Journal of
Clinical Medicine
Review
Arrhythmic Risk Stratification among Patients with
Hypertrophic Cardiomyopathy
Francesco Santoro 1, * , Federica Mango 1 , Adriana Mallardi 1 , Damiano D’Alessandro 1 , Grazia Casavecchia 1 ,
Matteo Gravina 2 , Michele Correale 1 and Natale Daniele Brunetti 1
Citation: Santoro, F.; Mango, F.;
Mallardi, A.; D’Alessandro, D.;
Casavecchia, G.; Gravina, M.;
Correale, M.; Brunetti, N.D.
Arrhythmic Risk Stratification among
Patients with Hypertrophic
Cardiomyopathy. J. Clin. Med. 2023,
12, 3397. https://doi.org/10.3390/
jcm12103397
Academic Editors: Sophie I.
Mavrogeni and Carlos Escobar
Received: 16 February 2023
Revised: 7 May 2023
Accepted: 9 May 2023
Published: 10 May 2023
Copyright: © 2023 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
J. Clin. Med. 2023, 12, 3397. https://doi.org/10.3390/jcm12103397
1 Cardiology Unit, Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy
2 Radiology Unit, University Polyclinic Hospital of Foggia, 71100 Foggia, Italy
* Correspondence: dr.francesco.santoro.it@gmail.com; Tel.: +39-3802695183
Abstract: Hypertrophic cardiomyopathy (HCM) is a cardiac muscle disorder characterized by gener-
ally asymmetric abnormal hypertrophy of the left ventricle without abnormal loading conditions
(such as hypertension or valvular heart disease) accounting for the left ventricular wall thickness or
mass. The incidence of sudden cardiac death (SCD) in HCM patients is about 1% yearly in adults,
but it is far higher in adolescence. HCM is the most frequent cause of death in athletes in the Unites
States of America. HCM is an autosomal-dominant genetic cardiomyopathy, and mutations in the
genes encoding sarcomeric proteins are identified in 30–60% of cases. The presence of this genetic
mutation carries more than 2-fold increased risk for all outcomes, including ventricular arrhythmias.
Genetic and myocardial substrate, including fibrosis and intraventricular dispersion of conduction,
ventricular hypertrophy and microvascular ischemia, increased myofilament calcium sensitivity and
abnormal calcium handling, all play a role as arrhythmogenic determinants. Cardiac imaging studies
provide important information for risk stratification. Transthoracic echocardiography can be helpful
to evaluate left ventricular (LV) wall thickness, LV outflow-tract gradient and left atrial size. Addition-
ally, cardiac magnetic resonance can evaluate the prevalence of late gadolinium enhancement, which
when higher than 15% of LV mass is a prognostic maker of SCD. Age, family history of SCD, syncope
and non-sustained ventricular tachycardia at Holter ECG have also been validated as independent
prognostic markers of SCD. Arrhythmic risk stratification in HCM requires careful evaluation of
several clinical aspects. Symptoms combined with electrocardiogram, cardiac imaging tools and
genetic counselling are the modern cornerstone for proper risk stratification.
Keywords: arrhythmias; genetic testing; hypertrophic cardiomyopathy; HCM; risk score; sudden
cardiac death
1. Introduction
Hypertrophic cardiomyopathy (HCM) is a cardiac muscle disorder characterized
by generally asymmetric abnormal hypertrophy of the left ventricle without abnormal
loading conditions (such as hypertension or valvular heart disease) accounting for the
left ventricular wall thickness or mass [1,2]. In most of the cases, mutations in the genes
encoding sarcomeric proteins are an autosomal dominant trait, responsible for the observed
abnormality [1,2]. It is a quite common disease with an estimated prevalence of 1:500 in the
general population, whereas in children the prevalence is much lower [3–5].
Sudden cardiac death (SCD), mainly caused by potentially fatal and unpredictable
malignant ventricular arrhythmias (VAs) is the most adverse complication of HCM [6,7],
with an annual incidence of SCD of approximately 1% in adult HCM patients and far
higher in subgroups, such as pediatric HCM patients [8]. It may occur as the initial disease
presentation, frequently in asymptomatic or mildly symptomatic young people and even
athletes [9].
Several mechanisms predispose HCM patients to re-entrant VA. Genetic and myocar-
dial substrate, including fibrosis and intraventricular dispersion of conduction, disruption
https://www.mdpi.com/journal/jcm
J. Clin. Med. 2023, 12, 3397 2 of 14

of intercalated discs and myofibrillar disarray, ventricular hypertrophy and microvascular

ischemia, increased myofilament calcium sensitivity and abnormal calcium handling all
play a role as arrhythmogenic determinants [10–12]. Precipitating factors include intense
physical exertion and participation in competitive sport or intrinsic features of the disease,
such as left ventricular outflow obstruction, which can trigger life-threatening ventricular
tachyarrhythmias [7].
Pharmacologic therapy has not proved to be effective alone in providing protection
from SCD if compared to implantable cardioverter defibrillators (ICDs). If ICD implan-
tation in secondary prevention is a well-established practice, the real challenge stands in
identifying a special subset of HCM patients who are at high risk of SCD prior to a first
event and would benefit from an ICD [13]. Therefore, systematic arrhythmic risk stratifica-
tion at initial evaluation and then periodically is strongly recommended by current clinical
guidelines [14]. The aim of this review is to highlight and discuss the most important factors
associated with SCD in HCM to guide more comprehensive and exhaustive arrhythmic
risk stratification.

