ESC Guidelines Cardiomyopathies
ESC Guidelines Cardiomyopathies
ESC Guidelines Cardiomyopathies
https://doi.org/10.1093/eurheartj/ehad194
* Corresponding authors: Elena Arbelo, Arrhythmia Section, Cardiology Department, Hospital Clínic, Universitat de Barcelona, Barcelona, Spain, IDIBAPS, Institut d’Investigació August Pi i
Sunyer (IDIBAPS), Barcelona, Spain, Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain, and European Reference Network for Rare, Low
Prevalence and Complex Diseases of the Heart, ERN GUARD-Heart, Barcelona, Spain. Tel: +34 93 22 75 55 11, E-mail: [email protected]; and Juan Pablo Kaski, Centre for
Paediatric Inherited and Rare Cardiovascular Disease, University College London, Institute of Cardiovascular Science, London, United Kingdom and Centre for Inherited Cardiovascular
Diseases, Great Ormond Street Hospital, London, United Kingdom. Tel: +44 78 29 88 39, E-mail: [email protected]
†
The two Chairpersons contributed equally to the document and are joint corresponding authors.
‡
The two Task Force Co-ordinators contributed equally to the document.
Author/Task Force Member affiliations are listed in author information.
1
Representing the Association for European Paediatric and Congenital Cardiology (AEPC)
2
Representing the European Society of Human Genetics (ESHG)
ESC Clinical Practice Guidelines (CPG) Committee: listed in the Appendix.
ESC subspecialty communities having participated in the development of this document:
Associations: Association of Cardiovascular Nursing & Allied Professions (ACNAP), European Association of Cardiovascular Imaging (EACVI), European Association of Preventive
Cardiology (EAPC), European Heart Rhythm Association (EHRA), Heart Failure Association (HFA).
Councils: Council on Cardiovascular Genomics.
Working Groups: Development Anatomy and Pathology, Myocardial and Pericardial Diseases.
Patient Forum
The content of these European Society of Cardiology (ESC) Guidelines has been published for personal and educational use only. No commercial use is authorized. No part of the ESC
Guidelines may be translated or reproduced in any form without written permission from the ESC. Permission can be obtained upon submission of a written request to Oxford
University Press, the publisher of the European Heart Journal, and the party authorized to handle such permissions on behalf of the ESC ([email protected]).
Disclaimer. The ESC Guidelines represent the views of the ESC and were produced after careful consideration of the scientific and medical knowledge and the evidence available at the time
of their publication. The ESC is not responsible in the event of any contradiction, discrepancy, and/or ambiguity between the ESC Guidelines and any other official recommendations or
guidelines issued by the relevant public health authorities, in particular in relation to good use of healthcare or therapeutic strategies. Health professionals are encouraged to take the
ESC Guidelines fully into account when exercising their clinical judgment, as well as in the determination and the implementation of preventive, diagnostic or therapeutic medical strategies;
however, the ESC Guidelines do not override, in any way whatsoever, the individual responsibility of health professionals to make appropriate and accurate decisions in consideration of each
patient’s health condition and in consultation with that patient and, where appropriate and/or necessary, the patient’s caregiver. Nor do the ESC Guidelines exempt health professionals from
taking into full and careful consideration the relevant official updated recommendations or guidelines issued by the competent public health authorities, in order to manage each patient’s case
in light of the scientifically accepted data pursuant to their respective ethical and professional obligations. It is also the health professional’s responsibility to verify the applicable rules and
regulations relating to drugs and medical devices at the time of prescription.
© The European Society of Cardiology 2023. All rights reserved. For permissions please email: [email protected].
2 ESC Guidelines
Document Reviewers: Philippe Charron, (CPG Review Co-ordinator) (France), Massimo Imazio, (CPG Review
Co-ordinator) (Italy), Magdy Abdelhamid (Egypt), Victor Aboyans (France), Michael Arad (Israel), Folkert
W. Asselbergs (Netherlands), Riccardo Asteggiano (Italy), Zofia Bilinska (Poland), Damien Bonnet (France),
Henning Bundgaard (Denmark), Nuno Miguel Cardim (Portugal), Jelena Čelutkienė (Lithuania), Maja Cikes
(Croatia), Gaetano Maria De Ferrari (Italy), Veronica Dusi (Italy), Volkmar Falk (Germany), Laurent Fauchier
(France), Estelle Gandjbakhch (France), Tiina Heliö (Finland), Konstantinos Koskinas (Switzerland), Dipak Kotecha
(United Kingdom), Ulf Landmesser (Germany), George Lazaros (Greece), Basil S. Lewis (Israel), Ales Linhart
All experts involved in the development of these guidelines have submitted declarations of interest. These have
been compiled in a report and simultaneously published in a supplementary document to the guidelines. The
report is also available on the ESC website www.escardio.org/Guidelines
See the European Heart Journal online for supplementary documents that include background information and
evidence tables.
6.8.3.2. Pre- and post-test genetic counselling (proband) ......... 33 7.2. Dilated cardiomyopathy ............................................................................ 60
6.8.3.3. Genetic counselling for cascade testing ............................. 33 7.2.1. Diagnosis ................................................................................................. 60
6.8.3.4. Pre-natal or pre-implantation genetic diagnosis ............ 34 7.2.1.1. Index case ....................................................................................... 60
6.9. Diagnostic approach to paediatric patients ...................................... 35 7.2.1.2. Relatives .......................................................................................... 60
6.9.1. Infantile and early childhood-onset cardiomyopathy ........... 36 7.2.1.3. Diagnostic work-up .................................................................... 60
6.10. General principles in the management of patients with 7.2.1.4. Echocardiography ........................................................................ 60
cardiomyopathy ..................................................................................................... 37 7.2.1.5. Cardiac magnetic resonance .................................................. 61
Recommendation Table 21 — Recommendations for indications for Table 10 Overview of genes associated with monogenic,
cardiac pacing in patients with obstruction .................................................... 55 non-syndromic cardiomyopathies, and their relative contributions
Recommendation Table 22 — Recommendations for chest pain on to different cardiomyopathic phenotypes ....................................................... 28
exertion in patients without left ventricular outflow tract obstruction 55 Table 11 Utility of genetic testing in cardiomyopathies ............................ 31
Recommendation Table 23 — Additional recommendations for Table 12 Specific issues to consider when counselling children ............ 32
prevention of sudden cardiac death in patients with hypertrophic Table 13 Key discussion points of pre- and post-test genetic
cardiomyopathy .......................................................................................................... 59 counselling ..................................................................................................................... 34
©ESC 2023
useful/effective, and in some cases
© ESC 2023
may be harmful.
© ESC 2023
ESC Guidelines 9
entire financial support from the ESC without any involvement from recommendations for each individual cardiomyopathy phenotype; in-
the healthcare industry. stead, the aim is to provide a guide to the diagnostic approach to car-
The ESC Clinical Practice Guidelines (CPG) Committee supervises diomyopathies, highlight general evaluation and management issues,
and co-ordinates the preparation of new guidelines and is responsible and signpost the reader to the relevant evidence base for the
for the approval process. ESC Guidelines undergo extensive review recommendations.
by the CPG Committee and external experts, including members Adoption of morphological and functional disease definitions means
from across the whole of the ESC region and from relevant ESC that the number of possible aetiologies is considerable, particularly in
1
Clinical scenario
4 5 6
General Phenotype-
Phenotype
management principles specific management
Symptom management
LVOTO management
HCM
SCD risk prediction
Drug therapy
Mechanical circulatory
support/transplantation
Lifestyle
Exercise recommendations
GDMT for HF symptoms
Pregnancy
RCM PVR study to guide timing of
School, employment,
transplantation
psychological support
Figure 1 Central illustration. Key aspects in the evaluation and management of cardiomyopathies. ARVC, arrhythmogenic right ventricular cardiomyop-
athy; CMR, cardiac magnetic resonance; DCM, dilated cardiomyopathy; GDMT, guideline-directed medical therapy; HCM, hypertrophic cardiomyopathy; HF,
heart failure ICD, implantable cardioverter defibrillator; LVOTO, left ventricular outflow tract obstruction; MCS, mechanical circulatory support; NDLVC,
non-dilated left ventricular cardiomyopathy; PVR, pulmonary vascular resistance; RCM, restrictive cardiomyopathy; SCD, sudden cardiac death.Image %:
ESC Guidelines 11
Phenotype
RCM NDLVC
Arrhythmias/conduction disease
(atrial, ventricular, atrioventricular block)
Pedigree analysis Genetic testing Extracardiac involvement
Additional traits
Laboratory markers Pathology
Figure 2 Clinical diagnostic workflow of cardiomyopathy. ARVC, arrhythmogenic right ventricular cardiomyopathy; CMP, cardiomyopathy; CMR, cardiac
magnetic resonance; DCM, dilated cardiomyopathy; ECG, electrocardiogram; HCM, hypertrophic cardiomyopathy; NDLVC, non-dilated left ventricular car-
diomyopathy; RCM, restrictive cardiomyopathy.
(iv) differential disease expression in families; and (v) emerging phenotypic descriptions and to simplify terminology, while simultan-
aetiology-focused therapies. eously providing a conceptual framework for diagnosis and treatment.
The Task Force concluded that a single classification system that em- This nomenclature prompts clinicians to consider cardiomyopathy as
braces all possible causes of disease and every clinical scenario remains the cause of several clinical presentations (e.g. arrhythmia, heart failure),
an aspiration that is outside the scope of this clinical guideline. Instead, and focuses on morphological and functional characteristics of the
the Task Force updated the existing clinical classification to include new myocardium (Figure 2). It is important to recognize that different
12 ESC Guidelines
cardiomyopathy phenotypes may coexist in the same family, and that Table 3 Morphological and functional traits used to de-
disease progression in an individual patient can include evolution scribe cardiomyopathy phenotypes
from one cardiomyopathy phenotype to another. Nevertheless, the
Morphological traits
Task Force recommends an approach to disease nomenclature and
diagnosis that is based on the predominant cardiac phenotype at Ventricular hypertrophy: left and/or right
presentation. Ventricular dilatation: left and/or right
While recognizing the fact that genes encoding cardiac ion channels Non-ischaemic ventricular scar and other myocardial tissue
© ESC 2023
not persuaded that there is sufficient evidence to consider cardiac chan-
Ventricular systolic dysfunction (global, regional)
nelopathies as cardiomyopathies, in keeping with the approach taken by
Ventricular diastolic dysfunction (restrictive physiology)
other recent ESC Guidelines.3
The most important changes in this guideline relate to the group of
conditions variously included under the umbrella term ‘arrhythmogenic
cardiomyopathies’. This term refers to a group of conditions that fea- the focus of this guideline is on genetic cardiomyopathies, the system-
ture structural and functional abnormalities of the myocardium (identi- atic approach to diagnosis starting from the phenotype at presenta-
fied by cardiac imaging and/or macroscopic and microscopic tion described in this guideline enables clinicians to reach precise
pathological investigation) and ventricular arrhythmia. This nosology diagnoses that may also include non-genetic (e.g. inflammatory, toxic,
has evolved in response to the recognition of the clinical and genetic and multisystem diseases) causes. It is important to note that cardio-
overlap between right ventricular (RV) and LV cardiomyopathies, but myopathies can coexist with ischaemic, valvular, and hypertensive dis-
a lack of a generally accepted definition has meant that the term encom- ease and that the presence of one does not exclude the possibility of
passes a broad range of diverse pathologies and has introduced a num- the other.
ber of inconsistencies and contradictions when applied in a clinical The morphological and functional traits used to describe the cardio-
setting.4 The term ‘arrhythmogenic right ventricular (dysplasia/) cardio- myopathy phenotypes are shown in Table 3. The major innovation is
myopathy’ (ARVC) was originally used by physicians who first discov- the specific inclusion of myocardial tissue characterization traits, includ-
ered the disease, in the pre-genetic and pre-CMR era, to describe a ing non-ischaemic ventricular scarring or fatty replacement, which can
new heart muscle disease predominantly affecting the right ventricle, occur with and without ventricular dilatation, wall motion abnormal-
whose cardinal clinical manifestation was the occurrence of malignant ities, or global systolic or diastolic dysfunction. This phenotype is im-
ventricular arrhythmias. Subsequently, autopsy investigations, geno- portant to recognize, as it may be the sole clue to the diagnosis of a
type–phenotype correlation studies and the increasing use of cardiomyopathy and has prognostic significance that varies with the
contrast-enhancement CMR led to the identification of fibro-fatty re- underlying aetiology.
placement of the myocardium as a key phenotypic feature of the dis- Atrial dilatation (left and/or right) is an important additional clinical
ease that affects the myocardium of both ventricles, with LV finding in the phenotypic description of cardiomyopathies. Ultra-rare,
involvement which may even exceed the severity of RV involvement. usually autosomal recessive, cases of pure dilated atrial cardiomyopathy
This has led to the catch-all term of arrhythmogenic cardiomyopathy are reported,8 but these are outside the scope of this guideline.
(ACM), which represents the evolution of the original term of
ARVC.5 Consistent with its general approach, the Task Force agreed 3.2. Cardiomyopathy phenotypes
to highlight the vital importance of arrhythmia as a diagnostic red flag
3.2.1. Hypertrophic cardiomyopathy
and prognostic marker across a range of clinical phenotypes, but did
Hypertrophic cardiomyopathy (HCM) is defined as the presence of in-
not recommend the use of the term ACM as a distinct cardiomyopathy
creased LV wall thickness (with or without RV hypertrophy) or mass
subtype as it lacks a morphological or functional definition consistent
that is not solely explained by abnormal loading conditions.2
with the existing classification scheme. While acknowledging that
‘ACM’ as an umbrella term that encompasses diverse clinical pheno-
types has been previously used, this decision will, it is hoped, help to re- 3.2.2. Dilated cardiomyopathy
solve many of the circular arguments that currently bedevil the field. Dilated cardiomyopathy (DCM) is defined as the presence of LV dilata-
The fundamental tenet throughout this guideline is that aetiology is vital tion and global or regional systolic dysfunction unexplained solely by ab-
to the management of patients with heart muscle disease and that a normal loading conditions (e.g. hypertension, valve disease, CHD) or
careful and consistent description of the morphological and functional CAD.2 Very rarely, LV dilatation can occur with normal ejection frac-
phenotype is a crucial first step in the diagnostic pathway, while the final tion (EF) in the absence of athletic remodelling or other environmental
diagnosis will ideally describe aetiology alongside the phenotype.6,7 factors; this is not in itself a cardiomyopathy, but may represent an early
manifestation of DCM. The preferred term for this is isolated left ven-
tricular dilatation.
3.1. Definitions Right ventricular dilatation and dysfunction may be present but are
A cardiomyopathy is defined as ‘a myocardial disorder in which the not necessary for the diagnosis. When dilatation or wall motion abnor-
heart muscle is structurally and functionally abnormal, in the absence malities are confined or predominant to the right ventricle, the possibil-
of coronary artery disease (CAD), hypertension, valvular disease, and ity of ARVC should be considered (see Section 3.2.4).
congenital heart disease (CHD) sufficient to cause the observed myo-
cardial abnormality’.2 This definition applies to both children and 3.2.3. Non-dilated left ventricular cardiomyopathy
adults and makes no a priori assumptions about aetiology (which Hitherto, the definition of DCM had a number of important limita-
can be familial/genetic or acquired) or myocardial pathology. While tions, most notably the exclusion of genetic and acquired disorders
ESC Guidelines 13
Figure 3 Examples of non-dilated left ventricular cardiomyopathy phenotypes and their aetiological correlates. BAG3, BAG cochaperone-3; DMD,
Duchenne muscular dystrophy; DSP, desmoplakin; FLNC, filamin C; LGE, late gadolinium enhancement; LMNA, lamin A/C; NDLVC, non-dilated left ven-
tricular cardiomyopathy; PLN, phospholamban; RBM20, RNA binding motif protein 20; TTN, titin. Distribution of LGE (arrowheads) in NDLVC and aetio-
logical correlates. Desmoplakin (DSP), filamin C (FLNC) and phospholamban (PLN) genotypes show a characteristic subepicardial, ring-like LGE pattern,
whereas titin (TTN), BAG3 (BAG3), lamin A/C (LMNA), DMD, RBM20 genotypes and myocarditis are more heterogeneous, but with overall less scar (some-
times without) and lower left ventricular ejection fraction.
that manifest as intermediate phenotypes that do not meet standard or fatty replacement regardless of the presence of global or regional
disease definitions in spite of the presence of myocardial disease on wall motion abnormalities (RWMAs), or isolated global LV hypokine-
cardiac imaging or tissue analysis. In a previous ESC statement, this sia without scarring.
phenomenon inspired the creation of a new disease category, hypo- The NDLVC phenotype will include individuals that up until now may
kinetic non-dilated cardiomyopathy.9 In this guideline, we propose have variably been described as having DCM (but without LV dilata-
replacement of this term with non-dilated left ventricular cardiomy- tion), arrhythmogenic left ventricular cardiomyopathy (ALVC), left-
opathy (NDLVC), which can be further characterized by the pres- dominant ARVC, or arrhythmogenic DCM (but often without fulfilling
ence or absence of systolic dysfunction (regional or global). diagnostic criteria for ARVC) (Figure 3). The simple worked example
Isolated LV dysfunction (regional or global) without scarring should (Figure 4) shows how the identification of an NDLVC phenotype should
also be considered under this diagnostic category. The NDLVC trigger a multiparametric approach that leads to a specific aetiological
phenotype is defined as the presence of non-ischaemic LV scarring diagnosis, with implications for clinical treatment.
14 ESC Guidelines
Non-dilated LV Previous
EF 55% classification Proposed phenotype-
Cardiac Subepicardial
morphology/ DCM
based integrated
scar
function ALVC approach
ACM
Autosomal dominant
Diagnostic DSP-related non-dilated LV
pathway cardiomyopathy phenotype
with subepicardial scar
Sinus rhythm, minor and low-normal EF
ECG/ intraventricular conduction
arrhythmia delay
200 VEs, few couplets
DSP Trp180*
Genetics
Figure 4 Worked example of the non-dilated left ventricular cardiomyopathy phenotype. ACM, arrhythmogenic cardiomyopathy; ALVC, arrhythmogenic
left ventricular cardiomyopathy; DCM, dilated cardiomyopathy; DSP, desmoplakin; ECG, electrocardiogram; EF, ejection fraction; LV, left ventricular;
NDLVC, non-dilated left ventricular cardiomyopathy; SCD, sudden cardiac death; VE, ventricular extrasystole. Worked example of the NDLVC phenotype
showing how a systematic multiparametric approach to clinical phenotyping, starting from the recognition of a clinical phenotype and integrating extended
phenotypic information and targeted diagnostics, including genetic testing, can be used to arrive at highly specific phenotypic descriptions that can result in
personalized treatment plans. In this worked example, the diagnosis transforms from a simplistic categorization to a complex genetic disorder characterized
by myocardial scar and a propensity to ventricular arrhythmia.
3.2.4. Arrhythmogenic right ventricular Over time, the clinical paradigm of ARVC has moved from a focus on
cardiomyopathy severe RV disease and malignant ventricular arrhythmia to a broader
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is concept that includes concealed or subclinical phenotypes and biventri-
defined as the presence of predominantly RV dilatation and/or dys- cular or even left-dominant disease. This has led to a plethora of new
function in the presence of histological involvement and/or terms, including ‘arrhythmogenic left ventricular cardiomyopathy
electrocardiographic abnormalities in accordance with published (ALVC)’, ‘left and right dominant cardiomyopathy’, ‘arrhythmogenic di-
criteria.10 lated cardiomyopathy’, and most recently, the catch-all term ‘arrhyth-
For decades, ARVC has been one of the principal cardiomyopathy mogenic cardiomyopathy’. The term ARVC can be used to describe
subtypes. It has been defined in accordance with published consensus the original variant in which ventricular dilatation or wall motion abnor-
criteria that comprise RV dysfunction (global or regional), histological malities are predominantly confined to the right ventricle, with or with-
abnormalities in the form of fibro-fatty replacement of cardiomyocytes, out LV involvement, and the 2010 modified Task Force criteria for the
electrocardiographic characteristics, ventricular arrhythmia of RV ori- diagnosis of ARVC can be applied.10 Predominant LV disease can also
gin, and the presence of familial disease and/or pathogenic variants in occur in the same family;5 see Section 7.3 for recommendations on as-
desmosomal protein genes. sessment and management of this phenotype.
ESC Guidelines 15
3.2.5. Restrictive cardiomyopathy function usually normalizes over a period of days to weeks, and recur-
Restrictive cardiomyopathy (RCM) is defined as restrictive left and/or rence is rare. The same kind of reversible myocardial dysfunction is oc-
RV pathophysiology in the presence of normal or reduced diastolic vo- casionally encountered in patients with intracranial haemorrhage or
lumes (of one or both ventricles), normal or reduced systolic volumes, other acute cerebral accidents (neurogenic myocardial stunning).
and normal ventricular wall thickness.2 Takotsubo syndrome is sometimes referred to as takotsubo or
Restrictive cardiomyopathy commonly presents as biatrial enlarge- stress cardiomyopathy. Given the transient nature of the phenomenon,
ment. Left ventricular systolic function can be preserved, but it is rare the Task Force does not recommend its classification as a
chest pain and have diffuse T wave inversion (TWI), sometimes pre- children and adolescents
ceded by ST-segment elevation and mild cardiac enzyme elevation. RCM Rare Childhood incidence:
Most reported cases occur in post-menopausal women. Symptoms 0.0003%34
are often preceded by emotional or physical stress. Norepinephrine
ARVC, arrhythmogenic right ventricular cardiomyopathy; DCM, dilated cardiomyopathy;
concentration is elevated in most patients and a transient, dynamic out- HCM, hypertrophic cardiomyopathy; NDLVC, non-dilated left ventricular
flow tract pressure gradient is reported in some cases. Left ventricular cardiomyopathy; RCM, restrictive cardiomyopathy.
16 ESC Guidelines
4.1. Special populations relevant specialties as well as the general cardiologist, general practi-
Several forms of cardiomyopathy previously considered secondary to tioner, and the family/carer. In addition, the integration of genetics
external factors were recently proved to have genetic contributors, into mainstream cardiology services requires expertise from different
leading to the ‘second hit theory’, and a genetic aetiology should be specialties:
kept in mind for family history taking and genetic testing.
• Adult and paediatric cardiologists subspecialized in cardiogenetic
• Titin gene truncating variants (TTNtv) represent a prevalent genetic conditions.
Cardiomyopathy Patient
specialists support
Figure 5 Multidisciplinary care of cardiomyopathies. aThe list presented is not exhaustive and represents examples of specialties that often interact in the
care of cardiomyopathy patients.Image %:
care from paediatric to adult services, including joint is the need for clinicians to consider a diagnosis of cardiomyopathy as
I C
consultations, is recommended in all adolescents the cause of several common adult and paediatric clinical presentations.
with cardiomyopathy.58,59 The identification of a cardiomyopathy phenotype is only the beginning
a
Class of recommendation. of the diagnostic process and should prompt a systematic search for the
b
Level of evidence. underlying aetiology, which may be genetic or acquired.
