Review
Non-­invasive markers for sudden cardiac death
1
Department of Cardiovascular
Sciences, University of Leicester,
Leicester, UK
2
NIHR Leicester Biomedical
Research Centre, Leicester, UK
3
Department of Cardiology,
University Hospitals of Leicester
NHS Trust, Leicester, UK
4
School of Engineering,
University of Leicester College
of Science and Engineering,
Leicester, UK
Correspondence to
Professor G Andre Ng,
Cardiovascular Sciences,
University of Leicester, Leicester
LE3 9QP, UK; g​ an1@​le.​ac.​uk
Received 5 July 2021
Accepted 23 September 2021
Published Online First
20 October 2021
© Author(s) (or their
employer(s)) 2022. No
commercial re-­use. See rights
and permissions. Published
by BMJ.
To cite: Pooranachandran V,
Nicolson W, Vali Z, et al. Heart
2022;108:998–1004.
998   Pooranachandran V, et al. Heart 2022;108:998–1004. doi:10.1136/heartjnl-2021-319971
risk stratification in dilated cardiomyopathy
Vivetha Pooranachandran,1,2 Will Nicolson,1,3 Zakariyya Vali,1,3 Xin Li,1,4
G Andre Ng  ‍ ‍1,2,3
ABSTRACT
Dilated cardiomyopathy (DCM) is a common yet
challenging cardiac disease. Great strides have been
made in improving DCM prognosis due to heart failure
but sudden cardiac death (SCD) due to ventricular
arrhythmias remains significant and challenging to
predict. High-­risk patients can be effectively managed
with implantable cardioverter defibrillators (ICDs)
but because identification of what is high risk is very
limited, many patients unnecessarily experience the
morbidity associated with an ICD implant and many
others are not identified and have preventable mortality.
Current guidelines recommend use of left ventricular
ejection fraction and New York Heart Association class
as the main markers of risk stratification to identify
patients who would be at higher risk of SCD. However,
when analysing the data from the trials that these
recommendations are based on, the number of patients
in whom an ICD delivers appropriate therapy is modest.
In order to improve the effectiveness of therapy with an
ICD, the patients who are most likely to benefit need to
be identified. This review article presents the evidence
behind current guideline-­directed SCD risk markers and
then explores new potential imaging, electrophysiological
and genetic risk markers for SCD in DCM.
INTRODUCTION
Sudden cardiac death (SCD) remains a major global
public health problem, estimated to cause 4–5
million deaths worldwide.1 While the majority of
SCD occurs due to coronary artery disease, approx-
imately 10%–15% of cases are in patients with
non-­ischaemic cardiomyopathies (NICMs). Many
of these events occur in patients who may not have
had any prior signs or symptoms of cardiac disease,
and thus would not have been considered to be at
an increased risk.2
Treatment of pump failure due to dilated cardio-
myopathy (DCM) has been revolutionised over the
last 40 years and great strides continue to be made
with new medications such as sacubitril valsartan
and sodium-­glucose co-­transporter-­2 inhibitors.3 4
But SCD assessment and prevention has at best not
progressed and at worst reversed with the 2016
DANISH paper failing to show implantable cardio-
verter defibrillator (ICD) benefit in patients with
DCM (1%–2% SCD vs >2% non-­SCD death per
year).5 6
Current European Society of Cardiology/Amer-
ican College of Cardiology/American Heart Asso-
ciation/National Institute of Health and Care
Excellence (ESC/ACC/AHA/NICE) guidelines
recommend the use of left ventricular ejection
fraction (LVEF) and New York Heart Association
(NYHA) classification to identify patients at high
risk of SCD.7 8 Use of LVEF and NYHA is based
on data from the historical ICD trials but these
measures have always been known to perform
poorly; for example, in the SCD-­HeFT trial, the
number of patients receiving appropriate device
therapy after a mean 5-­year follow-­up period was
only ~20%.5 6 9
There is a strong need to improve the accuracy
of SCD risk assessment in patients with DCM. This
review will summarise the evidence in patients
with DCM for recognised markers of SCD risk and
will go on to describe promising new markers and
avenues for the future (table 1 and figure 1).