2. Demographic and Clinical Characteristics

SCD can occur independently both in male and female HCM patients. However, the
role of gender is still a matter of debate. While male patients more frequently show fibrosis
on histological examination and consequently usually suffer more often from VA, no study
has succeeded in proving a significant association between sex and SCD [2]. Age is a crucial
point in SCD related to HCM. Given the potential lifetime risk of SCD in HCM patients,
the incidence of SCD is far higher in adolescence and early adulthood, especially in those
under the age of 35, with HCM being the most frequent cause of death in athletes in the
US [15]. It is generally infrequent in patients older than 60 years as proved by Spirito et al.,
who demonstrated a significant reduction in SCD risk with increasing age [16].
Family history of SCD (FHSCD) is one of the major factors associated with arrhythmic
risk in HCM patients. Personal anamnesis positive for FHSCD events, especially if multiple
or occurring at a younger age, carries an increased risk of SCD among individuals of ap-
proximately 20% if compared to family without an obvious family history [17]. Nonetheless,
definitions of FHSCD may vary considerably—with FHSCD generally considered when
one or more first-degree relatives under 40 or 50 years of age dies incidentally within 1 h
(witnessed) or 24 h (asymptomatic observation) after the symptom appears—thus influ-
encing the effective individual’s risk [18]. However, the average hazard ratio of FHSCD
(irrespective of definition) was 1.27 (95% confidence interval (CI) 1.16–1.38) in a systematic
review [19]. Different mechanisms responsible for FHSCD have been pointed out, although
it is often a dilemma to identify the exact cause of death in the relatives. Considering the
genetic nature of the disease, with affected relatives sharing the same genetic defect and
with specific mutations associated with a worse prognosis, the extent of the environmental
exposure cannot be adequately measured, all translating into a significant variability as to
the genotype-phenotype correlation [20,21].
Syncope is defined as a temporary loss of consciousness secondary to transient global
cerebral hypoperfusion. Spirito et al. defined unexplained syncope as syncope “of un-
known origin, when it occurred in circumstances not clearly consistent with a neurally
mediated event, i.e., without apparent explanation at rest or during ordinary daily activities,
or during an intense effort” [16]. Multiple studies have shown that there is a significant
association between unexplained syncope and SCD. In addition, since there are several
causes of syncope in HCM including arrhythmias (sustained ventricular arrhythmias,
supraventricular tachycardias, atrial fibrillation, brady-arrhythmias), exercise-related left
ventricular outflow-tract obstruction (LVOTO), mitral regurgitation, ischemia and microvas-
cular angina, although even neurally mediated syncope (vasovagal and situational) and
orthostatic hypotension are possible, it is very important to deeply analyze the clinical
context in which the syncope takes place [22,23]. Given such a high possibility of causes,
clues from the patient and the witnesses may help. Additional attention should also be
J. Clin. Med. 2023, 12, 3397 3 of 15