18 ESC Guidelines
6.1. Clinical presentation an aetiological diagnosis, looking for specific signs and symptoms
Patients with cardiomyopathy may access health services through sev- and laboratory markers suggestive of a specific diagnosis; the pres-
eral pathways. Referral from primary care (e.g. general practitioners ence of ventricular and atrial arrhythmia and conduction disease to
and general paediatricians) may be triggered by symptoms (most aid diagnosis, suggest specific causes, and monitor disease progres-
commonly dyspnoea, chest pain, palpitation, syncope) or incidental sion and risk stratification; and clues from the pedigree to suggest
findings (e.g. an abnormal electrocardiogram [ECG] in the context of specific inheritance patterns and identify at-risk relatives. This ap-
community, school, work-related medical check-ups, or sports pre- proach should result in a timely and accurate diagnosis to enable early
© ESC 2023
created to aid in diagnosis, provide clues to
6.2. Initial work-up underlying aetiology, determine inheritance pattern,
The cardiomyopathy-oriented approach is based on interpreting clinic- and identify at-risk relatives.64–66
al and instrumental findings to suspect and ultimately generate a
ECG, electrocardiogram.
phenotype-based aetiological diagnosis to guide disease-specific man- a
Class of recommendation.
agement.62 This approach requires deliberate analysis of multipara- b
Level of evidence.
metric investigations in the individual and their relatives and an
integrated probabilistic analysis of clinical investigations. Re-analysis of
clinical data is required as new information emerges, and family infor- 6.4. History and physical examination
mation can provide important clues to the diagnosis, given the variable Age is one of the most important factors to take into account when
expression and incomplete penetrance of most cardiomyopathies, and considering the possible causes of cardiomyopathy. For example, inher-
can result in differences in diagnostic criteria between probands and re- ited metabolic disorders and congenital dysmorphic syndromes are
latives. In this context, relatives of individuals with cardiomyopathy can more common in neonates and infants (see Section 6.9.1) than in older
have non-diagnostic morphological and electrocardiographic abnor- children or adults, whereas wild-type transthyretin amyloidosis
malities that can indicate mild and early phenotypic expression of dis- (ATTRwt) is a disease mostly of adults over the age of 65 years (see
ease and can increase diagnostic accuracy for predicting disease in Section 7.6).
genotyped populations. The identification of diagnostic clues, or red Construction of a three- to four-generation family pedigree helps to
flags, is a crucial aspect of the initial work-up. identify Mendelian forms of inheritance and identifies other family
members who may be at risk of disease development.62 Specific fea-
6.3. Systematic approach to diagnosis of tures to note in the family history include premature deaths (taking
cardiomyopathy into account that SCDs may sometimes be reported as accidental
deaths, e.g. drowning, unexplained traffic accident, and, rarely, as still-
A multiparametric approach to the evaluation of patients with sus-
birth or sudden infant death syndromes), unexplained heart failure, car-
pected cardiomyopathy is recommended, with the aims of: (i) establish-
diac transplantation, pacemaker and defibrillator implants, and evidence
ing and characterizing the presence of a cardiomyopathy phenotype;
for systemic disease (e.g. stroke at a young age, skeletal muscle weak-
and (ii) identifying the underlying aetiological diagnosis.62 Clinicians
ness, renal dysfunction, diabetes, deafness). Most Mendelian forms of
should approach a patient with suspected cardiomyopathy using a ‘car-
cardiomyopathy are autosomal dominant and are therefore character-
diomyopathy mindset’ (Figure 2):
ized by the presence of affected individuals across generations, with
• Use multimodality imaging to characterize the phenotype and iden- transmission from parents of either sex (including male-to-male) and
tify abnormal ventricular morphology (e.g. hypertrophy, dilatation) a 50% risk of allele transmission to offspring (although, due to incom-
and function (systolic/diastolic, global/regional), and detect abnormal- plete penetrance, the proportion of affected individuals in an individual
ities of tissue characterization (e.g. non-ischaemic myocardial scar pedigree will be lower). X-linked inheritance should be suspected if
and fatty replacement). males are the most severely affected individuals and there is no
• Use a combination of personal and family history, clinical examin- male-to-male transmission. Autosomal recessive inheritance, the least
ation, electrocardiography, and laboratory investigations to achieve common pattern, is likely when both parents of the proband are
ESC Guidelines 19
Table 5 Examples of inheritance patterns that should raise the suspicion of specific genetic aetiologies, grouped ac-
cording to cardiomyopathy phenotype
HCM Sarcomeric X
Anderson–Fabry X
© ESC 2023
FLNC X
BAG3 X
RASopathy X (X)
AD, autosomal dominant; AR, autosomal recessive; ARVC, arrhythmogenic right ventricular cardiomyopathy; DCM, dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy; NDLVC,
non-dilated left ventricular cardiomyopathy; RCM, restrictive cardiomyopathy; TTR, transthyretin; DNA, deoxyribonucleic acid; RASopathies, Ras/mitogen-activated protein kinase pathway
dysregulation.
(X) indicates the presence of a correlation between a cardiomyopathy and a pattern of inheritance.
unaffected and consanguineous, although severe autosomal recessive 6.5. Resting and ambulatory
cardiomyopathies can also occur in the absence of familial consanguin-
electrocardiography
ity.67,68 When women—but not men—transmit the disease to children
The resting 12-lead ECG is often the first test that suggests the possi-
of either sex, mitochondrial DNA variants should be considered
bility of cardiomyopathy. Although the ECG can be normal in a small
(Table 5). It is important to note that the absence of familial disease
proportion of individuals with cardiomyopathy, standard ECG abnor-
does not exclude a genetic origin (see Section 6.8). malities are common in all cardiomyopathy subtypes and can precede
Patients with cardiomyopathy may experience dyspnoea, chest pain, the development of an overt morphological or functional phenotype
palpitation, and syncope and/or pre-syncope, although many individuals by many years; for example, in genotype-positive individuals identified
complain of few, if any, symptoms (see Section 6.4 for assessment of during family screening. When interpreted in conjunction with findings
symptoms in specific cardiomyopathy subtypes). A number of non- on echocardiography and CMR imaging, features that would normally
cardiac symptoms act as pointers for specific diagnoses (Table 6). indicate other conditions, such as myocardial ischaemia or infarction,
Similarly, general physical examination can provide diagnostic clues in can—with age at diagnosis, inheritance pattern, and associated clinical
patients with syndromic or metabolic causes of cardiomyopathy.62 features—suggest an underlying diagnosis or provide clues to the
20 ESC Guidelines
Table 6 Examples of signs and symptoms that should raise the suspicion of specific aetiologies, grouped according to
cardiomyopathy phenotype
ARVC, arrhythmogenic right ventricular cardiomyopathy; ATTR, transthyretin amyloidosis; ATTRv, hereditary transthyretin amyloidosis; DCM, dilated cardiomyopathy; DSP, desmoplakin;
HCM, hypertrophic cardiomyopathy; NDLVC, non-dilated left ventricular cardiomyopathy; NSML, Noonan syndrome with multiple lentigines; RCM, restrictive cardiomyopathy; TTR,
transthyretin.
a
Cornea verticillata, characteristic of Anderson–Fabry disease, does not cause visual impairment per se.
ESC Guidelines 21
underlying diagnosis. For this reason, the ECG is recommended at the including bradyarrhythmias and tachyarrhythmias, ranging from symp-
first clinic visit in all individuals with known or suspected cardiomyop- tomatic atrial/ventricular premature beats to life-threating ventricular
athy and should be repeated whenever there is a change in symptoms arrhythmias. The frequency of arrhythmias detected during ambula-
in patients with an established diagnosis. Although the ECG is often tory electrocardiographic monitoring is age related and variable
non-specific, there are particular features that can suggest a certain aeti- across different cardiomyopathy subtypes. Some arrhythmias are
ology or morphological diagnosis, including atrioventricular (AV) block, relatively common in the context of cardiomyopathy (e.g. atrial fibril-
ventricular pre-excitation pattern, distribution of repolarization abnor- lation [AF] or ventricular premature beats), while others may suggest
Table 7 Examples of electrocardiographic features that should raise the suspicion of specific aetiologies, grouped
according to cardiomyopathy phenotype
ARVC, arrhythmogenic right ventricular cardiomyopathy; AV, atrioventricular; DCM, dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy; LVH, left ventricular hypertrophy;
NDLVC, non-dilated left ventricular cardiomyopathy; PKP2, plakophilin 2; PLN, phospholamban; PRKAG2, protein kinase AMP-activated non-catalytic subunit gamma 2; QRS, Q, R, and S
waves of an ECG; RBBB, right bundle branch block; RCM, restrictive cardiomyopathy.
a
In the absence of obesity, pericardial effusion, chronic obstructive pulmonary disease, abnormalities of the chest, or other reasons that may cause low voltage.
Adapted from Rapezzi et al.62
22 ESC Guidelines
6.6. Laboratory tests to move hierarchically from simpler and cheaper to more complex
Routine laboratory testing aids the detection of extracardiac conditions and expensive tests. A bi-directional flow of information between the
that cause or exacerbate ventricular dysfunction (e.g. thyroid disease, clinician and the imager is key to maximizing appropriateness: clinicians
renal dysfunction, and diabetes mellitus) and secondary organ dysfunc- should formulate and share clear pre-test hypotheses, based on avail-
tion in patients with severe heart failure. High levels of brain natriuretic able information, to aid the interpretation of novel findings. The imager
peptide (BNP), N-terminal pro-brain natriuretic peptide (NT-proBNP), should respond in a similarly focused fashion, assessing the likelihood of
and high-sensitivity cardiac troponin T (hs-cTnT) are associated with alternative diagnoses and refraining from diagnoses that are not com-
in patients with cardiomyopathy and extracardiac wall thickness other than at the basal interventricular septum or poster-
IIa C
features to aid in detection of metabolic and ior wall. The Task Force recommends using the normative data from
syndromic causes, following specialist evaluation. the Paediatric Heart Network consortium.82
a
Class of recommendation.
b
Level of evidence. Recommendation Table 4 — Recommendation for
c
See Table 8. echocardiographic evaluation in patients with
cardiomyopathy
based techniques, CMR imaging, computed tomography (CT), and nu- cardiomyopathy at initial evaluation, and during
clear techniques, such as positron emission tomography (PET) and scin- follow-up, to monitor disease progression and aid
tigraphy (Figure 6).1,71,72 Physicians should always consider the yield of risk stratification and management.78,83–102
actionable results vs. the costs, advantages, and limitations of each tech-
LV, left ventricular; RV, right ventricular.
nique, as well as patient safety and patient exposure to ionizing radi- a
Class of recommendation.
ation and contrast media. Standardized algorithms should be in place b
Level of evidence.
ESC Guidelines 23
Table 8 First-level (to be performed in each patient) and second-level (to be performed in selected patients following
specialist evaluation to identify specific aetiologies) laboratory tests, grouped by cardiomyopathy phenotype
© ESC 2023
• Urine and plasma protein • Urine organic acids and
• Urine organic acids and plasma amino acids
plasma amino acids
ARVC, arrhythmogenic right ventricular cardiomyopathy; BNP, brain natriuretic peptide; CK, creatinine kinase; DCM, dilated cardiomyopathy; Gb3, globotriaosylceramide; HCM,
hypertrophic cardiomyopathy; NDLVC, non-dilated left ventricular cardiomyopathy; NT-proBNP, N-terminal pro-brain natriuretic peptide; PTH, parathyroid hormone; RCM, restrictive
cardiomyopathy.
a
Alternatively, BNP can be considered depending on the local availability.
6.7.3. Cardiac magnetic resonance amyloidosis, or of iron deposition in haemochromatosis), and should
Cardiac magnetic resonance imaging (MRI) combines the advantages of be considered in all patients with cardiomyopathy.
non-invasiveness and independence of acoustic window with the ability
for tissue characterization. The latter advantage is particularly import- 6.7.3.1. Special considerations
ant in the diagnosis of NDLVC, ARVC, myocarditis, amyloidosis, sar-
coidosis and other forms of inflammatory disease, and iron overload/ • Recently developed rapid CMR techniques allow scans to be performed
haemochromatosis. Cardiac magnetic resonance is particularly useful without general anaesthesia even in very young children.103 In children
if echocardiography provides poor image quality. Initial evaluation (and adults) unable to undergo CMR without general anaesthesia, the
should routinely include cine imaging sequences, T2-weighted se- relative risks and benefits of the procedure should be considered.
quences, pre- and post-contrast T1 mapping, and late gadolinium en- • Imaging artefacts caused by cardiac implantable electronic devices
hancement (LGE). When suspecting haemochromatosis, T2* have posed limitations for CMR imaging in the past.104–110 A number
mapping should be employed. Cardiac magnetic resonance findings of solutions are available to reduce artefacts, including reducing in-
can provide important aetiological clues (Figure 7), with potential thera- homogeneity, technical adjustments, and the use of special sequences,
peutic implications (Table 9) and should be assessed collectively with which reduce the rate of uninterpretable studies to one in five.111,112
genetic results and other clinical features by experienced operators Cardiac magnetic resonance can therefore be considered in patients
in cardiac imaging and the evaluation of heart muscle disease. Serial with conditional devices and nearly all non-conditional devices pro-
follow-up CMR, every 2–5 years depending on initial severity and clin- vided appropriate protocols are put in place.113
ical course, can assist in evaluating disease progression as well as the • Nephrogenic systemic fibrosis is a rare complication reported in pa-
benefits of therapy (e.g. evaluation of extracellular volume [ECV] in tients with first-generation linear unstable gadolinium chelates and
24 ESC Guidelines
Targeted studies
Disease progression
Bone scintigraphy
(follow-up)
Amyloidosis
PET-CT
Myocardial inflammation
Figure 6 Multimodality imaging process in cardiomyopathies. CMR, cardiac magnetic resonance; CTCA, computed tomography coronary angiography;
LGE, late gadolinium enhancement; LV, left ventricular; PET, positron emission tomography.
Recommendations Class a
Level b diagnosis, contrast-enhanced CMR may be
IIb C
considered in phenotype-negative family members to
Contrast-enhanced CMR is recommended in aid diagnosis and detect early disease.10,128
patients with cardiomyopathy at initial I B
CMR, cardiac magnetic resonance.
evaluation.10,90,116,119–143 a
Class of recommendation.
b
Continued Level of evidence.
ESC Guidelines 25
Figure 7 Examples of cardiac magnetic resonance imaging tissue characterization features that should raise the suspicion of specific aetiologies, grouped
according to cardiomyopathy phenotype. ARVC, arrhythmogenic right ventricular cardiomyopathy; CMR, cardiac magnetic resonance; DCM, dilated cardio-
myopathy; DES, desmin; DSP, desmoplakin; EMF, endomyocardial fibrosis; FLNC, filamin C; HCM, hypertrophic cardiomyopathy; LGE, late gadolinium en-
hancement; LV, left ventricular; LVH, left ventricular hypertrophy; NDLVC, non-dilated left ventricular cardiomyopathy; RCM, restrictive
cardiomyopathy; RV, right ventricular. Examples of CMR tissue characterization features that should raise the suspicion of specific aetiologies (column
4), grouped according to cardiomyopathy phenotype (column 1). CMR images features (column 3) correspond to the listed findings (column 2).Image %:
26 ESC Guidelines
Table 9 Frequently encountered actionable results on artery from the pulmonary artery [ALCAPA] or anomalous pulmonary
multimodality imaging venous return). Standard CT imaging provides additional information
regarding concomitant pulmonary disease (e.g. sarcoidosis), pericardial
Parameter/finding Action disease, and chest wall deformities affecting the heart.
RWMAs on echocardiography or Raise suspicion of concomitant CAD,
Recommendation Table 6 — Recommendations for
CMR myocarditis, ARVC, NDLVC, or
computed tomography and nuclear imaging
sarcoidosis
© ESC 2023
18F-FDG-PET scanning should be considered for the
pulmonary pressures IIa C
diagnostic work-up in patients with cardiomyopathy
Tissue characterization on CMR Diagnosis; risk assessment in whom cardiac sarcoidosis is suspected.164,172,173
© ESC 2023
Computed tomography-based imaging is primarily used in patients investigations suggest myocardial inflammation,
with a suspicion of cardiomyopathy to rule out CAD, either as an alter- infiltration, or storage that cannot be identified by
native diagnosis (e.g. in individuals with DCM, NDLVC, or ARVC phe- other means.174–177
notypes) or as a comorbidity affecting clinical manifestations and
EMB, endomyocardial biopsy.
course. In children and adolescents, CT angiography can be useful to ex- a
Class of recommendation.
b
clude congenital vascular malformations (e.g. anomalous left coronary Level of evidence.
ESC Guidelines 27
6.8. Genetic testing and counselling factors. Once a genetic cause is established in one family member, then
other family members may undergo testing for only the causative
6.8.1. Genetic architecture
variant.
Familial forms of cardiomyopathies show diverse modes of inheritance.
Genetic testing in an individual with cardiomyopathy (known as con-
Gene identification has, over the last three decades, primarily focused
firmatory testing or diagnostic testing) is recommended for their direct
on the identification of Mendelian (monogenic) disease genes that most
benefit: (i) to confirm the diagnosis; (ii) where it may inform prognosis;
commonly display autosomal dominant inheritance, although other inher-
(iii) where it may inform treatment selection; or (iv) where it may in-
Table 10 Overview of genes associated with monogenic, non-syndromic cardiomyopathies, and their relative contribu-
tions to different cardiomyopathic phenotypes
ABCC9 a
ACTA1
ACTC1
ACTN2b
ALPK3
ANKRD1
BAG3 a a
Myofibrillar myopathy
CACNA1C c c
Timothy syndrome
CACNB2
CALR3
CASQ2
CAV3 a a
Caveolinopathy
CDH2
COX15 a a
Leigh syndrome
CRYAB a a
Alpha-B crystallinopathy
CSRP3
CTF1
CTNNA3
DES c c
Desminopathy
DMD c c
X-linked progressive MD
DMPK
DSC2
DSG2
DSP
DTNA
EYA4
FHL1 c c
Emery–Dreifuss MD
FLNC c c
Myofibrillar myopathy
FHOD3
FXN a a
Friedreich ataxia
GAA a a
Pompe disease
Continued
ESC Guidelines 29
GATA4
GATAD1
GLA c c
Anderson–Fabry disease
HCN4
JPH2
JUP a
Naxos disease (cardiocutaneous syndrome)
KCNQ1
KLF10
LAMA4
LAMP2 c c
Danon disease
LDB3 a a
Myofibrillar myopathy
LMNA
LRRC10
MIB1
MYBPC3
MYH6
MYH7
MYL2
MYL3
MYLK2
MYOM1
MYOZ2
MYPN
NEBL
NEXN
NKX2–5
NNT
NONO
NPPA
OBSCN
PDLIM3
PKP2
PLEKHM2
PLN b
Continued
30 ESC Guidelines
PRDM16
PRKAG2 c c
PRKAG2 cardiomyopathy
PSEN1
PSEN2
RAF1 c c
Noonan syndrome
RBM20
RIT1 c c
Noonan syndrome
RYR2
SCN5A
SGCD
SLC25A4 a a
Mitochondrial disease
TAZ
TBX5
TBX20
TCAP
TGFB3
TJP1
TMEM43 a
TMEM70
TMPO
TNNC1
TNNI3
TNNI3K
TNNT2
TPM1
TRIM63
TTN
© ESC 2023
TTR c c
Transthyretin amyloidosis
VCL
ARVC, arrhythmogenic right ventricular cardiomyopathy; DCM, dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy; LVH, left ventricular hypertrophy; MD, muscular dystrophy;
NDLVC, non-dilated left ventricular cardiomyopathy; RCM, restrictive cardiomyopathy.
Based on ClinGen gene validation efforts;189–191a ooo: very common (>10% of tested cases); oo: common (1–10% of tested cases); o: less common (<1% of tested cases); blue circle:
definitive/strong evidence; light blue circle: moderate evidence; white circle: limited, no association or refuted/dispute evidence; blank cells: not classified; grey circle: has been described
(generally rare, sporadic cases), yet not classified/evaluated by ClinGen. The yield may be higher in subgroups with more specific phenotypes, e.g. the yield of testing LMNA is higher in
groups with DCM and conduction disease. As NDLVC is a new phenotypic description, genes have not been formally curated for associations with this phenotype. Values shown are
based on curations for related cardiomyopathies where the phenotypic spectrum is understood to include NDLVC.
a
indicates genes associated with syndromic presentations that can include cardiomyopathy as a feature, but where cardiomyopathy is not expected to occur as the only or presenting feature
of the syndrome.
b
ACTN2 and PLN can present a mixed phenotypic picture that may not fit into classical cardiomyopathy descriptions.
c
indicates genes associated with syndromic presentations that can include cardiomyopathy as a feature, and where cardiomyopathy may be the only or presenting feature of the syndrome. These
are sometimes referred to as genocopies. E.g. GLA is shown as definitive for HCM, because it causes Anderson–Fabry disease which can present with LVH fulfilling diagnostic criteria for HCM.
ESC Guidelines 31
+ + - + + + - +
- - + - - + + + - + - - + +
Rare pathogenic variant Rare Mendelian variant Intermediate effect variant Common variants (GWAS)
Population MAF <0.01% Population MAF <1–2% Population MAF >1–5%
Intermediate effect variant
Small effect common variant
Non-genetic factors
Figure 8 The genetic architecture of the cardiomyopathies. GWAS, genome-wide association studies; MAF, minor allele frequency. Cardiomyopathy can be
Mendelian, caused by genetic variants that are ultra-rare in the general population and have large effect sizes. Such variants can display complete penetrance; i.e. all
individuals with the variant in the family manifest the disease (panel A). However, individual variants are often insufficient to yield a disease phenotype in isolation, and
their effect is modulated by the co-inheritance of modulatory genetic factors and by non-genetic factors (panel B). Besides increasing disease penetrance, such mod-
ulatory variants also affect the severity of the disease (panel B). Modulatory genetic factors are thought to comprise common variants with individually small-effect
sizes and intermediate-effect variants that have population frequencies and effect sizes between rare and common variants. Some patients have a more complex
aetiology (non-Mendelian/polygenic inheritance) in which a substantial number of non-Mendelian genetic factors and non-genetic factors are required to reach the
threshold for disease (panel C). Such patients typically have a sporadic presentation or present with a less pronounced familial clustering of the disease. Family trees
demonstrate the male (square) and female (circle) family members that are affected (black filled), with incomplete phenotype (grey filled) or unaffected (white filled).
The presence or absence of the variant of interest is noted with “+” or “-”, respectively.
• Diagnosis: for the affected individual, the diagnosis of cardiomyopathy is primarily made on the basis of a phenotypic definition of disease, without reference to
genetic aetiology. However, with appropriate genetic counselling and acknowledging the caveat that the finding will only be clinically actionable when a P/LP
variant is found, genetic testing may be of value in clarifying borderline cases (e.g. where LVH is observed in the context of mild or controlled hypertension, but
the clinician is not able to confidently distinguish between early sarcomeric HCM and a hypertensive phenocopy). Genetic testing can also identify genocopies:
distinct genetic conditions that mimic a particular cardiomyopathy.
• Prognosis: for an increasing number of conditions, a genetic diagnosis can provide prognostic information. For example, DCM due to variants in LMNA has an
adverse prognosis requiring more frequent surveillance and shifting therapeutic decision thresholds with a lower threshold for primary prevention ICD
implantation.
• Therapy: a genetic diagnosis may directly stratify choice of therapy. In addition to decisions on primary prevention ICD implantation, an increasing number of
treatments are either established or under trial for a specific molecular subtype of cardiomyopathy. In addition, with an increasingly sophisticated toolbox for
Continued
32 ESC Guidelines
manipulation of the genome, further waves of therapies aiming to replace, alter, or remove abnormal genes and transcripts responsible for cardiomyopathies are
anticipated once a precise molecular aetiology is established in a patient.
• Reproductive advice: a genetic diagnosis informs reproductive advice and management for an affected adult and/or the parents of an affected child, enabling
tailored advice on inheritance patterns and the risk of transmission to future children, and opening the door to management of risk; e.g. through pre-natal
diagnostics or pre-implantation genetic diagnosis.
For relatives
© ESC 2023
long-term longitudinal surveillance. Genetic testing can eliminate this uncertainty: an individual who does not carry the genetic variant proved to be responsible
for disease in their family can be confidently reassured and discharged without surveillance, while an individual who carries a disease-causing variant can be
followed closely, and potentially treated early.
DCM, dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy; ICD, implantable cardioverter defibrillator; LMNA, lamin A/C; LVH, left ventricular hypertrophy; P/LP, pathogenic/likely pathogenic.
6.8.2.1. Non-Mendelian cardiomyopathies and implications for American Heart Rhythm Society (LAHRS) Expert Consensus
genetic testing Statement on the state of genetic testing for cardiac diseases.3
The preceding discussion has focused on genetic testing to identify
monogenic forms of cardiomyopathy. The recognition that an import- 6.8.3. Genetic counselling
ant proportion of cardiomyopathies have a more complex genetic
Genetic counselling is a process that aims to support patients and their
architecture has important implications for the use of genetic tests.
families to understand and adapt to the medical, psychosocial, and familial
The absence of a monogenic disease-causing variant on conventional
impact of genetic diseases.201,202 It should be performed by healthcare
genetic testing (i.e. sequencing for rare variants of large effect) leaves
professionals with specific training, such as genetic counsellors, genetic
three possibilities: (i) either there is a monogenic cause that has not
nurses, or clinical/medical geneticists, regardless of whether genetic testing
been identified (i.e. not detected or recognized as causative by current
is being considered. Genetic counselling can include a discussion of inher-
testing); (ii) the cardiomyopathy does not have a genetic aetiology; or
itance risks, provide education including the need for clinical evaluation,
(iii) the cardiomyopathy is attributable to the effects of multiple variants
perform pre- and post-genetic test counselling, review variant classifica-
of individually smaller effect (Figure 8). Recent data suggest that for many
tions, obtain a three-generation family history, and provide psychosocial
cardiomyopathies, the absence of a rare causative variant on comprehen-
support.203–205 For patients with a new diagnosis of cardiomyopathy, there
sive testing indicates that the disease is unlikely to have a monogenic aeti-
can be difficulty adjusting to life with an inherited cardiomyopathy, chal-
ology.182,183,194 This, in turn, implies a different inheritance pattern, with a
lenges living with an implantable cardioverter defibrillator (ICD), and on-
lower risk to first-degree relatives, such that ongoing surveillance may
going trauma and grief for those who have experienced a young SCD in
not be indicated if an initial clinical evaluation is reassuring. The use of gen-
their family. Attention to the psychological support needs of patients is
etic testing to identify families in whom the disease is unlikely to be
therefore critical (see Section 6.12). Indeed, in the general setting, genetic
monogenic represents a likely new application of conventional testing,
counselling can improve knowledge, recall, and patient empowerment; in-
which is gathering evidence but not yet established.
crease satisfaction with decision-making; and reduce anxiety.206–209
Polygenic risk scores (PRS) (sometimes known as genomic risk
scores) are another form of genetic test that may, in the future, have
relevance in the management of cardiomyopathies. Instead of trying 6.8.3.1. Genetic counselling in children
to identify a single genetic variant that is responsible for disease, There are specific issues to be considered when counselling children
many variants across the genome are evaluated, each associated with and their families and considering clinical screening and cascade genetic
a small effect on disease risk, and a score representing the aggregate testing,75,210,211 (Table 12) and a patient-centred approach that takes in
risk is calculated.182,183,195–197 To date, the value of a PRS in the clinical
management of cardiomyopathies has not yet been demonstrated, and Table 12 Specific issues to consider when counselling
access to genetic counselling will be even more important in conveying children
risks and uncertainties to patients and families.
