Prognostic Impact of Different Types of Ventricular Tachyarrhythmias Stratified by Underlying Cardiac Disease

Limited data regarding the outcome of patients with different types of ventricular tachyarrhythmias is available. This study sought to assess the prognostic impact of different types of ventricular tachyarrhythmias stratified by underlying cardiac disease. A large retrospective registry was used including all consecutive patients presenting with ventricular tachycardia (VT) and fibrillation (VF) on admission from 2002 to 2016. Patients with non-sustained VT (ns-VT), sustained VT (s-VT) and VF were compared using uni- and multivariable Cox regression models. Risk stratification was performed after stratification by underlying cardiac disease (i.e., acute myocardial infarction (AMI), ischemic heart disease (IHD), non-ischemic cardiomyopathy (NICM) and patients considered as lower-risk for ventricular tachyarrhythmias). The primary endpoint was defined as all-cause mortality at 2.5 years. Secondary endpoints were cardiac death at 24 h, all-cause mortality at 5 years, cardiac rehospitalization and a composite arrhythmic endpoint at 2.5 years. In 2422 consecutive patients with ventricular tachyarrhythmias, most patients were admitted with VF (44%), followed by ns-VT (30%) and s-VT (26%). Patients with VF suffered most commonly from AMI (42%), whereas heart failure was more common in s-VT patients (32%). In patients with AMI (HR = 1.146; 95% CI 0.751–1.750; p = 0.527) and in the lower-risk group (HR = 1.357; 95% CI 0.702–2.625; p = 0.364), the risk of all-cause mortality did not differ in VF and s-VT patients. In IHD patients, VF was associated with impaired prognosis compared to s-VT (HR = 2.502; 95% CI 1.936–3.235; p = 0.001). In conclusion, VF was associated with worse long-term prognosis compared to s-VT in IHD patients, whereas the risk of all-cause mortality among VF and s-VT patients did not differ in patients with AMI, NICM and in patients considered at lower risk for ventricular tachyarrhythmias.


Introduction
As a consequence of preventive measures and nationwide resuscitation programs in the Western world, cardiovascular mortality has decreased within the last decades [1]. About 17 million deaths per year are still caused by cardiovascular diseases and approximately 25% are related to sudden cardiac death (SCD) [1][2][3][4]. Underlying pathologies for SCD are manifold, including most frequently coronary artery disease (CAD) and acute myocardial infarction (AMI), followed by non-ischemic cardiomyopathies (NICM) and rare causes, including electrolyte disorders, subarachnoidal haemorrhage, pulmonary embolism and idiopathic ventricular tachyarrhythmias [2,5,6]. Although heart failure with severely

Study Patients, Design and Data Collection
The present study included all patients presenting with ventricular tachyarrhythmias from 2002 until 2016 at one institution. Using the electronic hospital information system, all relevant clinical data related to the index event were documented. Further data being documented contained baseline characteristics, prior medical history, prior medical treatment, length of index stay, detailed findings of laboratory values at baseline, data derived from all non-invasive or invasive cardiac diagnostics and device therapies, such as coronary angiography, electrophysiological examination, and data being derived from prior or newly implanted cardiac devices, including already implanted at index and ICD at follow-up. Every re-visit at the out-patient clinic or leading to rehospitalization was documented when related to recurrent ventricular tachyarrhythmias and adverse cardiac events. Documentation period lasted from index event until 2016. Documentation of all medical data was performed by independent cardiologists at the time of the patients' individual period of clinical presentation, being blinded to final data analyses.
The present study is derived from an analysis of the "Registry of Malignant Arrhythmias and Sudden Cardiac Death-Influence of Diagnostics and Interventions (RACE-IT)" and represents a single-center registry including consecutive patients presenting with ventricular tachyarrhythmias and aborted cardiac arrest being acutely admitted to the University Medical Center Mannheim (UMM), Germany (clinicaltrials.gov identifier: NCT02982473) from 2002 until 2016. The registry was carried out according to the principles of the Declaration of Helsinki and was approved by the Medical Ethics Committee II of the Medical Faculty Mannheim, University of Heidelberg, Germany.
The medical center includes a general emergency department (ED) for emergency admission of traumatic, surgical, neurological and cardiovascular conditions. Interdisciplinary consultation is an inbuilt feature of this 24/7 service, and connects to a stroke unit, four intensive care units (ICU) with extracorporeal life support, and a chest pain unit (CPU) to alleviate rapid triage of patients. The cardiologic department itself includes a 24 h catheterization laboratory, an electrophysiologic laboratory, a hybrid operating room and telemetry units.