J. Clin. Med. 2023, 12, 3397 exercise-related left ventricular outflow-tract obstruction (LVOTO), mitral regurgitation, 3 of 15
exercise-related
ischemia left ventricular
and microvascular outflow-tract
angina, although even obstruction
neurally (LVOTO),
mediatedmitral syncope regurgitation,
(vasovagal
J. Clin. Med. 2023, 12, 3397 ischemia
and and microvascular
situational) and orthostatic angina, although even
hypotension neurallyitmediated
are possible, syncope (vasovagal
is very important to deeply3 of 14
J. Clin. Med. 2023, 12, 3397
and situational)
analyze the clinical
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in which the syncope
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(LVOTO), very mitral
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from the the syncope
patient and takes
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ischemia and microvascular angina, although even neurally mediated syncope (vasovagal place
witnesses [22,23].
may Given
help. such a high
Additional
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paidfrom
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or recurrent witnesses if may help.inAdditional
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occurs the young
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occurs initthe is very
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recent past
attention
and in
analyze the should
recent also
past be
(<6 paid
months)to exertional
[24]. or recurrent syncope if it occurs insuch ayoung
the
(<6 the clinical
months)
exercise-related left context
[24].
ventricular in which the syncope
outflow-tract takes place
obstruction (LVOTO), [22,23]. Given
mitral regurgitation, high
and in the recent
There
possibility is no
of past (<6
particular
causes, cluesmonths)
association
from [24].
the between
patient andNYHAthe functionalmay
witnesses classhelp.and Additional
the risk of
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and is no particular association between NYHA functional class (vasovagal
and the risk of
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attention is microvascular
withshould
SCD no being
particular
also be paid
angina,
association
reported to
although
in all NYHA
exertional between
or
evenNYHAneurally
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recurrent
mediated
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However,
syncope if it
syncope
class
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occurs and in the
factors
the risk
young of
are
and SCD, with
situational) SCD
and being
orthostatic reported in
hypotension all NYHA
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itHowever,However,
is very important several factors are
to deeply
SCD,
involved
and in with
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functional
recent past reported
limitations
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HCM
[24].the NYHA classes
including [25].
the degree of several
diastolic factors
dysfunction, are
analyzeinvolved
the in functional
clinical context limitations
in which insyncope
HCM including
takes the [22,23].
place degree of diastolic
Given suchdysfunction,
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involved
LVOTO, There inisfunctional
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particular and in HCM
microvascular
association including
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NYHA the
and degree
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arrhythmias,
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especially
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LVOTO,
possibility of cardiac
causes, ischemia
clues and
from microvascular
the patient andangina
the and atrial
witnesses arrhythmias,
may help. especially
Additional
J. Clin. Med. 2023, 12, 3397 LVOTO,
atrial
SCD, with cardiac
fibrillation
SCD (Tableischemia
(Table
being and microvascular
1) [26].
reported in all NYHA angina [25].
classes and atrial
However, arrhythmias,
several especially
3 of 15
atrial
fibrillation
attention should
fibrillation also be
(Table
1)
1)
[26]. to exertional
paid
[26]. or recurrent syncope if it occurs in factors
the young are
involved
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[24].HCM including the degree of diastolic dysfunction,
Table Demographic characteristics associated with the risk of sudden cardiac death.
LVOTO, Table
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Legend:
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exercise-related left and magnetic
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place of sudden
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magnetic [24].
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consider
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microvascular
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cal abnormalities in HCM, occurring at younger ages
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(ECG, someBlood
Systolic of thePressure
ECG parameters(SBP) including
Response
atrial fibrillation tomicrovolt
Exercise, T-wave
NYHA class
alternans, T-peak/T-end no particular association degree
🔴
interval, fragmented QRS complexes and QT duration were found of diastolic
Cardiopulmonary
3.1. Electrocardiogram Exercise
and Holter Test) ECG
to be well correlated with myocardial fibrosis and arrhythmic dysfunction,
additional
events LVOTO,Given its fast
attention
[27,28].
3.Unexplained
3.1. Electrocardiogram
Non-Invasive
The syncope
Markers
twelve-lead and Holter strong
(ECG,ECG Systolic
electrocardiogram association
Blood Pressure
(ECG) has (SBP) beenResponse used toangina
Exercise,
and easy-to-perform evaluation, surface ECG analysis should microvascular
required betoincluded
if exertional
always evaluate
orand in each
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The twelve-lead
electrophysiological Exercise Test)
electrocardiogram (ECG)
abnormalities in HCM, and some of theatrial has been used
ECGfibrillation to
parameters including evaluate
patient evaluation. recurrent
electrophysiological
microvolt
3.1. T-wave
Electrocardiogram
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alternans,
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Holter ECG in HCM,
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(ECG,T-peak/T-end
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with
Blood
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electrocardiogram fragmented
myocardial
Pressure
(ECG) has fibrosis
(SBP)
in theconsider QRS and
Response
amplitude
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usedarrhythmic
to
or the and
Exercise,
to morphology
evaluateQT of
events
functional
duration
[27,28]. were
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the T-wave. The
electrophysiological found
its fast to
and
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easy-to-perform
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in HCM,inand myocardial
evaluation,
patients
somewithsurface
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HCM ECGmay and
analysis arrhythmic
should
possibly
parameters be events
always
explained as
including
limitations, including
[27,28].
be included
a
microvolt
3.1. Given
result in
T-waveits
of
Electrocardiogrameachfast and
patient
inhomogeneous
alternans, easy-to-perform
evaluation.
and Holterno action,
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ECG evaluation,
potential surface
propagation
interval, fragmented ECG
and analysis
heterogeneous
QRS should
complexes always
repolarization
and QT
NYHA class particular association degree of diastolic
be included
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were in
microvolteach
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alternans
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found to beelectrocardiogram (MTWA)
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[29]. Özyılmaz
myocardial of microscopic
S et al.
fibrosis tried alternans
to assess measured
the relationship
The
The twelve-lead
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dysfunction, usedarrhythmic
LVOTO,
to measured events
evaluate
in microvolts
between
[27,28]. Given on
the
its every
presence
fast and heartbeat
of MTWA and (MTWA)
easy-to-perform is evidenced
and the consists
in the
predicted
evaluation, of microscopic
amplitude
5-year
surface oforSCD
risk analysis
ECG alternans
the among
morphology
should patients
always of with
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in microvolts on every abnormalities
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evidenced in theofamplitude
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or the angina
morphologyincluding
and of
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be T-wave.
hypertrophic
included The alternation
cardiomyopathy
in eachalternans, of T-waves
patient evaluation. (HCM). in patients
Authors with
found HCMthat may
patientspossibly
with be
MTWA explained
on a Holter
microvolt
the T-wave. T-wave
The alternation T-peak/T-end
of T-waves in interval,with
patients fragmented
HCM atrial
mayQRS complexes
fibrillation
possibly be and QT
explained
as aTheresult
ECG had of
microvolthigherinhomogeneous
risk
T-wave of ventricular
alternans action,
(MTWA) potential
arrhythmias
consists propagation
[30].
of microscopic and
alternansheterogeneous
measured
duration
as microvolts
a resultwereof found to be well
inhomogeneous correlated
action, with myocardial
potential fibrosis and
propagation and arrhythmic
heterogeneous events
in Akbo onğa et al.heartbeat
every [31] tried and to evaluate
is evidenced theinelectrocardiographic
the amplitude or the T-wave
morphology peak of to end
[27,28]. Given
3. Non-Invasive its fast
Markersand easy-to-perform
(ECG, Systolic evaluation,
Blood Pressure surface
(SBP) ECG analysis
Response should
toHCM.
Exercise,always
the interval
T-wave. The (Tp–e) and
alternation Tp–e/QT corrected (QTc) ratio among patients
of T-waves in patients with HCM may possibly be explained with The patients
be included
Cardiopulmonary in each patient evaluation.
Exercise Test)
as aThewere
resultdivided
of into two groups:
inhomogeneous those with
action, VA (n = propagation
potential 26) and those without and VA (n = 40). Tp–e
heterogeneous
microvolt
3.1. Electrocardiogram
interval T-wave
and Holter
was significantly alternans
ECG (MTWA)
longer consists ratio
and Tp–e/QTc of microscopic
were significantlyalternans measured
higher in HCM
in microvolts
patients on
withevery
VA. heartbeat and is evidenced in the amplitude or the morphology of
The twelve-lead electrocardiogram (ECG) has been used to evaluate
the T-wave. The alternation of T-waves in patients with HCM may possibly be explained
electrophysiological abnormalities in HCM, and some of the ECG parameters including
as a result of inhomogeneous action, potential propagation and heterogeneous
microvolt T-wave alternans, T-peak/T-end interval, fragmented QRS complexes and QT
duration were found to be well correlated with myocardial fibrosis and arrhythmic events
[27,28]. Given its fast and easy-to-perform evaluation, surface ECG analysis should always
be included in each patient evaluation.
J. Clin. Med. 2023, 12, 3397 4 of 14

The fragmented QRS (fQRS) complex reflects intraventricular conduction delay and
may then be a superficial marker for myocardial fibrosis. Myocardial fibrosis in HCM
patients usually has a patchy distribution, and it may not always be detected by patho-
logical Q-waves on a 12-lead ECG. Konno T. et al. demonstrated that fQRS may have a
substantially higher sensitivity and diagnostic accuracy if compared to pathological QRS
in detecting myocardial fibrosis in HCM patients [32]. Considering its strong association
with myocardial fibrosis, according to Ki-Woon Kang et al., fQRS may be a good candidate
marker for prediction of VA in HCM patients [33].
Non-sustained ventricular tachycardia (NSVT), defined as three or more consecutive
ventricular beats with a frequency of at least 120 beats per minute (bpm) lasting for less
than 30 s, and not causing hemodynamic instability, is a very common finding in HCM
patients and is often documented in Holter monitoring [34].
NSVT is more frequent with increasing hypertrophy, which may automatically reflect
an increased grade of fibrosis and myofibrillar disarray, which themselves are useful
predictors of the intrinsic arrhythmic risk of the disease [35,36].
Maron et al. [37] and McKenna et al. [38] showed that in HCM patients NSVT is more
common in SCD patients. However, several studies examined the relationship between
NSVT and SCD in HCM patients with a prevalence of NSVT ranging between 17% and
32% due to a non-uniform NSVT definition [39,40]. Even though a high incidence rate of
NSVT (approximately 20–30%) in HCM patients over the age of 40 is reported, the risk of
SCD linked to NSVT seems to be lower in older patients. According to Monserrat et al.,
a 4-fold increase in the risk of SCD was observed in patients aged ≤30 years with NSVT,
(univariable HR, 4.35; 95% CI, 1.54–12.28; p = 0.006), but no effects were observed in older
patients (univariable HR, 2.16; 95% CI, 0.82–5.69; p = 0.1), with frequency, duration and rate
of NSVT not having predictive value [41].

