Investigations into the Sarcomeric Protein and Ca2+-Regulation Abnormalities Underlying Hypertrophic Cardiomyopathy in Cats (Felix catus).

Andrew E Messer,Jasmine Chan,David J Connolly,O'Neal Copeland,Steven B Marston,Alex Daley

doi:10.3389/fphys.2017.00348

Andrew E Messer, Jasmine Chan + Show 4 more

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https://doi.org/10.3389/fphys.2017.00348

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Abstract

Hypertrophic cardiomyopathy (HCM) is the most common single gene inherited cardiomyopathy. In cats (Felix catus) HCM is even more prevalent and affects 16% of the outbred population and up to 26% in pedigree breeds such as Maine Coon and Ragdoll. Homozygous MYBPC3 mutations have been identified in these breeds but the mutations in other cats are unknown. At the clinical and physiological level feline HCM is closely analogous to human HCM but little is known about the primary causative mechanism. Most identified HCM causing mutations are in the genes coding for proteins of the sarcomere. We therefore investigated contractile and regulatory proteins in left ventricular tissue from 25 cats, 18 diagnosed with HCM, including a Ragdoll cat with a homozygous MYBPC3 R820W, and 7 non-HCM cats in comparison with human HCM (from septal myectomy) and donor heart tissue. Myofibrillar protein expression was normal except that we observed 20–44% MyBP-C haploinsufficiency in 5 of the HCM cats. Troponin extracted from 8 HCM and 5 non-HCM cat hearts was incorporated into thin filaments and studied by in vitro motility assay. All HCM cat hearts had a higher (2.06 ± 0.13 fold) Ca2+-sensitivity than non-HCM cats and, in all the HCM cats, Ca2+-sensitivity was not modulated by troponin I phosphorylation. We were able to restore modulation of Ca2+-sensitivity by replacing troponin T with wild-type protein or by adding 100 μM Epigallocatechin 3-gallate (EGCG). These fundamental regulatory characteristics closely mimic those seen in human HCM indicating a common molecular mechanism that is independent of the causative mutation. Thus, the HCM cat is a potentially useful large animal model.

Highlights

Feline HCM Mutations and IncidenceHypertrophic cardiomyopathy (HCM) is identified in about 1 in 500 people
We made a careful examination of the clinical records, echocardiography and histology data, and scored the strength of HCM or non-HCM diagnosis for this cat population using the criteria described in the methods section
All the samples were studied by gel electrophoresis and eight HCM cats and five non-HCM cats with the highest certainty of diagnosis were selected for further investigation by in vitro motility assay (IVMA)

Summary

Introduction

Hypertrophic cardiomyopathy (HCM) is identified in about 1 in 500 people It is the leading cause of sudden cardiac death in young adults and results in significant disability in survivors. HCM is inherited as an autosomal dominant trait with variable penetrance (Maron et al, 2014), the causative mutation cannot be identified in about half of the cases. This may be explained by either existence of rare sarcomeric or non-sarcomeric genetic variants, the influence of modifier genes or the presence of phenocopies (Maron et al, 2010; Lopes et al, 2015). Alterations in two genes, β-myosin heavy chain and myosin-binding protein C (MYBPC3) account for ∼75% of cases where an underlying mutation has been identified (Alfares et al, 2015)

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