Definition of Study Groups, Inclusion and Exclusion Criteria
For the present analysis, patients presenting with ventricular tachyarrhythmias on admission were included. Ns-VT, s-VT or VF were defined according to current European guidelines [1]. S-VT was defined by duration of more than 30 s or causing hemodynamic collapse within 30 s. Ns-VT was defined by duration of less than 30 s along with wide QRS complex (≥120 milliseconds) at a rate greater than 100 beats per minute [1]. Ventricular tachyarrhythmias were documented by 12-lead echocardiogram (ECG), ECG tele-monitoring, ICD or, in case of unstable course or during resuscitation, by external defibrillator monitoring. Documented VF was treated by external defibrillation and, in case of prolonged instability, with additional intravenous anti-arrhythmic drugs during cardiopulmonary resuscitation (CPR). Patients with episodes of VT plus VF were included in the VF group, whereas patients with ns-VT plus s-VT were included in the s-VT group.
Overall exclusion criteria comprised patients without complete follow-up data regarding mortality. Each patient was counted only once for inclusion when presenting with the first episode of ventricular tachyarrhythmias. Patients without documented ventricular tachyarrhythmias were excluded.
Risk stratification for the comparisons of ns-VT, s-VT and VF was performed according to the presence of AMI, IHD, NICM, and for patients considered at "lower risk". AMI was defined as previously described according to current international guidelines [14]. ST-segment myocardial infarction (STEMI) was defined as a novel rise in the ST segment in at least two contiguous leads with ST-segment elevation ≥ 2.5 mm in men < 40 years, ≥2 mm in men ≥ 40 years, or ≥1.5 mm in women in leads V2-V3 and/or 1 mm in the other leads. Non-ST-segment myocardial infarction (NSTEMI) was defined as the presence of an acute coronary syndrome with a troponin I increase of above the 99th percentile of a healthy reference population in the absence of ST segment elevation, but persistent or transient ST segment depression, inversion or alteration of T wave, or normal ECG, in the presence of a coronary culprit lesion.
IHD group comprised patients with evidence of at least one coronary artery stenosis of at least 50% in at least one major epicardial coronary artery, or prior percutaneous coronary intervention (PCI) irrespective of the degree of LVEF in the absence of AMI [15].
The NICM group comprised patients with LVEF < 55% in the absence of CAD, valvular and congenital heart disease sufficient to cause the observed myocardial abnormality. The NICM group comprised dilated cardiomyopathy, hypertrophic (non-)obstructive cardiomyopathy, arrhythmogenic right ventricular dysplasia and non-compaction cardiomyopathy.
Finally, patients with none of the mentioned underlying cardiac disease, no evidence of channelopathy and preserved LVEF (i.e., LVEF ≥ 55%) were included in the lower-risk group.

Study Endpoints
The primary endpoint was all-cause mortality at 2.5 years of follow-up according to the median follow-up period of the study population. Secondary endpoints comprised cardiac death at 24 h, all-cause mortality at 5 years, cardiac rehospitalization at 2.5 years and a composite arrhythmic endpoint (defined as recurrent ventricular tachyarrhythmias or appropriate ICD therapy) at 2.5 years of follow-up.
For the evaluation of the primary endpoint all-cause mortality and the secondary endpoint cardiac death at 24 h and all-cause mortality at 5 years, all patients were included, whereas only patients surviving the index event and being discharged alive were included for the evaluation of the secondary endpoints of cardiac rehospitalization and the composite arrhythmic endpoint.
Overall follow-up period lasted until 2016. All-cause mortality was documented using our electronic hospital information system and by directly contacting state resident registration offices ("Bureau of Mortality Statistics") across Germany. Identification of patients was verified by name, surname, day of birth and registered living address. Lost to follow-up rate was 1.7% (n = 48) regarding survival until the end of the follow-up period.
Cardiac rehospitalization comprised rehospitalization due to recurrent VT or VF, AMI, acute heart failure, CPR and inappropriate ICD therapies. Recurrences of ventricular tachyarrhythmias and appropriate ICD therapies for the evaluation of the composite endpoint were documented reviewing ICD protocols. Device recordings were re-evaluated retrospectively by independent cardiologists being blinded to final data analysis. Appropriate ICD therapies included anti-tachycardia pacing (ATP), ICD-related shock or both ATP and shock in the presence of documented ventricular tachyarrhythmias.