Issue Implications
6.8.2.2. Genetic test reports and variant interpretation Autonomy Competence of child to decide on testing
Many genetic diagnostic laboratories use a standardized framework to Informed consent Appropriate to understanding of child
interpret and report diagnostic genetic test results.3,198–200 A negative Right to know/not to know Consider wishes of child and family
genetic test result in a proband indicates that no causative variant has the result
been found in a known disease-associated gene. This does not necessar- Confidentiality Context of family history
ily mean the patient does not have a genetic disease, but reflects our Incomplete and age-related Symptoms/features of disease may not
limited knowledge of the genetic architecture of inherited cardiomyop- penetrance become apparent for many years
athies at this point in time. Aspects concerning the genetic testing ap-
Lifestyle School, sports, employment
proach, genetic testing methods, and variant interpretation are
Life stages and transition Moving from primary to secondary
© ESC 2023
Minimize healthcare
Explore worry Preferences of Respectful
burden of unnecessary Age of the child
and fear the parents discussion
clinical screening
Genotype-positive Genotype-negative
Figure 9 A patient-centred approach to cascade genetic testing of children. Factors to consider when supporting families to decide whether to pursue
cascade genetic testing in children.
to account the experiences and values of the family is needed (Figure 9). the return of the results (post-test). Key discussion points during pre-
The guiding principle remains that any testing, clinical or genetic, should and post-test counselling are summarized in Table 13.
be in the best interests of the child and have an impact on management,
lifestyle, and/or ongoing clinical testing.75 With appropriate multidiscip-
linary support in a paediatric setting, psychosocial outcomes in children 6.8.3.3. Genetic counselling for cascade testing
undergoing clinical screening and cascade genetic testing are no differ- Once a P/LP variant has been identified within an index patient follow-
ent than those of the general population.212 ing investigations of relevant disease genes associated with the specific
phenotype, it is possible to offer cascade genetic testing of first-degree
6.8.3.2. Pre- and post-test genetic counselling (proband) at-risk relatives, including pre-test genetic counselling (see Section 6.8).
One critical role for genetic counselling is that it should be done along- In a scenario where a first-degree relative has died, evaluation of close
side genetic testing (see Section 6.8.2).3 This includes a discussion prior relatives of the deceased individual (i.e. second-degree relatives of the
to a decision to undertake genetic testing (pre-test), and at the time of index patient) should also be considered.
34 ESC Guidelines
Table 13 Key discussion points of pre- and post-test Table 14 Pre-natal and pre-implantation options and
genetic counselling implications
Pre-test genetic Detailed family history
Issue Implications
counselling Genetic education
Process and logistics of genetic testing and Chorionic villus sampling • Transcervical or transabdominal sampling of
return of the result the placenta at 10–14 weeks of gestation.
The procedure-related foetal loss rate is
© ESC 2023
effects for those undergoing the procedure.
© ESC 2023
The right assignment of the level of pathogenicity of a variant is cru- 6.8.3.4. Pre-natal or pre-implantation genetic diagnosis
cial for cascade genetic testing. Inappropriate use of genetic testing in a Pre-natal or pre-implantation genetic testing can be offered to par-
family has the potential to introduce unnecessary worry and fear, as ents who have had a previous affected child with an inherited cardio-
well as potential harm related to the misinterpretation of genetic var- myopathy due to a single or multiple pathogenic variant(s), or to
iants. Variants should therefore be classified by a specialized multidiscip- couples where one or both partners carries a known pathogenic (fa-
linary cardiac genetic team with an appropriate level of expertise. milial) variant. The decision to pursue pre-natal or pre-implantation
Systematic reclassification of identified variants and communication genetic testing should consider a spectrum of disease- and
to families is crucial. Conveying information on the importance of clin- parent-related aspects, including cultural, religious, legal, and avail-
ical and genetic testing of at-risk relatives is typically reliant on the pro- ability issues.218 Options for pre-natal or pre-implantation genetic
band in the family understanding the information and passing it on to diagnosis should be discussed as part of the genetic counselling pro-
the appropriate relatives. Common barriers to communication can in- cess and in a timely manner. If pre-natal diagnostics are performed, it
clude poor family relationships, guilt regarding passing a causative vari- should be done early enough in pregnancy to give the patient options
ant on to children, psychosocial factors including distress, and regarding pregnancy continuation, or co-ordination of pregnancy, de-
comprehension of the result.214,215 A patient will often selectively com- livery, and neonatal care.219
municate genetic information to relatives, assessing their ability to Options for pre-natal and pre-implantation genetic diagnosis are
understand and cope with the information, their life stage, and their summarized in Table 14. Most reproductive diagnostic testing op-
risk status.216 Poor health literacy is an important barrier to effectively tions are for established pregnancies, except pre-implantation genet-
communicating genetic risk information to relatives, highlighting the ic diagnosis which allows for selective implantation of unaffected
need for targeted resources and mechanisms for support.217 embryos.
ESC Guidelines 35
© ESC 2023
in pregnancy, to allow decisions regarding I C phenotype-negative relative of a patient with
III C
continuation or co-ordination of pregnancy to be cardiomyopathy in the absence of a confident genetic
made. diagnosis (i.e. a P/LP variant) in the family.
A discussion about reproductive genetic testing
P/LP, pathogenic/likely pathogenic.
options with an appropriately trained healthcare a
Class of recommendation.
IIa C b
professional should be considered for all families with Level of evidence.
a genetic diagnosis.
Index patients
Genetic testing is recommended in patients fulfilling 6.9. Diagnostic approach to paediatric
diagnostic criteria for cardiomyopathy in cases where patients
it enables diagnosis, prognostication, therapeutic Traditionally, cardiomyopathies in children have been considered to be
stratification, or reproductive management of the I B distinct entities from adolescent and adult cardiomyopathies, with dif-
patient, or where it enables cascade genetic ferent aetiologies, natural history, and management. Although substan-
evaluation of their relatives who would otherwise be tially rarer than in adults, contemporary data have shown that, beyond
enrolled into long-term surveillance.227–231,237,238 the first year of life, in most cases, paediatric cardiomyopathies re-
Genetic testing is recommended for a deceased present part of the spectrum of the same diseases that are seen in ado-
individual identified to have cardiomyopathy at lescents and adults.245 Given their rarity, data on clinical management
I C and outcomes are more limited than in adults, but large population-
post-mortem if a genetic diagnosis would facilitate
based or international consortium data have provided important
management of surviving relatives.239–243
information on clinical presentation, natural history, and outcomes of
Genetic testing may be considered in patients
cardiomyopathies in children.245 Paediatric-onset cardiomyopathies of-
fulfilling diagnostic criteria for cardiomyopathy when
ten represent two opposite ends of the spectrum of heart muscle dis-
it will have a net benefit to the patient, considering
ease: (i) severe, early-onset disease, with rapid disease progression and
the psychological impact and preference, even if it IIb C
poor prognosis, in keeping with the most severe presentations in adults;
does not enable diagnosis, prognostication, or or (ii) early phenotypic expression of adult cardiomyopathy
therapeutic stratification, or cascade genetic phenotypes, increasingly identified as a result of family screening. For
screening of their relatives. this reason, the Task Force highlights the principle of considering car-
Genetic testing in patients with a borderline diomyopathies in all age groups as single disease entities, with recom-
phenotype not fulfilling diagnostic criteria for a
IIb C
mendations applicable to paediatric and adult populations throughout
cardiomyopathy may be considered only after this guideline, accepting that the evidence base for many of the recom-
detailed assessment by specialist teams. mendations is significantly more limited for children. Where there are
Continued age-related differences, these are specifically highlighted.
36 ESC Guidelines
The general approach to paediatric and adult cardiomyopathies is In infantile and early childhood-onset cardiomyopathies, clinical
based on age of onset, clinical presentation, and cardiac and systemic presentation, cardiac phenotype, and aetiology are the main determi-
phenotype.246 When a syndromic or metabolic disease is suspected, nants of management.2 Severe clinical onset of infantile cardiomyop-
a step-by-step approach taking into consideration age of onset, consan- athies is generally managed in intensive or subintensive care units by
guinity and family history, cardiac and systemic involvement, ECG and neonatologists and paediatric cardiologists, for respiratory distress
imaging, and laboratory work-up is recommended to define phenotype, and/or metabolic acidosis, and/or hypoglycaemia, and/or hypo-
aetiology, and tailored management.247 As in adults, clinical presenta- tonia.247,250–252 A comprehensive clinical approach, taking into con-
Inheritance
patterna
Concentric LVH GSD Friedreich Danon Mitochondrial
ECGb Global
GSD Mitochondrial Friedreich Desmosomal
hypokinesia
Posterolateral-
Dystrophin
akinesia
Pulmonary
RASopathy
Echocardiogram stenosis/CHD
Dysmorphia,
RASopathy
skeletal abnormalities
Skin
RASopathy Desmosomal
abnormalities
Metabolic
Mitochondrial Barth
acidosis
Hypoglycaemia,
Systemic GSD
AST/ALT
phenotype
Ataxia Friedreich
HCM
Muscle Dystrophin/
Friedreich Mitochondrial MYH7
DCM weakness NMD
Figure 10 Clinical approach to infantile and childhood cardiomyopathy. ALT, alanine aminotransferase; ARVC, arrhythmogenic right ventricular cardio-
myopathy; AST, aspartate transaminase; CHD, congenital heart disease; DCM, dilated cardiomyopathy; ECG, electrocardiogram; GSD, glycogen storage dis-
order; HCM, hypertrophic cardiomyopathy; LSD, lysosomal storage disease; LVH, left ventricular hypertrophy; MYH7, myosin heavy chain 7; NDLVC,
non-dilated left ventricular cardiomyopathy; NSML, Noonan syndrome with multiple lentigines; RCM, restrictive cardiomyopathy. aSee Table 5. bSee
Table 7.Image %:
ESC Guidelines 37
In infants with HCM, after exclusion of reversible causes (maternal dia- develop symptoms, often many years after the appearance of ECG or
betes,253 twin–twin syndrome, corticosteroid use254,255), it is important to imaging evidence of disease. In infants, symptoms and signs of heart fail-
define, along with the pattern of hypertrophy (asymmetric, concentric, bi- ure include tachypnoea, poor feeding, excessive sweating, and failure to
ventricular), the presence of LVOTO, diastolic and/or systolic dysfunc- thrive. Older children, adolescents, and adults complain of fatigue and
tion,1,256 and RV involvement. Early-onset sarcomeric disease (including dyspnoea as well as chest pain, palpitations, and syncope. Because the
double/compound variants) should be excluded even in the absence of a New York Heart Association (NYHA) classification to grade heart fail-
family history for HCM and SCD; these infants present with severe heart ure is not applicable to children under the age of 5 years, the Ross
withdrawal of these drugs frequently leads to improvement in symp- 6.10.2.2. Cardiac transplantation
toms and should be considered. Orthotopic cardiac transplantation should be considered in patients
Heart failure with an LVEF >40–50% recovered from HFrEF or with moderate-to-severe drug-refractory symptoms (NYHA function-
HFmrEF (improved LVEF306) is not separately considered in the 2021 al class III–IV) who meet standard eligibility criteria (see the 2021 ESC
ESC Guidelines for the diagnosis and treatment of acute and chronic heart Guidelines for the diagnosis and treatment of acute and chronic heart fail-
failure, but is particularly important for genetic DCM, as a substantial ure).69 This may include patients with RCM and HCM with normal LVEF
proportion of patients with HFrEF or HFmrEF will improve their but severe drug-refractory symptoms (NYHA functional class III–IV)
© ESC 2023
ventricular arrhythmia refractory to medical/invasive/
tients are young with no or only mild symptoms, and where asymptom-
device therapy, and who do not have absolute
atic patients are frequently discovered through cascade screening.
Because heart failure medication has proved to affect LV remodelling contraindications.317–319
in symptomatic patients with LV dysfunction, first-line heart failure NYHA, New York Heart Association.
a
therapy may be considered in patients with early forms of DCM/ Class of recommendation.
b
NDLVC to prevent progression of LV dilatation and dysfunction (e.g. Level of evidence.
ACE-I, ARBs, beta-blockers and MRAs, Class IIb Level C). Biomarkers 6.10.2.3. Left ventricular assist devices
may help to identify pre-symptomatic patients who might benefit
As there are increasing numbers of patients with end-stage heart fail-
from early neuro-hormonal blockade.308 The effect of heart failure
ure, and the organ donor pool remains limited, mechanical circulatory
drugs to prevent progression into overt disease in genetic carriers of
support (MCS) with an LVAD or biventricular assist device is
DCM-/NDLVC-causing variants is currently unsettled. A placebo-
controlled trial (EARLY-Gene trial) is under way to test the utility of Recommendation Table 10 — Recommendation for
candesartan to prevent LV dysfunction/dilatation in this scenario left ventricular assist device therapy in patients with
(EudraCT: 2021-004577-30). cardiomyopathy
Management in other asymptomatic affected patients with diagnoses
of HCM, ARVC, and RCM should be decided individually, as medication Recommendation Classa Levelb
has not been proved to affect disease expression. Mechanical circulatory support therapy should be
There is no evidence to support the use of current pharmacological considered in selected cardiomyopathy patients with
agents for the prevention of disease development in non-affected car- advanced heart failure (NYHA class III–IV) despite
riers. Randomized controlled trials are warranted in order to address optimal pharmacological and device treatment, who
the value of new pharmacologic agents in this scenario.309 IIa B
are otherwise suitable for heart transplantation, to
Heart failure therapies are given to children with cardiomyopathies,
improve symptoms and reduce the risk of heart failure
applying the evidence from adults to children or based on a limited
hospitalization from worsening heart failure and
number of clinical studies.310 Heart failure therapies routinely used in
premature death while awaiting a transplant.320–324
children with LV dysfunction are ACE-Is, beta-blockers, diuretics, and
Mechanical circulatory support therapy should be
aldosterone antagonists. Angiotensin receptor blockers are an alterna-
tive for ACE-Is. Early results of the multicentric randomized control considered in selected cardiomyopathy patients with
PANORAMA-HF Trial and the subsequent Food and Drug advanced heart failure (NYHA class III–IV) despite
Administration (FDA) approval for ARNI in children have paved the optimal pharmacological and device therapy, who are
IIa B
way for this newer class of drugs for paediatric patients with symptom- not eligible for cardiac transplantation or other
© ESC 2023
atic heart failure with systemic left ventricle systolic dysfunction, 1 year surgical options, and without severe right ventricular
of age and older. Dosing recommendations in younger children are cur- dysfunction, to reduce the risk of death and improve
rently pending,311 but for children <40 kg a starting dose of 1.6 mg/kg symptoms.321,325–330
titrated to a maximum of 3.1 mg/kg has been suggested.312 There are
NYHA, New York Heart Association.
currently no clinical trial or efficacy data available for SGLT-2 inhibitors a
Class of recommendation.
in children. b
Level of evidence.
ESC Guidelines 39
increasingly used as a bridge to transplant. Long-term MCS should also and diabetes mellitus, among others.332,333 The CHA2DS2-VASc (con-
be considered as destination therapy for cardiomyopathy patients with gestive heart failure or left ventricular dysfunction, hypertension, age
advanced heart failure despite optimal medical therapy who are not eli- ≥75 [doubled], diabetes, stroke [doubled]-vascular disease, age 65–
gible for transplantation.69 74, sex category [female]) score has not been specifically tested in pa-
tients with cardiomyopathies,369 and retrospective evidence suggests
that it may perform suboptimally with respect to stroke prediction in
6.10.3. Management of atrial arrhythmias
HCM and ATTR amyloidosis.334,365,371–374 For this reason, although
HCM 17–39%331–334,365,413,421–428 2.8– Always (if no Beta-blockers (preferred) Rhythm control is preferred
4.8%332,333,365 contraindication)371,429 Verapamil or diltiazem (only if Amiodarone, dofetilide Ablation397,412,415,416,418,430–
preserved LVEF) a 435
disopyramide, sotalol,
Digoxin b
dronedarone
AV node ablation + CRT or
physiological pacing388–390
DCM 25–49%331–333,426,436,437 3.8–5.5%332,333 According to cardio-embolic Beta-blockers (preferred) Rhythm control preferred in case of symptoms or/and heart failure or
LMNA related438–441 risk Digoxin LV dysfunction
(always if HF or reduced AV node ablation + CRT or Amiodarone, sotalola Ablation
c 388–390
LVEF) physiological pacing
NDLVC 39.2–43.1%d 442–444 4.4–12%d According to cardio-embolic Beta-blockers (preferred) Rhythm control preferred in case of symptoms or/and heart failure or
442,444,445
risk Digoxin LV dysfunction
(always if HF or reduced Verapamil or diltiazem (only if Flecainidee, amiodarone, sotalola Ablation446
LVEF) LVEF ≥40%)
AV node ablation + CRT or
physiological pacing388–390
ARVC 9–30%331–333,437,447–451 2.1–2.8%332,333 According to cardio-embolic Beta-blockers (preferred) Rhythm control preferred in case of symptoms or/and heart failure or
risk Verapamil or diltiazem (only if LV dysfunction
(always if HF or reduced LVEF ≥40%) Flecainidee (associated with Ablation
LVEF) AV node ablation + CRT or beta-blockers)
physiological pacing388–390 Amiodarone, sotalola
331–333 332,333 d
RCM 45–51% 4.5–10.3% Always (if no Beta-blockers (preferred) Rhythm control is preferred
contraindication) Digoxinf Amiodarone No data
Verapamil or diltiazem (only if
≥40%)
AV node ablation + CRT or
physiological pacing388–390
© ESC 2023
AF, atrial fibrillation; ARVC, arrhythmogenic right ventricular cardiomyopathy; AV, atrioventricular; CrCl, creatinine clearance; CRT, cardiac magnetic resonance; DCM, dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy; HF, heart failure;
HFpEF, heart failure with preserved ejection fraction; LMNA, lamin A/C; LV, left ventricular; LVEF, left ventricular ejection fraction; NDLVC, non-dilated left ventricular cardiomyopathy; QRS, Q, R, and S waves of an ECG; RCM, restrictive
cardiomyopathy.
a
Use with caution as evidence suggests that it may be associated with increased all-cause mortality.452
b
Dronedarone is not contraindicated in LV hypertrophy but has no significant studies in HCM.
c
LMNA-related DCM: increased risk of stroke (8–22%).368,440
d
Extrapolated from studies reporting prevalent and incident AF in HFpEF.
e
Contraindicated in patients with ischaemic heart disease or reduced LVEF. Should not be used in patients with CrCl <35 mL/min/1.73 m2 and significant liver disease. Should be discontinued in case of QRS widening >25% above baseline and patients
with left bundle branch block or any other conduction block >120 ms. Caution when sinoatrial/atrioventricular conduction disturbances.
f
In cardiac amyloidosis, beta-blockers in low dosage and digoxin with caution.453,454 Non-dihydropyridine calcium channel blockers may worsen LV systolic function and heart failure.455
ESC Guidelines
levels is needed, as observational data suggest higher mortality in pa- reduction in all-cause mortality and hospitalizations, and should be con-
tients with AF, regardless of heart failure; the risk of death was related sidered as a first-line option. In the general AF population, the Early
to serum digoxin concentration and was highest in patients with con- Treatment of Atrial Fibrillation for Stroke Prevention Trial
centrations ≥1.2 ng/mL. On the contrary, a lower mortality with beta- (EAST-AFNET 4) randomized 2789 patients with early AF and associated
blocker therapy in AF patients with concomitant heart failure has been cardiovascular comorbidities to an early rhythm control strategy or usual
observed. Non-dihydropyridine calcium channel blockers (CCBs) (ver- care (28.6% with heart failure).402 The trial was stopped early after a me-
apamil or diltiazem) may only be used in patients with LVEF ≥40%.336 dian follow-up of 5.1 years for a lower occurrence of the primary out-
Oral anticoagulation to reduce the risk of stroke and The 2022 ESC Guidelines for the management of patients with ventricu-
thrombo-embolic events should be considered in lar arrhythmias and the prevention of sudden cardiac death provide de-
IIa C
patients with RCM and AF or atrial flutter (unless tailed recommendations on acute and long-term management of
contraindicated). ventricular arrhythmias in patients with cardiomyopathies.299 Limited
data exist addressing ventricular arrhythmia management in patients
Oral anticoagulation to reduce the risk of stroke and
with specific genetic cardiomyopathies. Nonetheless, some general
thrombo-embolic events should be considered in
IIa B
concepts can be highlighted:
therapy of intercurrent conditions is recommended VT ablation, as well as the dose–response relationship, therefore its
I B
to reduce AF burden and symptom severity in usage should be limited to compassionate cases or within prospective
patients with cardiomyopathy.347,508–513 clinical studies.
AAD, antiarrhythmic drug; AF, atrial fibrillation; ARVC, arrhythmogenic right ventricular • The acute as well as the chronic management of patients with cardio-
cardiomyopathy; CHA2DS2-VASc, congestive heart failure or left ventricular dysfunction, myopathies and refractory ventricular arrhythmias, particularly in
hypertension, age ≥75 (doubled), diabetes, stroke (doubled)-vascular disease, age 65–74, case of concomitant moderate-to-severe ventricular dysfunction,
sex category (female) (score); DCM, dilated cardiomyopathy; HCM, hypertrophic
cardiomyopathy; LV, left ventricular; LVEF, left ventricular ejection fraction; NDLVC,
should involve an integrated evaluation by a heart team including car-
non-dilated left ventricular cardiomyopathy; QoL, quality of life; RCM, restrictive diomyopathy specialists, electrophysiologists with specific experi-
cardiomyopathy. ence in catheter ablation of ventricular arrhythmias and
a
Class of recommendation. neuromodulation, anaesthesiologists, and cardiac surgeons.
b
Level of evidence.
require several replacements during their lifetimes. Implantable cardio- Secondary prevention
verter defibrillators reduce mortality in survivors of cardiac arrest and
Implantation of an ICD is recommended:d
in patients who have experienced haemodynamically compromising
• in patients with HCM, DCM, and ARVC who have
sustained ventricular arrhythmias.521–523 An ICD is recommended in
such patients when the intent is to increase survival; the decision to im- survived a cardiac arrest due to VT or VF, or who
have spontaneous sustained ventricular arrhythmia I B
plant should consider the patient’s view and their QoL, as well as the
absence of other diseases likely to cause death within the following causing syncope or haemodynamic compromise in
6.10.6. Routine follow-up of patients with history and other factors. In families where there is only one affected
cardiomyopathy individual and where no genetic variant has been identified, the fre-
In general, patients with cardiomyopathy require lifelong follow-up to quency and duration of clinical follow-up may be reduced (see
detect changes in symptoms, risk of adverse events, ventricular func- Figure 11).
tion, and cardiac rhythm. Generally, the frequency of the clinical cardiac evaluation in relatives
The frequency of monitoring is determined by the severity of disease, will be based on the inheritance pattern, the risk of events in the af-
age, and symptoms. A clinical examination, including 12-lead ECG and fected individual(s), and the quality-adjusted life-year. It would also de-
imaging is recommended in patients with recommended in first-degree relatives who have the
I C
cardiomyopathy whenever there is a substantial or same disease-causing variant as the
unexpected change in symptoms. proband.178,544,547
ECG, electrocardiogram. Following cascade genetic testing, it is recommended
a
Class of recommendation. that first-degree relatives without a phenotype who
b
Level of evidence.
do not have the same disease-causing variant as the
proband are discharged from further follow-up but I C
advised to seek re-assessment if they develop
6.11. Family screening and follow-up symptoms or when new clinically relevant data
evaluation of relatives emerge in the family.
