Hypertrophic Cardiomyopathy and Phenocopies: New Therapies for Old Diseases-Current Evidence and Future Perspectives

Abstract

The hypertrophic cardiomyopathy (HCM) clinical phenotype includes sarcomeric HCM, which is the most common form of inherited cardiomyopathy with a population prevalence of 1:500, and phenocopies such as cardiac amyloidosis and Anderson-Fabry disease, which are considered rare diseases. Identification of cardiac and non-cardiac red flags in the context of multi-organ syndrome, multimodality imaging, including echocardiography, cardiac magnetic resonance, and genetic testing, has a central role in the diagnostic pathway. Identifying the specific disease underlying the hypertrophic phenotype is very important since many disease-modifying therapies are currently available, and phase 3 trials for new treatments have been completed or are ongoing. In particular, many chemotherapy agents (alkylating agents, proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies targeting clonal cells) allowing one to treat AL amyloidosis, transthyretin stabilizers (tafamidis and acoramidis), and gene silencers (patisiran and vutrisiran) are available in transthyretin cardiac amyloidosis, and enzyme replacement therapies (agalsidase-alpha, agalsidase-beta, and pegunigalsidase-alpha) or oral chaperone therapy (migalastat) can be used in Anderson-Fabry disease. In addition, the introduction of cardiac myosin inhibitors (mavacamten and aficamten) has deeply modified the treatment of hypertrophic obstructive cardiomyopathy. The aim of this review is to describe the new disease-modifying treatments available in HCM and phenocopies in light of current scientific evidence.

Keywords: cardiac magnetic resonance; cardiomyopathy; disease-modifying therapy; genetic test.

Figure 1

Flowchart of the treatment of obstructive HCM: differences between ESC guidelines and AHA/ACC guidelines regarding the indication for cardiac myosin inhibitors.

Figure 2

Diagnostic flowchart in CA. In the presence of signs and symptoms, electrocardiographic, echocardiographic, or CMR features suggestive of CA, the diagnostic pathway includes non-invasive criteria, i.e., bone scintigraphy combined with planar and single-photon emission computed tomography (SPECT) and exclusion of a clonal dyscrasia through serum free light-chain assays, serum, and urine protein electrophoresis with immunofixation. In cases of positive bone scintigraphy (Perugini grade 2 or 3) and the exclusion of monoclonality, a TTR genetic test is required to distinguish ATTRv from ATTRwt; otherwise, if the Perugini grade is 1 or there is a positive immunofixation, histological confirmation (cardiac or extracardiac) is mandatory.

Figure 3

Diagnostic pathway in AFD.