Non-invasive evaluation of arrhythmic risk in dilated cardiomyopathy: From imaging to electrocardiographic measures

Table 1 The main studies evaluating the association between myocardial fibrosis assessed by cardiac magnetic resonance and the risk of arrhythmic and non-arrhythmic events

Ref.	Clinical setting	Number of patients	CMR parameters	End-points(mean follow-up)	Results
Assomoul et al[26], 2006	NIDCM	101	Midwall fibrosis (LGE)	All-cause death and hospitalization (follow-up 658 ± 355 d)	Independent association with death and hospitalization
Wu et al[27], 2008	NIDCM and LVEF ≤ 35%	65	Presence and extent of LGE	Composite end-point (hospitalization for heart failure, appropriate ICD firing, cardiac death) (Follow-up median 24 mo)	Presence of LGE was associated with a greater risk of primary outcome
Iles et al[28], 2011	IDCM/NIDCM before ICD implantation	103	Regional fibrosis with LGE	Arrhythmic events and appropriate ICD therapy (follow-up 573 d)	LGE was associated with arrhythmic events and appropriate ICD therapy during follow-up
Lehrke et al[29], 2011	NIDCM	184	Presence of LGE	Composite end-point (hospitalization for decompensated heart failure, cardiac death, cardioverter defibrillator discharge) (follow-up 31 mo)	Presence of LGE was associated with composite endpoint
Gao et al[30], 2012	IDCM/NIDCM	124	Presence and quantification of LGE	Primary composite outcome: occurrence of appropriate ICD therapy, SCA, SCD (follow-up 632 ± 262 d)	Myocardial scar quantification by LGE-CMR predicts arrhythmic events in patients being evaluated for ICD eligibility
Neilan et al[31], 2013	NIDCM	162	Presence and quantification of LGE	Major adverse cardiac events (cardiovascular death and appropriate ICD therapy) (follow-up: 29 ± 18 mo)	Presence of LGE was a strong predictor of major cardiac events
Li et al[32], 2013	NIDCM	293	Presence and extent of LGE	All-cause mortality (follow-up: 3.2 yr)	Presence of LGE is an independent predictor of increased all-cause mortality Diffuse LGE is associated with higher mortality
Gulati et al[33], 2013	NIDCM	472	Presence and extent of midwall fibrosis	Primary end-point: all cause mortality Secondary end-point: cardiovascular mortality or cardiac transplantation Arrhythmic and HF secondary end-points (follow-up 5.3 yr)	Midwall fibrosis assessed with LGE-CMR provided independent prognostic information and improved risk stratification beyond LVEF for all-cause mortality and SCD

CMR: Cardiac magnetic resonance; IDCM: Ischemic dilated cardiomyopathy; LGE: Late gadolinium enhancement; NIDCM: Non ischemic dilated cardiomyopathy; SCA Survived cardiac arrest; SCD: Sudden cardiac death; ICD: Implantable cardioverter defibrillator.

Table 2 Main studies evaluating the role of dynamic ventricular repolarization measures in predicting arrhythmic and non arrhythmic events

Ref.	Clinical setting	Number of patients	Parameter evaluated	Cut-off suggested	End-points(mean follow-up)	Results
Chevalier et al[46], 2003	Acute myocardial infarction	265	QT dynamicity and HRV (24-h Holter) LVEF Late potential	QTe slope: 0.18	Sudden death and total mortality (follow-up 81 ± 27 mo)	Increased diurnal QTe dynamicity independently associated with sudden death
Haigney et al[47], 2004	Postinfarction patients (low LVEF)	871	QT variability (QTVN) QTVI (QTVN adjusted for heart rate variance)		Arrhythmic events (VT or VF) (follow-up 2 yr)	Increased QT variability associated with an increased risk for VT/VF
Jensen et al[48], 2005	Postinfarction patients	481	QT/RR slope and intercept QT/RR VR LVEF VPB and VT		All-cause mortality (follow-up 3 yr)	VR, LVEF, VPB and age made up the optimal Cox model for risk stratification. VR was a promising risk factor for identifying sudden arrhythmic death
Iacoviello et al[49], 2007	NIDCM (no history of SVT/VF)	179	QTe slope (24 h Holter) LVEF NSVT QRS duration QTc and QTd at ECG	QTe-slope: 0.19	Major arrhythmic events, (VT or VF or SCD) (follow-up 39 ± 22 mo)	Increased QTe slope is associated with occurrence of major arrhythmic events. The presence of NSVT and/or QTe slope > 0.19 showed 90% sensitivity and 60% specificity in identifying patients with arrhythmic events
Cygankiewicz et al[50], 2009	CHF patients. IDCM/NIDCM LVEF ≥ 35%	294	QTe slope SDNN TS LVEF	QTe slope: 0.21	Primary endpoint: total mortality Secondary endpoint: sudden death (follow-up 44-mo)	Combination of SDNN, TS, and QTe slope is a predictor of increased risk of mortality and sudden death