All first-degree relatives of patients with cardiomyopathy should be of- It is recommended that when no P/LP variant is
fered clinical screening with ECG and cardiac imaging (echocardiogram identified in the proband or genetic testing is not
[ECHO] and/or CMR). In families in whom a disease-causing genetic performed, an initial clinical evaluation using a I C
variant has been identified, cascade genetic testing should be offered multiparametric approach that includes ECG and
(see Section 6.8.3). Individuals found not to carry the familial variant
cardiac imaging is performed in first-degree relatives.
and who do not have a clinical phenotype can usually be discharged,
When no P/LP variant is identified in the proband or
with advice to seek re-assessment if they develop symptoms or when
genetic testing is not performed, regular, long-term
new clinically relevant data emerge in the family. Those relatives har-
clinical evaluation using a multiparametric approach IIa C
bouring the familial genetic variant(s) should undergo regular clinical
evaluation with ECG, multimodality cardiac imaging, and additional in- that includes ECG and cardiac imaging should be
vestigations (e.g. Holter monitoring) guided by age, family phenotype, considered in first-degree relatives.
and genotype (Figure 11). Similarly, if a genetic cause of the disease During cascade screening, where a first-degree
© ESC 2023
has not been identified, either because P/LP variants are absent in the relative has died, clinical evaluation of close relatives
IIa C
proband or because genetic testing has not been performed, clinical of the deceased individual (i.e. second-degree
follow-up of all first-degree relatives is recommended; in families with- relatives of the index patient) should be considered.
out a known disease-causing variant, children should be offered ongoing
ECG, electrocardiogram, P/LP, pathogenic/likely pathogenic.
clinical surveillance, due to age-related penetrance, and ongoing surveil- a
Class of recommendation.
lance should also be offered to adult relatives dependent on family b
Level of evidence.
ESC Guidelines 45
With some exceptions using the current diagnostic criteria, the pene- 6.11.1. Special considerations in family screening
trance of the disease in women has been shown to be delayed (shifted) If the comprehensive study of the index cardiomyopathy patient (includ-
by 10 years compared with men.178,545–548 ing negative genetic testing) and first-degree relatives from informative
Cardiac screening in: (i) carriers of genetic P/LP variants associated families (i.e. with a large enough pedigree) leads to the conclusion that
with cardiomyopathies; or (ii) in those with demonstration of a familial the cardiomyopathy presents in isolation (i.e. the index patient is the
disease should be offered from childhood to old age. The proposed fre- only individual affected), termination of periodic surveillance could be
quency of screening is every 1–3 years with ECG and ECHO (plus add- considered in first-degree relatives ≥50 years of age with normal cardiac
No variant/genetic
P/LP variant VUS
testing not performed
Reconsider
other causes
Variant positive
Cardiomyopathy
+/- clinical Variant negative Normal
phenotype
phenotype
Figure 11 Algorithm for the approach to family screening and follow-up of family members. P/LP, pathogenic/likely pathogenic, VUS, variant of unknown
significance. aIf no additional affected relatives and no variant identified on genetic testing, consider earlier termination of clinical screening.
46 ESC Guidelines
phenotype may express later in life; and (iii) follow-up in families with those who are young or who have experienced multiple shocks and/or
more than one likely or definitively pathogenic variant (oligo- have poor baseline psychosocial functioning.553,554,557 The SCD of a
polygenicity) should be discussed in the cardiomyopathy team. young relative not only leads to profound grief, but one in two relatives
report post-traumatic stress or prolonged grief on average 6 years after
the death.558 Clinical psychological support for patients and their fam-
6.12. Psychological support in
ilies affected by inherited cardiomyopathies is an important aspect of
cardiomyopathy patients and family the multidisciplinary team’s care approach and should be available as re-
New diagnosis • Stigma associated with cardiovascular disease and misconception that it only affects older people.
• Fear of sudden cardiac death can shake confidence and create anxiety around exercise.
• Fear of inheritance risk to other relatives, especially children.
• Confidence and self-efficacy to manage their disease.
• Direct experience with the disease will affect perceptions about prognosis.211
ICD • Most patients will adjust well following ICD insertion, although there might be an initial decline in health-related quality of life and
psychological well-being, this often returns to normal.552,560,561
• Up to 30% will develop anxiety and/or symptoms of post-traumatic stress and need additional support.562
• Those who are young, who experience multiple ICD shocks, and/or have poor baseline psychological functioning are at greater risk
of poor psychological outcomes.553–555,561,563
• In young people, especially women, body image concerns can be a major consideration.554
• Decision-making for those recommended to have an ICD should be patient-centred and include balanced discussion of benefits
and risks and careful attention to questions and concerns.564
Exercise restrictions • Physical inactivity is a major determinant of poor health outcomes.
• Can reduce health-related quality of life for those who become fearful of performing even low-intensity exercise.
• Athletes who are recommended to reduce their activity levels can experience a profound grief and difficulty adjusting to this
advice.565
• Patient-centred discussions and careful attention to concerns is critical in helping to support people make drastic lifestyle
changes.566–568
Family history of young • Relatives who experience the SCD of a young relative have significant risk of poor psychological functioning, including
SCD post-traumatic stress and prolonged grief.558
• Grief is a normal response to a loss. Prolonged grief occurs when the grieving process becomes ‘stuck’.569
• Those who witness the death or discover the decedents body have a greater risk of psychological difficulties.558
• Mothers of the decedent have greater anxiety.558
• Psychological support for family members is an important and often unmet need following a young SCD.570,571
Children and adolescents • Diagnosis during childhood can raise anxiety especially among parents. Access to resources to support practical issues like
information for schools is important.
• Navigating transition from paediatric to adult care can be challenging for children and their families.
• Decision-making regarding genetic testing of asymptomatic children can often benefit from the inclusion of a clinical psychologist to
support adjustment to the result.
Symptomatic disease • Those managing symptoms will likely perceive a greater impact on their health-related quality of life. Factors influencing self-efficacy
will impact on a patient’s ability to manage their disease, including medication adherence.572
• Need for major intervention such as cardiac transplantation can raise significant psychological challenges and clinical psychological
support is very important.573
© ESC 2023
Genetic testing • Despite potential adjustment issues, most patients who undertake genetic testing do not report distress.574
• Genetic counselling should cover any psychosocial concerns or needs.204
• Additional support to patients to convey the genetic risk information to at-risk family members should be provided as necessary.575
Recommendation Table 15 — Recommendations for Relatives: the clinical diagnosis of HCM in adult first-degree relatives
psychological support in patients and family members of patients with unequivocal disease is based on the presence of LV wall
with cardiomyopathies thickness ≥13 mm. In child first-degree relatives with LV wall thickness
z-scores of <2, the presence of associated morphological or ECG ab-
Recommendations Classa Levelb
normalities should raise the suspicion but are not on their own diagnos-
It is recommended that psychological support by an tic for HCM.
appropriately trained health professional be offered
© ESC 2023
patients and families with an inherited IIa C marizes the key imaging features to assess in patients with suspected
cardiomyopathy and in particular for those issues or confirmed HCM. Several imaging features can point to a specific diag-
described in the text.c nosis (Table 18 and Section 6).62
a
Identification of LVOTO is important in the management of
Class of recommendation.
b
Level of evidence.
symptoms and assessment of SCD risk (see Section 7.1.5).
c
See Table 16. Two-dimensional and Doppler echocardiography during a Valsalva
manoeuvre in the sitting and semi-supine position—and then on
standing if no gradient is provoked—is recommended in all patients
6.13. The patient pathway (Figure 12).587,588 Exercise stress echocardiography is recom-
The systematic, multiparametric approach to diagnosis and evaluation mended in symptomatic patients if bedside manoeuvres fail to in-
of patients with suspected cardiomyopathy described in this section al- duce LVOTO ≥50 mmHg. Pharmacological provocation with
lows clinicians to establish the presence of a cardiomyopathy and iden- dobutamine is not advised, as it is not physiological and can be
tify its aetiology and guides the management of symptoms and poorly tolerated.
prevention of disease-related complications. While many of the aspects
of clinical care and the accompanying recommendations are common
to all cardiomyopathy phenotypes, achieving an aetiological diagnosis
Recommendation Table 16 — Recommendation for
is key to delivering disease-specific management; this is discussed in de-
evaluation of left ventricular outflow tract obstruction
tail in the subsequent sections of this guideline (see Section 7).
Recommendations Classa Levelb
In symptomatic patients with HCM and inconclusive remodelling and the extent of LGE is associated with a higher incidence
non-invasive cardiac imaging, left and right heart of RWMAs. Late gadolinium enhancement varies substantially with the
© ESC 2023
catheterization may be considered to assess the IIb C quantification method used but the 2-standard deviation technique is
severity of LVOTO and to measure LV filling the only one validated against necropsy.605
pressures.603 Although CMR rarely distinguishes the causes of HCM by their
magnetic properties alone, the distribution and severity of intersti-
2D, two-dimensional; HCM, hypertrophic cardiomyopathy; LV, left ventricular; LVOTO, tial expansion can, in context, suggest specific diagnoses (see Section
© ESC 2023
33–84%), typically in a patchy mid-wall pattern in areas of hypertrophy ASA or myectomy to assess the extent and
IIb C
and at the anterior and posterior RV insertion points.604 Late gadolin- distribution of hypertrophy and myocardial
ium enhancement is unusual in non-hypertrophied segments except in fibrosis.606,607
advanced stages of disease, when full-thickness LGE in association with
ASA, alcohol septal ablation; CMR, cardiac magnetic resonance.
wall thinning is common.604 Late gadolinium enhancement may be as- a
Class of recommendation.
b
sociated with increased myocardial stiffness and adverse LV Level of evidence.
LV wall thickness ECHO/CMR • All LV segments from base to apex examined in end-diastole, preferably in the 2D short-axis view,
ensuring that the wall thickness is recorded at mitral, mid-LV, and apical levels.
• CMR is superior in the detection of LV apical and anterolateral hypertrophy, aneurysms,580 and
thrombi,581 and is more sensitive in the detection of subtle markers of disease in patients with
sarcomeric protein gene variants (e.g. myocardial crypts, papillary muscle abnormalities).159,582,583
Systolic function (global ECHO/CMR • Ejection fraction is a suboptimal measure of LV systolic performance when hypertrophy is present.
and regional) • Doppler myocardial velocities and deformation parameters (strain and strain rate) are typically reduced
at the site of hypertrophy despite a normal EF and may be abnormal before the development of
increased wall thickness in genetically affected patients.
Diastolic function ECHO • Routine examination should include mitral inflow assessment, tissue Doppler imaging, pulmonary vein
flow velocities, pulmonary artery systolic pressure, and LA size/volume.
Mitral valve ECHO • Assess presence and degree of SAM and mitral regurgitation. The presence of a central- or anteriorly
directed jet of mitral regurgitation should raise suspicion of an intrinsic/primary mitral valve abnormality
and prompt further assessment.
LVOT ECHO • See Figure 12.
LA dimensions ECHO/CMR • Provides important prognostic information.365,525,584
• Most common mechanisms of LA enlargement are SAM-related mitral regurgitation and elevated LV
filling pressures.
Myocardial fibrosis/LGE CMR • The distribution and severity of interstitial expansion can suggest specific diagnoses. Anderson–Fabry
disease is characterized by a reduction in non-contrast T1 signal and the presence of posterolateral
© ESC 2023
LGE.134,155 In cardiac amyloidosis, there is often global, subendocardial or segmental LGE and a highly
specific pattern of myocardial and blood-pool gadolinium kinetics caused by similar myocardial and
blood T1 signals.585,586
2D, two-dimensional; CMR, cardiac magnetic resonance; ECHO, echocardiogram; EF, ejection fraction; LA, left atrium; LGE, late gadolinium enhancement; LV, left ventricular; LVOT, left
ventricular outflow tract; SAM, systolic anterior motion; SCD, sudden cardiac death.
ESC Guidelines 49
© ESC 2023
sarcomeric HCM, Anderson–Fabry disease, Friedreich ataxia
RVOTO Noonan syndrome and associated disorders
Apical sparing pattern on longitudinal strain imaging Amyloidosis
2D, two-dimensional; AV, atrioventricular; HCM, hypertrophic cardiomyopathy; LV, left ventricular; LVH, left ventricular hypertrophy; PRKAG2, protein kinase AMP-activated non-catalytic
subunit gamma 2; RV, right ventricular; RVOTO, right ventricular outflow tract obstruction; TTR, transthyretin.
Modified from Rapezzi et al.62
Repeat
Maximum provoked peak
N Symptoms Asymptomatica echocardiogram
LVOTO ≥50 mmHg
at 1 year
Y Symptomatic
Exercise stress
echocardiogram
(Class I)
Figure 12 Protocol for the assessment and treatment of left ventricular outflow tract obstruction. 2D, two-dimensional; LVOTO, left ventricular outflow
tract obstruction. aExercise echocardiography may be considered in individual patients when the presence of an left ventricular outflow tract gradient is
relevant to lifestyle advice and decisions on medical treatment.
variant inherited from a parent or due to de novo variants that were not infancy, sarcomere protein gene variants account for 55–75% of cases
carried by the parents or, less commonly, due to autosomal recessive of childhood-onset HCM,616–619 and even in infancy, sarcomeric dis-
inheritance. In those who undergo genetic testing, ∼40–60% will have ease is present in up to 40% of cases.616,620 Although rarer, inborn er-
a single variant identified as the cause of their disease, although this is rors of metabolism and malformation syndromes can also present for
influenced by the cohort studied.124 The likelihood of finding a causal the first time in older children and adolescents (see Section 7.6).614
variant is highest in young patients with familial disease and lowest A thorough and comprehensive diagnostic work-up is essential in the
in older patients and individuals with non-classical features. diagnosis of childhood-onset HCM in order to confirm the diagnosis,
Rate/rhythm control
Atrial fibrillation Y
Anticoagulation
N
Still symptomatic
Resting/provocable
LVOTO management Y
LVOTO ≥50 mmHg?
Consider MCS/cardiac
transplantation
Figure 13 Algorithm for the treatment of heart failure in hypertrophic cardiomyopathy. ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin
receptor blocker; ARNI, angiotensin receptor neprilysin inhibitor; LVEF, left ventricular ejection fraction; LVOTO, left ventricular outflow tract obstruction;
MCS, mechanical circulatory support; MRA, mineralocorticoid receptor antagonist; NYHA, New York Heart Association; SGLT2i, sodium–glucose co-
transporter 2 inhibitor.Image %:
ESC Guidelines 51
7.1.4.1. Management of left ventricular outflow tract obstruction the dose reduced if it exceeds 500 ms. Disopyramide should be avoided
By convention, LVOTO is defined as a peak instantaneous Doppler LV in patients with glaucoma, in men with prostatism, and in patients taking
outflow tract gradient of ≥30 mmHg, but the threshold for invasive other drugs that prolong the QT interval, such as amiodarone and so-
treatment is usually considered to be ≥50 mmHg (the threshold at talol. Disopyramide may be used in combination with verapamil.633
which theoretical models examining the relationship between the gra- Verapamil (starting dose 40 mg three times daily to maximum
dient and stroke volume predict that this becomes haemodynamically 480 mg daily) can be used when beta-blockers are contraindicated or
significant).587,624,625 Most patients with a maximum resting or pro- ineffective but, based on limited data, should be used cautiously in pa-
control should be considered before invasive at 16 and 32 weeks.642,643 Small CMR and ECHO substudies suggest
IIa C
management of LVOTO in patients with new-onset that mavacamten may also lead to positive myocardial remodelling,
or poorly controlled AF.629,630 with reduction in myocardial mass, LV wall thickness, and left atrial vol-
AF, atrial fibrillation; LVOTO, left ventricular outflow tract obstruction. ume.644–646 Aficamten, a next-in-class cardiac myosin inhibitor, was
a
Class of recommendation. also recently shown in a Phase II randomized placebo-controlled study
b
Level of evidence. (Randomized Evaluation of Dosing With CK-3773274 in Obstructive
Outflow Disease in HCM [REDWOOD-HCM]) to significantly reduce
7.1.4.1.2. Drug therapy. Figure 14 describes the management of LVOT gradients and NT-proBNP levels in adult patients with symp-
LVOTO in patients with HCM. By consensus, patients with symptom- tomatic obstructive HCM.647
atic LVOTO have been treated initially with non-vasodilating beta- In the absence of a direct head-to-head comparison, the Task Force
blockers titrated to the maximum tolerated dose, but there are very was unable to recommend the use of cardiac myosin ATPase inhibitors
few studies comparing individual beta-blockers. A recent small, rando- as first-line medical therapy, but did consider the evidence sufficiently
mized placebo-controlled trial showed reduction of resting and exer- robust to support the recommendation that their use as second-line
tional LVOTO, and improvement in symptoms and QoL with therapy should be considered when optimal medical therapy with beta-
metoprolol therapy.631 blockers, calcium antagonists, and/or disopyramide is ineffective or
If beta-blockers alone are ineffective, disopyramide, titrated up to a poorly tolerated. In the absence of evidence to the contrary, cardiac
maximum tolerated dose (usually 400–600 mg/day), may be myosin ATPase inhibitors should not be used with disopyramide, but
added.632–634 This class IA AAD can abolish basal LV outflow pressure may be coadministered with beta-blockers or calcium antagonists.
gradients and improve exercise tolerance and functional capacity with a Up-titration of medication to a maximum dose of 15 mg should be
low risk of proarrhythmic effects and without an increased risk of monitored in accordance with licensed recommendations using echo-
SCD.632,633 Dose-limiting anticholinergic side effects include dry eyes cardiography. In patients with contraindications or known sensitivity
and mouth, urinary hesitancy or retention, and constipation.632,633,635 to beta-blockers, calcium antagonists, and disopyramide, cardiac my-
The QTc interval should be monitored during dose up-titration and osin ATPase inhibitors may be considered as monotherapy.
52 ESC Guidelines
Beta-blockers or verapamil
Symptoms N may be considered
(Class IIb)
Y
Verapamil Diltiazem
OR
(Class I) (Class I)
Still symptomatic
Disopyramide Mavacamten
OR
(Class I) (Class IIa)
Still symptomatic
Figure 14 Flow chart on the management of left ventricular outflow tract obstruction. LVOTO, left ventricular outflow tract obstruction.Image %:
considered in addition to a beta-blocker (or, if this is The cautious use of low-dose diuretics may be
not possible, with verapamil or diltiazem) to improve considered in symptomatic LVOTO to improve IIb C
symptoms in adult patients with resting or provokedc exertional dyspnoea.
LVOTO.622,642–646
ATPase, adenosine triphosphatase; i.v., intravenous; LV, left ventricular; LVEF, left
Continued ventricular ejection fraction; LVOTO, left ventricular outflow tract obstruction.
a
Class of recommendation.
b
Level of evidence.
c
Provocation with Valsalva manoeuvre, upright exercise, or oral nitrates if unable to
exercise.
d
QTc interval should be monitored during up-titration of disopyramide and the dose
reduced if it exceeds 500 ms.
ESC Guidelines 53
7.1.4.1.3. Invasive treatment of left ventricular outflow tract (septal (NYHA functional class III–IV), and/or exertional or unexplained recur-
reduction therapy). There are no data to support the use of invasive rent syncope in spite of maximally tolerated drug therapy. Invasive ther-
procedures to reduce LVOTO in asymptomatic patients, regardless apy may also be considered in patients with mild symptoms (NYHA
of its severity. However, some retrospective data suggest that indivi- class II) refractory to medical therapy who have a resting or maximum
duals with high LVOT gradients, even if minimally symptomatic, have provoked gradient of ≥50 mmHg (exercise or Valsalva) and
a higher mortality than those without markedly elevated gradients.651 moderate-to-severe systolic anterior motion-related mitral regurgita-
Delay in SRT may have an impact on long-term outcomes, particularly tion, AF, or moderate-to-severe left atrial dilatation in expert centres
3 Assess MV anatomy/function
MV prolapse
Other intrinsic MV abnormalities
Figure 15 Pre-assessment checklist for patients being considered for invasive septal reduction therapies. AF, atrial fibrillation; MV, mitral valve; RVOTO,
right ventricular outflow tract obstruction; SAM, systolic anterior motion.
54 ESC Guidelines
abolishes or substantially reduces LV outflow tract gradients in over that the long-term outcome of patients after ASA with implanted per-
90% of cases, reduces systolic anterior motion-related mitral regurgita- manent pacemaker is similar to those without pacemaker.705 Repeat
tion, and improves exercise capacity and symptoms. Long-term symp- ASA or myectomy procedure is reported in 7–20% of patients after
tomatic benefit is achieved in >80% of patients with a long-term survival ASA, which is higher than reported following surgical myectomy.702
comparable to that of the general population.655–665 Pre-operative de- Septal ablation may be less effective in patients with very severe hyper-
terminants of a good long-term outcome are age <50 years, left atrial trophy (≥30 mm), but systematic data are limited.706 In general, the
size <46 mm, absence of AF, and male sex.663 risk of ventricular septal defect following septal myectomy is very small
Mitral valve replacement may be considered in obstruction can be relieved by transaortic myectomy, a transapical ap-
patients with a resting or maximum provoked proach, or combined transaortic and transapical incisions, with good
LVOTO gradient ≥50 mmHg when there is IIb C short-term outcomes but uncertain long-term survival.731,732
moderate-to-severe mitral regurgitation following Left ventricular apical aneurysms by themselves rarely need treatment.
isolated myectomy.661,674,714,716 A few patients develop monomorphic ventricular tachycardia related to
adjacent apical scarring, which may be amenable to mapping and ablation
Surgical AF ablation and/or left atrial appendage
(see Section 7.1.5).730,733 Rarely, thrombi are present within the aneur-
© ESC 2023
© ESC 2023
a dual-chamber ICD (instead of a single-lead device) IIb C Ranolazine may be considered to improve symptoms
© ESC 2023
may be considered, to reduce the LV outflow tract in patients with angina-like chest pain even in the IIb C
gradient or to facilitate medical treatment with 738,739
absence of LVOTO or obstructive CAD.
beta-blockers and/or verapamil.633,719–724,726
CAD, coronary artery disease; LVOTO, left ventricular outflow tract obstruction.
a
ASA, alcohol septal ablation; AV, atrioventricular; ICD, implantable cardioverter Class of recommendation.
b
defibrillator; LV, left ventricular; LVOTO, left ventricular outflow tract obstruction. Level of evidence.
a
Class of recommendation.
b
Level of evidence.
7.1.4.2.2. Cardiac resynchronization therapy. Regional heterogen-
eity of LV contraction and relaxation can be seen in patients with
Left ventricular mid-cavity obstruction and apical aneurysms. Left ventricu- HCM, and LV dyssynchrony may be a marker of poor prognosis.745
lar mid-cavity obstruction occurs in ∼10% of patients with HCM.727,728 Data on the impact of CRT on symptoms, LV function, and prognosis
Patients with mid-cavity obstruction tend to be very symptomatic and, in patients with non-obstructive HCM remain limited, but new evi-
in a number of studies, have shown an increased risk of progressive heart dence has emerged since the 2014 ESC Guidelines on diagnosis and man-
failure and SCD.727–729 Approximately 25% of patients also have an LV agement of hypertrophic cardiomyopathy.746,747 There is one small study
apical aneurysm (see Section 7.1.5).580,727,728,730 Patients with LV mid- using a blinded crossover design of biventricular and sham pacing and a
cavity obstruction should be treated with high-dose beta-blockers, ver- pre-specified analysis stratified by changes in LV end-diastolic volume
apamil, or diltiazem, but the response is often suboptimal. Limited experi- (LVEDV) with exercise at baseline.748 Biventricular pacing was asso-
ence, mostly from single centres, suggests that mid-ventricular ciated with significant increases in LVEDV and stroke volume in patients
56 ESC Guidelines
who had a reduction in exercise LVEDV pre-pacing (consistent with the did not include these as specific recommendations, given the limited
relief of diastolic ventricular interaction). This translated into improve- evidence base.
ments in peak maximum oxygen consumption (VO2) (1.4 mL/kg/min)
and QoL scores.748 Together, they suggest that symptomatic responses 7.1.5. Sudden cardiac death prevention in
to CRT may occur in individual patients, but that these are not asso- hypertrophic cardiomyopathy
ciated with consistent changes in LVEF or evidence for a reduction in Most contemporary series of adult patients with HCM report an annual
progression to end-stage heart failure. incidence for cardiovascular death of 1–2%, with SCD, heart failure, and
Table 19 Major clinical features associated with an increased risk of sudden cardiac death
Age • The effect of age on SCD has been examined in a number of studies86,525,584,760–764 and two have shown a significant
association, with an increased risk of SCD in younger patients.525,584
• Some risk factors appear to be more important in younger patients, most notably NSVT,765 severe LVH,766 and
unexplained syncope.584
• Sudden cardiac death is very rare below the age of 6 years,535,767 and there are some data to suggest a peak of SCD in
childhood HCM between 9 and 15 years;757 however, the association between age at diagnosis and SCD risk in
childhood HCM remains unclear.