Statistical Methods
Quantitative data are presented as mean ± standard error of mean (SEM), median and interquartile range (IQR), and ranges depending on the distribution of the data, and were compared using the Student's t test for normally distributed data or the Mann-Whitney U test for nonparametric data. Deviations from a Gaussian distribution were tested by the Kolmogorov-Smirnov test. Spearman's rank correlation for nonparametric data was used to test univariate correlations. Qualitative data are presented as absolute and relative frequencies and compared using the Chi 2 test or the Fisher's exact test, as appropriate.
Uni-and multivariable Cox regression models were applied for the evaluation of the primary and secondary endpoints in patients with AMI, IHD, NICM and within the lower risk group. Multivariable Cox regression models were performed for the endpoints all-cause mortality at 2.5 years and 5 years, cardiac rehospitalization and the composite endpoint. Logistic regression models were performed for the endpoint cardiac death at 24 h. Multivariable models were applied using the "foreward selection" and adjusted for the following covariables: age, sex, diabetes mellitus, chronic kidney disease (glomerular filtration rate < 60 mL/min/1.73 m 2 ), LVEF < 35%, chronic obstructive pulmonary disease (COPD), the presence of a prior AMI, coronary artery bypass grafting (CABG) and the presence of a coronary chronic total occlusion (CTO), that were demonstrated to increase the risk of long-term all-cause mortality within the present study population [16][17][18][19][20][21].
The result of a statistical test was considered significant for p < 0.05. SAS, release 9.4 (SAS Institute Inc., Cary, NC, USA) and SPSS (Version 25, IBM, Armonk, NY, USA) were used for statistics.

Study Cohort
This real-life cohort comprised a total of 2422 consecutive patients admitted with ventricular tachyarrhythmias. Most patients had episodes of VF (44%), followed by ns-VT (30%) and s-VT (26%) (Figure 1; Flow chart).

Subgroup of AMI Patients
From a total of 691 patients with AMI, most patients had episodes of VF (64%), fol-

Subgroup of AMI Patients
From a total of 691 patients with AMI, most patients had episodes of VF (64%), followed by ns-VT (35%) and s-VT (13%). At 2.5 years, the primary endpoint all-cause mortality occurred in 64% of patients with s-VT, 51% in VF and 31% of patients admitted with ns-VT. Accordingly, the risk of all-cause mortality at 2. Finally, the risk of cardiac rehospitalization was not affected by the type of index arrhythmia after multivariable adjustment.

