Discussion
Regarding cardiomyopathies, the CRYAB mutation gene has been linked to
HCM as a common mutation gene, according to the ESC guidelines6. However, after performing a review of the available
medical literature in the major clinical databases (Pubmed, Google
Scholar, and Scielo), we found some manuscripts describing a relation
between the CYRAB mutation and DCM in humans 2,4,7,8.
Regarding DCM It’s important to keep in mind that it’s defined by the
presence of left ventricular dilatation and systolic dysfunction
unexplained solely by abnormal loading conditions or coronary artery
disease (CAD) 6. In our case abnormal loading
conditions were ruled out, as CAD by right and left coronary
arteriography without epicardial lesions.
According to epidemiology, familial DCM accounts for 30–40% of all DCM
cases; in 20–40% of those cases, a gene has been found4,6. According to the ESC guidelines the very common,
common or less common genes associated with DMC include ABCC9, ACTC1,
ACTN2, ANKRD1, BAG3, CSRP3, CTF1, DES, DMD, DSG2, DSP, DTNA, EYA4, FLNC,
GATAD1, ILK, JPH2, LAMA4, LDB3, LMNA, LRRC10, MIB1, MYBPC3, MYH6, MYH7,
MYL2, MYL3, MYPN, NEBL, NEXN, NKX2-5,NPPA, OBSCN, PDLIM3, PKP2,
PLEKHM2,PLN, PRDM16, PSEN1, PSEN2, RBM20, SCN5A, SGCD, TBX20, TCAP,
TMEM43, TMP0, TMNC1, TNNI3, TNNI3K, TNNT2, TPM1, TTN and VCL6.
Despite the CRYAB mutation not being included in the previous list, in
the last years this mutation has been described as a pathogenic mutation
in DCM in several articles 2,4,7,8 . In our case, a
heterozygous CRYAB mutation was detected after excluding other causes of
secondary DCM and may be as novo due to the absence of documented
cardiomyopathies in his relatives.
Respect the physiopathology why this mutation causes cardiomyopathy; in
mouse models it has been found that an R120G missense mutation causes
“desmin-related cardiomyopathy,” which is characterised by the
formation of aggregates of oligomeric amyloid containing CRYAB and
desmin with accumulation of them within cardiac muscle, generating
mitochondrial deficiencies, activation of apoptosis, and heart failure9,10. These oligomeric amyloid intermediates have also
been seen in cardiomyocytes from many humans with dilated and
hypertrophic cardiomyopathies 9,10.
Besides, it has even been shown that this mutation in vitro
cardiomyocytes leads to mitochondrial dysfunction and subsequent
apoptosis, which eventually results in cardiomyocyte death, dilatation,
and heart failure 11.
Regarding the treatment of chronic heart failure with reduced ejection
fraction, it must be according to the international guidelines provided
by the ESC and ACC guidelines, among other relevant guidelines12-14. However, regarding the treatment of genetic
DCM, it’s important to assess if the patient carries some specific
mutations associated with increased risk of sudden cardiac death, like
FLNC, DES, DSP, PLN, LMNA, TMEM43, and RMB20, among others6. In our case these mutations were ruled out.
Although predicting SCD is a challenging aspect of the clinical care of
patients with DCM mainly in primary prevention because in secondary
prevention they have demonstrated to reduce mortality among survivors of
cardiac arrest and in whom have experienced sustained ventricular
arrhythmias with haemodynamic compromise 6.
Nevertheless, a LEVF ≤35% has been reported as an independent risk
marker of all cause and cardiac death in DCM despite its modest ability
to identify DCM patients with a higher risk of SCD; also, DCM patients
harbouring DCM-causing variants in high-risk genes (LMNA, EMD, TMEM43,
DSP, RBM20, PLN, FLNC-truncating variants) should be considered as
patients with a high-risk genetic background for SCD, and primary
prevention ICD implantation should be considered with LVEF thresholds
higher than 35% 6. In our case, these conditions were
absent, so actually an indication to implant an ICD for primary
prevention is not considered.
Finally, in an interesting way, voluntary exercises have shown a
significant improvement in survival among a mouse model, also reducing
the accumulation of preamyloid due to the CRYAB mutation, slowing the
progression of heart failure in this animal model. Nevertheless, more
research is needed to confirm this finding in humans15.