heart failure...pmk cardiology review cardiac implantable electronic device heart failure 1 นพ....

PMK Cardiology ReviewPMK Cardiology Review

Cardiac Implantable Electronic Device Heart Failure

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นพ. ธรณิศ จันทรารัตน์ รพ พระมงกุฎเกล้า


Scope of presentation

• Impact of Problem

• Mechanism of SCD- Ventricular arrhythmia

• Prevention according to guidelines

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Pathophysiology-Structure

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Arrhythmogenic substrate priorto the index eventMost patients survive their first ACS. Owing to progression of ar-teriosclerosis, a second acute event will often occur despitemaximal preventive therapy. Patients who suffer from an acute cor-onary event with pre-existing reduced LV function and myocardial

scars are at risk for sustained VA in the acute and sub-acute phaseof a MI. Echocardiographic signs of markedly reduced LV functionor ECG signs of an old MI can identify such patients. Furthermore,patients with increased sympathetic activity, or taken to theextreme of cardiogenic shock, are at increased risk of sustained VAin the setting of a ‘recurrent’ acute coronary event. Recent evidence

Inherited cardiomyopathies:

Long QT,short QT,WPW,Brugada,ARVC,HCM,DCM

Common genetic variants

Prior infarct

Pre-existing myocardial damage

Acuteischaemia

Autonomicimbalance

Acute strain

VT

VF

Cellular and tissueproarrhythmia

-scar-focal fibrosis-hypertrophy

-altered ion homeostasis-loss of intercellular connection

Leading to focal electrical activityconduction disturbance

II

V1

Figure1 Schemeofdrivers forarrhythmias in acute coronary syndromes.Apre-existing substrate for ventriculararrhythmias, either secondary toan old myocardial infarction, due to a cardiomyopathy, or secondary to a genetic predisposition to ventricular arrhythmias, interacts with acute is-chaemia, autonomic tone, and acute left ventricular strain to create triggered activity and ventricular arrhythmias.4 ARVC, arrhythmogenic right ven-tricular cardiomyopathy; DCM, dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy; VF, ventricular fibrillation; VT, ventriculartachycardia; WPW, Wolf-Parkinson-White syndrome (Adapted from Heart, Kirchhof P, Breithardt G, Eckardt L. Primary prevention of suddencardiac death, 92, 1873–8, Copyright 2006, with permission from BMJ Publishing Group Ltd and from J Cardiovasc Pathol, 19, Basso C, Rizzo S,Thiene G. The metamorphosis of myocardial infarction following coronary recanalization, 22–8, Copyright 2010, with permission from Elsevier).

Cardiac arrhythmias in acute coronary syndromes 1657

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Dilated Cardiomyopathy

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Personalizing Risk Stratification in DCM

STATE OF THE ART

Circulation. 2017;136:215–231. DOI: 10.1161/CIRCULATIONAHA.116.027134 July 11, 2017 225

Figure 3. Detecting myocardial fibrosis using cardiovascular magnetic resonance. This figure demonstrates the acquired and genetic insults implicated in the pathogenesis of dilated cardiomyopathy (DCM) followed by the common genetic mutations associated with DCM (incidence of mutations in cases of idiopathic DCM followed by the protein encoded by the gene2) and data on disease outcomes. Abs indicates antibodies; LVRR, left ventricular reverse remodeling; phaeo, phaeochromocytoma; and SCD indicates sudden cardiac death.

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Genome


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Arrhythmogenic substrate priorto the index eventMost patients survive their first ACS. Owing to progression of ar-teriosclerosis, a second acute event will often occur despitemaximal preventive therapy. Patients who suffer from an acute cor-onary event with pre-existing reduced LV function and myocardial

scars are at risk for sustained VA in the acute and sub-acute phaseof a MI. Echocardiographic signs of markedly reduced LV functionor ECG signs of an old MI can identify such patients. Furthermore,patients with increased sympathetic activity, or taken to theextreme of cardiogenic shock, are at increased risk of sustained VAin the setting of a ‘recurrent’ acute coronary event. Recent evidence

Inherited cardiomyopathies:

Long QT,short QT,WPW,Brugada,ARVC,HCM,DCM

Common genetic variants

Prior infarct

Pre-existing myocardial damage

Acuteischaemia

Autonomicimbalance

Acute strain

VT

VF

Cellular and tissueproarrhythmia

-scar-focal fibrosis-hypertrophy

-altered ion homeostasis-loss of intercellular connection

Leading to focal electrical activityconduction disturbance

II

V1

Figure1 Schemeofdrivers forarrhythmias in acute coronary syndromes.Apre-existing substrate for ventriculararrhythmias, either secondary toan old myocardial infarction, due to a cardiomyopathy, or secondary to a genetic predisposition to ventricular arrhythmias, interacts with acute is-chaemia, autonomic tone, and acute left ventricular strain to create triggered activity and ventricular arrhythmias.4 ARVC, arrhythmogenic right ven-tricular cardiomyopathy; DCM, dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy; VF, ventricular fibrillation; VT, ventriculartachycardia; WPW, Wolf-Parkinson-White syndrome (Adapted from Heart, Kirchhof P, Breithardt G, Eckardt L. Primary prevention of suddencardiac death, 92, 1873–8, Copyright 2006, with permission from BMJ Publishing Group Ltd and from J Cardiovasc Pathol, 19, Basso C, Rizzo S,Thiene G. The metamorphosis of myocardial infarction following coronary recanalization, 22–8, Copyright 2010, with permission from Elsevier).

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Electrical Instability

Pathophysiology-Drivers


Pathophysiology

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therapy. Thus, not all mechanisms of HF diseaseregression, and the therapeutic interventions thatproduce them, can reduce the burden of VAs.Although ablation may not offer a survival benefit,selected cases may require catheter ablation forelimination of VA. More bedside-to-bench research isrequired to identify the individual patient’s substratefor the genesis of VAs and the personalized therapiesthat could reduce the risk of sudden cardiac death inthe A-HF patient.