Subgroup of Patients with IHD
Within the IHD group, most patients were admitted with episodes of s-VT (35%), followed by ns-VT (33%) and s-VT (32%). At 2.5 years, the primary endpoint all-cause mortality occurred in 58% in patients with VF, 31% with s-VT and 28% with ns-VT. Accordingly, the risk of all-cause mortality at 2.5 years (HR = 2.502; 95% CI 1.936-3.235; p = 0.001), 24 h (OR = 4.169; 95% CI 2.535-6.854; p = 0.001) and 5 years (HR = 1.990; 95% CI 1.582-2.504; p = 0.001) was increased in VF compared to s-VT patients within univariable risk prediction models (Figure 4). On the other hand, the risk of all-cause mortality at 2.5 years (HR = 1.178; 95% CI 0.873-1.591; p = 0.284) and 5 years (HR = 1.162; 95% CI 0.901-1.497; p = 0.247) did not differ among s-VT and ns-VT patients, whereas the risk of cardiac death at 24 h was increased in s-VT patients (OR = 2.348; 1.102-5.003; p = 0.027). Further- Figure 3. Forest plots demonstrating the uni-and multivariable hazard ratios (HR) with 95% confidence intervals (CI) for the primary endpoint all-cause mortality at 2.5 years, as well as for secondary endpoints all-cause mortality at 24 h, all-cause mortality at 5 years, the composite arrhythmic endpoint (i.e., recurrent ventricular tachyarrhythmias, appropriate ICD therapies) at 2.5 years and cardiac rehospitalization at 2.5 years in AMI patients. Multivariable models were adjusted for age, sex, diabetes, chronic kidney disease, LVEF < 35%, COPD, the presence of a prior AMI, CABG and the presence of a CTO. HRs with corresponding 95% CI were calculated for the comparisons of patients with VF compared to s-VT, s-VT versus ns-VT and ns-VT versus s-VT and VF.
After multivariable adjustment, the risk of all-cause mortality at 2.5 years (HR = 2.002; 95% CI 1.475-2.717; p = 0.001), cardiac death at 24 h (OR = 2.365; 95% CI 1.298-4.310; p = 0.005) and all-cause mortality at 5 years (HR = 1.573 (1.198-2.065; p = 0.001) was still increased in VF compared to s-VT patients. In line with this, the risk of cardiac death at 24 h was still higher in s-VT compared to ns-VT (OR = 4.023; 95% CI 1.021-5.907; p = 0.045), whereas long-term mortality at 2.5 years (HR = 1.193; 95% CI 0.851-1.674; p = 0.306) and 5 years (HR = 1.244; 95% CI 0.937-1.653; p = 0.131) did not differ among patients with s-VT or ns-VT ( Figure 4). Furthermore, the risk of the composite arrhythmic endpoint did not differ within patients with VF, s-VT or ns-VT. However, patients with ns-VT were associated with the highest risk of cardiac rehospitalization at 2.5 years (HR = 1.524; 95% CI 1.038-2.237; p = 0.031).  . Forest plots demonstrating the uni-and multivariable hazard ratios (HR) with 95% confidence intervals (CI) for the primary endpoint all-cause mortality at 2.5 years, as well as for secondary endpoints all-cause mortality at 24 h, all-cause mortality at 5 years, the composite arrhythmic endpoint (i.e., recurrent ventricular tachyarrhythmias, appropriate ICD therapies) at 2.5 years and cardiac rehospitalization at 2.5 years in IHD patients. Multivariable models were adjusted for age, sex, diabetes, chronic kidney disease, LVEF < 35%, COPD, the presence of a prior AMI, CABG and the presence of a CTO. HRs with corresponding 95% CI were calculated for the comparisons of patients with VF compared to s-VT, s-VT versus ns-VT and ns-VT versus s-VT and VF.
After multivariable adjustment, the risk of the composite endpoint (HR = 2.495; 95% CI 1.131-5.506; p = 0.024) was still higher in s-VT compared to ns-VT patients, whereas the risk of cardiac rehospitalization did not reach statistical significance (HR = 2.467; 95% CI 0.849-7.168; p = 0.097). Forest plots demonstrating the uni-and multivariable hazard ratios (HR) with 95% confidence intervals (CI) for the primary endpoint all-cause mortality at 2.5 years, as well as for secondary endpoints all-cause mortality at 24 h, all-cause mortality at 5 years, the composite arrhythmic endpoint (i.e., recurrent ventricular tachyarrhythmias, appropriate ICD therapies) at 2.5 years and cardiac rehospitalization at 2.5 years in IHD patients. Multivariable models were adjusted for age, sex, diabetes, chronic kidney disease, LVEF < 35%, COPD, the presence of a prior AMI, CABG and the presence of a CTO. HRs with corresponding 95% CI were calculated for the comparisons of patients with VF compared to s-VT, s-VT versus ns-VT and ns-VT versus s-VT and VF.