NSVT • NSVT (defined as ≥3 consecutive ventricular beats at ≥120 b.p.m. lasting <30 s) occurs in 20–30% of patients during
ambulatory ECG monitoring and is an independent predictor of SCD.81,525,535,590,764,765,768–773
• There is no evidence that the frequency, duration, or rate of NSVT influences the risk of SCD.765,774
• NSVT occurring during or immediately following exercise is very rare, but may be associated with a high risk of SCD.768
Maximum LV wall thickness • The severity and extent of LVH measured by TTE are associated with the risk of SCD.81,535,592,593,763,765,770–772,775–780
• Several studies have shown the greatest risk of SCD in patients with a maximum wall thickness of ≥30 mm; however,
there are few data in patients with extreme hypertrophy (≥35 mm).525,592,763,765,769,781–784
Family history of sudden cardiac death • While definitions vary,525,592,762,782 a family history of SCD is usually considered clinically significant when one or
at a young age more first-degree relatives have died suddenly aged <40 years with or without a diagnosis of HCM, or when SCD has
occurred in a first-degree relative at any age with an established diagnosis of HCM.
• Family history of SCD does not appear to be an independent risk factor for SCD in childhood HCM.81,535 This may be
due to a higher prevalence of de novo variants in childhood HCM, the inclusion of non-sarcomeric disease, and/or
under-reporting of family history in paediatric cohorts.
Syncope • Syncope is common in patients with HCM but is challenging to assess, as it has multiple causes.785
• Non-neurocardiogenic syncope for which there is no explanation after investigation is associated with an increased
risk of SCD.81,525,535,584,590,755,761,768,769,781,786–788
• Episodes within 6 months of evaluation may be more predictive of SCD.584
Left atrial diameter • Several studies have reported a positive association between LA size and SCD.81,525,535,584,772,789 There are no data
on the association between SCD and LA area or volume. Measurement of LA size is also important in assessing the
risk of AF (see Section 6.10.3).
LV outflow tract obstruction • A number of studies have reported a significant association between LVOTO and SCD risk.86,525,590,762,768,790 Several
© ESC 2023
unanswered questions remain, including the prognostic importance of provocable LVOTO and the impact of
treatment (medical or invasive) on SCD.
• In childhood HCM, there are conflicting data on the association between LVOTO and SCD risk.81,535,772,777
AF, atrial fibrillation; b.p.m., beats per minute; ECG, electrocardiogram; HCM, hypertrophic cardiomyopathy; LA, left atrium; LV, left ventricular; LVH, left ventricular hypertrophy; LVOTO,
left ventricular outflow tract obstruction; NSVT, non-sustained ventricular tachycardia; SCD, sudden cardiac death; TTE, transthoracic echocardiogram.
ESC Guidelines 57
7.1.5.1. Left ventricular apical aneurysms more studies have been published (see Supplementary data online,
Left ventricular apical aneurysms are defined as a discrete thin-walled Table S1). In aggregate, the data show that LGE is common and, that
dyskinetic or akinetic segment of the most distal portion of the left when extensive (expressed as a percentage of LV mass), is associated
ventricle and are often associated with a mid-cavity gradient. Their with an increase in SCD risk and other events, particularly in the pres-
prevalence in unselected patients is uncertain but they were re- ence of other markers of disease severity including LV systolic impair-
ported in 3% of individuals in the prospective Hypertrophic ment. A meta-analysis of nearly 3000 patients from several studies
Cardiomyopathy Registry (HCMR).124 The first descriptions of LV suggests that the presence of LGE is associated with a 2.32-fold in-
for primary prevention ICD implantation in patients with a low or cohorts and a meta-analysis of available published data, relevant to
intermediate risk category. the 2014 ESC Guidelines on diagnosis and management of hypertrophic
cardiomyopathy performance, for SCD prevention has shown that
7.1.5.5. Sarcomeric variants pooled estimates are concordant with the observed SCD risk in pa-
tients designated as high or low risk.821–824 In children, risk stratification
A small number of studies have explored the prognostic value of sarco-
for SCD has traditionally been based on risk factors extrapolated from
meric variants in HCM. Despite initial attempts to classify variants as
adults with HCM, but this approach does not identify the children most
‘malignant’ or ‘benign’,803–807 no studies have shown an independent
Intermediate risk
≥1 clinical risk factorsa
5-year risk ≥4 to <6%
shared
ICD ICD ICD
decision
(Class IIb) (Class IIb) (Class IIa)
making
Secondary prevention
Figure 16 Flow chart for implantation of an implantable cardioverter defibrillator in patients with hypertrophic cardiomyopathy. 2D, two-dimensional;
CMR, cardiac magnetic resonance; ECG, electrocardiogram; HCM, hypertrophic cardiomyopathy; ICD, implantable cardioverter defibrillator; LGE, late gado-
linium enhancement; LV, left ventricular; LVEF, left ventricular ejection fraction; NSVT, non-sustained ventricular tachycardia; SCD, sudden cardiac death; VF,
ventricular fibrillation; VT, ventricular tachycardia. aClinical risk factors: extensive LGE (>15%) on CMR; LVEF <50%.
porary cohorts,185,186,853,854 and between 10 and 15% in Psychiatric drugs Clozapine, olanzapine; chlorpromazine, risperidone,
chemotherapy-induced, alcoholic, or peripartum DCM.42–44 Although lithium; methylphenidate; tricyclic antidepressants
the prevalence of genetic variants is higher in familial DCM, causative Other drugs All-trans retinoic acid; antiretroviral agents; phenothiazines
genetic variants are also identified in over 20% of non-familial DCM
HIV, human immunodeficiency virus; SARS-CoV-2, severe acute respiratory syndrome
cases.185,854,855 Finding a causative gene variant in a patient with coronavirus 2.
DCM allows better prediction of the disease outcome and progression,
62 ESC Guidelines
may contribute to the indications for device implantation, informs gen- 7.2.5. Sudden cardiac death prevention in dilated
etic counselling, and allows familial screening for relatives. Moreover, cardiomyopathy
genetic testing in DCM has long-term implications in terms of cost- Predicting SCD is a challenging aspect of the clinical care of patients
effectiveness by identifying at-risk family members with positive geno- with DCM. Implantable cardioverter defibrillators are effective at treat-
types, and thus reducing the number of family members requiring serial ing potentially lethal ventricular arrhythmias and preventing SCD, but
clinical follow-up.229 Genetic testing can therefore be beneficial in all are also associated with complications, particularly in young patients,
patients with DCM, including children856,857 and those with alcohol-/ who will require several replacements during their lifetimes (see
ICD
LVEF <35% Y
(Class IIa)
N
N
ICD
High risk Y
(Class IIa/IIb)b
N
ICD
Additional risk factorsc
(Class IIb)
Figure 17 Implantation of implantable cardioverter defibrillators in patients with dilated cardiomyopathy or non-dilated left ventricular cardiomyopathy
flowchart. CMR, cardiac magnetic resonance; DCM, dilated cardiomyopathy; ICD, implantable cardioverter defibrillator; LGE, late gadolinium enhancement;
LVEF, left ventricular ejection fraction; NDLVC, non-dilated left ventricular cardiomyopathy; VE, ventricular ectopic beats; VT, ventricular fibrillation. aSee
Table 21. bStrength of recommendation depends on gene and context. cAdditional risk factors include syncope, LGE presence on CMR.
p.Arg14del variant, variant-specific [https://plnriskcalculator.shinyapps. standard heart failure criteria from the 2021 ESC Guidelines for the diag-
io/final_shiny])542 risk-prediction scores have been developed that con- nosis and treatment of acute and chronic heart failure.185,867,872
sider genotype characteristics and additional phenotypic features. In patients without a high-risk genotype and LVEF >35%, the pres-
Where such scores are available, they should be used to guide primary ence and extent of myocardial scarring determined by LGE on CMR im-
prevention ICD implantation (Figure 17). As discussed in Section 7.1.5, aging can be helpful in risk stratification in patients with DCM.873,874
the Task Force acknowledges the challenges associated with defining Late gadolinium enhancement is observed in 25–35% of patients with
universal thresholds for acceptable risk across different cardiomyop- DCM and its presence is a strong risk marker for all-cause mortality
athy phenotypes, but is of the opinion that a similar approach to that and ventricular arrhythmias, both in retrospective and prospective
taken in risk stratification for HCM is reasonable. Although the 2022 studies. A recent prospective study of 1020 DCM patients with a me-
ESC Guidelines for the management of patients with ventricular arrhythmias dian follow-up of 5.2 years showed that myocardial scar had a strong
and the prevention of sudden cardiac death have suggested a higher and incremental prognostic value for predicting SCD, while LVEF
threshold of 10% risk at 5 years to guide primary prevention ICD im- ≤35% was not associated with SCD.138 In another study, a risk calcula-
plantation in patients with DCM and LMNA variants,3 this Task Force tor was developed that among others, incorporated the presence of
recommends shared decision-making based on real-world data as LGE on CMR imaging540, although this has not yet been externally va-
well as individual preferences, beliefs, circumstances, and values. Gaps lidated. There are at least two ongoing trials of ICD therapy according
in evidence should be shared with patients, and competing risks related to the presence of scar on CMR imaging, including DCM patients
to the disease (heart failure, stroke), and to age and comorbidity, as well (NCT04558723 and NCT03993730), but the Task Force’s opinion is
as device-related complications, should be discussed. In support of this, that the existing level of evidence can support using LGE to guide
a recent study validating the LMNA-risk VTA calculator overestimated ICD implantation in subgroups of patients with DCM (Figure 17).
arrhythmic risk when using ≥7% predicted 5-year risk as threshold Additional risk factors, such as syncope or the presence of NSVT and
(specificity 26%, C-statistic 0.85), despite a high sensitivity.871 burden of ventricular ectopy (VE), may also help guide ICD implant-
Importantly, there are also data to suggest that other genotypes (e.g. ation. There are no data currently to support a specific threshold for
TTN truncating variants) are associated with recovery of LVEF with VE burden, and this will depend on the underlying genotype and other
64 ESC Guidelines
clinical factors.542,867,872 In patients with unexplained syncope, pro- Table 21 High-risk genotypes and associated predic-
grammed electrical stimulation (PES) may provide additional informa- tors of sudden cardiac death
tion on the underlying cause.875 There are no definitive data
supporting the routine use of PES for primary prevention risk stratifica- Gene Annual Predictors of SCD
tion in patients with DCM, but this may be beneficial in patients with SCD rate
DCM and myotonic dystrophy with an independent indication to elec- LMNA185,186,438,541,865,878,879 5–10% Estimated 5-year risk of
trophysiological study to assess conduction disturbances,876 although life-threatening arrhythmia
© ESC 2023
LVEF < 45%
DCM, symptomatic heart failure, and LVEF ≤35%
despite >3 months of OMT.861,885 RBM20869 3–5% LGE on CMR
LVEF < 45%
The patient’s genotype should be considered in the
IIa B
estimation of SCD risk in DCM.185,186,869,886 CMR, cardiac magnetic resonance; DSP, desmoplakin; ECG, electrocardiogram; FLNC,
filamin C; LGE, late gadolinium enhancement; LMNA, lamin A/C; LVEF, left ventricular
An ICD should be considered in patients with DCM
ejection fraction; NSVT, non-sustained ventricular tachycardia; PLN, phospholamban;
with a genotype associated with high SCD risk and RMB, RNA binding motif protein; SCD, sudden cardiac death; VE, ventricular ectopic beats.
IIa C
LVEF >35% in the presence of additional risk factors
(see Table 21).541,542,867,869,873,878,881,886
by the presence of LGE on CMR) that is unexplained solely by abnormal
An ICD may be considered in selected patients with
loading conditions (hypertension, valve disease) or CAD. Global LV sys-
DCM with a genotype associated with high SCD risk
IIb C tolic dysfunction is defined by abnormal LVEF (i.e. <50%).9
and LVEF >35% without additional risk factors (see
869,873,881,886
Table 21).
An ICD may be considered in patients with DCM
7.3.1.2. Relatives
Clinical testing in relatives may reveal non-diagnostic abnormalities. In
© ESC 2023
Echocardiography and CMR are both central to the diagnosis. 7.3.1.7. Nuclear medicine
Additional laboratory tests, exercise testing, EMB, and cardiac catheter- The role of radionuclide imaging in NDLVC is limited. Measurement of
ization may also be considered (see Section 6). 18F-FDG uptake using PET, with focal or focal-on-diffuse FDG uptake
patterns, especially if concomitant abnormal 18F-FDG-PET uptake in
7.3.1.4. Electrocardiographic features extracardiac tissues, can be useful in suspected cardiac sarcoidosis.849
Recommendations on resting and ambulatory ECG testing are de- Isolated cardiac uptake has also been described in patients with
NDLVC caused by DSP variants.888
pacing and cardiac resynchronization therapy, and the 2022 ESC Guidelines to consider primary prevention ICD implantation in patients with
for the management of patients with ventricular arrhythmias and the pre- NSVT, a family history of SCD, or significant LGE. Additional risk fac-
vention of sudden cardiac death,69,299,336,724 and are discussed in tors, such as the burden of VE, may also help guide ICD implantation,
Section 6.10.2. but there are no data currently to support a specific threshold for
VE burden, and this will depend on the underlying genotype and other
7.3.5. Sudden cardiac death prevention in non-dilated clinical factors.542,867,872 In patients with unexplained syncope, PES may
left ventricular cardiomyopathy provide additional information on the underlying cause.875 There are no
7.4. Arrhythmogenic right ventricular has been challenged in patients with ARVC for showing poor sensitiv-
ity and specificity.5,899 It has been noted that epsilon waves are fre-
cardiomyopathy quently overdiagnosed and that there is poor agreement even
7.4.1. Diagnosis between experts regarding their presence.900 Furthermore, it has
7.4.1.1. Index case been demonstrated that they occur in the presence of severe struc-
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is charac- tural disease and thus add little to the diagnosis.900,901 Therefore, ep-
terized structurally by a progressive myocardial atrophy with fibro-fatty silon waves and SAECG should be utilized for diagnostic purposes
© ESC 2023
presentation. The presence of right pre-cordial TWI (V1–V3) in routine Annual ambulatory ECG monitoring is
ECG testing should also be suspected for ARVC.10,892 Less common recommended in patients with ARVC to aid in I C
ECG changes include low QRS voltages in the peripheral leads and ter- diagnosis, management, and risk stratification.902
minal activation delay in the right pre-cordial leads.893 Right ventricular
dilatation on 2D echocardiography is also a frequent reason for patient ARVC, arrhythmogenic right ventricular cardiomyopathy; ECG, electrocardiogram.
a
Class of recommendation.
referral. Less common presentations are RV or biventricular heart fail- b
Level of evidence.
ure that can mimic DCM or NDLVC.894 Patients with multiple variants
are thought to develop a more severe phenotype, and patients with a
DSP or DSG2 variant are more prone to develop heart failure.895,896
7.4.1.5. Echocardiography and cardiac magnetic resonance
In children and young adults, syncope, palpitations, and ventricular
arrhythmias are also the usual presenting symptoms.897 However, A comprehensive cardiac imaging assessment is recommended for all
chest pain, dynamic ST-T wave changes on basal 12-lead ECG, and myo- ARVC patients.71,73 Structural and functional alterations assessed by
cardial enzymes release in the setting of normal coronary arteries are echocardiography and CMR are key to ARVC diagnosis.10 The key fea-
often reported, requiring differential diagnosis with myocarditis or ture is the presence of wall motional abnormalities such as RV akinesia,
acute myocardial infarction.898 dyskinesia, or bulging, and the determinant of the diagnostic perform-
ance is the level of RV dilatation or dysfunction (major and minor cri-
teria). Cardiac magnetic resonance should be considered the first-line
7.4.1.2. Relatives test for assessment of the RV functional structural abnormalities criter-
Clinical testing in relatives often reveals non-diagnostic abnormalities. In ion as it has demonstrated superior sensitivity.10 Contrast-enhanced
this context, the presence of RV systolic global or regional dysfunction, CMR is the only tool allowing the detection of LV involvement which
or additional electrocardiographic abnormalities (e.g. repolarization ab- remains otherwise underestimated by applying the 2010 Task Force
normalities, prolonged terminal activation duration, low QRS voltages, Criteria. Tissue characterization by CMR or indirectly by electroanato-
frequent ventricular extrasystoles [>500 per 24 h], or NSVT) in a first- mical voltage mapping may show signs of fibro-fatty replacement that
degree relative of an individual with ARVC (or a first-degree relative can be present in either ventricle.889,903,904
with autopsy-proven ARVC) is highly suggestive of ARVC and warrants
close follow-up.
7.4.1.6. Endomyocardial biopsy
Differential diagnosis in patients with suspected ARVC includes inflam-
7.4.1.3. Diagnostic work-up matory processes affecting the right ventricle such as myocarditis and
The key elements of the diagnostic work-up for all patients with ARVC sarcoidosis. In some instances, especially when dealing with probands
are defined by the diagnostic criteria used for the identification of af- with a sporadic form, EMB may be helpful to rule out myocarditis
fected individuals. The revised Task Force criteria for the diagnosis of and sarcoidosis.72,892,905 Endomyocardial biopsy can also be useful in
ARVC published by Marcus et al. in 2010 have been used for the diag- selected patients in whom non-invasive assessment is inconclusive.4,72
nosis of ARVC for more than a decade.10 More recently, the Padua cri- Electroanatomic voltage mapping-guided EMB may be considered in se-
teria have offered an updated iteration to include LV involvement but lected cases, particularly in case of negative CMR.906
are yet to be externally validated.5 Key elements of the diagnostic work-
up include ECG, Holter monitoring, cardiac imaging, genetic testing, 7.4.1.7. Nuclear medicine
and, in specific circumstances, EMB.4,10,892 Additional laboratory tests, Measurement of 18F-FDG uptake using PET, with focal or
exercise testing, and cardiac catheterization should also be considered, focal-on-diffuse FDG uptake patterns, can be useful in suspected car-
as detailed in Section 6. diac sarcoidosis.849 However, it has been demonstrated that patients
with ARVC can also show myocardial 18F-FDG-PET uptake.888,907
7.4.1.4. Electrocardiography and Holter monitoring Therefore, there is a limited role for radionuclide imaging in ARVC un-
Abnormalities of the repolarization and depolarization as well as ar- less there is concomitant abnormal 18F-FDG-PET uptake in extracar-
rhythmias are key to the diagnosis of ARVC.5 The diagnostic utility diac tissues, or other clinical features suggestive of cardiac
of late potentials on signal-averaged electrocardiogram (SAECG) sarcoidosis.904,908
68 ESC Guidelines
the most common causes of SCD in registries around the world.935–937 can remain informative due to its excellent discriminative performance.
Sudden cardiac death seems to be more prevalent in young athletic in- Furthermore, one study suggested that the updated 2019 ARVC risk
dividuals affected by the disease.935,938 calculator performs best in PKP2 patients, but its performance is
more limited in gene-negative individuals.524
7.4.5.1. Secondary prevention of sudden cardiac death Therefore, a combination of these approaches is recommended to
individualize risk quantification that can aid clinicians in balancing the
Implantable cardioverter defibrillators reduce mortality in survivors of
risks and benefits of ICD implantation. The final decision should be
cardiac arrest and in patients who have experienced sustained symp-
the outcome of interest is fast VT (>250 b.p.m.) rather than any sus- diastolic impairment at diagnosis.951 Cardiac catheterization should
tained VT. The largest of these studies (n = 864) has led to the develop- be performed in cases where the diagnosis is in doubt and to aid in
ment of a separate score for the prediction of unstable VT/VF.945 Due to the assessment for and timing of cardiac transplantation.953 Cardiac
the lack of any external validation studies, there is insufficient informa- MRI distinguishes RCM from constrictive pericarditis, provides informa-
tion to support the applicability of this risk score outside of its develop- tion on the presence and extent of myocardial fibrosis, and contributes
ment cohorts. Furthermore, a specific rate cut-off is also not well to distinguishing metabolic from inflammatory diseases.951,954
evidence-based and its performance to predict SCD remains unclear. Endomyocardial biopsy is a precision diagnostic tool in restrictive
ICDa
Cardiac arrest or syncopal VT Y
(Class I)
ICDa
Non-syncopal sustained VT Y
(Class IIa)
N
ICD
High risk featuresb
(Class IIa)
Figure 18 Algorithm to approach implantable cardioverter defibrillator decision-making in patients with arrhythmogenic right ventricular cardiomyopathy.
ARVC, arrhythmogenic right ventricular cardiomyopathy; ICD, implantable cardioverter defibrillator; LVEF, left ventricular ejection fraction; NSVT, non-
sustained ventricular tachycardia; PES, programmed electrical stimulation; RVEF, right ventricular ejection fraction; SMVT, sustained monomorphic ventricu-
lar tachycardia; VT, ventricular tachycardia. aClinicians should aim to control ventricular arrhythmia with pharmacological or invasive antiarrhythmic therapies
in addition to offering an ICD. bHigh-risk features are defined as either cardiac syncope, NSVT, RVEF <40%, LVEF <45%, SMVT at PES or as per the updated
2019 ARVC risk calculator.539
ESC Guidelines 71
Endocardial fibroelastosis
Storage Endocardial neoplasms Fibrosis
Desmin Iatrogenic/drug toxicity Radiation
AFD Chemotherapy
Glycogenoses Inflammatory/granulomatous
Iron overload/storage
disorders
Non-genetic
Drugs (e.g. chloroquine)
RCM
Myocardial diseases with occasional restrictive physiology, often in the context of LVH
Figure 19 Spectrum of restrictive heart diseases. AFD, Anderson–Fabry disease; LVH, left ventricular hypertrophy; PRKAG2, Protein kinase
AMP-activated non-catalytic subunit gamma 2; RCM, restrictive cardiomyopathy. For a more detailed spectrum of restrictive heart disease, please refer
to Supplementary data online, Table S4.Image %:
implicates factors beyond the specific variant in the determination of symptoms and heart failure phenotype and severity,967 and is described
ultimate clinical manifestation of disease.966 Hereditary infiltrative dis- in Section 6.10.2. Precision diagnosis (phenotype and cause) is key to time-
eases can also cause RCM, the most common of which is amyloidosis ly planning of heart transplantation as it guarantees the exclusion of all
caused by pathogenic variants in the TTR gene, although this is usually in genetic and acquired phenocopies that may be amenable to alternative
the presence of LVH (see Section 7.7). treatment. Prevention of heart transplantation in all RCM patients with
alternative treatments is a major goal for all adult and paediatric RCM.
7.5.3. Assessment of symptoms Precise diagnosis is also essential for genetic phenocopies with avail-
able target treatments: ERT for Anderson–Fabry disease or glycogeno-
Patients with RCM often develop symptoms of heart failure, although
sis such as Pompe disease; therapeutic phlebotomy for
this can occur some years after the appearance of the initial abnormal-
haemochromatosis; immunosuppressive therapeutics for sarcoidosis;
ities. Assessment of symptoms in patients with cardiomyopathies is de-
new biological drugs for systemic diseases (e.g. autoimmune diseases
scribed in Section 6.10.1.
with cardiac involvement that can reverse or stabilize by treating the
disease itself); and removal of the toxic causes (see Figure 19 and
7.5.4. Management Supplementary data online, Table S4). Precision diagnosis today is es-
The administration of heart failure medications and device implantation, sential due to the increasing availability of disease-specific treatments
including ventricular assist device as a bridge-to-candidacy is guided by and diagnostic tools to exclude geno/phenocopies.