MECHANISMS: VAs AS A BASIS OF

DISEASE PROGRESSION IN HF

Given the overlapping mechanisms of disease pro-gression and arrhythmogenesis, with respect todevelopment of arrhythmia triggers and substrate, itis not surprising that VAs are frequent in the moreadvanced cardiomyopathic stage. A cycle of HF dis-ease progression, marked by maladaptive hypertro-phic, fibrotic myocardial remodeling, andmechanical/bioenergetic inefficiency, with orwithout dyssynchronous contraction, includes thepotential for generating and maintaining the wholespectrum of VAs (frequent ventricular prematuredepolarizations, couplets, nonsustained VT, sus-tained VT, or VF). In turn, these VAs may play an

important role in enhancing the maladaptiveneurohormonal and metabolic reprogramming thatmakes HF patients “sicker,” increasing the risk ofhemodynamic decompensation over time (Figure 1).In the COMPANION study of patients with ambula-tory advanced NYHA functional class III/IV HF, thepresence of an appropriate shock for sustained VAswas associated, not only with a significant increasein sudden cardiac death (odds ratio [OR]: 2.97;p ¼ 0.03), but also with a significant increase inadjudicated pump failure death or hospitalization(OR: 2.45; p < 0.0001) (5). In this study, the eventrate of pump failure death or hospitalization due toHF reached almost 50% at 1 year in the subset ofpatients who received appropriate defibrillation forVAs. These results raise the question of whetherappropriate ICD shocks constituted a “marker” ofdisease progression in HF or whether the shocktherapy itself was a potential cause of worseningpump failure. In the landmark ALTITUDE Survival byRhythm Study, the question was answered with themortality risk of appropriate shock being associatedwith the underlying rhythm (monomorphic VT OR:1.65; p < 0.0001; VF/polymorphic VT OR: 2.10;p < 0.0001) and no increased mortality risk aftershocks due to sinus tachycardia or noise/artifact(OR: 0.97; p ¼ 0.76) (32). The specific mechanisms by

FIGURE 1 Schema Illustrating the Pathophysiological Cycle of VAs in A-HF

• Myocardial Adverse Remodeling• Hemodynamic decompensation with peripheral hypoperfusion• “Peripheral” Metabolic adaptation• Systemic Insulin Resistance

ACC/AHAStage

Heart Failure Disease Progression

• Dyssynchronous myocardium (RV + LV)• Mechanical / Bioenergetic Uncoupling• Myocardial (“central”) Metabolic Adaptation –shift back to lipids/ketones

• Myocardial Fibrosis• Progression of Arrhythmogenic Substrate• Electrical Remodeling (Connexin 43, Ca++

cycling/NCX, QT, QRS prolongation)• Increased “triggers” (neurohormonal activation, metabolic dysregulation)

Pathophysiological Cycle of Ventricular Arrhythmias and Progressive Pump Failure

B C D

A-HF ¼ advanced heart failure; ACC ¼ American College of Cardiology; AHA ¼ American Heart Association; LV ¼ left ventricle; RV ¼ rightventricle; VA ¼ ventricular arrhythmia.

Santangeli et al. J A C C V O L . 6 9 , N O . 1 4 , 2 0 1 7

Management of VT in Advanced HF A P R I L 1 1 , 2 0 1 7 : 1 8 4 2 – 6 0

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Downloaded for Anonymous User (n/a) at Mahidol University from ClinicalKey.com by Elsevier on August 05, 2017.For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved.

Structural Electrical

Neurohormonal


Arrhythmogenesis

• changes in electrical, structural,neurohormonal

• Remodelling ( Maladaptive) processes and arrhythmogenic events

»-renin angiotensin aldosterone system (RAAS),»-beta-adrenergic pathway, »-Ca-Calmodulin-dependent kinase II (CaMKII)- »-calcineurin-mediated signalling

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Ionic/Electrical change• potassium (K) channels

• sarcolemmal Na/Ca exchanger

• Ca-stored intracellularly in the sarcoplasmic reticulum (SR) and Ca turnover

• late Na current and transient outward current (Ito)

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Ca-Mechanism

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Late I Na Mechanism

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Late I Na

Na/Ca exchanger

Na CaNa/Ca

exchanger

CaDADPVC PAC


Triggers

• The ‘external’ triggers of arrhythmias

• mechanical stretch (volume)

• neurohumoral activation

• stressors (e.g. systemic inflammation)

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Phase of LV injury

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such as an increased late Na current and a reduced transient out-ward current (Ito). The microdomain of the calcium-release channelof the SR (ryanodine receptor) is altered. This further prolongs anddestabilizes the AP, leading to heterogeneities in APs between ven-tricular regions, which will favour re-entrant arrhythmias. The Catransient is severely reduced in amplitude and increased in duration.Moreover, there is an increased diastolic Ca concentration, whichlimits performance further.

In the whole heart, the normal cavity wall thickness ratio is nolonger present (dilatation). Conduction is further slowed, interstitialfibrosis more dominantly present, energetics reduced with mito-chondrial dysfunction, increased oxygen stress, and apoptosis: allfactors reinforcing the negative turns. Additionally, these changesin chamber geometry and altered activation patterns facilitate thepathogenesis of complex arrhythmias.

In summary, arrhythmias in HF are a consequence of alteredcardiomyocyte properties and myocardial tissue composition inHF facilitates sustained arrhythmias.

Detection of arrhythmiasRhythm evaluation in HF aims to: (i) establish diagnosis and monitorpatients with suspected arrhythmia-related symptoms, (ii) assess therisk of SCD or arterial embolism, and (iii) identify asymptomatic (‘si-lent’) arrhythmias that may contribute to the progression of LVdysfunction.138,139

Palpitations or syncope raise the suspicion for paroxysmal ar-rhythmias, but patients may present with less specific symptoms.140

Arrhythmias are common in HF and should be considered as a trig-ger of clinical deterioration. However, recorded rhythm abnormal-ities need to be correlated with concurrent symptoms. Broadcomplex tachycardia in HF patients should be managed as VT inthe absence of convincing evidence for aberrant conduction of a su-praventricular rhythm.141 Sustained VTs (30 s) are rarely asymp-tomatic in HF patients, and the diagnostic approach is guided bythe presence of symptoms and degree of structural heart disease.As in general, arrhythmias are very common in HF patients, theaim for rhythm monitoring and its value for the managementdepends on the clinical condition (Table 2).