Figure 5.
Forest plots demonstrating the uni-and multivariable hazard ratios (HR) with 95% confidence intervals (CI) for the primary endpoint all-cause mortality at 2.5 years, as well as for Figure 5. Forest plots demonstrating the uni-and multivariable hazard ratios (HR) with 95% confidence intervals (CI) for the primary endpoint all-cause mortality at 2.5 years, as well as for secondary endpoints all-cause mortality at 24 h, all-cause mortality at 5 years, the composite arrhythmic endpoint (i.e., recurrent ventricular tachyarrhythmias, appropriate ICD therapies) at 2.5 years and cardiac rehospitalization at 2.5 years in NICM patients. Multivariable models were adjusted for age, sex, diabetes, chronic kidney disease, LVEF < 35% and COPD. HRs with corresponding 95% CI were calculated for the comparisons of patients with VF compared to s-VT, s-VT versus ns-VT and ns-VT versus s-VT and VF.
Even after multivariable adjustment, s-VT was associated with increased risk of allcause mortality at 2.5 years (HR = 3.845; 95% CI 1.763-8.389; p = 0.001), cardiac death at 24 h (OR = 32.767; 95% CI 3.426-313.352; p = 0.002) and all-cause mortality at 5 years (HR = 3.850; 95% CI 1.818-8.155; p = 0.001). Figure 6. Forest plots demonstrating the uni-and multivariable hazard ratios (HR) with 95% confidence intervals (CI) for the primary endpoint all-cause mortality at 2.5 years, as well as for secondary endpoints all-cause mortality at 24 h, all-cause mortality at 5 years, the composite arrhythmic endpoint (i.e., recurrent ventricular tachyarrhythmias, appropriate ICD therapies) at 2.5 years and cardiac rehospitalization at 2.5 years in patients considered at lower risk. Multivariable models were adjusted for age, sex, diabetes, chronic kidney disease and COPD. HRs with corresponding 95% CI were calculated for the comparisons of patients with VF compared to s-VT, s-VT versus ns-VT and ns-VT versus s-VT and VF. Figure 6. Forest plots demonstrating the uni-and multivariable hazard ratios (HR) with 95% confidence intervals (CI) for the primary endpoint all-cause mortality at 2.5 years, as well as for secondary endpoints all-cause mortality at 24 h, all-cause mortality at 5 years, the composite arrhythmic endpoint (i.e., recurrent ventricular tachyarrhythmias, appropriate ICD therapies) at 2.5 years and cardiac rehospitalization at 2.5 years in patients considered at lower risk. Multivariable models were adjusted for age, sex, diabetes, chronic kidney disease and COPD. HRs with corresponding 95% CI were calculated for the comparisons of patients with VF compared to s-VT, s-VT versus ns-VT and ns-VT versus s-VT and VF.

Discussion
The present study aims to evaluate the characteristics of patients with different types of ventricular tachyarrhythmias (i.e., ns-VT, s-VT or VF) stratified by underlying cardiac diseases including a total of 2422 consecutive patients admitted with ventricular tachyarrhythmias. The following were the main findings of the study: 1.
VF was shown to be the most common type of ventricular tachyarrhythmias in patients admitted with AMI and patients considered at lower risk for ventricular tachyarrhythmias, whereas s-VT was more frequently observed in patients with IHD.

2.
In patients with AMI and in patients considered at lower risk for ventricular tachyarrhythmias, s-VT and VF were associated with comparable risk of all-cause mortality, whereas s-VT was associated with impaired prognosis compared to ns-VT.

3.
Patients admitted with VF showed a higher risk of all-cause mortality compared to s-VT within IHD patients, whereas the risk of long-term mortality was comparable in s-VT and ns-VT.