CURRENT GUIDELINE-MANDATED MARKERS OF
SCD RISK
Left ventricular ejection fraction
The primary prevention ICD trials all use reduced
LVEF as an important risk stratification marker to
identify patients at risk of SCD. A meta-­analysis
of 16 ICD trials (n=3959) assessing the effect of
LVEF on ICD therapy demonstrated improved
LVEF >35% following ICD implant (n=1622)
is associated with reduced risk of ventricular
arrhythmia (VA) and mortality (incidence rate ratio:
0.52; CI: 0.38 to 0.70, p<0.001) over a median
follow-­up period of 2.9 years.10 Nevertheless, alter-
native studies have demonstrated a poor correlation
between LVEF and SCD.11 The Oregon Sudden
Unexpected Death Study showed 58 of 121 SCD
victims presented with normal LVEF (>55%) and
27 patients had mild to moderately reduced LVEF
(36%–54%).12
New York Heart Association
NYHA is a method of assessing functional capacity
in patients with heart failure (HF), and is a marker
used to select ICD candidates. Mortality risk
increases with worsening functional class due to
pump failure.13 The MERIT-­ HF trial involving
3991 patients demonstrated death from congestive
HF was higher than SCD in NYHA class IV (n=27;
56% vs 33%) compared with NYHA class II patients
(n=104; 12% vs 64%).14 This was further observed
by Briongos-­Figuero et al who studied 621 patients
with HF and reported a significantly higher cardio-
vascular mortality risk in NYHA class III (26 of 109
patients) compared with class I (7 of 101 patients),
HR: 4.7, CI: 1.7 to 12.8, p=0.002. Nevertheless,
no difference in arrhythmia free survival was seen
between the functional classes, suggesting the risk
of arrhythmic death is somewhat equal across the
functional classes.13
 Review

Table 1  Electrophysiological parameters and their ability to predict adverse arrhythmic events
Positive Negative
predictive predictive value,
reference
Category Parameter Studies, n Events/patients, n (%) value, % % OR P value
Demographics New York Heart Association III/IV23 5 175/1326 (13.2) N/A N/A 1.37 (0.77 to 2.46)* 0.29
Non-­sustained ventricular tachycardia15 18 403/2746 (14.7) 20.7 90.3 2.49 (1.40 to 4.40) 0.004
Cardiac imaging Left ventricular ejection fraction15 12 293/1804 (16.2) 21.9 90.2 2.87 (2.09 to 3.95) <0.001
Presence of LGE18 29 272/1305 (20.8) 20.8 95.3 4.3 (3.0 to 6.2) <0.001
Circulating biomarkers NT-­proBNP ≥1177 pg/mL6 1 145/582 (24.9) N/A N/A 0.99 (0.73 to 1.36)* 0.96
Autonomic nervous Heart rate variability15 4 83/630 (13.2) 16.9 89.7 1.72 (0.80 to 3.73) 0.13
system Heart rate turbulence15 3 66/434 (15.2) 22.1 88.1 2.57 (0.64 to 10.36) 0.16
QT Variability Index22 1 50/233 (21.4) 38 82 2.4 (1.3 to 4.3)* 0.005
Surface ECG based QRS15 10 262/1797 (14.6) 18.5 87.6 1.51 (1.13 to 2.01) 0.010
Fragmented QRS15 2 65/652 (10.0) 24.0 94.8 6.73 (3.85 to 11.76) <0.001
Positive signal-­averaged ECG15 10 152/1119 (13.6) 18.9 89.5 2.11 (1.18 to 3.78) 0.017
T wave alternans15 12 177/1631 (10.9) 14.8 97.0 4.66 (2.55 to 8.53) <0.001
QRS-­T angle15 1 97/455 (21.3) 25.4 85.5 2.01 (1.22 to 3.31) 0.006
Magnetocardiography—presence of 1 13/51 (25.5) N/A N/A 4.28 (1.30 to 19.39)* 0.015
LiDC42
Regional Restitution Instability Index/ 1 9/50 (18.0) 40.0 100.0 3.2 (1.2 to 8.8)* 0.02
Peak ECG Restitution Slope45
Genetics Genetics48 1 37/98 (37.8) N/A N/A 1.9 (1.1 to 3.4)* 0.02
Adapted from Kober et al, Goldberger et al, Di Marco et al, Oosterhoff et al, Sammani et al, Kawakami et al, Nicolson et al and Ebert et al.6 15 18 22 23 42 45 48
*Hazard Ratio.