In patients with advanced HF (EF ,35%), NSVTs are very com-mon on 24 h ambulatory ECGs (60–80% of patients), but not inde-pendently associated with worse outcomes.142,143 In HF patientswith less severely reduced EF (35–50%), NSVTs may indicate an in-creased risk,144 but at present there is no evidence that suppressionof NSVTs improves prognosis.

The role of rhythm monitoring in HF-pEF patients has not beenestablished. Therefore, routine ambulatory screening for VAs inHF patients without related symptoms is not recommended. Fol-lowing acute MI, the incidence of both AF and VAs is increased. Inthe CARISMA study, continuous arrhythmia monitoring by animplantable loop recorder in patients with reduced EF (,40%)for 2 years following acute MI detected potentially relevant arrhyth-mias in 46% of all patients, which were mostly (86%) asymptomat-ic,80 suggesting a potential benefit of closer rhythm monitoring inpatients following acute MI.

Initiating event:

Compensated

Temporarilycompensated

Decompensated

Decompensated

Time

Arrhythmias

Cardiacoutput

Acute MI, valve abnormality,toxin, virus etc.

Figure 1 Arrhythmogenesis during the transition to chronic heart failure.

EHRA/HFA joint consensus document on arrhythmias in heart failure 19


Risk Stratification Technique

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Halliday et al

July 11, 2017 Circulation. 2017;136:215–231. DOI: 10.1161/CIRCULATIONAHA.116.027134218

for those with a life expectancy <1 year.12,13 The risk of death from nonsudden causes is especially relevant in older patients and in those with more comorbidities. In planned subgroup analysis of the DANISH trial, patients >68 years of age had a trend toward increased mortali-ty with ICD implantation (HR, 1.19; 95% CI, 0.81–1.73; P=0.38), in contrast to patients <59 years of age who had a lower mortality with an ICD (HR, 0.51; 95% CI, 0.29–0.92; P=0.02).7 In addition, a meta-analysis of tri-als of primary prevention ICDs in ischemic and nonisch-emic HF demonstrated the absence of survival benefit in patients with an estimated glomerular filtration rate of <60 mL·min−1·1.73 m−2.23 This highlights the role that age and measures of kidney function may have in iden-tifying patients who are unlikely to gain benefit from ICD implantation.

Risk scores such as the Seattle Heart Failure Model have been developed to predict prognosis in patients with HF, incorporating variables such as NYHA class and prescription of medical therapies with age and kidney function.24 The Seattle model has been shown to be more accurate in the stratification of the risk of nonsudden death compared with SCD in populations with ischemic and nonischemic HF.25 For example, pa-tients with a score of 3 and 4 compared with those with a score of 0 have a relative risk of HF death of 38.4 and 87.6 and a relative risk of SCD of only 6.5 and 6.5, respectively. This highlights that although the risk of SCD rises with worsening HF, the rise in the risk of HF death is even greater, reducing the chances of

gaining quality-adjusted life-years from ICD therapy. Although similar models have been developed for the prediction of SCD in HF populations and the wider general population, they are limited by an inability to reliably discriminate between the risk of SCD and nonsudden death and therefore have limited clinical utility.26–28

There is growing interest in the use of circulating biomarkers of myocardial stress and fibrosis such as natriuretic peptides, troponin, galectin-3, and soluble ST2 to predict prognosis. However, these biomarkers generally reflect the severity of cardiac dysfunction rather the specific risk of SCD. They may be used to identify patients who are unlikely to benefit from ICD therapy because of a high risk of death resulting from the progression of HF. In prespecified subgroup analy-sis of DANISH, patients with a N-terminal pro-B-type natriuretic peptide >1177pg/mL randomized to ICD therapy had an all-cause mortality similar to that of those in the control arm (HR, 0.99; 95% CI, 0.73–1.36; P=0.96), whereas mortality was lower in those assigned to an ICD when N-terminal pro-B-type natriuretic pep-tide was <1177pg/mL (HR, 0.59; 95% CI, 0.38–0.91; P=0.02).7 Similarly, Ahmad and colleagues29 demon-strated a stronger association between N-terminal pro-B-type natriuretic peptide, galectin-3, and soluble ST2 and HF death compared with SCD in patients with ischemic and nonischemic HF. In summary, biomarkers, in combination with clinical variables and prognostic scores, offer the most potential for the identification

Figure 1. Flowchart of the potential techniques that may be used to improve risk stratification. Also shown are the main characteristics of the condition assessed by each technique and the interaction of these characteris-tics with the risk of either sudden cardiac death or nonsudden death. LGE-CMR indicates late gadolinium–enhanced cardio-vascular magnetic resonance; MIBG, metaiodobenzylguanidine; MTWA, microvolt T-wave alternans; NYHA, New York Heart Association; SCD, sudden cardiac death; and SHFM, Seattle Heart Failure Model.

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Electrical Markers for VA

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STATE OF THE ART


of patients with an excessively high risk of death result-ing from competing causes who are thus unlikely to benefit from ICD therapy. The threshold at which the risk of death from competing causes outweighs the risk of SCD and the benefit from ICD therapy becomes un-likely is not clear.

MARKERS OF ELECTRIC INSTABILITY AND SCD RISKMany studies have evaluated the ability of electric mea-surements to predict the risk of SCD in DCM.30 These have included ECG findings such as QRS duration, QRS fragmentation, microvolt T-wave alternans (MTWA), left bundle-branch block, and late potentials on signal averaging; markers of autonomic tone, including baro-reflex sensitivity, heart rate variability, and heart rate turbulence; and ventricular ectopy and nonsustained VT on monitoring or after programmed stimulation. The results of these, often small, studies have been in-consistent, and their combined utility is limited by the use of different end points.30

A large meta-analysis combined 45 studies including 6088 patients with nonischemic DCM in an attempt to summarize existing data.30 When available, arrhythmic end points, including SCD, ventricular arrhythmia, or ap-propriate ICD discharge, were used; all-cause mortality was used as an alternative when they were not avail-able. Although interstudy reproducibility was poor for the majority of variables, the authors concluded that the most promising for the prediction of adverse events were QRS complex fragmentation (odds ratio [OR], 6.73; 95% CI, 3.85–11.76; P<0.001) and the presence of MTWA (OR, 4.66; 95% CI, 2.55–8.53; P<0.001). The ORs for the majority of the remaining parameters were between 1.5 and 3.0, suggesting lower predictive value (Table 2).

