline recommendations. On the other hand, ICD treatment is generally recommended for patients with VT/VF occurring over 48 h after onset.^27–29 There were only 5 survivors of VT/VF occurring >48 h after AMI onset in the present study, so further large-scale studies are required to address this issue.

EPS performed in the early phase after AMI onset is useful for risk stratification of SCD or VT/VF occurrence, and early ICD treatment is recommended in patients with inducible VT and reduced LVEF.³¹ The wearable cardioverter-defibrillator (WCD; Life Vest 4000, Zoll, Pittsburgh, PA, USA) is expected to prevent SCD due to sustained VT/VF and act as an effective bridge therapy until the indication for an ICD can be determined.³² The WCD might be a promising therapeutic choice to prevent SCD in the early phase after hospital discharge, which seems to be relatively high-risk period for SCD.

Differences Between VT and VF in Patient Characteristics and Predictors

According to the recent application of concepts derived from the theory of non-linear dynamics of wave propagation of modern mapping techniques, VF seems to be induced by either a single rapidly drifting rotor or a stationary rotor with exceedingly high excitation frequency, resulting in intermittent block in multiple areas and complex patterns of propagation. In contrast, VT is thought to result from a rotor, whose frequency of rotation is within a range that allows 1 : 1 excitation of both ventricles.³³ In the setting of AMI, VT/VF is still the leading cause of SCD in the prehospital phase, although we still do not fully understand their electrophysiologic mechanisms. There is also a lack of data examining the differences in patient characteristics and predictors between VF and VT occurring in the acute phase, and its effect on in-hospital and mid-term outcomes. Our results indicated that VT seems to be related to broad ischemia of the heart complicated with severely impaired LV function and pulmonary edema, whereas VF was not related to these factors. Although the majority of VF cases occurred by the end of PCI, those of VT occurred with the same frequency by the end of PCI as after PCI. Thus, the characteristics of VT and VF are clearly different, indicating that the mechanism of these arrhythmias is different. Further studies are needed to elucidate the mechanism of these life-threatening ventricular tachyarrhythmias occurring in the acute phase of AMI.

VF is considered to originate from focal Purkinje arrhythmogenicity at specific endocardial areas around the scar border, whereas VT often has multiple coexisting circuits surrounded by large scars in the endocardium, epicardium or deep within the myocardium, which may become substrate for VT recurrence in the long-term.¹⁷ Thus we performed additional survival analysis to examine whether these life-threatening ventricular tachyarrhythmias have different effects on the mid-term clinical outcomes after hospital discharge. Our results indicated that VT occurrence during hospitalization had no effect.

Intravenous Medications and Possible Involvement of Purkinje Fibers in VT

Previous studies have demonstrated the possible involvement of Purkinje fibers in the development of VT/VF during the acute phase of AMI,^14–17 identified by measuring the QRS duration during VT.¹⁸ The mean QRS duration of VT in our study was comparable to that in the previous study.¹⁸ In our study, 12% of patients with VT/VF required ECMO support due to refractory VT/VF despite treatment with antiarrhythmic agents, indicating that medical treatment was not sufficient to suppress refractory VT/VF in the acute phase of AMI. In fact, in patients treated with intravenous amiodarone against refractory VT/VF, recurrence occurred frequently within a few hours, and only 26% of the patients remained VT/VF recurrence-free at 48 h after amiodarone infusion.³⁴ In addition, 5 of 6 AMI patients treated with intravenous amiodarone developed refractory VT.¹⁸ One of the reasons why Purkinje network-mediated arrhythmias are refractory to intravenous amiodarone may be the weak effect of amiodarone on refractoriness of the His-Purkinje system.³⁵ Therefore, in cases of refractory VT/VF for electrical defibrillation/cardioversion and antiarrhythmic agents, sedation and ECMO support should be on hand for termination of VT/VF and hemodynamic stabilization.

Study Limitations

There are several to report. First, this was a retrospective single-center study that covered 19 years, during which time PCI devices³⁶ and antiplatelet therapies³⁷ have advanced, which may influence the incidence of VT/VF and clinical outcomes. However, interventional techniques and management of patients during hospitalization have not changed significantly, except for the use of intravenous amiodarone, which gives better survival than lidocaine³⁸ and was approved for refractory VT/VF in 2007 in Japan. The patients who were admitted to hospital before 2007 were not administered amiodarone. Second, we analyzed the data at hospital discharge, so subsequent changes in medications and laboratory data were not considered in this study. Third, missed follow-up exists due to the retrospective nature of the study, which may affect the results. Fourth, LVEF, known as the most important prognostic factor in AMI patients, was not uniformly assessed in all patients. Fifth, ECG monitoring was not performed throughout the hospitalization, so missed identification of VT/VF possibly occurred. Sixth, this study did not reveal the outcome specifically in AMI patients with VT/VF occurring >48 h from onset because of the small number of patients who were discharged from hospital. Seventh, asymptomatic VT/VF was possibly undetected during follow-up of patients without an ICD. Finally, the study population may not have been large enough, and a longer follow-up is required.

Conclusions

The treatment strategy for AMI is well-established and widespread, but our results clearly indicated that VT/VF remains a serious complication of AMI even in current clinical practice. We need to identify the patients at high risk of developing VT/VF either by the end of PCI or after PCI, and ensure careful observation and appropriate intervention for them. We also need to understand that antiarrhythmic agents are not sufficient to suppress refractory VT/VF in the acute phase of AMI because of the possible involvement of Purkinje fibers.

Acknowledgment

The authors thank Machiko Kogawa for technical support.

Disclosures

H.T. received research funding from Boehringer-Ingelheim, Bayer, Daiichi-Sankyo, and Pfizer, and Speakers’ Bureau/Honorarium from Boehringer-Ingelheim, Bayer, Daiichi-Sankyo, and Bristol-Myers Squibb. K.O. received Speakers’ Bureau/Honorarium from Johnson and Johnson, Medtronic, Daiichi-Sankyo, and Boehringer-Ingelheim. The other authors have no conflicts of interest.

IRB Information

The Ethical Committee of the Hirosaki University Graduate School of Medicine (approval no. 2020-070).

Data Availability

The deidentified participant data will not be shared.

Supplementary Files

Please find supplementary file(s);

https://doi.org/10.1253/circj.CJ-23-0023

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