LGE, late gadolinium enhancement; LiDC, left intraventricular disorganised conduction; N/A, not available; NT-­proBNP, N-­terminal pro-­brain natriuretic peptide.

QRS duration
Prolongation of QRS duration >120 ms depicts a delayed ventric-
ular depolarisation, and in combination with other risk markers
has been associated with an increased mortality risk. Data
obtained from Goldberger et al’s meta-­analysis demonstrated
262 of 1797 patients with a prolonged QRS duration experi-
enced an event, however the relative risk (RR) compared with
other evaluated risk markers was low (RR: 1.43, CI: 1.11 to
1.83, p<0.010).15 Similarly, Mercier et al’s non-­ischaemic study
demonstrated QRS duration to be an independent predictor

Figure 1  Non-­invasive ECG risk markers to predict sudden cardiac death.

Pooranachandran V, et al. Heart 2022;108:998–1004. doi:10.1136/heartjnl-2021-319971 999
 Review
of SCD (HR: 1.01 CI: 1.00 to 1.01, p=0.022).11 However,
when compared with other evaluated risk markers, both studies
demonstrated relatively low RR and HR.
POTENTIAL SCD RISK MARKERS NOT CURRENTLY FEATURED
IN GUIDELINES
24-hour ECG
Non-­sustained ventricular tachycardia (NSVT) and ventricular
ectopy are not uncommon findings in patients with impaired LV
function. NSVT was a key part of the inclusion criteria in the
DEFINITE trial of 458 patients with LVEF <36%, NYHA class
I–III for an ICD. This cohort of patients demonstrated a signif-
icant reduction in SCD when treated with an ICD; (HR: 0.20,
CI: 0.06 to 0.71, p=0.006).5 However, evidence for NSVT in
DCM is mixed, as some studies have not shown it to be a useful
predictor. For example, Zecchin et al, studied 319 patients and
found NSVT did not increase the risk of SCD in patients with
LVEF <35% (HR: 0.93, CI: 0.3 to 2.81).16 Likewise, Gold-
berger et al’s meta-­analysis demonstrated a marginally lower
positive predictive value (PPV) of 20.7% compared with LVEF
(21.9%), suggesting a poor prediction of SCD compared with
other potential markers.15
Circulating biomarkers
Brain natriuretic peptide (BNP) and N-­ terminal pro-­ BNP
(NT-­proBNP) is a common biomarker used in routine clinical
practice to identify patients with HF. Previous studies have
found NT-­ proBNP to be associated with all-­ cause mortality,
and interestingly in the recent DANISH DCM trial, patients
with an NT-­proBNP  ≥1177 pg/mL derived no mortality
benefit from ICD therapy when compared with the control arm
(HR: 0.99, CI: 0.73 to 1.36, p=0.96). Whereas patients with
NT-­proBNP <1177 pg/mL demonstrated a mortality benefit
from ICD therapy (HR: 0.59, CI: 0.38 to 0.91, p=0.02).1 6
This was a prespecified subgroup and suggests NT-­proBNP may
play a significant role in identifying those who are less likely to
benefit from an ICD and are at higher risk of HF death.
Cardiac MRI
Myocardial fibrosis is a distinctive pathological feature of DCM;
it forms due to increased collagen in the extracellular matrix and
myocyte cell death (figure 2). Myocardial fibrosis and in partic-
ular the grey zone between fibrosis and viable myocardium is
thought to act as a substrate for VA. A distinctive pattern of mid-­
wall fibrosis is seen in ~30% of patients and has shown to be
associated with increased risk of SCD; in the largest of which by
Gulati et al, 142 of 472 patients with DCM had mid-­wall fibrosis
and 29.6% reached the composite endpoint of VA/SCD vs 7.0%
of patients without mid-­wall fibrosis (HR: 5.24; CI: 3.15 to
8.72; p<0.001).17 A subsequent meta-­analysis demonstrated 272
of 1305 patients with myocardial fibrosis experienced an event
(OR: 4.3, CI: 3.0 to 6.2, p<0.001).18 However, there is as yet
no standardised approach and no clear threshold at which mid-­
wall fibrosis conveys additional risk (table 2). Studies to date are
typically single centre and observational in nature. The ongoing
CMR GUIDE research study, while also including patients with
ischaemic heart disease, will be of interest as the first multicentre
study using late gadolinium enhancement to stratify patients to
ICD implant.19
Assessment of the autonomic nervous system
The role of the autonomic nervous system (ANS) has been
identified as an important factor in HF and DCM, and is
1000
Figure 2  Example cardiac MRI scans for patients with dilated
cardiomyopathy. Short axis views (top images), long axis views (bottom
images). (A and C) An example with late gadolinium enhancement. (B
and D) An example without late gadolinium enhancement.