3.2. Systolic Blood Pressure (SBP) Response to Exercise

An abnormal blood pressure response to exercise testing, defined as either a drop of at
least 20 mmHg during effort or a failure to increase from rest to peak exercise by at least
20 mmHg, is a quite common finding in HCM patients, occurring in more than one out of
three HCM patients [42].
Several mechanisms have been studied and are believed to be responsible for this phe-
nomenon, including a hemodynamic hypothesis with an inappropriate drop in systemic vas-
cular resistance, despite an appropriate increase in cardiac output, and/or LVOTO [43,44].
Although the prognostic role of systemic blood pressure response to exercise is still de-
bated [45], it has been introduced as an additional risk factor from the European society of
Cardiology (ESC) SCD 2022 guidelines and should be evaluated among patients with an
intermediate SCD risk.

3.3. Cardiopulmonary Exercise Test

Cardiopulmonary exercise testing (CPET) data have been shown to improve the risk
stratification of patients with heart failure. In the context of hypertrophic cardiomyopathy,
a reduced oxygen consumption peak, an increased ventilation/carbon dioxide production
slope and chronotropic incompetence correlate with a worse prognosis [46].
Two research groups of Magri et al. [47] and Masri et al. [48] showed that a reduced
VO2 peak (i.e., <50%) and high VE/VCO2 slope are associated with overall mortality and
SCD in HCM. Recently, the 2020 Guidelines on sports cardiology from ESC included in
the indications for the execution of CPET the evaluation of exercise-induced symptoms or
arrhythmias and the assessment of systolic blood pressure changes during exercise [49]
(Table 2).
 possibility
and of causes,
infibrillation
atrial the recent clues
past (<6
(Table from [24].
1) months)
[26]. the patient and the witnesses may help. Additional
attention should also be paid to exertional
There is no particular association between or recurrent
NYHAsyncope
functional if itclass
occurs
andin the
the risk
youngof
and
Tablein
SCD, 1. the
with recent
SCD being
Demographic past (<6 months)
andreported [24].
in all NYHAassociated
clinical characteristics classes [25]. However,
with the severalcardiac
risk of sudden factors are
death.
There
Legend:
involved inisfunctional
CMR =nocardiac
particular
magneticassociation
limitations resonance,
in HCM between
FHSCD NYHA
including the functional
= family class
historyofofdiastolic
degree sudden and the risk
cardiac of
death,
dysfunction,
SCD, with
LVOTO
LVOTO, leftSCD
= cardiac being
ventricular
ischemiareported in all
outflow-tract NYHA angina
obstruction,
and microvascular classes
NHYA [25].
= New
and However, several
Yorkarrhythmias,
atrial Heart factors
Association, VAare=
especially
J. Clin. Med. 2023, 12, 3397 5 of 14
ventricular
involved
atrial inarrhythmias.
functional
fibrillation (Tablelimitations
1) [26]. in HCM including the degree of diastolic dysfunction,
LVOTO, cardiac ischemia and microvascular angina and atrial arrhythmias, especially
atrial 1.
Table fibrillation
Demographic (Table
and1)clinical
[26]. characteristics associated with the risk of sudden cardiac death.
TableCMR2. Non-invasive test and prognostic role in patients male patients
withhistory
hypertrophic show more
cardiomyopathy.
Legend:
Sex = cardiac magnetic resonance,
no FHSCD
significant = family
association of sudden cardiac death,
LVOTO
Table 1. =Demographic
left ventricularandoutflow-tract obstruction,
clinical characteristics NHYA with
associated = New fibrosis
theYork on
risk Heart CMR and death.
Association,
of sudden cardiac VA =
Type of Test Evaluation Prognostic
experience Role
VA more often
ventricular
Legend: CMR arrhythmias.
= cardiac magnetic resonance, FHSCD = family history of sudden cardiac death,
LVOTO = left ventricular outflow-tract obstruction,
Non-sustained NHYA = New York Heart Association, VA =
ventricular
Holter ECG
ventricular
Age arrhythmias. tachycardia
strong association especially
Can stratifyin adolescence
arrhythmic risk
male patients show more
Sex no significant
Systolic association
blood pressure during and early adulthood
Exercise Testing fibrosis on CMR and
exercise test 🔴
male patients
Sex no significant association
Prognostic
experience VAshow
role ismore more
still debated
often
FHSCD strong association particularly
fibrosis on CMR and or
if multiple
occurring
experience atVA younger
more ages
often
AgeCardiopulmonary Exercise strong association
Vo2 peak$Ve/Vco2 especially
Reduced Vo2 in peak
adolescence
(<50%);
Test 🔴Highearly
Ve/Vco2 slope is associated
and adulthood
Age strong association additional
with overallin
especially attention
mortality
adolescence
Unexplained syncope strong association 🔴
required
and earlyifadulthood
exertional or
FHSCD strong association particularly if multiple or
4. Role of Genetics recurrent
🔴
occurring at younger ages
FHSCDHCM is an autosomal-dominant strong association
genetic cardiomyopathy, 🟡
particularly
and mutationsif multiple or genes
in the
🔴
consider functional
encoding sarcomeric proteins are identified in 30–60% ofadditional occurring
index cases. at younger ages
Eight sarcomeric
attention
Unexplained syncope
are the moststrong association limitations, including
gene mutations common described in literature required if exertional or MYH7b,
🔴 for HCM: MYBPC3,
NYHA
MYL2, class
MYL3, TNNT2, TNNI3, no particular ACTC1 (Table 3)degree
TPM1 andassociation [14]. The
additional of diastolic