Although the small number of studies limits the abil-ity to interpret the predictive ability of QRS fragmen-tation, a large number of studies support the poten-tial of MTWA, and a meta-analysis of patients with nonischemic DCM31 has corroborated the findings of Goldberger and colleagues.30 A study in a mixed isch-emic and nonischemic population has suggested that the presence of MTWA may be a stronger predictor of arrhythmia when present in patients taking β-blockers (patients on β-blockers: HR, 5.39; 95% CI, 2.68–10.84; P<0.001; entire population: HR, 1.95; 95% CI, 1.29–2.96; P=0.002).32 Others have emphasized the negative predictive value of a negative MTWA test33; however, it should be noted that even a coin toss has a high nega-tive predictive value when the event rate is low.34 Hohn-loser and Cohen35 have proposed the use of MTWA testing to select patients with an LVEF <35% who are unlikely to benefit from ICD implantation, but this has not been validated.

ECHOCARDIOGRAPHYEchocardiography is the first-line imaging investigation in the workup of patients with DCM. Use of echocar-diography measurements to predict arrhythmic events is therefore an attractive concept. The ability of global longitudinal strain and mechanical dispersion, a mea-sure of mechanical dyssynchrony, to predict sustained ventricular arrhythmia or SCD was investigated in 94 patients with nonischemic DCM over 22 months by Haugaa and colleagues.36 They found that both mea-sures independently predicted the major arrhythmic end point (per 1% increase in strain: HR, 1.26; 95% CI, 1.03–1.54; P=0.02; per 10-millisecond increase in mechanical dispersion: HR, 1.20; 95% CI, 1.03–1.40; P=0.02). They also demonstrated that both variables had larger areas under the curve on receiver-operating

Table 2. Electrophysiological Parameters and Their Ability to Predict Adverse Arrhythmic Events

Category Parameter Studies, nOutcome Events/

Patients, n (%)OR

(95% CI)

Positive Predictive

Value, %

Negative Predictive

Value, % P Value

Autonomic Baroreflex sensitivity 2 48/359 (13.4) 1.98 (0.60–6.59) 16.3 89.9 0.23

Heart rate turbulence 3 66/434 (15.2) 2.57 (0.64–10.36) 22.1 88.1 0.16

Heart rate variability 4 83/630 (13.2) 1.72 (0.80–3.73) 16.9 89.7 0.13

Surface electric QRS duration and left bundle-branch block 10 262/1797 (14.6) 1.51 (1.13–2.01) 18.5 87.6 0.01

Fragmented QRS 2 65/652 (10.0) 6.73 (3.85–11.76) 24.0 94.8 <0.001

Positive signal-averaged electrocardiogram 10 152/1119 (13.6) 2.11 (1.18–3.78) 18.9 89.5 0.017

T-wave alternans 12 177/1631 (10.9) 4.66 (2.55–8.53) 14.8 97.0 <0.001

QRS-T angle 1 97/455 (21.3) 2.01 (1.22–3.31) 25.4 85.5 0.006

Arrhythmia Positive electrophysiological study 15 146/936 (15.6) 2.49 (1.40–4.40) 29.2 86.9 0.004

Nonsustained ventricular tachycardia 18 403/2746 (14.7) 2.92 (2.17–3.93) 20.7 90.3 <0.001

CI indicates confidence interval; and OR, odds ratio. Adapted from Goldberger et al30 with permission from the publisher. Copyright © 2014, Elsevier..

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of patients with an excessively high risk of death result-ing from competing causes who are thus unlikely to benefit from ICD therapy. The threshold at which the risk of death from competing causes outweighs the risk of SCD and the benefit from ICD therapy becomes un-likely is not clear.

MARKERS OF ELECTRIC INSTABILITY AND SCD RISKMany studies have evaluated the ability of electric mea-surements to predict the risk of SCD in DCM.30 These have included ECG findings such as QRS duration, QRS fragmentation, microvolt T-wave alternans (MTWA), left bundle-branch block, and late potentials on signal averaging; markers of autonomic tone, including baro-reflex sensitivity, heart rate variability, and heart rate turbulence; and ventricular ectopy and nonsustained VT on monitoring or after programmed stimulation. The results of these, often small, studies have been in-consistent, and their combined utility is limited by the use of different end points.30

A large meta-analysis combined 45 studies including 6088 patients with nonischemic DCM in an attempt to summarize existing data.30 When available, arrhythmic end points, including SCD, ventricular arrhythmia, or ap-propriate ICD discharge, were used; all-cause mortality was used as an alternative when they were not avail-able. Although interstudy reproducibility was poor for the majority of variables, the authors concluded that the most promising for the prediction of adverse events were QRS complex fragmentation (odds ratio [OR], 6.73; 95% CI, 3.85–11.76; P<0.001) and the presence of MTWA (OR, 4.66; 95% CI, 2.55–8.53; P<0.001). The ORs for the majority of the remaining parameters were between 1.5 and 3.0, suggesting lower predictive value (Table 2).

Although the small number of studies limits the abil-ity to interpret the predictive ability of QRS fragmen-tation, a large number of studies support the poten-tial of MTWA, and a meta-analysis of patients with nonischemic DCM31 has corroborated the findings of Goldberger and colleagues.30 A study in a mixed isch-emic and nonischemic population has suggested that the presence of MTWA may be a stronger predictor of arrhythmia when present in patients taking β-blockers (patients on β-blockers: HR, 5.39; 95% CI, 2.68–10.84; P<0.001; entire population: HR, 1.95; 95% CI, 1.29–2.96; P=0.002).32 Others have emphasized the negative predictive value of a negative MTWA test33; however, it should be noted that even a coin toss has a high nega-tive predictive value when the event rate is low.34 Hohn-loser and Cohen35 have proposed the use of MTWA testing to select patients with an LVEF <35% who are unlikely to benefit from ICD implantation, but this has not been validated.