well recognised in the pathogenesis of VA and SCD. Sympa-
thetic stimulation has direct electrophysiological effects on the
ventricle that may lead to life-­threatening arrhythmias.20 Direct
measurement of ANS activity is technically challenging and inva-
sive; therefore, assessment is usually made through surrogate
surface ECG markers.
A number of studies have investigated the predictive value of
these ECG risk markers, including heart rate variability (HRV),
heart rate turbulence (HRT) and QT variability (QTV).15 21 22
However, on their own, markers of autonomic dysfunction were
deemed to be poor as they predict both sudden (arrhythmic)
and non-­sudden (non-­arrhythmic) cardiac death.23 Karcz et al
assessed HRV in 69 patients with DCM and found a low SD of
normal to normal intervals (<80 ms) to significantly correlate
with both cardiac death and heart transplantation (HR: 1.35,
CI: 1.11 to 1.63, p=0.002).24 Whereas studies assessing HRT
and QTV index demonstrated abnormal HRT or high QTV
index were associated with increased risk of sudden and non-­
SCD (p<0.05).22 25 The poor prediction of SCD therefore limits
their utility as lone markers in the selection of patients most
likely to benefit from an ICD.
Vector ECG: QRS-T angle
Vector ECG involves recording the magnitude and direction of
cardiac electrical signals in three dimensions. A vector ECG can
be acquired directly or a standard 12-­lead ECG can be converted
into a vector ECG. QRS-­T angle (QTA) is the angle measured
between QRS and T wave loops and can be performed as spatial
QTA using three dimensions or as frontal QTA using the 2D
frontal projection.
Yamazaki et al carried out a large population-­ based study
assessing QTA in 46 573 patients. The study demonstrated
frontal angle above 100° to be associated with cardiac mortality
(HR: 3.6, CI: 3.0 to 4.2, p<0.0001).26 Kors et al studied QTA
in the general population and found a spatial angle over 135° to
be associated with SCD (HR: 4.4, CI: 2.8 to 6.9).27 However,
Pooranachandran V, et al. Heart 2022;108:998–1004. doi:10.1136/heartjnl-2021-319971

Table 2  Strengths and weaknesses of the different non-­invasive sudden cardiac death risk markers
Markers
Current guideline-­ Left ventricular ejection
mediated markers fraction
New York Heart Association
QRS duration
Available markers Non-­sustained ventricular
tachycardia
NT-­proBNP
Cardiac MRI
Heart rate variability
Heart rate turbulence
QT Variability Index
QRS-­T angle
Signal-­averaged ECG
Microvolt T wave alternans
Fragmented QRS
Magnetocardiography
Potential new markers R2I2 and PERS
Genetics
ACC/AHA, American College of Cardiology/American Heart Association; AF, atrial fibrillation; EP, electrophysiology; ESC, European Society of Cardiology; HF, heart failure; ICD, implantable cardioverter defibrillator; NICE,
National Institute of Health and Care Excellence; NT-­proBNP, N-­terminal pro-­brain natriuretic peptide; PERS, Peak ECG Restitution Slope; R2I2, Regional Restitution Instability Index.