72 ESC Guidelines
Restrictive cardiomyopathy is associated with the worst prognosis of 7.6. Syndromic and metabolic
all the cardiomyopathy phenotypes. Survival data are limited to small
windows of observation. The prognosis of RCM largely depends on
cardiomyopathies
It is beyond the scope of these guidelines to provide a detailed review
the restrictive physiology, regardless of the underlying cause.968–971
and recommendations on specific cardiomyopathy genocopies and
More than 50% of children with RCM are at risk of death (including
phenocopies. Instead, the Task Force refers the reader to detailed pos-
SCD) or transplantation shortly after diagnosis; clinical features puta-
ition statements and consensus documents published on behalf of the
tively associated with increased risk of death or transplantation include:
Abnormal facial features NGS panel testing for RASopathy Noonan syndrome Cardiologist Beta-blockers/CCBs
Cryptorchidism Costello syndrome Geneticist Selective management of RVOTO/
Progressive limb ataxia NGS testing for bi-allelic expansion Friedreich ataxia Cardiologist No specific treatment
Diabetes mellitus of GAA repeats in the FXN gene Neurologist
Pes cavus Endocrinologist
Reduced native T1 at Orthopaedic surgeon
CMR imaging Neuromuscular
disease expert
DPD/HMDP Tc99 scintigraphy
18F-FDG-PET, 18F-fluorodeoxyglucose positron emission tomography; AL, amyloid light chain; ATTR, transthyretin amyloidosis; ATTR-CA: transthyretin cardiac amyloidosis; AV,
atrioventricular; CCB, calcium channel blocker; CK, creatinine kinase; CMR, cardiac magnetic resonance; DBS, deep brain stimulation; DMD, Duchenne muscular dystrophy; DPD,
3,3-diphosphono-1,2-propanodicarboxylic acid; ECG, electrocardiogram; Gb3, globotriaosylceramide; HCM, hypertrophic cardiomyopathy; HMDP, hydroxymethylene diphosphonate;
LGE, late gadolinium enhancement; LMNA, lamin A/C; LVH, left ventricular hypertrophy; MELAS, mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes
(syndrome); MERRF, mitochondrial epilepsy with ragged-red fibres; MRI, magnetic resonance; mtDNA, mitochondrial DNA; NGS, next-generation sequencing; PRKAG2, protein kinase
AMP-activated non-catalytic subunit gamma 2; RVOTO, right ventricular outflow tract obstruction; SCD, sudden cardiac death; TIA, transient ischaemic attack; VE, ventricular ectopic beats.
a
Patisiran and inotersen approved for treatment of familial polyneuropathy with/without cardiomyopathy.
High focal/global T2
Data from the North American Pediatric Cardiomyopathy Registry1005
Laboratory Elevated high-sensitivity troponin cohort show poorer survival rates among patients with RAS-HCM
Elevated NT-proBNP compared with non-syndromic HCM, particularly in patients who
CMR, cardiac magnetic resonance; ECG, electrocardiogram; LVH, left ventricular have been diagnosed before 1 year of age. Disease-specific risk factors
hypertrophy; NT-proBNP, N-terminal pro-brain natriuretic peptide. for SCD are currently an area of debate, and may include the degree of
LV hypertrophy, prolonged QTc interval, ECG risk score for HCM,771
7.6.1.4. Management and the HCM Risk-Kids score >6%.81,826
Specific treatment strategies, including enzyme replacement or
pharmacological chaperone, have limited efficacy in advanced cases 7.6.2.4. Management
with irreversible organ damage, so early initiation appears to be import- Non-vasodilating beta-blockers should be titrated to maximum toler-
ant. Enzyme replacement therapy is indicated in all symptomatic ated dose in patients with RAS-HCM, particularly in cases of severe
76 ESC Guidelines
Male
If genetic study, include
Enzymatic activity Reduced GLA in HCM panel
Figure 20 Anderson–Fabry disease diagnostic algorithm. α-Gal A, alpha-galactosidase A; AFD, Anderson–Fabry disease; CMR, cardiac magnetic resonance;
Gb3, globotriaosylceramide; HCM, hypertrophic cardiomyopathy; LVH, left ventricular hypertrophy; lyso Gb3, globotriaosylsphingosine; P/LP, pathogenic/
likely pathogenic; VUS, variant of unknown significance. aSee Table 23. bGenetic analysis must include the study of possible large deletions or a copy number
variation not detected by the Sanger method. cThe finding of increased plasma and/or urinary Gb3, or plasma lyso Gb3 and its analogues in the evaluation of
male or female patients with a VUS and normal (in female patients) or lowered α-Gal A activity provides additional diagnostic information, but the role of
biomarkers in such patients still requires validation. dLow native T1 values reinforce or generate suspicion of Fabry disease. Normal native T1 values do not
exclude Fabry disease, as they are rarely observed in untreated patients with mild LVH (mostly females), or in advanced disease due to pseudonormalization.
e
An endomyocardial biopsy is recommended, but could be done in other affected organs such as the kidneys and skin. It should be evaluated by expert
pathologists and always include electron microscopy studies to detect lamellar bodies and intracellular inclusions. Of note, some drugs may produce
drug-induced phospholipidosis with an intracellular accumulation of phospholipids in different organs that can mimic zebra bodies on electron
microscopy.982,983
biventricular obstruction.248,1002,1006–1008 Calcium channel blockers gene,1016–1019 leading to HCM, progressive neuromuscular symptoms,
may be considered as a second-line option in patients >6 months of and extracardiac manifestations, including diabetes mellitus.1016,1020,1021
age when beta-blocker therapy is ineffective or not tolerated.267,639
Surgical myectomy and orthotopic heart transplantation may be con- 7.6.3.2. Diagnosis, clinical work-up, and differential diagnosis
sidered in high-volume centres after multidisciplinary assessment by
Although several diagnostic criteria have been proposed to suspect
the heart team.265,266,1009–1011 Pulmonary valvuloplasty may be consid-
Friedreich ataxia,1022,1023 genetic testing with identification of
ered in children and infants with severe RV outflow tract obstruction
bi-co-allelic GAA expansion in the first intron of the FTX gene or com-
(RVOTO).1012–1015
pound heterozygosis is required for diagnosis.1024,1025
Cardiovascular involvement usually manifests as hypertrophic non-
7.6.3. Friedreich ataxia obstructive cardiomyopathy, with hypokinetic end-stage disease pro-
7.6.3.1. Definition gression and impaired perfusion reserve,1026 leading to advanced heart
Friedreich ataxia is an autosomal recessive disorder caused by a failure and death.248,1005,1027–1029 There appears to be no specific rela-
homozygous GAA triplet repeat expansion in the frataxin (FTX) tionship between the extent of neurological involvement and cardiac
ESC Guidelines 77
phenotype.248,1005,1027–1029,1005,1027–1030,1030 Mitochondrial iron stor- antiarrhythmic therapy, and indications for the implantation of devices
age is the pathologic hallmark of the disease.1031 are included in Section 6.10.
7.6.4.2. Diagnosis, clinical work-up, and differential diagnosis 7.7.2. Diagnosis, clinical work-up, and differential
diagnosis
Despite wide clinical heterogeneity, a presentation within the first few
months of life, hypotonia, failure to thrive, generalized muscle weak- Cardiac amyloidosis should be suspected in patients with increased LV
ness, and severe non-obstructive HCM with concentric pattern fol- wall thickness in the presence of cardiac or extracardiac red flags and/or
lowed by hypokinetic end-stage cardiomyopathy, usually within the in specific clinical situations, as detailed in Figure 21, particularly in pa-
first year of life, are typical of GSD IIa.259,268,1041,1042 Short PR interval tients >65 years of age.375
and increased ECG voltages may represent useful diagnostic clues for Cardiac amyloidosis can be diagnosed using both invasive and non-
GSDs.1042,1043 PRKAG2 syndrome should be suspected in the setting invasive diagnostic criteria.375 Invasive diagnostic criteria apply to all
of autosomal dominant transmission and association with conduction forms of cardiac amyloidosis, whereas non-invasive criteria are ac-
system disease including ventricular pre-excitation, sick sinus syn- cepted only for ATTR. Invasive criteria include demonstration of amyl-
drome, AF, AV block, intraventricular conduction delays or sinoatrial oid fibrils within cardiac tissue or, alternatively, demonstration of
blocks.1043–1047 An X-linked pattern of inheritance is typical of amyloid deposits in an extracardiac biopsy accompanied either by char-
Danon disease (GSD IIb). Skeletal myopathy, in association with learn- acteristic features of cardiac amyloidosis on echocardiography or
ing disability, retinal involvement and ventricular pre-excitation, has CMR.375 Non-invasive criteria include typical echocardiographic/CMR
been detected in males affected by Danon disease, while the cardiac findings combined with planar and single-photon emission computed
phenotype can be isolated in affected females.1048–1052 tomography (SPECT) grade 2 or 3 myocardial radiotracer uptake in
99m
technetium-pyrophosphate (99mTc-PYP) or 3,3-diphosphono-1,2-
propanodicarboxylic acid (DPD) or hydroxymethylene diphosphonate
7.6.4.3. Clinical course, management, and risk stratification
(HMDP) scintigraphy and exclusion of a clonal dyscrasia by all the fol-
In the absence of therapeutic intervention, Pompe disease has a poor lowing tests: serum free light chain assay, serum and urine protein elec-
prognosis, mainly due to end-stage heart failure.268,1041 Recently, data trophoresis with immunofixation.168 Tomographic scintigraphy should
from a large multicentre European registry have shown that Danon dis- be considered in order to reduce the number of misclassifications.1060
ease runs a malignant phenotype, but there are insufficient data to iden- False negative scans may rarely occur in certain ATTRv genotypes; false
tify candidate risk factors for sudden death.1049 Sudden cardiac death positives may be due to AL, recent myocardial infarction, or long-term
occurs in almost 10% of patients with PRKAG2 syndrome, mainly as chloroquine use.370 Therefore, planar and SPECT scintigraphy coupled
a consequence of advanced AV block, supraventricular tachycardia de- with assessment for monoclonal proteins followed by CMR and/or car-
generated to VF, or massive hypertrophy.1044,1053,1054 diac/extracardiac biopsy if necessary allows appropriate diagnosis in pa-
tients with suggestive signs/symptoms, as described in Figure 22.375
7.6.4.4. Management However, the DPD/PYP/HMDP scan cannot distinguish between wild-
Enzyme replacement therapy is recommended in patients with GSD type and mutated ATTR, and therefore TTR genetic testing is required.
IIa.269,274,275,1055,1056 To date, there are no approved aetiological ther- Of note, TTR genetic testing is recommended in all transthyretin amyl-
apies for PRKAG2 syndrome and Danon disease. Heart failure therapy, oid cardiomyopathy (ATTR-CM) patients regardless of age, as 5% of
78 ESC Guidelines
Hypotension or normotensive
Peripheral polyneuropathy
Proteinuria
Skin bruising
AV conduction disease
Figure 21 Screening for cardiac amyloidosis. ATTR, transthyretin amyloidosis; AV, atrioventricular; ECG, electrocardiogram; ECV, extracellular volume;
LGE, late gadolinium enhancement; MGUS, monoclonal gammopathy of undetermined significance.
ATTR-CM patients ≥70 years (and 10% among females) have chains.1064 Prognosis in ATTR depends on the variant, degree of cardiac
ATTRv.375,1061 involvement, and neurologic phenotype.1065–1068 Several multipara-
metric biomarker-based staging systems have been developed for
AL1069,1070 and ATTR cardiac amyloidosis1066–1068 (see
7.7.3. Clinical course and risk stratification
Supplementary data online, Table S5).
Cardiac amyloidosis is a progressive disease with poor outcomes if left
untreated. Amyloid light chain cardiac amyloidosis is associated with
more rapid progression of heart failure and worse prognosis than 7.7.4. Management
ATTR.1058,1062,1063 Fortunately, the prognosis of AL amyloidosis has The treatment of cardiac amyloidosis includes treating and preventing
significantly improved with the introduction of very effective therapies complications and stopping or delaying amyloid deposition by specific
capable of dramatically reducing the production of the cardiotoxic light treatment.375,1071 There is no evidence to support the use of standard
ESC Guidelines 79
Scintigraphy grade 0 Scintigraphy grade 1–3 Scintigraphy grade 0 Scintigraphy grade 1–3
Haematologic tests - Haematologic tests - Haematologic tests + Haematologic tests +
AL amyloidosis?
Histological Histological
Histological
AL/ATTR cardiac confirmation confirmation
Cardiac ATTR Amyloidosis confirmation
amyloidosis (cardiac/ (cardiac/
amyloidosis unlikely (usually cardiac)
unlikely extracardiac) extracardiac)
to subtype
to diagnose to diagnose
If suspicion
persists TTR genetic
consider repeat testing
CMR followed ATTRwt/ATTRv
by biopsy
Figure 22 Diagnosis of cardiac amyloidosis. AL, amyloid light chain; ATTR, transthyretin amyloidosis; ATTRv, variant transthyretin amyloidosis; ATTRwt,
wild-type transthyretin amyloidosis; CMR, cardiac magnetic resonance; DPD, 3,3-diphosphono-1,2-propanodicarboxylic acid; ECG, electrocardiogram;
ECHO, echocardiogram; HMDP, hydroxymethylene diphosphonate; PYP, pyrophosphate; TTR, transthyretin.
heart failure therapy, which often is not well tolerated, apart from mortality and cardiovascular hospitalizations in ATTR, with the largest
diuretics (see Section 6.10.2).1072,1073 effect achieved in patients at NYHA functional class I and II.1078
The natural history of cardiac amyloidosis associates electrical con- Additional studies are being conducted with other stabilizing agents
duction disease of the heart with symptomatic bradycardia and ad- and other molecules that reduce TTR production.1078a
vanced AV block.375,1074,1075 The clinical threshold for pacemaker
indication should be low, as the disease progresses and implantation
of the device allows rate response to exercise and medication adjust- 8. Other recommendations
ment.375,1074 The role of ICD in cardiac amyloidosis for SCD preven-
tion is not clearly known, but available data do not support their use 8.1. Sports
in primary prevention.1076,1077 8.1.1. Cardiovascular benefits of exercise
Regular physical activity and systematic exercise confer several cardio-
7.7.4.1. Specific therapies vascular, psychological, and QoL benefits. Through curbing risk factors
Therapy for AL cardiac amyloidosis is based on treatment of the under- for atherosclerosis, such as obesity and insulin resistance,1079 hyperten-
lying haematological problem with chemotherapy or autologous stem- sion,1080 and hyperlipidaemia,1081 regular physical activity is associated
cell transplant.1064 with an up to 50% risk reduction in an adverse event from CAD in
Transthyretin stabilization and reduction of its production are the middle-aged and older individuals.1082,1083 Individuals who exercise
basis of TTR cardiac amyloidosis treatment. Tafamidis reduced all-cause regularly live 5–7 years longer than their sedentary counterparts,1084
80 ESC Guidelines
and have a lower risk of cerebrovascular accidents1085 and certain ma- 8.1.4. Exercise recommendations in arrhythmogenic
lignancies.1085–1087 These benefits that can be derived later in life also right ventricular cardiomyopathy
apply to individuals with established cardiovascular disease. For a defin- Arrhythmogenic right ventricular cardiomyopathy is a recognized cause of
ition of exercise intensity levels, please refer to Supplementary data exercise-related SCD in young asymptomatic individuals,40,890 postulated
online, Table S6. to result from ventricular stretch leading to myocyte detachment with
subsequent inflammation and fibro-fatty replacement of the ventricular
myocardium. Fatal arrhythmias may occur during the inflammatory pro-
8.2.2.3. Timing and mode of delivery contraindicated because of the risk of foetal intracranial bleeding.
The timing and mode of delivery should be personalized according to Haemorrhagic complications in the mother occur with all regimens,
the type of cardiomyopathy, ventricular function, NYHA class, arrhyth- but the incidence is lower with VKA than with LMWH/UFH through-
mic risk, and thrombo-embolic risk. Vaginal delivery is associated with out pregnancy.1130
less blood loss and lower risk of infection, venous thrombosis, and em- VKA should be continued until pregnancy is achieved. Continuation
bolism than caesarean section and should be advised for most women. of VKAs throughout pregnancy should be considered when the dose is
Caesarean section should be considered for obstetric indications, pa- low (see Table 7 in the 2018 ESC Guidelines for the management of car-
EF <20%, severe mitral regurgitation, RV failure, AF, and/or 8.3. Recommendations for non-cardiac
hypotension.1143
surgery
Cardiomyopathies, in general, are associated with an increased inci-
8.2.2.7. Peripartum cardiomyopathy
dence of peri-operative heart failure and arrhythmias, although the sig-
Genetic studies in patients with PPCM have revealed genetic similarity nificant variability in the phenotypic expression of cardiomyopathies
between PPCM and DCM. Specifically, an overrepresentation of trun- must be considered. Special attention should be given to the clinical sta-
cating variants has been demonstrated in TTN, FLNC, BAG3, and DSP,
Driving • Most patients should be eligible for an ordinary Table 24 summarizes some of the key issues that should be discussed
driving licence and can continue driving unless with patients, relatives, and carers. When appropriate (e.g. when con-
they experience distracting or disabling sidering pregnancy, see Section 8.2), patients should be referred to
symptoms. other specialist services.
• Advice on driving licences for heavy goods or
passenger-carrying vehicles should be in line
with local legislation. 11. Sex differences in
AF, atrial fibrillation; ARVC, arrhythmogenic right ventricular cardiomyopathy; DCM, dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy; LVOTO, left ventricular outflow tract
obstruction.
+, degree of positive association; −, absence of definitive association; ?, unknown association.
ESC Guidelines 87
(5) Multimodality imaging to characterize the cardiac phenotype (23) In DCM and NDLVC patients, ICD should be considered for cer-
(morphology and function)—including tissue characterization tain genetic forms even if LVEF is >35%.
for non-ischaemic myocardial scar detection—is necessary, (24) It is of importance to define aetiology for a tailored management
in combination with a detailed personal and family history, in patients with syndromic and metabolic cardiomyopathies (i.e.
clinical examination, electrocardiography, and laboratory ERT/chaperone in lysosomal storage disease; tafamidis in
investigations. ATTRwt, etc.).
(6) Imaging results should always be interpreted in the overall clinical (25) Pregnancy and the post-partum period are associated with in-
(d) Lack of studies addressing the optimal timing to start ERT in (12) Sports:
adolescents and adults with late-onset Pompe disease. (a) ‘Return to play’ for patients with low-risk cardiomyopathies
(e) Lack of standardized protocols to treat cross-reactive im- (and how to define low risk in relation to exercise).
munologic material-negative patients. (b) SCD risk and exercise recommendations in phenotype-
(f) Lack of standardization of clinical endpoints in ERT/chaper- negative gene carriers.
one therapy trials. (c) Role of exercise in disease expression and progression.
(g) Lack of head-to-head comparisons between agalsidase alpha (d) Large, adequately powered randomized prospective studies are
16. ‘What to do’ and ‘What not to do’ messages from the Guidelines
Genetic counselling
Genetic counselling, provided by an appropriately trained healthcare professional and including genetic education to inform decision-making
and psychosocial support, is recommended for families with an inherited or suspected inherited cardiomyopathy, regardless of whether I B
genetic testing is being considered.
Continued
90 ESC Guidelines
It is recommended that genetic testing for cardiomyopathy is performed with access to a multidisciplinary team, including those with
expertise in genetic testing methodology, sequence variant interpretation, and clinical application of genetic testing, typically in a specialized I B
cardiomyopathy service or in a network model with access to equivalent expertise.
Pre- and post-test genetic counselling is recommended in all individuals undergoing genetic testing for cardiomyopathy. I B
If pre-natal diagnostic testing is to be pursued by the family, it is recommended that this is performed early in pregnancy, to allow decisions
I C
regarding continuation or co-ordination of pregnancy to be made.
General recommendations
Implantation of a cardioverter defibrillator is only recommended in patients who have an expectation of good quality survival >1 year. I C
It is recommended that ICD implantation be guided by shared decision-making that:
• is evidence-based;
I C
• considers a person’s individual preferences, beliefs, circumstances, and values; and
• ensures that the person understands the benefits, harm, and possible consequences of different treatment options.
It is recommended that prior to ICD implantation, patients are counselled on the risk of inappropriate shocks, implant complications, and
I C
the social, occupational, and driving implications of the device.
It is not recommended to implant an ICD in patients with incessant ventricular arrhythmias until the ventricular arrhythmia is controlled. III C
Secondary prevention
Primary prevention
Comprehensive SCD risk stratification is recommended in all cardiomyopathy patients who have not suffered a previous cardiac arrest/
I C
sustained ventricular arrhythmia at initial evaluation and at 1–2 year intervals, or whenever there is a change in clinical status.
The use of validated SCD algorithms/scores as aids to the shared decision-making when offering ICD implantation, where available is
I B
recommended in patients with HCM.
Choice of ICD
Primary prevention
The HCM Risk-SCD calculator is recommended as a method of estimating risk of sudden death at 5 years in patients aged ≥16 years for
I B
primary prevention.
Validated paediatric-specific risk-prediction models (e.g. HCM Risk-Kids) are recommended as a method of estimating risk of sudden death
I B
at 5 years in patients aged <16 years for primary prevention.
It is recommended that the 5-year risk of SCD be assessed at first evaluation and re-evaluated at 1–2 year intervals or whenever there is a
I B
Recommendations for the antiarrhythmic management of patients with arrhythmogenic right ventricular cardiomyopathy
Beta-blocker therapy is recommended in ARVC patients with VE, NSVT, and VT. I C
Recommendations for sudden cardiac death prevention in patients with arrhythmogenic right ventricular cardiomyopathy
Secondary prevention
An ICD is recommended to reduce the risk of sudden death and all-cause mortality in patients with ARVC who have survived a cardiac
I A
arrest or have recovered from a ventricular arrhythmia causing haemodynamic instability.
Recommendations for the management of patients with restrictive cardiomyopathy
It is recommended that multimodality imaging be used to differentiate RCM from HCM or DCM with restrictive physiology. I C
It is recommended that baseline cardiac and non-cardiac investigations are performed to assess involvement of the neuromuscular system
I C
or other syndromic disorders.
Cardiac catheterization is recommended in all children with RCM to measure pulmonary artery pressures and PVR at diagnosis and at 6–12
I B
monthly intervals to assess change in PVR.
ICD implantation is recommended to reduce the risk of sudden death and all-cause mortality in patients with RCM who have survived a
I C
cardiac arrest or have recovered from a ventricular arrhythmia causing haemodynamic instability.
Exercise recommendations for cardiomyopathy patients
All cardiomyopathies
Regular low- to moderate-intensity exercise is recommended in all able individuals with cardiomyopathy. I C
An individualized risk assessment for exercise prescription is recommended in all patients with cardiomyopathy. I C
HCM
High-intensity exercise, including competitive sport, is not recommended in high-risk individuals and in individuals with left ventricular
III C
outflow tract obstruction and exercise-induced complex ventricular arrhythmias.
ARVC
Moderate- and/or high-intensity exercise, including competitive sport, is not recommended in individuals with ARVC. III B
DCM and NDLVC
High-intensity exercise, including competitive sport, is not recommended in symptomatic individuals, those with a left ventricular ejection
III C
fraction ≤40%, exercise-induced arrhythmias, or pathogenic variants in LMNA or TMEM43.
Recommendations for reproductive issues in patients with cardiomyopathy
Pre-pregnancy risk assessment and counselling are recommended in all women using the mWHO classification of maternal risk. I C
Continued
ESC Guidelines 93
Counselling on safe and effective contraception is recommended in all women of fertile age and their partners. I C
Counselling on the risk of disease inheritance is recommended for all men and women before conception. I C
Vaginal delivery is recommended in most women with cardiomyopathies, unless there are obstetric indications for caesarean section, severe
I C
heart failure (EF <30% or NYHA class III–IV), or severe outflow tract obstructions, or in women presenting in labour on oral anticoagulants.
It is recommended that medication be carefully reviewed for safety in advance of pregnancy and adjusted according to tolerability in
I C
pregnancy.
© ESC 2023
Recommendation for management of cardiovascular risk factors in patients with cardiomyopathy
Identification and management of risk factors and concomitant diseases is recommended as an integral part of the management of
I C
cardiomyopathy patients.
2D, two-dimensional; AAD, antiarrhythmic drug; AF, atrial fibrillation; ARVC, arrhythmogenic right ventricular cardiomyopathy; ASA, alcohol septal ablation; ATTR, transthyretin amyloidosis;
BNP, brain natriuretic peptide; CHA2DS2-VASc, congestive heart failure or left ventricular dysfunction, hypertension, age ≥75 (doubled), diabetes, stroke (doubled)-vascular disease, age 65–
74, sex category (female) (score); CMR, cardiac magnetic resonance; CRT, cardiac resynchronization therapy; DCM, dilated cardiomyopathy; DPD,
3,3-diphosphono-1,2-propanodicarboxylic acid; ECG, electrocardiogram; EF, ejection fraction; HCM, hypertrophic cardiomyopathy; HMDP, hydroxymethylene diphosphonate; ICD,
implantable cardioverter defibrillator; LMWH, low-molecular-weight heparin; LV, left ventricular; LVOT, left ventricular outflow tract; LVOTO, left ventricular outflow tract obstruction;
mWHO, modified World Health Organization; NCS, non-cardiac surgery; NDLVC, non-dilated left ventricular cardiomyopathy; NSVT, non-sustained ventricular tachycardia;
NT-proBNP, N-terminal pro-brain natriuretic peptide; NYHA, New York Heart Association; P/LP, pathogenic/likely pathogenic; PVR, pulmonary vascular resistance; PYP,
pyrophosphate; RCM, restrictive cardiomyopathy; RV, right ventricular; SCD, sudden cardiac death; SRT, septal reduction therapy; TTE, transthorasic echocardiogram; VE, ventricular
ectopic beats; VF, ventricular fibrillation; VKA, vitamin K antagonist; VT, ventricular tachycardia.
a
Class of recommendation.
b
Level of evidence.