ECHOCARDIOGRAPHYEchocardiography is the first-line imaging investigation in the workup of patients with DCM. Use of echocar-diography measurements to predict arrhythmic events is therefore an attractive concept. The ability of global longitudinal strain and mechanical dispersion, a mea-sure of mechanical dyssynchrony, to predict sustained ventricular arrhythmia or SCD was investigated in 94 patients with nonischemic DCM over 22 months by Haugaa and colleagues.36 They found that both mea-sures independently predicted the major arrhythmic end point (per 1% increase in strain: HR, 1.26; 95% CI, 1.03–1.54; P=0.02; per 10-millisecond increase in mechanical dispersion: HR, 1.20; 95% CI, 1.03–1.40; P=0.02). They also demonstrated that both variables had larger areas under the curve on receiver-operating

Table 2. Electrophysiological Parameters and Their Ability to Predict Adverse Arrhythmic Events

Category Parameter Studies, nOutcome Events/

Patients, n (%)OR

(95% CI)

Positive Predictive

Value, %

Negative Predictive

Value, % P Value

Autonomic Baroreflex sensitivity 2 48/359 (13.4) 1.98 (0.60–6.59) 16.3 89.9 0.23

Heart rate turbulence 3 66/434 (15.2) 2.57 (0.64–10.36) 22.1 88.1 0.16

Heart rate variability 4 83/630 (13.2) 1.72 (0.80–3.73) 16.9 89.7 0.13

Surface electric QRS duration and left bundle-branch block 10 262/1797 (14.6) 1.51 (1.13–2.01) 18.5 87.6 0.01

Fragmented QRS 2 65/652 (10.0) 6.73 (3.85–11.76) 24.0 94.8 <0.001

Positive signal-averaged electrocardiogram 10 152/1119 (13.6) 2.11 (1.18–3.78) 18.9 89.5 0.017

T-wave alternans 12 177/1631 (10.9) 4.66 (2.55–8.53) 14.8 97.0 <0.001

QRS-T angle 1 97/455 (21.3) 2.01 (1.22–3.31) 25.4 85.5 0.006

Arrhythmia Positive electrophysiological study 15 146/936 (15.6) 2.49 (1.40–4.40) 29.2 86.9 0.004

Nonsustained ventricular tachycardia 18 403/2746 (14.7) 2.92 (2.17–3.93) 20.7 90.3 <0.001

CI indicates confidence interval; and OR, odds ratio. Adapted from Goldberger et al30 with permission from the publisher. Copyright © 2014, Elsevier..

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CMR

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Halliday et al

July 11, 2017 Circulation. 2017;136:215–231. DOI: 10.1161/CIRCULATIONAHA.116.027134220

curve analyses for the prediction of the primary out-come compared with LVEF (area under the curve: strain, 0.82; mechanical dispersion, 0.80; LVEF, 0.72). Another study investigated 124 patients with nonischemic DCM before primary-prevention ICD implantation.37 Longi-tudinal strain was independently associated with the primary end-point of appropriate ICD therapy, albeit to a modest degree (per 1% increase: HR, 1.12; 95% CI, 1.01–1.20; P=0.032). Importantly, however, it appears unlikely that functional techniques such as strain mea-surement will provide adequate discrimination between the risk of SCD and death resulting from HF.

THE ROLE OF MYOCARDIAL FIBROSIS IN SCD RISK STRATIFICATIONOne of the characteristic pathological features of DCM is the formation of myocardial fibrosis, a consequence of an increase in collagen formation in the extracellular matrix

and myocyte cell death.38 Histological studies have dem-onstrated 2 forms of fibrosis: replacement and interstitial fibrosis.38 Replacement fibrosis describes discrete areas of myocardial scarring that develop as a result of myocyte cell death, whereas interstitial fibrosis is the result of ex-pansion of the interstitium with accumulation of collagen in the absence of cell death (Figure 2).22 Fibrosis is the result of activation of the renin-angiotensin-aldosterone system and the β-adrenergic axis, which occurs as part of the HF syndrome.39 Other environmental insults, implicat-ed in the origin of DCM such as chemotherapy and viral myocarditis, play a role through the activation of inflam-matory networks and the production of reactive oxygen species.39 The result is the activation of myofibroblasts, the production of collagen, and myocyte cell death.38,39

Fibrosis is thought to provide a substrate for ventric-ular arrhythmia. An electric mapping study in patients with DCM demonstrated that only those with replace-ment fibrosis, identified by late gadolinium-enhanced

Figure 2. Detecting myocardial fibrosis using cardiovascular magnetic resonance. A, Late gadolinium enhancement cardiovascular magnetic resonance image of a midventricular short-axis slice in a healthy control subject. B, Native T1 map of a midventricular short-axis slice in a healthy control with a mean myocardial T1 of 1240 milliseconds. C, Late gadolinium enhancement image of a midventricular short-axis slice in a patient with dilated cardiomyopa-thy (DCM) demonstrating linear midwall enhancement. D, Native T1 map of a midventricular short-axis slice in a patient with DCM with a mean myocardial T1 of 1375 milliseconds. Scans were performed on a 3-T Siemens Skyra (Erlangen, Germany). E, Microscopic examination of a sample taken from the septum of an explanted heart after transplantation demonstrating the presence of replacement fibrosis (blue arrow) and pericellular interstitial fibrosis (yellow arrow).

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Figure 3. Detecting myocardial fibrosis using cardiovascular magnetic resonance. This figure demonstrates the acquired and genetic insults implicated in the pathogenesis of dilated cardiomyopathy (DCM) followed by the common genetic mutations associated with DCM (incidence of mutations in cases of idiopathic DCM followed by the protein encoded by the gene2) and data on disease outcomes. Abs indicates antibodies; LVRR, left ventricular reverse remodeling; phaeo, phaeochromocytoma; and SCD indicates sudden cardiac death.