Pooranachandran V, et al. Heart 2022;108:998–1004. doi:10.1136/heartjnl-2021-319971
Principle/guideline
ESC/ACC/AHA/NICE7 8
Studies typically measure using transthoracic
echocardiogram (ESC 2017, ACC/AHA 2016,
NICE 2014 Guidelines)
Breathlessness severity (ESC 2017, ACC/AHA
2016, NICE 2014 Guidelines)
Detected on 12-­lead ECG (ESC 2017, ACC/AHA ► Simple, widely available measure
2016, NICE 2014 Guidelines)
Consecutive ventricular premature beats: ≥3
and lasting <30 s
Marker of heart failure severity
Late gadolinium enhancement detects
patterns of scar/fibrosis
Autonomic function assessment using, for
example, a 24-­hour heart monitor
Autonomic function assessment using, for
example, a 24-­hour heart monitor
Autonomic function assessment using short
duration recordings
Measured from a 12-­lead ECG; frontal vector ► Non-­invasive technique
or computer-­assisted analysis software; spatial ► No specialist analysis required
vector
Computer-­assisted analysis software
Detected on ECG (24-­hour heart monitor/
exercise tolerance test)
Detailed analysis requires computer-­assisted
software
Detected on 12-­lead ECG
Non-­contact body surface map
Obtained using an EP study retrograde curve
or an exercise tolerance test
Specific mutations may be associated with
sudden cardiac death
Strengths
► Principal marker in the key studies and in all ► Low sensitivity and specificity
the guidelines
► Low cost
► Low cost
► Easy to obtain
► QRS duration and morphology (eg, left
bundle branch block) key discriminator for
biventricular pacing
► Has been applied across a range of
aetiologies
► Low cost
► Easily accessible
► Detects patients who are likely to be at
risk of HF death and less likely to benefit
from an ICD
► Easily accessible and cost effective
► Various techniques are being developed to
detect markers including diffuse fibrosis
► Can image anatomy, physiology and
function
► High-­spatial resolution
► Non-­invasive measurement
► Low cost
► Non-­invasive measurement
► Low cost
► A minimum of 10 s ECG required for
analysis
► Non-­invasive technique
► This method can be used in all patient
groups
► Helps visualise late potentials that may not
be detected on standard 12-­lead ECG
► No specialist analysis required
► Simple non-­invasive test once appropriate
device purchased
► High negative predictive value—helps
identify individuals who may not benefit
from ICD implantation
► Excluding patients with ventricular paced
rhythm, this method can be used in all other
patient groups
► No specialist analysis required
► Specific to cardiac electric activity and helps
measure and monitor direct current signals
in the heart
► Mobile unshielded magnetocardiography
being developed, expanding the usability
► Effective in patients with injuries or burns
due to non-­contact map
► Strong positive predictive value
► Shown to be predictive in a wide range
of aetiologies including ischaemic heart
disease and dilated cardiomyopathy
► Low-­cost technique
► No specialist analysis required
► May lead to screening of relatives
► Possibility of identifying a gene with a high
association with sudden cardiac death
Review
Weaknesses
► More patients with preserved ejection
fraction die of sudden cardiac death than do
patients with impaired ejection fraction
► Predominantly associated with non-­sudden
cardiac death
► Predominantly associated with non-­sudden
cardiac death
► Low positive predictive value
► Associated with both sudden and non-­sudden
cardiac death
► Poor prognostic value with positive and
negative studies
► Predominantly associated with non-­sudden
cardiac death
► Several contraindications including renal
failure and metal implants
► Limited availability
► Long scan time
► Lack of uniformity in technique
► High cost
► Specialist analysis required
► Unsuitable for patients with AF
► Predominantly associated with non-­sudden
cardiac death
► Unsuitable for patients with AF
► Predominantly associated with non-­sudden
cardiac death
► Limited evidence base in dilated
cardiomyopathy patient group
► Non-­specific to sudden cardiac death
► Cut-­off appears to vary between age and
gender—requires further research
► In published studies, different methods have
been used to calculate vector and this may
provide different QRS-­T angle
► Electrical interference can produce false
positive results
► Low positive predictive value for sudden
cardiac death
► No standardisation of technique
► Large proportion of tests is classified as
indeterminate due to patient compliance
(not achieving target heart rate), premature
beats, atrial arrhythmia or technical issues
such as noise
► Low positive predictive value
► Filter settings on ECG machine can impact
detection of fragmented QRS notches
► Mostly studied in men
► Current method is extremely complex and
expensive
► Currently requires shielded rooms to reduce
noise
► Prognostic value will need to be assessed in
patients with prolonged QRS complex
► Not usable in patients with cardiac devices
due to noise interference
► Results of larger multicentre studies awaited
► Involves minimally invasive test in patients
not able to perform an exercise tolerance test
► Limited number of known pathological
mutations
► Frequent genetic variants of uncertain
significance
► Time consuming
1001
 Review
QTA measured using either method may vary by gender and age,
with women having a smaller QTA in comparison with men.