rate
attentionof major adverse
Unexplained syncope strong association recurrent
cardiovascular events (MACEs) and premature death is dysfunction, significantly LVOTO,
required if exertionalin
higher orpatients
🟡
microvascular
carrying mutations in the genes encoding sarcomeric proteins recurrentfunctional and
consider
than in angina
negative ones [50].
Several analyses have shown that the presence of a mutation in the gene encoding sar-
atrial fibrillation
🟡
limitations, including including
comeric proteins carries a more than 2-fold increased risk for all outcomes,
NYHA class no particular association consider
degree offunctional
diastolic
ventricular arrhythmias,
3. Non-Invasive Markers (ECG, whichSystolic
are more frequent
Blood in this(SBP)
Pressure groupResponse
of patientsto[51]. Mutation of
Exercise,
limitations, including
dysfunction, LVOTO,by younger
the MYH7 geneExercise
Cardiopulmonary is associated
Test)with a more aggressive phenotype, characterized
NYHA class no particular association degree of diastolic
microvascular risk angina
of SCD,and
3.1. onset age, higher degree
Electrocardiogram of left
and Holter ECG ventricular hypertrophy and higher
dysfunction, LVOTO,
resulting
in a poor prognosis [52]. This group of patients also suffers atrialfrom
fibrillation
a higher incidence of
The fibrillation
atrial twelve-lead (AF),electrocardiogram
which is associated with (ECG)other has been
factors used
riskmicrovascular such asangina toleft evaluate
and (LA)
atrium
electrophysiological
enlargement, left abnormalities
ventricle (LV) in
wall HCM, and
thickness some
and LV of the ECG
atrial
outflow-tract parameters
fibrillation
obstruction. including
Compared
3. Non-Invasive Markers (ECG, Systolic Blood Pressure (SBP) Response to Exercise,
microvolt
with MYH7T-wave genealternans,
mutation, T-peak/T-end
patients withinterval,
MYBPC3fragmented
mutation usually QRS complexes
develop the and QT at
disease
Cardiopulmonary Exercise Test)
duration
laterwere
3. Non-Invasive found
aElectrocardiogram
age and to be
Markers
have well correlated
(ECG, with myocardial
Systolic Blood Pressure fibrosis
(SBP) and arrhythmic
Response to Exercise, events
3.1.
[27,28]. Given its fast andaeasy-to-perform
and
favorable
Holter ECG progression of the disease
evaluation, surface ECG
although
analysis
they
should
are associated
always
Cardiopulmonary
with a non-negligibleExercise Test)
risk of SCD compared to the healthy population. Because of the
Therisk,
be included twelve-lead
inintense
each patient electrocardiogram
evaluation. (ECG) has been used to evaluate
3.1. Electrocardiogram and Holter ECG be routinely discouraged, especially in patients with the
high exercise should
electrophysiological
The microvolt abnormalities
T-wave alternans
MYH7 gene mutation. Mutations in the TNNT2in HCM,
(MTWA) and somegene
consists ofofmicroscopic
themayECG parameters
manifestalternans including
with measured
mild LV wall
The
microvolt
in microvolts twelve-lead
T-wave electrocardiogram
alternans, T-peak/T-end (ECG)
interval, has
fragmented been QRS used
complexes to evaluate
and QT
thickeningon butevery
haveheartbeat
more severe andmyocyte
is evidenced in the
disarray, amplitude
younger or the
patients andmorphology
a high of
incidence
electrophysiological
duration
the of
T-wave.were found
The Given abnormalities
to be
alternation well in HCM,
correlated
of T-waves withand some
myocardial
in patients
patients carrying of
with HCM the ECG
fibrosis parameters
and
may possibly arrhythmic including
events
SCD [53]. the clinical profile, mutations in thebe explained
genes encoding
microvolt
[27,28].
as a resultT-wave
Given its alternans,
fast andshould
ofproteins T-peak/T-end
easy-to-perform
inhomogeneous action, interval,
evaluation,
potential fragmented
surface ECG
propagation QRS complexes
analysis
and shouldand
heterogeneous QT
always
sarcomeric benefit from more intensive clinical surveillance. The ESC
duration
be included were found to be
in each recommend well correlated
patient evaluation. with myocardial fibrosis and arrhythmic events
2022 guidelines genetic counselling and testing in all HCM patients (Class I,
[27,28]. Given its fast and easy-to-perform evaluation,
consistssurface ECG analysis should always
Level B), emphasizing alternans
The microvolt T-wave the value(MTWA)
of the genotype of
inmicroscopic
guiding clinical alternans measured
management and
be microvolts
in included inon each patient
every evaluation.
heartbeat and also
is evidenced
determining prognosis [14]. They representin anthe amplitude
additional riskorfactor
the morphology
for HCM patients of
the at The
T-wave.microvolt T-wave
The alternation
intermediate SCD riskalternans
of T-waves
[14]. (MTWA) consists
in patients withofHCMmicroscopic alternans
may possibly measured
be explained
in microvolts on every heartbeat and is evidenced in the
as a result of inhomogeneous action, potential propagation and heterogeneousamplitude or the morphology of
the Table
T-wave. The alternation of T-waves in patients with HCM
3. Sarcomeric gene mutation described in hypertrophic cardiomyopathy. may possibly be explained
as a result of inhomogeneous action, potential propagation and heterogeneous
Gene Population Frequency Protein
Thick Myofilament Protein
MYBPC3 25% Myosin binding protein-
MYH7B 20% Myosin heavy chain
MYL2 <1% Regulatory myosin light chain
MYL3 <1% Essential myosin light chain
J. Clin. Med. 2023, 12, 3397 6 of 14

Table 3. Cont.

