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.