A recent study demonstrated age to have a significant impact
on this measurement with individuals above the age of 65 years
exhibiting a wide QTA. This was independent of other ECG
abnormalities (P wave axis, QRS duration, QT interval and heart
rate) and respiratory status.28
Signal-averaged ECG
Signal-­averaged ECG (SAECG) is a non-­invasive method used
to assess subtle changes in the surface ECG that are not usually
visible to the naked eye. This allows identification of low-­
amplitude signals such as late ventricular potentials (LVPs), which
can indicate presence of substrate for VA such as scar tissue. Scar
tissue prolongs conduction through diseased myocardium; this
is often seen at the end of the standard QRS complex. Ashraf
et al demonstrated patients with cardiomyopathy had an RR of
2.8 (CI: 1.1 to 7.28, p=0.02) of having LVPs compared with
healthy controls.29 A subsequent meta-­analysis of 1119 patients
with DCM demonstrated SAECG to be a reasonable predictor
of VA, with positive SAECG associated with a higher arrhythmic
risk (13.6%, OR: 2.11, CI: 1.18 to 3.78, p=0.017).15 There may
be a role for SAECG in identifying high-­risk patients but first
further study and standardisation are needed.
Microvolt T wave alternans (TWA)
Microvolt T wave alternans (TWA) refers to beat-­to-­beat changes
in repolarisation and reflects heterogeneity between cells and
cell layers within the myocardium.30 The mechanism of TWA
can be explained by both action potential duration (APD) resti-
tution theory and calcium handling, which can either be spatially
concordant or discordant. Concordant alternans is when action
potential in neighbouring cells alternates in phase. This means
APD across all regions is long throughout one beat, and short
during the other. Discordant alternans is when APD alternates
out of phase, meaning APD is variable across regions during
each beat. The instability in the discordant phase is thought to
initiate arrhythmias. When the change in APD becomes spatially
discordant, a reduction in cycle length can subsequently result
in unidirectional block causing re-­entry and initiation of VA.31
TWA can also arise from instability in intracellular calcium
cycling. Under normal condition, the amount of calcium ions
released from the sarcoplasmic reticulum and reuptake of
calcium ions should be equal. However, in disease, there is an
exaggerated difference in the balance of ions, causing alternans
of the T wave. This has been shown in an animal model of HF
in which a transfer of SERCA2 + helped to reduce alternans of
the T wave and VAs.32
TWA using the spectral method initially emerged as a prom-
ising tool for risk stratification and was included in the ACC/
AHA/ESC guidelines (2006),33 however the MASTER trial
involving patients post-­myocardial infarction showed that the
risk of arrhythmic events did not differ according to TWA clas-
sification (HR: 1.26, CI: 0.76 to 2.09, p=0.37).34 A substudy
of SCD-­HeFT also found no statistically significant difference
in survival rates between patients who were TWA positive and
those who were negative (HR: 1.24, CI: 0.60 to 2.59, p=0.56).35
TWA using the modified moving average (MMA) technique
has been largely adopted in recent studies. Unlike the spec-
tral method, MMA does not require drugs washout or limit to
achieving a target heart rate. At present, the large observation
study, the EU-­CERT-­ICD, aims to assess the predictive value of
1002
TWA-­MMA in ICD patients at risk of appropriate shocks and
mortality.36
QRS fragmentation
Fragmented QRS (fQRS) is a common ECG finding in patients
with myocardial scar or fibrosis. fQRS is defined as the presence
of additional R’ waves or the notching of R or S wave in the
presence of a narrow QRS complex <120 ms.37
Fragmentation in a narrow QRS complex often represents an
injury to the myocardium, thus a potential substrate delaying