Gene Population Frequency Protein

Thin Myofilament protein:
TNNT2 1.3% Cardiac troponin T
TNNI3 1.3% Cardiac troponin I
TPM1 >5% Tropomyosin
ACTC1 <1% Cardiac α-actin

5. Cardiac Imaging (Echocardiogram and Cardiac Magnetic Resonance)

Cardiac imaging plays a crucial role in management of HCM patients. The gold stan-
dard for diagnosis of HCM, assessment of treatment efficacy and prognosis is transthoracic
echocardiography supported by cardiac magnetic resonance (CMR) imaging, which plays
a central role in the diagnostic process. In 2014, the ESC validated an SCD risk prediction
model that provides a 5-year SCD risk score for HCM patients. Echocardiography provides
three of the seven parameters required in the 5-year SCD risk stratification score (LV wall
thickness, LA size, LVOT gradient) [54]. LV hypertrophy is associated with increasing
prevalence of NSVT and exercise-induced VAs. Several studies showed a significant cor-
relation between severe hypertrophy of LV and SCD. Severe left ventricular hypertrophy
(LVH) may contribute to SCD due to its effects on myocardial architecture, intramural small
vessel disease and mass-to-coronary flow mismatch. A cut-off of maximum wall thickness
≥30 mm was used to indicate severe hypertrophy and was seen to be independently asso-
ciated with SCD [2]. The LV wall thickness must be measured accurately at end-diastole,
and elements attached to but not incorporated in the septum, such as papillary muscles,
false tendons and right ventricular (RV) trabeculation, should be excluded because wall
thickness could be overestimated. Left atrial diameter, quantified with echocardiography in
the parasternal long axis, has been associated with SCD in HCM. AF and left atrial size may
reflect the risk of SCD, as they may both relate to atrial remodeling secondary to increasing
ventricular fibrosis, which makes the myocardium more susceptible to arrhythmias [7].
Diastolic dysfunction is common in HCM and results in elevated filling pressures and left
atrial dilatation, so it is also a predictor of arrhythmic events. Patients with a restrictive
diastolic filling pattern have adverse outcomes and should be observed closely. LVOTO
is caused by systolic anterior movement of the mitral valve into the outflow tract, which
creates a physical barrier impeding the flow of blood from the ventricle to the aorta during
systole. Significant dynamic obstruction is defined as the presence of an instantaneous
peak basal gradient ≥30 mmHg or after provocative maneuvers (Valsalva, standing and
exercise) ≥50 mmHg [55]. Several studies reported a significant association between SCD
and LVOTO. LVOTO can cause SCD either through a severe reduction in cardiac output
or by myocardial ischemia due to the increase in left ventricular filling pressure, thus
creating a substrate for ventricular arrhythmias. Although not included in the ESC risk
calculator, additional factors, including LV systolic dysfunction, apical aneurysm, extensive
LGE on CMR and presence of sarcomeric mutations, should be considered as possible
modifiers of SCD risk [14]. Approximately 2–5% of patients with HCM, typically those
with mid-ventricular hypertrophy, develop a left ventricular apical aneurysm associated
with regional scarring. A higher incidence of clinical events during follow-up have been
reported in this subgroup, including SCD and ventricular arrhythmia [6]. CMR allows
accurate measurement of LV wall thickness, LV mass and LV ejection fraction and is the
gold standard method for tissue characterization and volumetric evaluation of cardiac
chambers. The extent of myocardial scarring on CMR has been shown to predict HCM-
related adverse events. Myocardial fibrosis plays a central role in the genesis of arrhythmias
through mechanisms of dispersion of electrical activity and formation of re-entry circuits
that are responsible for the genesis of ventricular arrhythmias; this, as assessed by CMR,
is independently associated with the occurrence of NSVT [56]. LGE is present in 65% of
 mass and LV ejection fraction and is the gold standard method for tissue characterization
and volumetric evaluation of cardiac chambers. The extent of myocardial scarring on
CMR has been shown to predict HCM-related adverse events. Myocardial fibrosis plays a
J. Clin. Med. 2023, 12, 3397 central role in the genesis of arrhythmias through mechanisms of dispersion of electrical 7 of 14
activity and formation of re-entry circuits that are responsible for the genesis of ventricu-
lar arrhythmias; this, as assessed by CMR, is independently associated with the occur-
rence of
HCM NSVT typically
patients, [56]. LGEinisapresent
patchy in 65% of pattern
mid-wall HCM patients,
in areas typically in a patchy
of hypertrophy and atmid-
the
wall pattern in areas of hypertrophy and at the anterior and posterior RV insertion
anterior and posterior RV insertion points (Figures 1 and 2). A multicenter study found points a
(Figures
linear 1 and 2). A
correlation multicenter
between study
the risk found
of SCD a linear
and amountcorrelation between the
of LGE. Extensive LGEriskonofCMR
SCD
and amount
defined of LGE.
as ≥15% of LVExtensive
mass hasLGE
beenon CMR defined
suggested as goodaspredictor
≥15% of of
LVSCD
mass hasappropriate
and been sug-
gested
ICD as goodinpredictor
therapies of SCD and appropriate ICD therapies in adults [57].
adults [57].

Figure 1.1. Asymmetric

Asymmetrichypertrophic
hypertrophic cardiomyopathy;
cardiomyopathy; thickening of the
thickening ofinterventricular septumseptum
the interventricular which
which
can be can be evaluated
evaluated with thewith the T1-TSE
T1-TSE four-chamber
four-chamber sequences
sequences (a); no(a); no evident
evident edema edema
in theinshort
the short
axis
axis T2-STIR
T2-STIR sequence
sequence (b); irregular
(b); irregular depositsdeposits of mesocardial
of mesocardial paramagnetic
paramagnetic contrast in
contrast medium medium
PSIR-TFE in
PSIR-TFE sequences
sequences in fourfor
in four chambers chambers
the studyforofthe study
“late of “late gadolinium
gadolinium enhancement” enhancement” (c); T1
(c); T1 mapping map-
analysis
ping analysis
showing showing
a diffuse a diffuse
increase increase
in signal of the in signalsegments
various of the various
of the segments
walls of theofleft
theventricle
walls of as
thefrom
left
ventricle as from minimal diffuse interstitial fibrotic deposits (d).
minimal diffuse interstitial fibrotic deposits (d).
J. Clin. Med. 2023, 12, 3397 8 of 14
J. Clin. Med. 2023, 12, 3397 8 of 14

Apical hypertrophic
Figure 2. Apical hypertrophic cardiomyopathy
cardiomyopathy with with concentric
concentric thickening
thickening ofof the left ventricular
wall
wall at four-chamber
four-chamber T1-TSE
T1-TSE sequences
sequences (a);
(a); absence
absence of
of edema
edema at
at four-chamber
four-chamber view
view T2-STIR
T2-STIR se-
se-
quence
quence (b);
(b); slight
slight increase
increase in
in meso-subendocardial
meso-subendocardial signal
signal evident
evident in
in PSIR-TFE
PSIR-TFE sequences
sequences inin four
four
and
and two
two chambers
chambers forfor the
the study
study of
of “late
“late gadolinium
gadolinium enhancement”
enhancement” (c,d)
(c,d) compatible
compatible with
with minimal
minimal
fibrotic deposits.
fibrotic deposits.