Center, Department of Cardiology, Rotterdam, Netherlands; Tim De Asteggiano (Italy), Zofia Bilinska (Poland), Damien Bonnet (France),
Winter (Belgium), ESC Patient Forum, Sophia Antipolis, France; Henning Bundgaard (Denmark), Nuno Miguel Cardim (Portugal),
Perry M. Elliott, UCL Institute of Cardiovascular Science Jelena Čelutkienė (Lithuania), Maja Cikes (Croatia), Gaetano Maria
University College London, London, United Kingdom, De Ferrari (Italy), Veronica Dusi (Italy), Volkmar Falk (Germany),
St. Bartholomew’s Hospital, London, United Kingdom; Marcus Laurent Fauchier (France), Estelle Gandjbakhch (France), Tiina Heliö
Flather, Norwich Medical School, University of East Anglia, (Finland), Konstantinos Koskinas (Switzerland), Dipak Kotecha
Norwich, United Kingdom, Department of Cardiology, Norfolk and (United Kingdom), Ulf Landmesser (Germany), George Lazaros
Swedish Society of Cardiology, Pyotr G. Platonov; Switzerland: Swiss 11. Rapezzi C, Aimo A, Barison A, Emdin M, Porcari A, Linhart A, et al. Restrictive cardio-
myopathy: definition and diagnosis. Eur Heart J 2022;43:4679–4693. https://doi.org/10.
Society of Cardiology, Ardan M. Saguner; Syrian Arab Republic:
1093/eurheartj/ehac543
Syrian Cardiovascular Association, Ahmad Rasheed Al Saadi; 12. van Waning JI, Caliskan K, Michels M, Schinkel AFL, Hirsch A, Dalinghaus M, et al.
Tunisia: Tunisian Society of Cardiology and Cardiovascular Surgery, Cardiac phenotypes, genetics, and risks in familial noncompaction cardiomyopathy. J
Ikram Kammoun; Türkiye: Turkish Society of Cardiology, Ahmet Am Coll Cardiol 2019;73:1601–1611. https://doi.org/10.1016/j.jacc.2018.12.085
13. Sedaghat-Hamedani F, Haas J, Zhu F, Geier C, Kayvanpour E, Liss M, et al. Clinical gen-
Celik; Ukraine: Ukrainian Association of Cardiology, Elena Nesukay;
etics and outcome of left ventricular non-compaction cardiomyopathy. Eur Heart J
and Uzbekistan: Association of Cardiologists of Uzbekistan, Timur 2017;38:3449–3460. https://doi.org/10.1093/eurheartj/ehx545
32. Maro EE, Janabi M, Kaushik R. Clinical and echocardiographic study of hypertrophic from the Nucleus of the Working Group on Myocardial and Pericardial Diseases of
cardiomyopathy in Tanzania. Trop Doct 2006;36:225–227. https://doi.org/10.1258/ the Portuguese Society of Cardiology. Rev Port Cardiol 2011;30:829–835. https://doi.
004947506778604904 org/10.1016/j.repc.2011.09.005
33. Basavarajaiah S, Wilson M, Whyte G, Shah A, McKenna W, Sharma S. Prevalence of 54. Barriales-Villa R, Gimeno-Blanes JR, Zorio-Grima E, Ripoll-Vera T, Evangelista-Masip A,
hypertrophic cardiomyopathy in highly trained athletes: relevance to pre-participation Moya-Mitjans A, et al. Plan of action for inherited cardiovascular diseases: synthesis of
screening. J Am Coll Cardiol 2008;51:1033–1039. https://doi.org/10.1016/j.jacc.2007.10. recommendations and action algorithms. Rev Esp Cardiol 2016;69:300–309. https://doi.
055 org/10.1016/j.recesp.2015.11.031
34. Nugent AW, Daubeney PE, Chondros P, Carlin JB, Cheung M, Wilkinson LC, et al. The 55. Vriz O, AlSergani H, Elshaer AN, Shaik A, Mushtaq AH, Lioncino M, et al. A complex
epidemiology of childhood cardiomyopathy in Australia. N Engl J Med 2003;348: unit for a complex disease: the HCM-Family Unit. Monaldi Arch Chest Dis 2021;92.
Association of Cardiovascular Imaging. Eur Heart J Cardiovasc Imaging 2019;20: 91. Leong DP, Chakrabarty A, Shipp N, Molaee P, Madsen PL, Joerg L, et al. Effects of myo-
1075–1093. https://doi.org/10.1093/ehjci/jez178 cardial fibrosis and ventricular dyssynchrony on response to therapy in new-
72. Haugaa KH, Basso C, Badano LP, Bucciarelli-Ducci C, Cardim N, Gaemperli O, et al. presentation idiopathic dilated cardiomyopathy: insights from cardiovascular magnetic
Comprehensive multi-modality imaging approach in arrhythmogenic cardiomyop- resonance and echocardiography. Eur Heart J 2012;33:640–648. https://doi.org/10.
athy–an expert consensus document of the European Association of Cardiovascular 1093/eurheartj/ehr391
Imaging. Eur Heart J Cardiovasc Imaging 2017;18:237–253. https://doi.org/10.1093/ 92. Yoerger DM, Marcus F, Sherrill D, Calkins H, Towbin JA, Zareba W, et al.
ehjci/jew229 Echocardiographic findings in patients meeting task force criteria for arrhythmogenic
73. Lang RM, Badano LP, Mor-Avi V, Afilalo J, Armstrong A, Ernande L, et al. right ventricular dysplasia: new insights from the multidisciplinary study of right ven-
Recommendations for cardiac chamber quantification by echocardiography in adults: tricular dysplasia. J Am Coll Cardiol 2005;45:860–865. https://doi.org/10.1016/j.jacc.
110. Vigen KK, Reeder SB, Hood MN, Steckner M, Leiner T, Dombroski DA, et al. 129. Aquaro GD, Barison A, Todiere G, Grigoratos C, Ait Ali L, Di Bella G, et al. Usefulness
Recommendations for imaging patients with cardiac implantable electronic devices of combined functional assessment by cardiac magnetic resonance and tissue charac-
(CIEDs). J Magn Reson Imaging 2021;53:1311–1317. https://doi.org/10.1002/jmri. terization versus task force criteria for diagnosis of arrhythmogenic right ventricular
27320 cardiomyopathy. Am J Cardiol 2016;118:1730–1736. https://doi.org/10.1016/j.
111. Bhuva AN, Feuchter P, Hawkins A, Cash L, Boubertakh R, Evanson J, et al. MRI for pa- amjcard.2016.08.056
tients with cardiac implantable electronic devices: simplifying complexity with a ‘one- 130. Petersen SE, Selvanayagam JB, Wiesmann F, Robson MD, Francis JM, Anderson RH,
stop’ service model. BMJ Qual Saf 2019;28:853–858. https://doi.org/10.1136/bmjqs- et al. Left ventricular non-compaction: insights from cardiovascular magnetic reson-
2018-009079 ance imaging. J Am Coll Cardiol 2005;46:101–105. https://doi.org/10.1016/j.jacc.2005.
112. Seewoster T, Lobe S, Hilbert S, Bollmann A, Sommer P, Lindemann F, et al.
148. Martinez-Naharro A, Abdel-Gadir A, Treibel TA, Zumbo G, Knight DS, Rosmini S, 168. Gillmore JD, Maurer MS, Falk RH, Merlini G, Damy T, Dispenzieri A, et al. Nonbiopsy
et al. CMR-verified regression of cardiac AL amyloid after chemotherapy. JACC diagnosis of cardiac transthyretin amyloidosis. Circulation 2016;133:2404–2412.
Cardiovasc Imaging 2018;11:152–154. https://doi.org/10.1016/j.jcmg.2017.02.012 https://doi.org/10.1161/CIRCULATIONAHA.116.021612
149. Fontana M, Martinez-Naharro A, Chacko L, Rowczenio D, Gilbertson JA, Whelan CJ, 169. Langer C, Lutz M, Eden M, Ludde M, Hohnhorst M, Gierloff C, et al. Hypertrophic car-
et al. Reduction in CMR derived extracellular volume with patisiran indicates cardiac diomyopathy in cardiac CT: a validation study on the detection of intramyocardial fi-
amyloid regression. JACC Cardiovasc Imaging 2021;14:189–199. https://doi.org/10. brosis in consecutive patients. Int J Cardiovasc Imaging 2014;30:659–667. https://doi.
1016/j.jcmg.2020.07.043 org/10.1007/s10554-013-0358-8
150. Martinez-Naharro A, Kotecha T, Norrington K, Boldrini M, Rezk T, Quarta C, et al. 170. Asferg C, Usinger L, Kristensen TS, Abdulla J. Accuracy of multi-slice computed tom-
Native T1 and extracellular volume in transthyretin amyloidosis. JACC Cardiovasc ography for measurement of left ventricular ejection fraction compared with cardiac
that are common in Chinese patients. Circ Genom Precis Med 2020;13:424–434. https:// 209. Ison HE, Ware SM, Schwantes-An TH, Freeze S, Elmore L, Spoonamore KG. The im-
doi.org/10.1161/CIRCGEN.119.002823 pact of cardiovascular genetic counseling on patient empowerment. J Genet Couns
189. Jordan E, Peterson L, Ai T, Asatryan B, Bronicki L, Brown E, et al. Evidence-based as- 2019;28:570–577. https://doi.org/10.1002/jgc4.1050
sessment of genes in dilated cardiomyopathy. Circulation 2021;144:7–19. https://doi. 210. Borry P, Evers-Kiebooms G, Cornel MC, Clarke A, Dierickx K. Public Professional
org/10.1161/CIRCULATIONAHA.120.053033 Policy Committee (PPPC) of the European Society of Human Genetics (ESHG).
190. James CA, Jongbloed JDH, Hershberger RE, Morales A, Judge DP, Syrris P, et al. Genetic testing in asymptomatic minors: background considerations towards ESHG
International evidence based reappraisal of genes associated with arrhythmogenic right recommendations. Eur J Hum Genet 2009;17:711–719. https://doi.org/10.1038/ejhg.
ventricular cardiomyopathy using the clinical genome resource framework. Circ Genom 2009.25
Precis Med 2021;14:e003273. https://doi.org/10.1161/CIRCGEN.120.003273 211. Ormondroyd E, Oates S, Parker M, Blair E, Watkins H. Pre-symptomatic genetic test-
ventricular dysplasia/cardiomyopathy patients and family members. Circ Cardiovasc devices versus medical therapy. Pediatr Crit Care Med 2018;19:442–450. https://doi.
Genet 2015;8:437–446. https://doi.org/10.1161/CIRCGENETICS.114.001003 org/10.1097/PCC.0000000000001503
231. Alfares AA, Kelly MA, McDermott G, Funke BH, Lebo MS, Baxter SB, et al. Results of 253. Ullmo S, Vial Y, Di Bernardo S, Roth-Kleiner M, Mivelaz Y, Sekarski N, et al. Pathologic
clinical genetic testing of 2,912 probands with hypertrophic cardiomyopathy: ex- ventricular hypertrophy in the offspring of diabetic mothers: a retrospective study. Eur
panded panels offer limited additional sensitivity. Genet Med 2015;17:880–888. Heart J 2007;28:1319–1325. https://doi.org/10.1093/eurheartj/ehl416
https://doi.org/10.1038/gim.2014.205 254. Yunis KA, Bitar FF, Hayek P, Mroueh SM, Mikati M. Transient hypertrophic cardiomy-
232. Ingles J, Yeates L, O’Brien L, McGaughran J, Scuffham PA, Atherton J, et al. Genetic test- opathy in the newborn following multiple doses of antenatal corticosteroids. Am J
ing for inherited heart diseases: longitudinal impact on health-related quality of life. Perinatol 1999;16:17–21. https://doi.org/10.1055/s-2007-993830
Genet Med 2012;14:749–752. https://doi.org/10.1038/gim.2012.47 255. Brickman WJ, Silverman BL. Cardiovascular effects of growth hormone. Endocrine
276. Lee TM, Hsu DT, Kantor P, Towbin JA, Ware SM, Colan SD, et al. Pediatric cardiomy- 297. Bariani R, Cipriani A, Rizzo S, Celeghin R, Bueno Marinas M, Giorgi B, et al. ‘Hot phase’
opathies. Circ Res 2017;121:855–873. https://doi.org/10.1161/CIRCRESAHA.116. clinical presentation in arrhythmogenic cardiomyopathy. Europace 2021;23:907–917.
309386 https://doi.org/10.1093/europace/euaa343
277. Chang RR, Allada V. Electrocardiographic and echocardiographic features that distin- 298. Ross RD. The Ross classification for heart failure in children after 25 years: a review
guish anomalous origin of the left coronary artery from pulmonary artery from idio- and an age-stratified revision. Pediatr Cardiol 2012;33:1295–1300. https://doi.org/10.
pathic dilated cardiomyopathy. Pediatr Cardiol 2001;22:3–10. https://doi.org/10.1007/ 1007/s00246-012-0306-8
s002460010142 299. Zeppenfeld K, Tfelt-Hansen J, de Riva M, Winkel BG, Behr ER, Blom NA, et al. 2022
278. Cooper LT, Baughman KL, Feldman AM, Frustaci A, Jessup M, Kuhl U, et al. The role of ESC Guidelines for the management of patients with ventricular arrhythmias and
endomyocardial biopsy in the management of cardiovascular disease: a scientific state- the prevention of sudden cardiac death. Eur Heart J 2022;43:3997–4126. https://doi.
318. Lund LH, Edwards LB, Kucheryavaya AY, Dipchand AI, Benden C, Christie JD, et al. collaboration with the European Association for Cardio-Thoracic Surgery (EACTS):
The Registry of the International Society for Heart and Lung Transplantation: the Task Force for the diagnosis and management of atrial fibrillation of the
Thirtieth Official Adult Heart Transplant Report–2013; focus theme: age. J Heart European Society of Cardiology (ESC) developed with the special contribution of
Lung Transplant 2013;32:951–964. https://doi.org/10.1016/j.healun.2013.08.006 the European Heart Rhythm Association (EHRA) of the ESC. Eur Heart J 2021;42:
319. Mehra MR, Canter CE, Hannan MM, Semigran MJ, Uber PA, Baran DA, et al. The 2016 373–498. https://doi.org/10.1093/eurheartj/ehaa612
International Society for Heart Lung Transplantation listing criteria for heart trans- 337. Lip GYH. The ABC pathway: an integrated approach to improve AF management. Nat
plantation: a 10-year update. J Heart Lung Transplant 2016;35:1–23. https://doi.org/ Rev Cardiol 2017;14:627–628. https://doi.org/10.1038/nrcardio.2017.153
10.1016/j.healun.2015.10.023 338. Proietti M, Romiti GF, Olshansky B, Lane DA, Lip GYH. Improved outcomes by inte-
320. Bansal A, Akhtar F, Desai S, Velasco-Gonzalez C, Bansal A, Teagle A, et al. Six-month grated care of anticoagulated patients with atrial fibrillation using the simple ABC
355. Yang PS, Sung JH, Jang E, Yu HT, Kim TH, Lip GYH, et al. Application of the simple atrial 377. Xiong Q, Lau YC, Senoo K, Lane DA, Hong K, Lip GYH. Non-vitamin K antagonist oral
fibrillation better care pathway for integrated care management in frail patients with anticoagulants (NOACs) in patients with concomitant atrial fibrillation and heart fail-
atrial fibrillation: a nationwide cohort study. J Arrhythm 2020;36:668–677. https://doi. ure: a systemic review and meta-analysis of randomized trials. Eur J Heart Fail 2015;17:
org/10.1002/joa3.12364 1192–1200. https://doi.org/10.1002/ejhf.343
356. Romiti GF, Proietti M, Vitolo M, Bonini N, Fawzy AM, Ding WY, et al. Clinical complex- 378. Noseworthy PA, Yao X, Shah ND, Gersh BJ. Stroke and bleeding risks in NOAC- and
ity and impact of the ABC (Atrial fibrillation Better Care) pathway in patients with at- warfarin-treated patients with hypertrophic cardiomyopathy and atrial fibrillation. J Am
rial fibrillation: a report from the ESC-EHRA EURObservational Research Programme Coll Cardiol 2016;67:3020–3021. https://doi.org/10.1016/j.jacc.2016.04.026
in AF General Long-Term Registry. BMC Med 2022;20:326. https://doi.org/10.1186/ 379. Lee HJ, Kim HK, Jung JH, Han KD, Lee H, Park JB, et al. Novel oral anticoagulants for
s12916-022-02526-7 primary stroke prevention in hypertrophic cardiomyopathy patients with atrial fibril-
cardiac arrest among patients with atrial fibrillation: the CABANA randomized clinical 419. Lapenna E, Pozzoli A, De Bonis M, La Canna G, Nisi T, Nascimbene S, et al. Mid-term
trial. JAMA 2019;321:1261–1274. https://doi.org/10.1001/jama.2019.0693 outcomes of concomitant surgical ablation of atrial fibrillation in patients undergoing
399. Di Biase L, Mohanty P, Mohanty S, Santangeli P, Trivedi C, Lakkireddy D, et al. Ablation cardiac surgery for hypertrophic cardiomyopathy. Eur J Cardiothorac Surg 2017;51:
versus amiodarone for treatment of persistent atrial fibrillation in patients with con- 1112–1118. https://doi.org/10.1093/ejcts/ezx017
gestive heart failure and an implanted device. Results from the AATAC multicenter 420. Gasperetti A, James CA, Chen L, Schenker N, Casella M, Kany S, et al. Efficacy of cath-
randomized trial. Circulation 2016;133:1637–1644. https://doi.org/10.1161/ eter ablation for atrial arrhythmias in patients with arrhythmogenic right ventricular
CIRCULATIONAHA.115.019406 cardiomyopathy–a multicenter study. J Clin Med 2021;10:4962. https://doi.org/10.
400. Packer DL, Piccini JP, Monahan KH, Al-Khalidi HR, Silverstein AP, Noseworthy PA, 3390/jcm10214962
et al. Ablation versus drug therapy for atrial fibrillation in heart failure: results from 421. Maron BJ, Olivotto I, Bellone P, Conte MR, Cecchi F, Flygenring BP, et al. Clinical profile
A/C mutation carriers. Eur J Heart Fail 2013;15:376–384. https://doi.org/10.1093/ setting of hypertrophic cardiomyopathy: a systematic review. J Atr Fibrillation 2019;
eurjhf/hfs191 12:2207. https://doi.org/10.4022/jafib.2207
440. Kumar S, Baldinger SH, Gandjbakhch E, Maury P, Sellal JM, Androulakis AF, et al. 461. Hsu JC, Huang YT, Lin LY. Stroke risk in hypertrophic cardiomyopathy patients with
Long-term arrhythmic and nonarrhythmic outcomes of lamin A/C mutation carriers. atrial fibrillation: a nationwide database study. Aging (Albany NY) 2020;12:24219–-
J Am Coll Cardiol 2016;68:2299–2307. https://doi.org/10.1016/j.jacc.2016.08.058 24227. https://doi.org/10.18632/aging.104133
441. Hasselberg NE, Haland TF, Saberniak J, Brekke PH, Berge KE, Leren TP, et al. Lamin A/ 462. Komatsu J, Imai RI, Nakaoka Y, Nishida K, Seki SI, Kubo T, et al. Importance of parox-
C cardiomyopathy: young onset, high penetrance, and frequent need for heart trans- ysmal atrial fibrillation and sex differences in the prevention of embolic stroke in hyper-
plantation. Eur Heart J 2017;39:853–860. https://doi.org/10.1093/eurheartj/ehx596 trophic cardiomyopathy. Circ Rep 2021;3:273–278. https://doi.org/10.1253/circrep.
442. Cikes M, Claggett B, Shah AM, Desai AS, Lewis EF, Shah SJ, et al. Atrial fibrillation in CR-20-0101
481. Packer DL, Kowal RC, Wheelan KR, Irwin JM, Champagne J, Guerra PG, et al. of the CAMERA MRI trial. JACC Clin Electrophysiol 2018;4:999–1007. https://doi.org/10.
Cryoballoon ablation of pulmonary veins for paroxysmal atrial fibrillation: first results 1016/j.jacep.2018.04.013
of the North American Arctic Front (STOP AF) pivotal trial. J Am Coll Cardiol 2013;61: 501. Kuck KH, Merkely B, Zahn R, Arentz T, Seidl K, Schluter M, et al. Catheter ablation
1713–1723. https://doi.org/10.1016/j.jacc.2012.11.064 versus best medical therapy in patients with persistent atrial fibrillation and congestive
482. Blandino A, Toso E, Scaglione M, Anselmino M, Ferraris F, Sardi D, et al. Long-term heart failure: the randomized AMICA trial. Circ Arrhythm Electrophysiol 2019;12:
efficacy and safety of two different rhythm control strategies in elderly patients with e007731. https://doi.org/10.1161/CIRCEP.119.007731
symptomatic persistent atrial fibrillation. J Cardiovasc Electrophysiol 2013;24: 502. Wazni OM, Marrouche NF, Martin DO, Verma A, Bhargava M, Saliba W, et al.
731–738. https://doi.org/10.1111/jce.12126 Radiofrequency ablation vs antiarrhythmic drugs as first-line treatment of symptomat-
483. Mont L, Bisbal F, Hernandez-Madrid A, Perez-Castellano N, Vinolas X, Arenal A, et al. ic atrial fibrillation: a randomized trial. JAMA 2005;293:2634–2640. https://doi.org/10.
with hypertrophic cardiomyopathy. Heart 2009;95:709–714. https://doi.org/10.1136/ 541. Wahbi K, Ben Yaou R, Gandjbakhch E, Anselme F, Gossios T, Lakdawala NK, et al.
hrt.2008.150656 Development and validation of a new risk prediction score for life-threatening ven-
522. Orgeron GM, James CA, Te Riele A, Tichnell C, Murray B, Bhonsale A, et al. tricular tachyarrhythmias in laminopathies. Circulation 2019;140:293–302. https://doi.
Implantable cardioverter-defibrillator therapy in arrhythmogenic right ventricular dys- org/10.1161/CIRCULATIONAHA.118.039410
plasia/cardiomyopathy: predictors of appropriate therapy, outcomes, and complica- 542. Verstraelen TE, van Lint FHM, Bosman LP, de Brouwer R, Proost VM, Abeln BGS, et al.
tions. J Am Heart Assoc 2017;6:e006242. https://doi.org/10.1161/JAHA.117.006242 Prediction of ventricular arrhythmia in phospholamban p.Arg14del mutation carriers-
523. Corrado D, Calkins H, Link MS, Leoni L, Favale S, Bevilacqua M, et al. Prophylactic im- reaching the frontiers of individual risk prediction. Eur Heart J 2021;42:2842–2850.
plantable defibrillator in patients with arrhythmogenic right ventricular cardiomyop- https://doi.org/10.1093/eurheartj/ehab294
athy/dysplasia and no prior ventricular fibrillation or sustained ventricular 543. Knops RE, Olde Nordkamp LRA, Delnoy PHM, Boersma LVA, Kuschyk J, El-Chami MF,
nonischemic cardiomyopathy treatment evaluation study. Arch Intern Med 2007;167: 583. Maron MS, Rowin EJ, Lin D, Appelbaum E, Chan RH, Gibson CM, et al. Prevalence and
2226–2232. https://doi.org/10.1001/archinte.167.20.2226 clinical profile of myocardial crypts in hypertrophic cardiomyopathy. Circ Cardiovasc
562. Ni SQ, Ni J, Yang N, Wang J. Effect of magnetic nanoparticles on the performance of Imaging 2012;5:441–447. https://doi.org/10.1161/CIRCIMAGING.112.972760
activated sludge treatment system. Bioresour Technol 2013;143:555–561. https://doi. 584. Spirito P, Autore C, Rapezzi C, Bernabo P, Badagliacca R, Maron MS, et al. Syncope and
org/10.1016/j.biortech.2013.06.041 risk of sudden death in hypertrophic cardiomyopathy. Circulation 2009;119:
563. von Kanel R, Baumert J, Kolb C, Cho E-Y, Ladwig K-H. Chronic posttraumatic stress 1703–1710. https://doi.org/10.1161/CIRCULATIONAHA.108.798314
and its predictors in patients living with an implantable cardioverter defibrillator. J 585. Vogelsberg H, Mahrholdt H, Deluigi CC, Yilmaz A, Kispert EM, Greulich S, et al.