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High Rate of VA

Nuclear Envelop (LMNA) Sarcomeric (MYH 6,7)

Sarcoplasmic Reticulum (PLN)


Invesigations in VA patients

• ECG ,EST, Imaging CT/CMR• EPS

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Echocardiography for assessment ofLV and RV function and detectionof structural heart disease isrecommended for patients at highrisk of developing serious VAs orSCD, such as those with dilated,hypertrophic or RVcardiomyopathies, survivors of acutemyocardial infarction or relatives ofpatients with inherited disordersassociated with SCD.

I B 100

Exercise testing plus imaging(exercise stress echocardiography testor nuclear perfusion, SPECT) isrecommended to detect silentischaemia in patients with VAs who havean intermediate probability of havingCAD by age or symptoms and inwhom an ECG is less reliable (digoxinuse, LV hypertrophy, .1-mmST-segment depression at rest, WPWsyndrome, or LBBB).

I B 102

Pharmacological stress testing plusimaging modality is recommended todetect silent ischaemia in patients withVAs who have an intermediateprobability of having CAD by age orsymptoms and are physically unable toperform a symptom-limited exercise test.

I B 103

CMR or CT should be considered inpatients with VAs whenechocardiography does not provideaccurate assessment of LV and RVfunction and/or evaluation of structuralchanges.

IIa B 1

ARVC ¼ arrhythmogenic right ventricular cardiomyopathy; CAD ¼ coronaryartery disease; CMR ¼ cardiac magnetic resonance; CPVT ¼ catecholaminergicpolymorphic ventricular tachycardia; CT ¼ computed tomography; ECG ¼electrocardiogram; LBBB ¼ left bundle branch block; LV ¼ left ventricular; RV¼right ventricular; SA-ECG ¼ signal-averaged ECG; SCD ¼ sudden cardiac death;SPECT ¼ single-photon emission computed tomography; VA ¼ ventriculararrhythmia; WPW ¼ Wolff–Parkinson–White.aClass of recommendation.bLevel of evidence.cReference(s) supporting recommendations.

Invasive evaluation of patients with suspected orknown ventricular arrhythmias

Recommendations Classa Levelb Ref.c

Coronary angiography

Coronary angiography should beconsidered to establish or excludesignificant obstructive CAD in patientswith life-threatening VAs or in survivorsof SCD, who have an intermediate orgreater probability of having CAD by ageand symptoms.

IIa C 104

Electrophysiological study

Electrophysiological study in patientswith CAD is recommended fordiagnostic evaluation of patients withremote myocardial infarction withsymptoms suggestive of ventriculartachyarrhythmias, including palpitations,presyncope and syncope.

I B 105

Electrophysiological study in patientswith syncope is recommended whenbradyarrhythmias or tachyarrhythmiasare suspected, based on symptoms (e.g.palpitations) or the results ofnon-invasive assessment, especially inpatients with structural heart disease.

I C 106

Electrophysiological study may beconsidered for the differential diagnosisof ARVC and benign RVOT tachycardiaor sarcoidosis.

IIb B 107

ARVC ¼ arrhythmogenic right ventricular cardiomyopathy; CAD ¼ coronaryartery disease; RVOT ¼ right ventricular outflow tract; SCD ¼ sudden cardiacdeath; VA ¼ ventricular arrhythmia.aClass of recommendation.bLevel of evidence.cReference(s) supporting recommendations.

A standard resting 12-lead ECG may reveal signs of inherited dis-orders associated with VAs and SCD such as channelopathies(LQTS, SQTS, Brugada syndrome, CPVT) and cardiomyopathies(ARVC and HCM). Other ECG parameters suggesting underlyingstructural disease include bundle branch block, atrio-ventricular(AV) block, ventricular hypertrophy and Q waves consistentwith ischaemic heart disease or infiltrative cardiomyopathy. Elec-trolyte disturbances and the effects of various drugs may resultin repolarization abnormalities and/or prolongation of the QRSduration.

Exercise ECG is most commonly applied to detect silentischaemia in adult patients with ventricular VAs. Exercise-inducednon-sustained VT was reported in nearly 4% of asymptomaticmiddle-age adults and was not associated with an increased riskof total mortality.108 Exercise testing in adrenergic-dependentrhythm disturbances, including monomorphic VT and polymorphicVT such as CPVT, is useful for diagnostic purposes and evaluatingresponse to therapy. Exercise testing in patients with life-threatening VAs may be associated with arrhythmias requiring car-dioversion, intravenous (i.v.) drugs or resuscitation, but may still bewarranted because it is better to expose arrhythmias and evaluaterisk under controlled circumstances. It should be performedwhere resuscitation equipment and trained personnel are immedi-ately available.

Continuous or intermittent ambulatory recording techniquescan aid in relating symptoms to the presence of the arrhythmia. Si-lent myocardial ischaemic episodes may also be detected. A 24- to48-h continuous Holter recording is appropriate whenever the ar-rhythmia is known or suspected to occur at least once a day. Forsporadic episodes, conventional event recorders are more usefulbecause they can record over extended periods. Implantable sub-cutaneous devices that continuously monitor the heart rhythm

ESC Guidelines2804

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Ischemic and Nonischemic Cardiomyopathy

• Premature ventricular complexes

• Non-sustained ventricular tachycardia

• Sustained monomorphic ventricular tachycardia

• Sustained polymorphic ventricular tachycardia/ ventricular fibrillation 18


Monomorphic VT

19

A negative test has been associated with better prognosis117 butwith only modest positive predictive value.118 The SAECG maybe most useful in identifying ARVCwhere a positive test forms aminor criterion in the diagnostic component for this disorder.39,119

Invasive electrophysiological studyPatients presenting with syncope or sustained palpitationswho have evidence of myocardial scar as well as those with awide-complex tachycardia for whom the diagnosis of VT isnot certain may benefit from a provocative EPS. Althoughthe standalone negative and positive predictive values of thistesting are limited,88,120 inducible SMVT is highly associ-ated with recurrent VT and may provide clues to the cause ofsyncope or other symptoms suggestive of a VA. Electro-anatomical mapping of the RV has been used to identifyotherwise unapparent RV scar.121,122