BRS: Baroreflex sensitivity; CHF chronic heart failure; EPS Electrophysiological study; ICD Implantable cardioverter defibrillator; IDCM: Ischemic dilated cardiomyopathy; HR Heart rate; HRV: Heart rate variability; LVEF: Left ventricular ejection fraction; MCE: Major cardiac events; NIDCM: Non ischemic dilated cardiomyopathy; NSVT: Non sustained ventricular tachycardia; OHR: Onset heart rate; QTc: QT interval corrected for heart rate; QTe: QT interval calculated at the end of T-wave; SCD: Sudden cardiac death; SDNN: Standard deviation of RR intervals; SR: Sinus rhythm; TS: Turbulence slope; PVB: Premature ventricular beats; VT: Ventricular tachycardia; VR: Variability ratio.

Table 3 Main studies evaluating the role of microvolt T-wave alternans in predicting arrhythmic and non arrhythmic events

Ref.	Clinical setting	Number of patients	Parameter evaluated	End-points(mean follow-up)	Results
Adachi et al[56], 1999	NIDCM	57	TWA, LVEF, NYHA, Signal average ECG, QT dispersion	Ventricular tachycardia	MTWA associated with VT
Klingenheben et al[57], 2000	CHF (no history SVT/VF)	107	TWA	Arrhythmic events (follow-up 18 mo)	MTWA is an independent predictor of arrhythmic events
Kitamura et al[58], 2002	NIDCM	146	Onset heart rate for TWA	SCD, documented sustained ventricular tachycardia/ventricular fibrillation (follow-up 21 ± 14 mo)	TWA and LVEF were independent predictors of arrhythmic events
Hohnloser et al[59], 2003	NIDCM (LVEF 29 ± 11%)	137	MTWA, FEVS, mean RR interval, HRV, BRS.	SCD, SCA, SVT or VF (follow-up 14 ± 6 mo)	MTWA is an independent predictor of ventricular tachyarrhythmic events
Bloomfield et al[60], 2004	IDCM (LVEF ≤ 30%)	177	MTWA, QRS measurement	All-cause mortality. (follow-up 20 ± 6 mo)	Compared to QRS duration, an abnormal MTWA is a stronger predictor of death
Salerno-Uriate et al[61], 2007	NIDCM (NYHA II-III LVEF ≤ 40%)	446	TWA, VO2 peak	Combined primary endpoint of cardiac death and life-threatening ventricular arrhythmias Secondary endpoint: total mortality, combination of arrhythmic death and life-threatening arrhythmias. (follow-up 18 to 24 mo)	Abnormal TWA associated with a 4-fold higher risk of cardiac death and life-threatening arrhythmias
Baravelli et al[62], 2007	NIDCM (NYHA II-III LVEF 29 ± 6.4%)	70	MTWA, VO2 peak	Combined primary endpoint of MCE: total cardiac death or VT/VF (including appropriate ICD shock) Secondary endpoint: MAE: SCD or SVT/VF (follow-up 19.2 ± 10.7 mo)	MTWA and peak VO2, but not the two single tests, were significant prognostic markers of both MCE and MA
Gold et al[63], 2008	CHF (IDCM/NIDCM, 71% NYHA II, LVEF 24 ± 7%)	490	TWA	Composite primary end point: SCD, SVT / VF, or appropriate ICD discharge (follow-up 30 mo)	MTWA not predictive of MAE or mortality
Costantini et al[64], 2009	IDCM LVEF ≤ 40%	566	TWA, EPS	Primary endpoint: appropriate ICD discharge or SCD at 1 yr follow-up (follow-up 1.6 ± 0.6 yr)	Strategies employing MTWA, EPS, or both might identify the subset of patients least likely to benefit from ICD implantation