Affect Disord 2011;131:344–352. https://doi.org/10.1016/j.jad.2010.12.002 Cardiovascular magnetic resonance in clinically suspected cardiac amyloidosis: non-
564. Lewis KB, Carroll SL, Birnie D, Stacey D, Matlock DD. Incorporating patients’ prefer- invasive imaging compared to endomyocardial biopsy. J Am Coll Cardiol 2008;51:
603. Geske JB, Cullen MW, Sorajja P, Ommen SR, Nishimura RA. Assessment of left ven- 623. Dybro AM, Rasmussen TB, Nielsen RR, Ladefoged BT, Andersen MJ, Jensen MK, et al.
tricular outflow gradient: hypertrophic cardiomyopathy versus aortic valvular stenosis. Effects of metoprolol on exercise hemodynamics in patients with obstructive hyper-
JACC Cardiovasc Interv 2012;5:675–681. https://doi.org/10.1016/j.jcin.2012.01.026 trophic cardiomyopathy. J Am Coll Cardiol 2022;79:1565–1575. https://doi.org/10.
604. Rudolph A, Abdel-Aty H, Bohl S, Boye P, Zagrosek A, Dietz R, et al. Noninvasive de- 1016/j.jacc.2022.02.024
tection of fibrosis applying contrast-enhanced cardiac magnetic resonance in different 624. Wigle ED, Auger P, Marquis Y. Muscular subaortic stenosis. The direct relation be-
forms of left ventricular hypertrophy relation to remodeling. J Am Coll Cardiol 2009;53: tween the intraventricular pressure difference and the left ventricular ejection time.
284–291. https://doi.org/10.1016/j.jacc.2008.08.064 Circulation 1967;36:36–44. https://doi.org/10.1161/01.CIR.36.1.36
605. Moon JCC, Reed E, Sheppard MN, Elkington AG, Ho SY, Burke M, et al. The histologic 625. Wigle ED, Henderson M, Rakowski H, Wilansky S. Muscular (hypertrophic) subaortic
basis of late gadolinium enhancement cardiovascular magnetic resonance in hyper- stenosis (hypertrophic obstructive cardiomyopathy): the evidence for true obstruc-
644. Spertus JA, Fine JT, Elliott P, Ho CY, Olivotto I, Saberi S, et al. Mavacamten for treat- 664. Hodges K, Rivas CG, Aguilera J, Borden R, Alashi A, Blackstone EH, et al. Surgical man-
ment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): agement of left ventricular outflow tract obstruction in a specialized hypertrophic ob-
health status analysis of a randomised, double-blind, placebo-controlled, phase 3 trial. structive cardiomyopathy center. J Thorac Cardiovasc Surg 2019;157:2289–2299.
Lancet 2021;397:2467–2475. https://doi.org/10.1016/S0140-6736(21)00763-7 https://doi.org/10.1016/j.jtcvs.2018.11.148
645. Saberi S, Cardim N, Yamani M, Schulz-Menger J, Li W, Florea V, et al. Mavacamten fa- 665. Nguyen A, Schaff HV, Nishimura RA, Dearani JA, Geske JB, Lahr BD, et al. Does septal
vorably impacts cardiac structure in obstructive hypertrophic cardiomyopathy: thickness influence outcome of myectomy for hypertrophic obstructive cardiomyop-
EXPLORER-HCM cardiac magnetic resonance substudy analysis. Circulation 2021; athy? Eur J Cardiothorac Surg 2018;53:582–589. https://doi.org/10.1093/ejcts/ezx398
143:606–608. https://doi.org/10.1161/CIRCULATIONAHA.120.052359 666. Altarabsheh SE, Dearani JA, Burkhart HM, Schaff HV, Deo SV, Eidem BW, et al.
646. Chuang C, Collibee S, Ashcraft L, Wang W, Vander Wal M, Wang X, et al. Discovery of Outcome of septal myectomy for obstructive hypertrophic cardiomyopathy in chil-
684. Veselka J, Krejci J, Tomasov P, Zemanek D. Long-term survival after alcohol septal ab- cardiomyopathy: managing the risk of procedure-related AV conduction disturbances.
lation for hypertrophic obstructive cardiomyopathy: a comparison with general popu- Int J Cardiol 2007;119:163–167. https://doi.org/10.1016/j.ijcard.2006.07.179
lation. Eur Heart J 2014;35:2040–2045. https://doi.org/10.1093/eurheartj/eht495 705. Veselka J, Liebregts M, Cooper R, Faber L, Januska J, Kashtanov M, et al. Outcomes of
685. Liebregts M, Faber L, Jensen MK, Vriesendorp PA, Januska J, Krejci J, et al. Outcomes of patients with hypertrophic obstructive cardiomyopathy and pacemaker implanted
alcohol septal ablation in younger patients with obstructive hypertrophic cardiomyop- after alcohol septal ablation. JACC Cardiovasc Interv 2022;15:1910–1917. https://doi.
athy. JACC Cardiovasc Interv 2017;10:1134–1143. https://doi.org/10.1016/j.jcin.2017.03. org/10.1016/j.jcin.2022.06.034
030 706. Veselka J, Jensen M, Liebregts M, Cooper RM, Januska J, Kashtanov M, et al. Alcohol
686. Veselka J, Jensen MK, Liebregts M, Januska J, Krejci J, Bartel T, et al. Long-term clinical septal ablation in patients with severe septal hypertrophy. Heart 2020;106:462–466.
outcome after alcohol septal ablation for obstructive hypertrophic cardiomyopathy: https://doi.org/10.1136/heartjnl-2019-315422
726. O’Mahony C, Lambiase PD, Quarta G, Cardona M, Calcagnino M, Tsovolas K, et al. 747. Gu M, Jin H, Hua W, Fan X-H, Niu H-X, Tian T, et al. Clinical outcome of cardiac re-
The long-term survival and the risks and benefits of implantable cardioverter defibril- synchronization therapy in dilated-phase hypertrophic cardiomyopathy. J Geriatr
lators in patients with hypertrophic cardiomyopathy. Heart 2012;98:116–125. https:// Cardiol 2017;14:238–244. https://doi.org/10.11909/j.issn.1671-5411.2017.04.002
doi.org/10.1136/hrt.2010.217182 748. Ahmed I, Loudon BL, Abozguia K, Cameron D, Shivu GN, Phan TT, et al. Biventricular
727. Minami Y, Kajimoto K, Terajima Y, Yashiro B, Okayama D, Haruki S, et al. Clinical im- pacemaker therapy improves exercise capacity in patients with non-obstructive hyper-
plications of midventricular obstruction in patients with hypertrophic cardiomyopathy. trophic cardiomyopathy via augmented diastolic filling on exercise. Eur J Heart Fail
J Am Coll Cardiol 2011;57:2346–2355. https://doi.org/10.1016/j.jacc.2011.02.033 2020;22:1263–1272. https://doi.org/10.1002/ejhf.1722
728. Efthimiadis GK, Pagourelias ED, Parcharidou D, Gossios T, Kamperidis V, 749. Elliott PM, Gimeno JR, Thaman R, Shah J, Ward D, Dickie S, et al. Historical trends in
Theofilogiannakos EK, et al. Clinical characteristics and natural history of hypertrophic reported survival rates in patients with hypertrophic cardiomyopathy. Heart 2006;92:
new model of maximalized follow-up. Eur Heart J 2010;31:3084–3093. https://doi.org/ 791. Yan L-R, Zhao S-H, Wang H-Y, Duan F-J, Wang Z-M, Yang Y-J, et al. Clinical charac-
10.1093/eurheartj/ehq308 teristics and prognosis of 60 patients with midventricular obstructive hypertrophic
770. Maron BJ, Spirito P, Ackerman MJ, Casey SA, Semsarian C, Estes NA III, et al. cardiomyopathy. J Cardiovasc Med (Hagerstown) 2015;16:751–760. https://doi.org/10.
Prevention of sudden cardiac death with implantable cardioverter-defibrillators in chil- 2459/JCM.0000000000000163
dren and adolescents with hypertrophic cardiomyopathy. J Am Coll Cardiol 2013;61: 792. Minami Y, Haruki S, Hagiwara N. Phenotypic overlap in hypertrophic cardiomyopathy:
1527–1535. https://doi.org/10.1016/j.jacc.2013.01.037 apical hypertrophy, midventricular obstruction, and apical aneurysm. J Cardiol 2014;64:
771. Ostman-Smith I, Sjoberg G, Rydberg A, Larsson P, Fernlund E. Predictors of risk for 463–469. https://doi.org/10.1016/j.jjcc.2014.03.003
sudden death in childhood hypertrophic cardiomyopathy: the importance of the 793. Ommen SR, Mital S, Burke MA, Day SM, Deswal A, Elliott P, et al. 2020 AHA/ACC
ECG risk score. Open Heart 2017;4:e000658. https://doi.org/10.1136/openhrt-2017- Guideline for the diagnosis and treatment of patients with hypertrophic cardiomyop-
810. Landstrom AP, Ackerman MJ. Mutation type is not clinically useful in predicting prog- paediatric hypertrophic cardiomyopathy: a UK National Cohort Study. Europace
nosis in hypertrophic cardiomyopathy. Circulation 2010;122:2441–2449;discussion 2021;23:400–408. https://doi.org/10.1093/europace/euaa307
2450. https://doi.org/10.1161/CIRCULATIONAHA.110.954446 829. Liebregts M, Faber L, Jensen MK, Vriesendorp PA, Hansen PR, Seggewiss H, et al.
811. Richard P, Charron P, Leclercq C, Ledeuil C, Carrier L, Dubourg O, et al. Validation of the HCM Risk-SCD model in patients with hypertrophic cardiomyopathy
Homozygotes for a R869G mutation in the beta-myosin heavy chain gene have a se- following alcohol septal ablation. Europace 2018;20:f198–f203. https://doi.org/10.1093/
vere form of familial hypertrophic cardiomyopathy. J Mol Cell Cardiol 2000;32: europace/eux251
1575–1583. https://doi.org/10.1006/jmcc.2000.1193 830. Veselka J, Liebregts M, Cooper R, Faber L, Januska J, Kashtanov M, et al. Prediction of
812. Richard P, Isnard R, Carrier L, Dubourg O, Donatien Y, Mathieu B, et al. Double het- sudden cardiac arrest after alcohol septal ablation for hypertrophic obstructive cardio-
erozygosity for mutations in the beta-myosin heavy chain and in the cardiac myosin myopathy: ASA-SCARRE risk score. Am J Cardiol 2022;184:120–126. https://doi.org/
and 2016–2018. A joint procedural position statement on imaging in cardiac sarcoid- 869. Hey TM, Rasmussen TB, Madsen T, Aagaard MM, Harbo M, Molgaard H, et al.
osis: from the Cardiovascular and Inflammation & Infection Committees of the Pathogenic RBM20-variants are associated with a severe disease expression in male
European Association of Nuclear Medicine, the European Association of patients with dilated cardiomyopathy. Circ Heart Fail 2019;12:e005700. https://doi.
Cardiovascular Imaging, and the American Society of Nuclear Cardiology. Eur Heart org/10.1161/CIRCHEARTFAILURE.118.005700
J Cardiovasc Imaging 2017;18:1073–1089. https://doi.org/10.1093/ehjci/jex146 870. Ebert M, Wijnmaalen AP, de Riva M, Trines SA, Androulakis AFA, Glashan CA, et al.
850. Fatkin D, Huttner IG, Kovacic JC, Seidman JG, Seidman CE. Precision medicine in the Prevalence and prognostic impact of pathogenic variants in patients with dilated car-
management of dilated cardiomyopathy: JACC state-of-the-art review. J Am Coll diomyopathy referred for ventricular tachycardia ablation. JACC Clin Electrophysiol
Cardiol 2019;74:2921–2938. https://doi.org/10.1016/j.jacc.2019.10.011 2020;6:1103–1114. https://doi.org/10.1016/j.jacep.2020.04.025
851. Merlo M, Cannata A, Sinagra G. Dilated cardiomyopathy: a paradigm of revolution in 871. Rootwelt-Norberg C, Christensen AH, Skjolsvik ET, Chivulescu M, Vissing CR,
888. Protonotarios A, Wicks E, Ashworth M, Stephenson E, Guttmann O, Savvatis K, et al. 908. Gasperetti A, Rossi VA, Chiodini A, Casella M, Costa S, Akdis D, et al. Differentiating
Prevalence of (18)F-fluorodeoxyglucose positron emission tomography abnormalities hereditary arrhythmogenic right ventricular cardiomyopathy from cardiac sarcoidosis
in patients with arrhythmogenic right ventricular cardiomyopathy. Int J Cardiol 2019; fulfilling 2010 ARVC Task Force Criteria. Heart Rhythm 2021;18:231–238. https://doi.
284:99–104. https://doi.org/10.1016/j.ijcard.2018.10.083 org/10.1016/j.hrthm.2020.09.015
889. Casella M, Gasperetti A, Sicuso R, Conte E, Catto V, Sommariva E, et al. Characteristics 909. Laredo M, Duthoit G, Gandjbakhch E, Redheuil A, Hebert J-L. Total pericardium agen-
of patients with arrhythmogenic left ventricular cardiomyopathy: combining genetic esis mistaken for arrhythmogenic right ventricular cardiomyopathy. Eur Heart J
and histopathologic findings. Circ Arrhythm Electrophysiol 2020;13:e009005. https:// Cardiovasc Imaging 2018;19:120. https://doi.org/10.1093/ehjci/jex251
doi.org/10.1161/CIRCEP.120.009005 910. Castelletti S, Crotti L, Dagradi F, Rella V, Salerno S, Parati G, et al. Partial pericardial
890. Thiene G, Nava A, Corrado D, Rossi L, Pennelli N. Right ventricular cardiomyopathy agenesis mimicking arrhythmogenic right ventricular cardiomyopathy. Clin J Sport
928. Assis FR, Krishnan A, Zhou X, James CA, Murray B, Tichnell C, et al. Cardiac sympath- 947. Bhonsale A, James CA, Tichnell C, Murray B, Gagarin D, Philips B, et al. Incidence and
ectomy for refractory ventricular tachycardia in arrhythmogenic right ventricular car- predictors of implantable cardioverter-defibrillator therapy in patients with arrhyth-
diomyopathy. Heart Rhythm 2019;16:1003–1010. https://doi.org/10.1016/j.hrthm. mogenic right ventricular dysplasia/cardiomyopathy undergoing implantable
2019.01.019 cardioverter-defibrillator implantation for primary prevention. J Am Coll Cardiol
929. Shen L-S, Liu L-M, Zheng L-H, Hu F, Hu Z-C, Liu S-Y, et al. Ablation strategies for ar- 2011;58:1485–1496. https://doi.org/10.1016/j.jacc.2011.06.043
rhythmogenic right ventricular cardiomyopathy: a systematic review and 948. Watkins DA, Hendricks N, Shaboodien G, Mbele M, Parker M, Vezi BZ, et al. Clinical
meta-analysis. J Geriatr Cardiol 2020;17:694–703. https://doi.org/10.11909/j.issn.1671- features, survival experience, and profile of plakophylin-2 gene mutations in partici-
5411.2020.11.001 pants of the arrhythmogenic right ventricular cardiomyopathy registry of South
930. Romero J, Patel K, Briceno D, Alviz I, Gabr M, Diaz JC, et al. Endo-epicardial ablation vs Africa. Heart Rhythm 2009;6(11 Suppl):S10–S17. https://doi.org/10.1016/j.hrthm.
967. Muchtar E, Blauwet LA, Gertz MA. Restrictive cardiomyopathy: genetics, pathogenesis, 992. Gripp KW, Morse LA, Axelrad M, Chatfield KC, Chidekel A, Dobyns W, et al. Costello
clinical manifestations, diagnosis, and therapy. Circ Res 2017;121:819–837. https://doi. syndrome: clinical phenotype, genotype, and management guidelines. Am J Med Genet A
org/10.1161/CIRCRESAHA.117.310982 2019;179:1725–1744. https://doi.org/10.1002/ajmg.a.61270
968. Mori H, Kogaki S, Ishida H, Yoshikawa T, Shindo T, Inuzuka R, et al. Outcomes of re- 993. Gripp KW, Hopkins E, Sol-Church K, Stabley DL, Axelrad ME, Doyle D, et al.
strictive cardiomyopathy in Japanese children–a retrospective cohort study. Circ J Phenotypic analysis of individuals with Costello syndrome due to HRAS p.G13C.
2022;86:1943–1949. https://doi.org/10.1253/circj.CJ-21-0706 Am J Med Genet A 2011;155A:706–716. https://doi.org/10.1002/ajmg.a.33884
969. Rivenes SM, Kearney DL, Smith EO, Towbin JA, Denfield SW. Sudden death and car- 994. Pierpont ME, Magoulas PL, Adi S, Kavamura MI, Neri G, Noonan J, et al.
diovascular collapse in children with restrictive cardiomyopathy. Circulation 2000;102: Cardio-facio-cutaneous syndrome: clinical features, diagnosis, and management guide-
876–882. https://doi.org/10.1161/01.CIR.102.8.876 lines. Pediatrics 2014;134:e1149–e1162. https://doi.org/10.1542/peds.2013-3189
1014. Anderson K, Cnota J, James J, Miller EM, Parrott A, Pilipenko V, et al. Prevalence of 1037. Di Prospero NA, Baker A, Jeffries N, Fischbeck KH. Neurological effects of high-dose
Noonan spectrum disorders in a pediatric population with valvar pulmonary stenosis. idebenone in patients with Friedreich’s ataxia: a randomised, placebo-controlled trial.
Congenit Heart Dis 2019;14:264–273. https://doi.org/10.1111/chd.12721 Lancet Neurol 2007;6:878–886. https://doi.org/10.1016/S1474-4422(07)70220-X
1015. Ko S, Komuro J, Katsumata Y, Shiraishi Y, Kawakami T, Yamada Y, et al. Peripheral 1038. Lynch DR, Perlman SL, Meier T. A phase 3, double-blind, placebo-controlled trial of
pulmonary stenosis with Noonan syndrome treated by balloon pulmonary angio- idebenone in Friedreich ataxia. Arch Neurol 2010;67:941–947. https://doi.org/10.
plasty. Pulm Circ 2020;10:2045894020954310. https://doi.org/10.1177/2045894020 1001/archneurol.2010.168
954310 1039. Lagedrost SJ, Sutton MS, Cohen MS, Satou GM, Kaufman BD, Perlman SL, et al.
1016. Durr A, Cossee M, Agid Y, Campuzano V, Mignard C, Penet C, et al. Clinical and gen- Idebenone in Friedreich ataxia cardiomyopathy–results from a 6-month phase III
etic abnormalities in patients with Friedreich’s ataxia. N Engl J Med 1996;335: study (IONIA). Am Heart J 2011;161:639–645.e1. https://doi.org/10.1016/j.ahj.
with increased left ventricular wall thickness. Eur Heart J 2016;37:1826–1834. https:// 1078. Maurer MS, Schwartz JH, Gundapaneni B, Elliott PM, Merlini G, Waddington-Cruz M,
doi.org/10.1093/eurheartj/ehv583 et al. Tafamidis treatment for patients with transthyretin amyloid cardiomyopathy. N
1059. Castano A, Narotsky DL, Hamid N, Khalique OK, Morgenstern R, DeLuca A, et al. Engl J Med 2018;379:1007–1016. https://doi.org/10.1056/NEJMoa1805689
Unveiling transthyretin cardiac amyloidosis and its predictors among elderly patients 1078a. Garcia-Pavia P, Aus dem Siepen F, Donal E, Lairez O, van der Meer P, Kristen AV,
with severe aortic stenosis undergoing transcatheter aortic valve replacement. Eur et al. Phase 1 Trial of Antibody NI006 for Depletion of Cardiac Transthyretin
Heart J 2017;38:2879–2887. https://doi.org/10.1093/eurheartj/ehx350 Amyloid. N Engl J Med 2023. https://doi.org/10.1056/NEJMoa2303765. Online ahead
1060. Asif T, Gomez J, Singh V, Doukky R, Nedeltcheva A, Malhotra S. Comparison of pla- of print.
nar with tomographic pyrophosphate scintigraphy for transthyretin cardiac amyloid- 1079. Boule NG, Haddad E, Kenny GP, Wells GA, Sigal RJ. Effects of exercise on glycemic
osis: perils and pitfalls. J Nucl Cardiol 2021;28:104–111. https://doi.org/10.1007/ control and body mass in type 2 diabetes mellitus: a meta-analysis of controlled clin-
American Heart Association and American College of Cardiology. J Am Coll Cardiol 1118. Pelliccia A, Sharma S, Gati S, Back M, Borjesson M, Caselli S, et al. 2020 ESC Guidelines
2015;66:2444–2446. https://doi.org/10.1016/j.jacc.2015.09.046 on sports cardiology and exercise in patients with cardiovascular disease. Eur Heart J
1099. Reineck E, Rolston B, Bragg-Gresham JL, Salberg L, Baty L, Kumar S, et al. Physical ac- 2021;42:17–96. https://doi.org/10.1093/eurheartj/ehaa605
tivity and other health behaviors in adults with hypertrophic cardiomyopathy. Am J 1119. Cruz FM, Sanz-Rosa D, Roche-Molina M, Garcia-Prieto J, Garcia-Ruiz JM, Pizarro G,
Cardiol 2013;111:1034–1039. https://doi.org/10.1016/j.amjcard.2012.12.018 et al. Exercise triggers ARVC phenotype in mice expressing a disease-causing mutated
1100. Sweeting J, Ingles J, Timperio A, Patterson J, Ball K, Semsarian C. Physical activity in version of human plakophilin-2. J Am Coll Cardiol 2015;65:1438–1450. https://doi.org/
hypertrophic cardiomyopathy: prevalence of inactivity and perceived barriers. 10.1016/j.jacc.2015.01.045
Open Heart 2016;3:e000484. https://doi.org/10.1136/openhrt-2016-000484 1120. Maron BJ, Haas TS, Murphy CJ, Ahluwalia A, Rutten-Ramos S. Incidence and causes of
1101. Olivotto I, Maron BJ, Tomberli B, Appelbaum E, Salton C, Haas TS, et al. Obesity and sudden death in U.S. college athletes. J Am Coll Cardiol 2014;63:1636–1643. https://
cardiomyopathies. Eur J Heart Fail 2011;13:584–594. https://doi.org/10.1093/eurjhf/ 1156. Cheng H, Lu M, Hou C, Chen X, Wang J, Yin G, et al. Relation between N-terminal
hfr040 pro-brain natriuretic peptide and cardiac remodeling and function assessed by cardio-
1138. Castrini AI, Lie OH, Leren IS, Estensen ME, Stokke MK, Klaeboe LG, et al. Number of vascular magnetic resonance imaging in patients with arrhythmogenic right ventricu-
pregnancies and subsequent phenotype in a cross-sectional cohort of women with lar cardiomyopathy. Am J Cardiol 2015;115:341–347. https://doi.org/10.1016/j.
arrhythmogenic cardiomyopathy. Eur Heart J Cardiovasc Imaging 2019;20:192–198. amjcard.2014.10.040
https://doi.org/10.1093/ehjci/jey061 1157. Chivulescu M, Lie OH, Popescu BA, Skulstad H, Edvardsen T, Jurcut RO, et al. High
1139. Platonov PG, Castrini AI, Svensson A, Christiansen MK, Gilljam T, Bundgaard H, et al. penetrance and similar disease progression in probands and in family members with
Pregnancies, ventricular arrhythmias, and substrate progression in women with ar- arrhythmogenic cardiomyopathy. Eur Heart J 2020;41:1401–1410. https://doi.org/10.
rhythmogenic right ventricular cardiomyopathy in the Nordic ARVC Registry. 1093/eurheartj/ehz570
1175. Sabater-Molina M, Saura D, Garcia-Molina Saez E, Gonzalez-Carrillo J, Polo L, 1191. Choudhary N, Tompkins C, Polonsky B, McNitt S, Calkins H, Mark Estes NA, et al.
Perez-Sanchez I, et al. A novel founder mutation in MYBPC3: phenotypic comparison Clinical presentation and outcomes by sex in arrhythmogenic right ventricular cardio-
with the most prevalent MYBPC3 mutation in Spain. Rev Esp Cardiol (Engl Ed) 2017; myopathy: findings from the North American ARVC registry. J Cardiovasc
70:105–114. https://doi.org/10.1016/j.recesp.2016.06.025 Electrophysiol 2016;27:555–562. https://doi.org/10.1111/jce.12947
1176. Adalsteinsdottir B, Burke M, Maron BJ, Danielsen R, Lopez B, Diez J, et al. 1192. Akdis D, Saguner AM, Shah K, Wei C, Medeiros-Domingo A, von Eckardstein A, et al.
Hypertrophic cardiomyopathy in myosin-binding protein C (MYBPC3) Icelandic Sex hormones affect outcome in arrhythmogenic right ventricular cardiomyopathy/
founder mutation carriers. Open Heart 2020;7:e001220. https://doi.org/10.1136/ dysplasia: from a stem cell derived cardiomyocyte-based model to clinical biomarkers
openhrt-2019-001220 of disease outcome. Eur Heart J 2017;38:1498–1508. https://doi.org/10.1093/
1177. Lakdawala NK, Olivotto I, Day SM, Han L, Ashley EA, Michels M, et al. Associations eurheartj/ehx011