the ventricular conduction. This was demonstrated in a histo-
pathology study of DCM hearts in which fQRS was associated
with strands of fibrous tissue.38 Das et al reported 31 of 153
presented with fQRS, with a 30% incidence rate of an arrhythmic
event (fQRS vs non-­ fQRS; HR: 15.09, CI: 3.30 to 69.06,
p<0.001).37 A meta-­analysis demonstrated 65 of 652 patients
with fQRS reached the endpoint of SCD (OR: 6.73, CI: 3.85
to 11.76, p<0.001).15 However, Cho et al’s 307 patient study
demonstrated QRS was associated with both cardiac and non-­
cardiac death. Patients with NICM with fQRS in the inferior
leads (n=44) had a higher incidence of sustained VA with SCD
(29.5% vs 10.9% vs 8.9%; p=0.001) and all-­cause mortality
(29.5% vs 18.2% vs 14.9%; p=0.068) when compared with the
non-­inferior fQRS (n=55) and non-­fQRS (n=208) groups.39
Magnetocardiography
Magnetocardiography (MCG) is a non-­ contact body surface
method used to measure the magnetic fields produced by elec-
trical currents within the heart. Abnormal repolarisation is a
known mechanism leading to VA and MCG has shown to offer
superior spatial resolution and better detection of currents in
patients with ICM and NICM.40 Korhonen et al studied 49
patients with DCM, 18 with a history of VA who demonstrated
prolonged T wave end with MCG compared with patients with
no VA.41 Similarly, Kawakami et al’s study of 51 patients with
DCM demonstrated left intraventricular disorganised conduc-
tion (LiDC) detected on MCG had an increased risk of major
adverse cardiac events (13 of 22 with LiDC and 3 of 29 without
LiDC, p<0.001).42 Currently, a prospective multicentre trial
(MAGNETO-­SCD) of 270 ICD patients (ischaemic and non-­
ischaemic) are being recruited to assess a new mobile unshielded
MCG device in predicting VA and SCD. It is hoped that this trial
will provide a new non-­invasive device with a prognostic value
in SCD.40
PROMISING FUTURE MARKERS OF VENTRICULAR
ARRHYTHMIA RISK
Cardiac electrical restitution
The cardiac restitution theory has been of great interest to elec-
trophysiologists. The term APD restitution refers to the relation-
ship between the duration of a cardiac action potential and its
preceding diastolic interval (DI). A short DI leads to a short APD
and vice versa. Hence, a change in heart rate creates oscillations
in DI and APD until a steady state is resumed. The relationship
between APD and DI can be plotted to form the ‘restitution
curve’.43
A steep curve causes increased electrical instability, as small
changes in DI lead to growth of oscillations in APD and DI dura-
tion, which can then cause wave-­break and become a substrate
for re-­entry and arrhythmia. With a flat, less steep restitution
curve, changes in the APD are not as marked, and a stable equi-
librium point is reached quicker. It is thought that a restitution
slope of greater than 1 is the critical point for development
Pooranachandran V, et al. Heart 2022;108:998–1004. doi:10.1136/heartjnl-2021-319971

of arrhythmia.43 In addition to the steepness of the restitution
curve, heterogeneity in the restitution properties of different
areas of the myocardium has been shown to be an important
factor in the initiation and maintenance of arrhythmia.43
Our research group has developed two novel surface ECG
biomarkers for SCD in ICM: the Regional Restitution Insta-
bility Index (R2I2) and Peak ECG Restitution Slope (PERS). Our
prospective observational study of 60 patients with ICM (16
of whom experienced VA/SCD) found R2I2 >1.03 and PERS
>1.21 were significant predictors of VA/SCD (p<0.0001).44
A blinded retrospective analysis of R2I2 and PERS in a
non-­ ischaemic population has also been carried out by our
research group. This study looked at 50 patients with NICM
and 29 controls (structurally normal hearts) who had under-
gone an electrophysiology study (EPS). Nine patients reached
endpoint (VA/SCD) during a median follow-­up of 5.6 years.
