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common, followed by pathogenic variants in DSP, DSG2, DSC2, and JUP [47,48] . Smaller subsets of ACM
patients carry disease-causing variants in SCN5A, LMNA, and TTN, which are also implicated in other ICCs
(i.e., DCM and Brugada syndrome [BrS]).

Genotype-negative ACM cases are similar regarding disease progression compared to genotype-positive
ACM. However, different causal genes are associated with different, sometimes worse outcomes among
[49]
genotype-positive ACM cases . For example, pathogenic variants in PLN and DSP are more likely to be
associated with heart failure . In addition, a disease-causing desmosomal variant among patients with
[50]
[38]
ACM often implies a worse arrhythmic course and a higher risk of SCD . ACM management includes
cascade testing for relatives and treatment for heart failure and arrhythmia .
[48]
LVNC
LVNC is a disorder of endomyocardial morphogenesis characterized by numerous and excessively
prominent ventricular trabeculations and deep intertrabecular recesses; it was first described in 1984 [51,52] .
The diagnosis requires cMRI or echocardiography [53,54] . Its pathogenesis is not yet fully understood,
explaining the lack of clarity of its genetic underpinnings. Nevertheless, because over 44% of pediatric
LVNC cases are familial, it is hypothesized that gene variants disrupt the physiological compaction of the
developing embryonic myocardium, resulting in LVNC [55,56] .

A genomic study of LVNC implicated some genes coding for proteins of the sarcomere, Z-disk, and
nuclear-envelope structures, including ACTC1, MYH7, MYBPC3, TNNT2, TPM1, TTN, LDB3, LMNA,
RBM20, and DTNA [56-59] . Genotype-positive LVNC patients have poor outcomes, and closer follow-up is
recommended for these patients [60,61] .

There have been difficulties in establishing a consensus for the management of LVNC because of the lack of
large clinical trials. Understandably, the standard of care for DCM has been extended to LVNC patients
with reduced ejection fraction, with an increased focus on anticoagulation (to reduce the risk of
thromboembolic stroke) and the primary prevention of SCD [62,63] . While the current management of LVNC
is prophylactic and symptomatic, more is needed to improve the guidelines.

Transthyretin amyloid cardiomyopathy
Transthyretin is a ubiquitous transporter protein produced by the liver. It is a tetramer but can potentially
dissociate into monomers and misfold into insoluble amyloid proteins. Transthyretin amyloid
cardiomyopathy (ATTR-CM) is a progressive, life-threatening disease caused by an end-organ
accumulation of these misfolded transthyretin amyloid proteins, with the nerves and heart being
[64]
exceptionally susceptible . The disease results in a slowly progressive peripheral sensorimotor or
autonomic neuropathy with progressive cardiomyopathy . ATTR-CM may be associated with aging
[65]
("wild-type", wtATTR-CM, i.e., the absence of any pathogenic variants in the TTR gene) or the TTR variant,
resulting in an inherent instability of the transthyretin protein (variant ATTR-CM). More than 110 TTR
gene variants have been classified as pathogenic for genotype-positive ATTR-CM .
[66]
While not a new disease entity, ATTR-CM has received more attention in the medical community in the
past decade because of the field’s rapid development. There are non-invasive diagnostics using nuclear
[65]
scintigraphy that supplant the previous invasive endomyocardial biopsy . More importantly, disease-
modifying treatment is now available in the TTR tetramer stabilizer Tafamidis, significantly improving
[67]
outcomes in patients with ATTR-CM .