6. Programmed
Programmed Electrical
Electrical Stimulation
Stimulation for Risk Stratification
The
The role of programmed electrical stimulationstimulation (PES)
(PES) to stratify arrhythmic
arrhythmic risk in
HCM patients is is still
still controversial.
controversial.Moreover,
Moreover,mostmostofofthe
thestudies
studiesonon the
the topic
topic date
date back
back to
thethe
to 1980s
1980sand
and arearedifficult
difficultto to
apply nowadays
apply nowadays as as
most of of
most thethe
studied
studiedpatients undergoing
patients undergo-
PESPES
ing would nownow
would be considered
be consideredhighhigh
risk by
riskcurrent guidelines
by current and thus
guidelines and already eligible
thus already for
eligi-
ICDfor
ble implantation
ICD implantation[58]. [58].
The largest study, performed in the late 1980s, proved that induction of ventricular
The
arrhythmias
arrhythmias withwith aggressive
aggressive PES resulted in a 5-year survival decrease [59]. Aggressive
stimulation protocol was able able to
to induce
induce polymorphic
polymorphic ventricular
ventricular tachycardia
tachycardia (VT)
(VT) inin 76%
76%
of inducible patients,
patients,with withpolymorphic
polymorphicVT VTbeing
beingthe most
the most commonly
commonly induced
inducedarrhythmia.
arrhyth-
Geibel
mia. et al.etstudied
Geibel the effect
al. studied of PES
the effect in HCM
of PES patients
in HCM withwith
patients or without documented
or without documented VA
through a standardized stimulation protocol [60]. In HCM patients, a stimulation
VA through a standardized stimulation protocol [60]. In HCM patients, a stimulation pro- protocol
with up
tocol to two
with up to extra
twostimuli was sufficient
extra stimuli to identify
was sufficient to patients
identify with documented
patients sustained
with documented
J. Clin. Med. 2023, 12, 3397 J. Clin. Med. 2023, 12, 3397 9 of 14

J. Clin. Med. 2023, 12, 3397 J. Clin. Med. 2023, 12, 3397 9 of 14
sustained monomorphic VT,sustained althoughmonomorphic there may be some VT, although
problemsthere withmay specificity.
be someThe problems wi
J. sample
Clin. Med.was 2023,very
12, 3397small, which
sustained monomorphic VT,sample prevented
sustained
although was very
further
monomorphic
there small,
may conclusions
bewhich
some prevented
VT, although from being
problems there further
with drawn.
may conclusions
specificity.
be someThe from bein
problems wi
J. sample Onwas
Clin. Med. the very
2023, other
12, 3397 hand,
small, more
which recently,
sample On
prevented the
was according
other
very
further hand,
small, to more
Gatzoulis
conclusions
which recently,
prevented
from et al., according
being inducibility
furtherdrawn. to
conclusionsGatzoulis
at PES fromet al.,
bein in
J. Clin. Med. 2023, 12, 3397 sustainedSCD monomorphic VT,predicts
sustained
although monomorphic
there may be someVT, although
problems therewithmay specificity.
be some 9
The of 14
problems wi
predictsOnwas the veryor
other appropriate
hand,which more device
recently,
Onwas SCD
therapy
the very or
according
other appropriate
in HCM
hand, towhichand
more
Gatzoulisdevice
non-inducibility
recently, therapy
et al., according in
inducibility is
HCM associated and
to Gatzoulis
at PES non-inducib
et al., in
J. Clin. Med. 2023, 12, 3397 J. sample
Clin. Med. 2023, 12, 3397small, sample
prevented further small, conclusions prevented
from being furtherdrawn. conclusions 9 of 14 from bein
with
predicts prolonged
SCD or event-free
appropriate survival
with
sustained
predicts
device prolonged
[61].
SCD monomorphic
therapy or event-free
appropriate
in HCM VT,survival
and although
device [61].
non-inducibility there
therapy may
in is
HCM be some
associated and problems
non-inducib wi
J. Clin. Med. 2023, 12, 3397 On
J. Clin. Med.
At themoment,
2023,
the other
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no explicit recently,
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consensus
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was according
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consensus
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ininducibility
on
HCM
further when totoGatzoulis
patients
conclusions at PES
9perform
of 14 from
for et
PES al.,
beininin
with
predicts prolonged
SCD event-free
orstratification
appropriate survival
with
sustained
predicts
device prolonged
[61].
SCD monomorphic
therapy event-free
orsome appropriate
inhand,
HCM VT,survival
and although [61]. there may be some problems wi
J. Clin. Med. 2023, 12, 3397
monomorphic
J. arrhythmic
Clin. Med.
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2023,moment,
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12, 3397
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and
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has
perform
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with
not been
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consensus
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considered
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in on
HCM
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HCM
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patientsPES
to
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and
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9perform
of
non-inducib
was
isfor
not
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PES al.,
beininin
very
with
sustained
risk small,
prolonged
stratification which
monomorphic in prevented
event-free
current VT,survival
withfurther
sustained
although
guidelines
risk
predicts prolonged
[61].
stratification
SCD conclusions
monomorphic
there
due orto event-free
may
in
its befrom
current some
VT,
invasiveness
appropriate being
survival
although
problems
guidelines
device drawn.
and [61]. there
also
due
therapy with
due
to mayspecificity.
its
into be some
invasiveness
the
HCM fact and The
thatproblems
and
non-inducib also wid
J. Clin. Med. 2023, 12, 3397 J. arrhythmic
Clin. Med.
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hand, no PES
more
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isprevented
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explicit
perform been
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et according
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inducibility
HCM when arrhythmic
toPES
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of
at not
14
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et al., in
sample
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sustained
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induced very
stratification by PES
monomorphic small,
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VAs
risk
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considered
with
VT,guidelines
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sustained
although was
prolonged
stratification
SCD
very
there
due
further
non-specific
by
monomorphic
orto
small,
PES
event-free
may
in
its
conclusions
bewhich
are
current still
[14].
some
VT,
invasiveness
appropriate althoughfrom
considered
survivalproblems
guidelines
device and [61]. being
there
also
due
therapy
further
with
due
to
drawn.
non-specific
may be to
conclusions
specificity.
its
into [14].
some
invasiveness
the
HCM fact and The
that
from
problems
and
PES
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also
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2023,risk
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stratification PES
towhich
more and
has
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isprevented
not been
recently,considered
et approved,
al., according forand
inducibility istoassociated
arrhythmic
PES
Gatzoulisis not
atperform
PES consider
et al., in
sample
VAs induced
sustained very
by
monomorphic small,
PES are which
still
VT, sample
VAs At
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sustained
although the
was
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further
non-specific
by
monomorphic
there small,
PES
event-free
may no
are
be explicit
conclusions
still
[14].
some
VT, consensus
from
considered
survival
although
problems [61]. being onmay
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J. Clin. Med. 2023, 12, 3397 10 of 14