R2I2 was significantly higher in cases compared with controls
(mean±SEM: 0.99±0.05 vs 0.63±0.04, p<0.001) and there
was a trend towards higher R2I2 in patients experiencing VA
or SCD (mean±SEM: 1.14±0.07 vs 0.95±0.05, p=0.12). Simi-
larly, higher PERS was seen in the study group (1.18 (0.63) vs
1.09 (0.54), p=0.07), and patients who experienced VA/death
(1.46 (0.49) vs 1.13 (0.62), p=0.22). In this study, the grouped
markers, R2I2 >1.03+PERS >1.21, significantly predicted
VA/death (HR: 3.2, CI: 1.2 to 8.8, p=0.02).45 R2I2 and PERS
have more favourable PPVs compared with other risk strati-
fication tools and are therefore better for identifying patients
likely to benefit from an ICD. Nicolson et al used an EPS pacing
protocol to obtain a variety of different diastolic intervals.45 A
non-­invasive method using an exercise stress ECG has since been
developed to plot restitution curves; this is currently undergoing
evaluation in a DCM cohort.
Genetics
The role of genetics in DCM SCD risk stratification, while
currently limited, is rapidly evolving. The mutation of Lamin
A/C gene is thought to cause ~5% of idiopathic DCM and
genetic studies found the frequency of VA was highest (50%) in
LMNA mutation with DCM phenotype (n=8 of 16; CI: 0.26 to
0.74, p=0.59).46
A recent study by Ge and He identified 228 differentially
expressed genes in 17 patients with DCM, of which 2, PPP2R5A
(HR: 1.2, CI: 1.0 to 1.5, p=0.05) and TOMM22 (HR: 1.4, CI:
1.1 to 1.9, p=0.021), were identified as high-­risk genes prone
to VA. The prediction model for survival time (calculated using
regression coefficients and expression value of the risk genes)
demonstrated the survival rates for high-­ risk patients (n=6)
were 37.5% at 2 years, meanwhile low-­ risk patients (n=12)
were 55.6% at 8 years.47 Although this study was limited by
sample size, the prediction model proposed a personalised treat-
ment option tailored for individual patients.
Similarly, in addition to LMNA, Ebert et al identified TTN,
PLN, SCN5A, RBM20 and DSP genes to be associated with
ventricular tachycardia in 37 of 98 patients with DCM. The
37 patients with a pathogenic variant were associated with a
reduced VT-­free survival (HR: 1.9, CI: 1.1 to 3.4; p=0.02).48
Conclusion
Recent studies have drawn into question the use of ICDs in the
treatment of patients with DCM. This highlights the need to
develop robust tools to identify patients most likely to benefit
from life-­saving device therapy. Current guidelines use methods
such as LVEF which have a poor PPV. The evidence base for
Pooranachandran V, et al. Heart 2022;108:998–1004. doi:10.1136/heartjnl-2021-319971
Review
novel approaches using cardiac MRI, electrical restitution-­based
biomarkers and genetics is growing and it is hoped that this will
lead to a more tailored approach that improves risk stratification
in the future.
Twitter G Andre Ng @g_andre_ng
Contributors  The authors confirm contribution to the paper as follows:
conception—VP; draft manuscript preparation—VP, WN, ZV, XL and GAN. All
authors reviewed and approved the final version of the manuscript.
Funding  VP and ZV are supported by the NIHR Leicester Biomedical Research
Centre with Research Fellowships. GAN is supported by a British Heart Foundation
Programme Grant (RG/17/3/32774). XL, WN and GAN are supported by a Medical
Research Council Biomedical Catalyst Developmental Pathway Funding Scheme (MR/
S037306/1).
Competing interests  GAN reports grants from Boston Scientific, grants and
personal fees from Abbott, personal fees from Biosense Webster, personal fees from
Catheter Precision, personal fees from Daiichi Sankyo, outside the submitted work.
The University of Leicester has applied for patents for the Regional Restitution
Instability Index and Peak ECG Restitution Slope techniques on behalf of WN and
GAN.
Patient and public involvement  Patients and/or the public were not involved in
the design, or conduct, or reporting, or dissemination plans of this research.
Patient consent for publication  Not required.
Provenance and peer review  Not commissioned; externally peer reviewed.
ORCID iD
G Andre Ng http://orcid.org/0000-0001-5965-0671
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