Testing for ischaemiaTransient myocardial ischaemia is an uncommon sole cause ofrecurrent sustained VT that is monomorphic. Most patients withcoronary artery disease who develop sustained MMVT have afixed region of myocardial scar that is a sequela of prior MI,often occurring many years earlier.95–97 Patients with a newpresentation of sustained MMVT should have a thoroughevaluation to define the presence or absence of underlying heartdisease, which includes echocardiography, exercise testing, andstress/perfusion imaging. For most patients where the coronaryartery disease is suspected as the underlying diagnosis, coronaryangiography should be considered.123–126 However, treatmentof ischaemia alone is unlikely to prevent recurrences of MMVT.Cardiac MRI and positron emission tomograph - computed

tomography may provide evidence for myocardial scar that isnot evident with other imaging modalities and may be especiallyuseful to differential occult SHD from idiopathic VT.127

TreatmentAcute therapy for sustained ventricular tachycardiaVentricular fibrillation should be immediately defibrillatedusing a non-synchronized mode. The use of intravenousamiodarone has been associated with a higher survivalprobability than when lidocaine is administered to patientsresuscitated from VF.128 The acute treatment of sustained VTis largely based on the patient’s symptoms and haemodynamictolerance of the arrhythmia. For patients with sustainedMMVT who are unconscious or who have experiencedhaemodynamic collapse, direct current cardioversionsynchronized to the QRS on the surface ECG should beimmediately performed. Patients who are conscious but havemarked hypotension or profound symptoms from VT shouldbe given prompt intravenous sedation and then cardioverted. Atrial of intravenous lidocaine (1 mg/ kg) may be given aspreparation is made for sedation, though the efficacy fortermination of sustained VT is only "15%.129 For patientswith sustained VT who are haemodynamically stable or haveonly mild symptoms, a 12-lead ECG should be recorded andcarefully analysed before therapy is initiated. For patientswithout SHD and a QRS morphology suggesting an idiopathicoutflow tract VT, a trial of a short-acting intravenous beta-blocker may be useful to terminate VT. However, for patientswith SHD with sustained VT, the most efficacious pharmaco-logical agent is intravenous amiodarone.129 This agent may beassociated with hypotension if administered rapidly, usually

Non-Ischaemic SHD

Optimize ICD programming

antiarrhythmic drugs preferred first line

Catheter ablation when drug-refractory

Optimize ICDprogramming

antiarrhythmic drugs or catheter ablation may be considered first line

Catheter ablation when drug-refractory

Evaluate cardiac structure and function

SHD No SHD

Treat SHD as appropriate ICD if indicated

Single episode VT: IIB

indication

VTsuppression

Recurrent VT: IIA

indication

VTsuppression

Ischaemic SHD

Beta-blockers, antiarrhythmic drugs, or

catheter ablation:may all be considered first line

(ICD required for rare malignant idiopathic VT)

Figure 5 Sustained monomorphic ventricular tachycardia evaluation and management. ICD ¼ implantable cardioverter-defibrillator; SHD ¼ structural heartdisease; VT ¼ ventricular tachycardia.

Heart Rhythm, Vol 11, No 10, October 2014e176

Amiodarone Beta Blockers

Xylocaine


Polymorphic VT

20

trigger PMVT or VF. Use of the Valsalva manoeuvre or highprecordial leads may improve the sensitivity of the 12-leadECG for detecting such triggers.167,168 In addition, the QRSand QT changes occurring after extrasystoles169 as well asduring standing170 may help to identify J-wave abnormalities

or abnormalities of the QT interval. Ambulatory monitoringmay help identifying QTc prolongation during sleep.The role of genetic testing has been recently reviewed4

and plays an important part in the evaluation of patients inwhom an inherited arrhythmia syndrome is suspected

ACS present

CAD treatment/prevention

EF >35%

Medical treatment

Resuscitation/defibrillation/ACLS

No ACS

Wearable defibrillator for high-risk patients

Re-evaluate LV EF after 40or 90 days**

SHDInherited

arrhythmiasyndrome

No SHD

Reversible cause?

EF <35%

No Yes

ConsiderICD

If incompletely reversible Treat reversiblecause / avoidance

of precipitatingfactors

Adjuvant therapy to reduceICD shocks

Figure 6 Sustained polymorphic ventricular tachycardia / ventricular fibrillation. **LV function should be reassessed at 40 days after MI or 90 days afterrevascularization. ACLS ¼ advance cardiovascular life support; ACS ¼ acute coronary syndrome; CAD ¼ coronary artery disease; ICD ¼ implantablecardioverter defibrillator; LVEF ¼ left ventricular ejection fraction; SHD ¼ structural heart disease.

Table 5 Conditions that can cause PVT/VF in the absence of SHD and potential therapies

Clues Tests to Consider Diagnoses Therapies

Long QT/T-wave alternans ECG/Monitor Congenital LQTS Beta-blockers/stellatectomyTdP pattern Epinephrine challenge Avoid QT prolonging drugsHistory of seizures Genetic testing Mexilitine/flecainide (LTQ3)Specific trigger (loud noise) Pacemaker/ICDLong QT/T-wave alternans ECG/Monitor Acquired LQTS Mgþþ/Kþ

TdP pattern Stop offending drugRenal failure Temporary pacingNew medication or drug abuseAV block ECG/Monitor Bradycardia PacemakerIncomplete RBBB with STE in leads V1 – V2 ECG BrS Isoproterenol/quinidineFever Drug challenge Anipyretic

Genetic testing AblationICD

Monomorhic PVC trigger ECG/Monitor Focal PVC origin Ablation/ICDJ-point elevation ECG Early repolarization ICDVentricular pre-excitation ECG WPW AblationShort QT interval ECG Short QTS ICDBidirectional VT pattern exercise-induced Digoxin level CPVT Stop digoxin