(vasovagal) etiology or related to LVOTO); LV apical aneurysm, independent of size; LV

systolic dysfunction (EF <50%). According to these guidelines, if any of these major risk
factors is present, ICD implantation is reasonable (class 2a indication).
If the decision to proceed to ICD implantation is still uncertain or the HCM patient
does not seem to have increased risk of SCD after assessment of the previous risk factors,
ICD may be considered in patients with extensive LGE determined by contrast-enhanced
CMR imaging or NSVT present on ambulatory monitoring (class 2b indication in HCM
patients aged ≥ 16 years; class 2a indication in HCM patients aged <16 years).
Moreover, additional parameters, including left atrial diameter and maximal LVOT
gradient, may be considered to calculate an estimated 5-year SCD risk through a predictive
risk score calculator available online (https://professional.heart.org/en/guidelines-and-
statements/hcm-risk-calculator accessed on 15 February 2023) to assist shared decision-
making between the physician and the patient for HCM patients ≥16 years old.
ESC guidelines [54] propose a more quantitative approach to SCD prediction through
a score that predicts the 5-year risk for SCD. Seven factors have been included: age, LV wall
thickness, LA size, LVOT gradient, NSVT, unexplained syncope and family history of SCD.
Using a multivariable regression model, an online calculator has been created, and HCM
patients are therefore stratified into a low (<4%), intermediate (with a risk of 4 to less than
6%) and high (≥6%) 5-year risk of SCD.
According to ESC Guidelines, in patients with a low 5-year risk of SCD, an ICD is
generally not indicated, whereas in patients with a high 5-year risk, an ICD should be
considered. In patients at intermediate risk, an ICD may be considered, taking into account
the risks and benefits of ICD implantation as well as the patient preferences in a view of a
more individualized approach.
The ESC risk score was later validated with variable results by several research
groups [64,65].
Neither the AHA-HCM-SCD calculator nor the ESC-HCM Risk-SCD score have been
validated in the following cohorts of patients and therefore should not be used in pediatric
patients (<16 years), elite/competitive athletes, HCM associated with metabolic diseases
(e.g., Anderson–Fabry disease) and syndromes (e.g., Noonan syndrome).
Regarding risk stratification for SCD in pediatric patients, important news came from
the ESC guidelines of 2022 [14]. These guidelines introduce The HCM Risk-Kids score [66]
that has been developed and externally validated [67] for children with HCM (1–16 years
of age). It includes unexplained syncope, maximal LV wall thickness, large left atrial
diameter, low LVOT gradient and NSVT (https://hcmriskkids.org accessed on 15 February
2023). In contrast to adults’ risk score, the age and family history of SCD did not improve
its performance.
The American guidelines, however, do not yet accept a pediatric risk score. For
the AHA/ACC 2020 guidelines on HCM, the decisions of ICD placement in pediatric
patients must be based on individual judgment for each patient, taking into account all
age-appropriate risk markers.

8. Future Perspectives
The increasing knowledge in several fields will provide additional insight for bet-
ter risk stratification. Indeed, several novel approaches for left ventricular outflow tract
may reduce arrhythmic risk. Apart from interventional therapy with surgery or radiofre-
quency [68], novel pharmacological treatment with selective and reversible inhibitors of
the cardiac myosin ATPase have been demonstrated to provide improvement in exercise
capacity, NYHA functional class and reduction in LVOT gradient [69]. Moreover, apart
from cardiac magnetic resonance quantification of LV scars, novel software that evaluate
scar features including border zone and conducting channels mass can better predict ICD
intervention and therefore could be included in arrhythmic risk stratification [70]. All
these data will be combined through artificial intelligence that could stratify different risk
phenotypes [71].
J. Clin. Med. 2023, 12, 3397 11 of 14

9. Conclusions
Arrhythmic risk stratification in HCM requires careful evaluation of several clinical
aspects. Symptoms combined with electrocardiogram, cardiac imaging tools and genetic
counselling are the modern cornerstone for proper risk stratification.

Author Contributions: Conceptualization, F.S. and N.D.B.; methodology, F.S.; software, F.S.; valida-
tion, M.C.; formal analysis, F.S.; investigation, F.M., A.M. and D.D.; resources, N.D.B.; data curation,
F.S.; writing—original draft preparation, F.M., D.D. and A.M.; writing—review and editing, F.S.;
visualization, G.C. and M.G.; supervision, G.C. and M.G.; project administration, N.D.B.; funding
acquisition, N.D.B. All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Conflicts of Interest: The authors declare no conflict of interest.

Abbreviations
AF = atrial fibrillation; ACC/AHA = American College of Cardiology/American Heart Associa-
tion; CMR = cardiac magnetic resonance; CPET = cardiopulmonary exercise testing; ESC = European
Society of Cardiology; FHSCD = family history of SCD; fQRS = fragmented QRS; ECG = electro-
cardiogram; HCM = hypertrophic cardiomyopathy; ICD = implantable cardioverter defibrillator;
LA = left atrium, LGE = late gadolinium enhancement; LV = left ventricle; LVH = left ventric-
ular hypertrophy; LVOTO = left ventricular outflow-tract obstruction; MACE = major adverse
cardiovascular events; MTWA= microvolt T-wave alternans; PES = programmed electrical stim-
ulation; NSVT = non-sustained ventricular tachycardia; NYHA = New York Heart Association;
SCD = sudden cardiac death; Tp–e = T-wave peak to end interval; VA = ventricular arrhythmia;
VT = ventricular tachycardia

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