42,893 research outputs found
Investigations into the Sarcomeric Protein and Ca2+-Regulation Abnormalities Underlying Hypertrophic Cardiomyopathy in Cats (Felix catus).
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
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Feline Hypertrophic Cardiomyopathy: A Spontaneous Large Animal Model of Human HCM.
Hypertrophic cardiomyopathy (HCM) is a common disease in pet cats, affecting 10-15% of the pet cat population. The similarity to human HCM, the rapid progression of disease, and the defined and readily determined endpoints of feline HCM make it an excellent natural model that is genotypically and phenotypically similar to human HCM. The Maine Coon and Ragdoll cats are particularly valuable models of HCM because of myosin binding protein-C mutations and even higher disease incidence compared to the overall feline population. The cat overcomes many of the limitations of rodent HCM models, and can provide enhanced translation of information from in vitro and induced small animal models to human clinical trials. Physicians and veterinarians working together in a collaborative and interdisciplinary approach can accelerate the discovery of more effective treatments for this and other cardiovascular diseases affecting human and veterinary patients
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A One Health Approach to Hypertrophic Cardiomyopathy.
Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disease in humans and results in significant morbidity and mortality. Research over the past 25 years has contributed enormous insight into this inherited disease particularly in the areas of genetics, molecular mechanisms, and pathophysiology. Our understanding continues to be limited by the heterogeneity of clinical presentations with various genetic mutations associated with HCM. Transgenic mouse models have been utilized especially studying the genotypic and phenotypic interactions. However, mice possess intrinsic cardiac and hemodynamic differences compared to humans and have limitations preventing their direct translation. Other animal models of HCM have been studied or generated in part to overcome these limitations. HCM in cats shows strikingly similar molecular, histopathological, and genetic similarities to human HCM, and offers an important translational opportunity for the study of this disease. Recently, inherited left ventricular hypertrophy in rhesus macaques was identified and collaborative investigations have been conducted to begin to develop a non-human primate HCM model. These naturally-occurring large-animal models may aid in advancing our understanding of HCM and developing novel therapeutic approaches to this disease. This review will highlight the features of HCM in humans and the relevant available and developing animal models of this condition
Molecular analysis of sarcomeric and non-sarcomeric genes in patients with hypertrophic cardiomyopathy.
Background: Hypertrophic cardiomyopathy (HCM) is a common genetic heart disorder characterized by
unexplained left ventricle hypertrophy associated with non-dilated ventricular chambers. Several genes
encoding heart sarcomeric proteins have been associated to HCM, but a small proportion of HCM patients
harbor alterations in other non-sarcomeric loci. The variable expression of HCM seems influenced by genetic
modifier factors and new sequencing technologies are redefining the understanding of genotype–phenotype
relationships, even if the interpretations of the numerous identified variants pose several challenges.
Methods and results: We investigated 62 sarcomeric and non-sarcomeric genes in 41 HCM cases and in
3 HCM-related disorders patients. We employed an integrated approach that combines multiple tools for
the prediction, annotation and visualization of functional variants. Genotype–phenotype correlations
were carried out for inspecting the involvement of each gene in age onset and clinical variability of HCM. The
80% of the non-syndromic patients showed at least one rare non-synonymous variant (nsSNV) and among
them, 58% carried alterations in sarcomeric loci, 14% in desmosomal and 7% in other non-sarcomeric ones
without any sarcomere change. Statistical analyses revealed an inverse correlation between the number of
nsSNVs and age at onset, and a relationship between the clinical variability and number and type of variants.
Conclusions: Our results extend the mutational spectrum of HCM and contribute in defining the molecular
pathogenesis and inheritance pattern(s) of this condition. Besides, we delineate a specific procedure for the
identification of the most likely pathogenetic variants for a next generation sequencing approach embodied in
a clinical context
Exercise and hypertrophic cardiomyopathy: Two incompatible entities?
A greater understanding of the pathogenic mechanisms underpinning hypertrophic cardiomyopathy (HCM) has translated to improved medical care and better survival of affected individuals. Historically these patients were considered to be at high risk of sudden cardiac death (SCD) during exercise; therefore, exercise recommendations were highly conservative and promoted a sedentary life style. There is emerging evidence that suggests that exercise in HCM has a favorable effect on cardiovascular remodeling and moderate exercise programs have not raised any safety concerns. Furthermore, individuals with HCM have a similar burden of atherosclerotic risk factors as the general population in whom exercise has been associated with a reduction in myocardial infarction, stroke, and heart failure, especially among those with a high-risk burden. Small studies revealed that athletes who choose to continue with regular competition do not demonstrate adverse outcomes when compared to those who discontinue sport, and active individuals implanted with an implantable cardioverter defibrillator do not have an increased risk of appropriate shocks or other adverse events. The recently published exercise recommendations from the European Association for Preventative Cardiology account for more contemporary evidence and adopt a more liberal stance regarding competitive and high intensity sport in individuals with low-risk HCM. This review addresses the issue of exercise in individuals with HCM, and explores current evidence supporting safety of exercise in HCM, potential caveats, and areas of further research
A next-generation sequencing approach to identify gene mutations in early-and late-onset hypertrophic cardiomyopathy patients of an Italian cohort
Sequencing of sarcomere protein genes in patients fulfilling the clinical diagnostic criteria for hypertrophic cardiomyopathy (HCM) identifies a disease-causing mutation in 35% to 60% of cases. Age at diagnosis and family history may increase the yield of mutations screening. In order to assess whether Next-Generation Sequencing (NGS) may fulfil the molecular diagnostic needs in HCM, we included 17 HCM-related genes in a sequencing panel run on PGM IonTorrent. We selected 70 HCM patients, 35 with early (≤25 years) and 35 with late (≥65 years) diagnosis of disease onset. All samples had a 98.6% average of target regions, with coverage higher than 20× (mean coverage 620×). We identified 41 different mutations (seven of them novel) in nine genes: MYBPC3 (17/41 = 41%); MYH7 (10/41 = 24%); TNNT2, CAV3 and MYH6 (3/41 = 7.5% each); TNNI3 (2/41 = 5%); GLA, MYL2, and MYL3 (1/41=2.5% each). Mutation detection rate was 30/35 (85.7%) in early-onset and 8/35 (22.9%) in late-onset HCM patients, respectively (p < 0.0001). The overall detection rate for patients with positive family history was 84%, and 90.5% in patients with early disease onset. In our study NGS revealed higher mutations yield in patients with early onset and with a family history of HCM. Appropriate patient selection can increase the yield of genetic testing and make diagnostic testing cost-effective
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