Exercise test Andersen-Tawil syndrome Beta-blockers/CCBs/flecainideGenetic testing Digoxin toxicity ICD

STE and chest pain Proactive testing Coronary spasm Vasodilators/coronary stent ICDShort-coupled PVC trigger ECG/Monitor Idiopathic ICD

BrS¼ Brugada syndrome; CCBs¼ calcium channel blockers; CPVT¼ catecholaminergic polymorphic ventricular tachycardia; ICD¼ implantable cardioverter-defibrillator; LQTS ¼ long QT syndrome; PVC ¼ premature ventricular complex; RBBB ¼ right bundle branch block; short QTS ¼ short QT syndrome; STE ¼ STelevation; TdP ¼ torsade de pointes; VT ¼ ventricular tachycardia; WPW ¼ Wolff-Parkinson-White (syndrome).

e179Pedersen et al EHRA/HRS/APHRS Expert Consensus on Ventricular Arrhythmias


AAD in CHF

21

which VAs predispose the failing heart to morepump failure requires further investigation. Wepropose that in the more advanced stage of HF,where the marked depletion of lipid and energystores results in a reprogramming to utilize ketonesas fuel (2,33), the presence of sustained dyssyn-chronous contraction from VAs results in delayedrecovery of myocardial function, possibly through aform of metabolic stunning. This, in turn, produces abioenergetic crisis that leads to more pump failure.Thus, the existing model of the failing myocardiumas an “engine out of fuel” (34) introduces the realpossibility of a “metabolic substrate” for the trig-gering and maintenance of the vicious cycle betweenVAs and progressive pump failure (Figure 1). In thiscontext, although the data are limited, it may bebeneficial to suppress VAs in the A-HF patient. Asmuch as stabilization of the VAs is a priority in allpatients, in patients with newly diagnosed HF and ahigh burden of VAs, it is important to consider thepossibility that an autoimmune or fulminantviral myocarditis may be present. Thus, performingan endomyocardial biopsy to rule out giant cellmyocarditis, myocardial sarcoidosis, or lymphocyticviral myocarditis, and coupling this with CMR orpositron emission tomography (PET) may be veryimportant in determining prognosis and therapeuticinterventions, including advanced therapies, such ascardiac transplantation and long-term MCS. Thelimitations of an endomyocardial biopsy are impor-tant to note, because the false-negative rate may beup to 50% due to inadequate sampling, and a diag-nosis is made at the time of LVAD implantation,when the histology of the myocardial core is exam-ined, or at the time of cardiac transplantation.

CLINICAL MANAGEMENT:

ANTIARRHYTHMIC DRUG THERAPY

Clinical data on efficacy and safety of antiarrhythmicdrug (AAD) therapy for VA suppression in patientswith A-HF are scant, and the overall evidence in pa-tients with structural heart disease is disappointing,with limited options and inconclusive benefits (35). Inpatients with A-HF, the negative inotropic effect ofmany AADs with the possibility of worsening of thehemodynamic status should also be considered(Table 1). Class I sodium-channel–blocking drugs havebeen associated with increased mortality in patientswith structural heart disease, and should be avoidedin patients with A-HF, given the significant negativeinotropic effects and potential for proarrhythmia(36,37). Two possible exceptions to this rule are rep-resented by quinidine and mexiletine, which have

been used alone or in conjunction with other class IIIAADs to achieve arrhythmia suppression in patientswith HF, albeit this indication has never beenformally evaluated in the context of randomizedcontrolled trials. Quinidine has been shown to haveminimal negative inotropic properties (38), whereasmexiletine is the class I agent most extensivelystudied as an adjunctive therapy to other class IIIAADs, such as sotalol or amiodarone (39). It isimportant to emphasize that mexiletine use in pa-tients with severe LV dysfunction has also beenshown to worsen the hemodynamic status via an in-crease in systemic vascular resistance, together with adecrease of cardiac and stroke volume indexes (40);therefore, mexiletine should be used with caution inpatients with A-HF. Class III antiarrhythmic agents(amiodarone, sotalol, and more recently, azimilideand celivarone) have been formally tested in ran-domized controlled trials for VA prevention in pa-tients with structural heart disease (Table 2) (41–44).In a recent systematic review of randomizedcontrolled trials, we reported pooled quantitativeestimates of the benefit of class III AADs (amiodarone,sotalol, azimilide, and celivarone) (35). Overall, 8trials were included in the analysis, with a total of2,268 patients and a mean follow-up duration of15 months (35). Pooled analysis showed a 34% reduc-tion of recurrent VA episodes leading to appropriateICD interventions with AADs compared with controlmedical therapy, which did not translate into a signif-icant effect on all-cause mortality. Notably, the treat-ment effect of different class III AADs was largely

TABLE 1 Hemodynamic Effects of Different Antiarrhythmic Agents in Patients With HF

Class and Drug ABP PCWP CO SVR

Predominant Effect

Vasodilation Myocardial Depression

Class IA þQuinidine Y ¼ [ Y

Disopyramide* ¼ [ Y ¼ þþClass IB

Lidocaine ¼ ¼ ¼ ¼Mexiletine [ [ Y [ þ

Class IC

Flecainide/propafenone* ¼/Y [ Y ¼ þþClass III

Amiodarone ¼/Y [ ¼/Y ¼/Y þ ¼/þSotalol Y [ Y ¼ ¼/þ þDronedarone* Y [ Y Y þþAzimilide† ¼/Y ¼/Y ¼/[ ¼/Y þCelivarone† Y ¼/[ Y Y þ þ

*Contraindicated in patients with HF. †Investigational agents.

¼ ¼ no significant effect; þ ¼ effect size; Y ¼ decrease; [ ¼ increase; ABP ¼ arterial blood pressure; CO ¼cardiac output; HF ¼ heart failure; PCWP ¼ pulmonary capillary wedge pressure; SVR ¼ systemic vascularresistance.

J A C C V O L . 6 9 , N O . 1 4 , 2 0 1 7 Santangeli et al.A P R I L 1 1 , 2 0 1 7 : 1 8 4 2 – 6 0 Management of VT in Advanced HF

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