4.
The type of index arrhythmia had no impact on long-term mortality in patients with NICM.
Studies investigating the prevalence and prognostic impact of ventricular tachyarrhythmias are heterogenous and usually rely on pre-selected study populations [1,22]. Data are derived either from patient cohorts suffering from acute coronary syndrome, cardiogenic shock or cardiac arrest [23][24][25][26], or focus only on patients undergoing coronary angiography or implantation of an ICD [25,[27][28][29]. There are also large reports based on nationwide statistical reports by health institutes, which focus more on broad disease groups, such as cardiac death, but do not allow further discrimination into underlying different types of ventricular tachyarrhythmias, exact comorbidities, or cardiac therapies and interventions [2,30], which represents a strength of the present study.
Ventricular tachyarrhythmias were reported to occur in approximately 8% of AMI patients [31]. However, despite earlier door-to-balloon times, an improved nationwide health-care supply and better revascularization strategies, the incidence of AMI-related ventricular arrhythmias has decreased [32,33]. AMI-related ventricular arrhythmias may result from zones of slow conduction and block leading to re-entry, or by focal triggers as a consequence of high sympathetic tone and mechanical stretching [34,35]; however, studies investigating the prognostic role of different types of ventricular tachyarrhythmias are scarce. The present study showed comparable risk of all-cause mortality in patients with s-VT and VF, along with an increased risk of the composite arrhythmic endpoint in s-VT, which may be related to an increased concomitant scar burden in patients with s-VT. Thus, specifically re-entry was shown to be a typical mechanism in patients with increased scar burden. Although only a minor part of the study population underwent cardiac magnet resonance tomography, we tried to adjust for the extent of scar burden by adjusting multivariable risk prediction models for the presence of prior AMI, CABG and CTO in patients with AMI and IHD.
Despite the risk of degeneration into VF, patients with VT and VF are often grouped together, although it was demonstrated that baseline characteristics of patients with VT and VF differ [36]. Thus, it was demonstrated that mean LVEF is typically lower in patients with VT [37,38], whereas higher rates of AMI were reported in VF patients [37]. These findings are in line with the present study, where increased rates of concomitant AMI were observed in VF patients and LVEF < 35% was most common in s-VT. However, studies focusing on ventricular tachyarrhythmias were predominantly published in the last century [37,38]. By now, the treatment of patients with cardiovascular disease has significantly improved, leading to increased rates of ICD implantation, higher supply with cardiovascular drugs and improved coronary revascularization strategies [39]. Along with this, patients' characteristics have significantly changed, leading to an older study population with an increased proportion of multi-morbid patients. Therefore, European guidelines state the need to re-evaluate treatment strategies for patients at increased risk of SCD in the current medicine era [7]. In line with this, more than two out of three patients had an ICD in the s-VT group in the present study, whereas ICD implantation rate was lower in VF, presumably as a consequence of a higher rate of reversible causes, such as AMI in patients admitted with VF.
There are few studies available focusing on arrhythmia recurrences related to the type of index tachyarrhythmia. A sub-study of the AVID trial found increased risk for appropriate ICD therapies in patients with VT compared to VF at 31 months of followup [36]. In line with this, the present study found the highest risk of recurrent ventricular tachyarrhythmias in patients with s-VT in the subgroup of patients with AMI and NICM, which may be related to an increased arrhythmogenic substrate and scar-related re-entry, and a lower rate of reversible causes of ventricular tachyarrhythmias [10,40].
This study has several limitations. This observational and retrospective registry-based analysis reflects a realistic picture of consecutive health-care supply of high-risk patients presenting with ventricular tachyarrhythmias. The lost to follow-up rate regarding the evaluated endpoint of all-cause mortality was minimal. Patients not surviving out of hospital CPR and not being transferred to the heart center were not included in this study. The proportion of patients with slow VT and polymorphic VT was too small (<3%) to merit a separate sub-analysis. Due to the single-center design of the study, rehospitalization rates, recurrent ventricular tachyarrhythmias, as well as appropriate ICD therapies, were documented at one institution only. Only a minor part of the study population underwent cardiac magnet resonance imaging; therefore, no adjustment for scar burden was performed. In line with this, the presence of prior AMI, CABG and CTO were used as surrogate parameters for scar burden in the AMI and IHD group. Since heart transplantation is not performed at our institution, the number of patients undergoing heart transplantation during follow-up was not assessed for the present study.
In conclusion, the present study suggested that higher rates of AMI and out-of-hospital cardiac arrest were observed in patients with VF, whereas s-VT patients presented with higher rates of prior heart failure and lower LVEF on admission. At 2.5 years, VF was associated with the highest risk of all-cause mortality in patients with IHD, whereas s-VT and VF were associated with comparable prognosis in patients with AMI and in patients considered as the lower-risk group.