BRS: Baroreflex sensitivity; CHF: Chronic heart failure; EPS: Electrophysiological study; HR: Heart rate; HRV: Heart rate variability; ICD: Implantable cardioverter defibrillator; LVEF: Left ventricular ejection fraction; MCE: Major cardiac events; MTWA: Microvolt T-Wave alternans; NYHA: New York Heart Association; NSVT: Non sustained ventricular tachycardia; OHR: Onset heart rate; SR: Sinus rhythm; SCA: Sudden cardiac arrest; SCD: Sudden cardiac death; SDNN: Standard deviation of RR intervals; VF: Ventricular fibrillation; VT: Ventricular tachycardia.

Table 4 The main studies evaluating the prognostic significance of heart rate turbulence and risk stratification

Ref.	Clinical setting	Number of patients	Cut-offproposed	End-points(mean follow-up)	Results
Schmidt et al[80], 1999	Postinfarction patients	577	TO 0% TS 2.5 ms/RR	All-cause mortality (follow-up 22 mo)	HRT2 predictive for all-cause mortality
Ghuran et al[81], 2002	Postinfarction patients (ATRAMI)	1212	TO 0% TS 2.5 ms/RR	Combined end-point of fatal and non fatal cardiac arrhythmias (follow-up 21 mo)	HRT associated with endpoints
Barthel et al[83], 2003	Postinfarction patients (ISAR-HRT)	1455	TO 0% TS 2.5 ms/RR	All-cause mortality (follow-up 22 mo)	HRT independent predictor of mortality in patients with LVEF ≥ 30%
Grimm et al[84], 2003	NIDCM, LVEF ≤ 30%	242	TO 0% TS 2.5 ms/RR	Transplant-free survival (follow-up: 41 mo)	TO predictor of transplant-free survival. TO and TS only as univariate predictor of MCE
Exner et al[85], 2007	Myocardial infarction (REFINE)	322	TO 0% TS 2.5 ms/RR	Cardiac death or resuscitated cardiac arrest (follow-up 47 mo)	HRT (10-14 wk after MI) predictive for cardiac death or resuscitated cardiac arrest
Cygankiewicz et al[86], 2008	CHF (IDCM/and NIDCM)	607	TO 0% TS 2.5 ms/RR	All-cause mortality, sudden death and heart failure death (follow-up: 44 mo)	Abnormal TS predictive for all-cause mortality, sudden death and heart failure death
Klingenheben et al[87], 2008	NIDCM (Mean LVEF 28%)	114	TO 0% TS 2.5 ms/RR	Arrhythmic events (follow-up 22 mo)	HRT non predictive for arrhythmic events
Miwa et al[88], 2009	IDCM (241) and NIDCM (134)	375	TO 0% TS 2.5 ms/RR	Cardiac mortality Combined endpoint of cardiac death and/or stable sustained VT (follow-up 15 mo)	Abnormal HRT predictive for cardiac mortality and combined endpoint Prognostic value observed in both ischemic and non-ischemic cardiomyopathy
Huikuri et al[89], 2009	Postinfarction CARISMA	312	TS 2.5 ms/RR	Primary endpoint of documented VT/TV (follow-up 2 yr)	TS evaluated at 6 wk after MI predictive for primary endpoint No prognostic value for HRT evaluated 1 wk after MI
Ikeda et al[90], 2011	NIDC	134	TO 0% TS 2.5 ms/RR	Combined endpoint of cardiac mortality and sustained VT (follow-up 15 mo)	Abnormal HRT predictive for combined endpoint
Miwa et al[91], 2012	IDCM / NIDCM (LVEF ≤ 40%)	299	TO 0% TS 2.5 ms/RR	Combined endpoint of sudden cardiac death and sustained VT (follow-up 32 mo)	Abnormal HRT predictive for combined endpoint

HRT: Heart rate turbulence; NIDCM: Non-ischemic dilated cardiomyopathy; TO: Turbulence onset; TS: Turbulence slope; MCE: Major cardiac events; LVEF: Left ventricular ejection fraction; CHF: Chronic heart failure; NYHA ICD: Implantable cardioverter defibrillator.