Beta-myosin Heavy Chain Gene Research Articles

Abstract P120: Effect Of Alamandine On Isoproterenol-induced Left Ventricular Dysfunction, Cardiac Remodeling And Immune Responses In Rat

Alamandine, a newly identified derivative of angiotensin II has been shown to exert antihypertensive and vasodilative actions, and may represent a novel component of cardioprotective axis of renin angiotensin system. We sought to determine the protective effects of alamandine on isoproterenol (ISO) induced cardiac remodeling and dysfunction in rats. Male SD rats (n=6 in each group) received a two-week subcutaneous infusion of vehicle, ISO (10 mg/kg/day) or a combination of ISO and alamandine (50 ng/kg/min). Compared with vehicle group, the ratio of heart/body weight (mg/g) in ISO treated rats was significantly (*P<0.05) elevated (3.93 ± 0.18 vs. 3.07 ± 0.08*), which was markedly attenuated by alamandine (3.50 ± 0.08*). Echocardiographic assessment showed that alamandine improved ISO-induced left ventricular (LV) dysfunction evidenced by reducing LV thickness (1.68 ± 0.07* vs 1.90 ± 0.02 mm), end diastolic and systolic volume. Rats treated with alamandine had reduced E/E' ratio (15.16 ± 1.04* vs 26.81 ± 3.79) and increased E'/A' ratio (1.09 ± 0.05 vs 0.57 ± 0.07 ** P<0.01), indicating the improved diastolic cardiac function. The reduced myocardial performance index (0.74 ± 0.06* vs. 1.24 ± 0.15) in alamandine treated rats demonstrated an improvement of global cardiac dysfunction. Histological analysis also revealed that alamandine attenuated ISO induced increase in cardiomyocyte size (372.46 ± 11.13** vs 551.99 ± 11.79 μm 2 ) and myocardial fibrosis (1.39 ± 0.16 ** vs 4.57 ± 0.35), along with reduced mRNA expression of hypertrophy biomarkers atrial natriuretic peptide (2.45 ± 0.71** vs 8.08 ± 0.74), brain natriuretic peptide (2.86 ± 0.35 ** vs 12.53 ± 1.12), beta myosin heavy chain (1.71 ± 0.25* vs 5.38 ± 0.95) and fibrosis genes – collagen-1 (1.97 ± 0.45* vs 4.25 ± 0.6), fibronectin (2.04 ± 0.32** vs 5.05 ± 0.74), α-smooth muscle actin (1.53 ± 0.1** vs 2.71 ± 0.17). Flow cytometry analysis unveiled that alamandine reduced neutrophil, CD8 T cells and M1 monocytes, but increased M2 monocytes of left ventricle, implying the reduction of inflammation of the heart. These data suggest that alamandine plays a cardioprotective role in improving cardiac hypertrophy and fibrosis, probably via an immune mechanism to alleviate inflammatory responses during cardiac remodeling.

Abstract P1164: Elevated Erk1/2 Signaling Contributes To The Development Of Diabetic Cardiomyopathy

Background: About 19%-26% of the obese patients develop diabetic cardiomyopathy (DCM) characterized by ventricular hypertrophy, fibrosis, and contractile dysfunction. Although many studies have investigated the potential causes of DCM, the pathophysiology of this disease has yet been to be fully characterized. Objective: To determine whether extracellular signal-regulated kinase 1/2 (ERK1/2) are involved in the development of DCM. Materials and Methods: Both streptozotocin (STZ)-induced type I and db/db type II diabetic mice were utilized to compare the ERK1/2 phosphorylation level in mouse hearts. To determine the gain-of-function of ERK1/2 signaling in DCM, both control and dual specific phosphatase 6 and 8 knockout mice (DKO) mice were administered streptozotocin (STZ) to induce elevated serum glucose. After 12 weeks of treatment, mouse body weight, heart weight/histology, and disease markers were compared. As a loss-of-function study, U0126 was utilized to inhibit ERK1/2 activity in both streptozotocin (STZ)-induced type I and db/db type II diabetic mice to determine whether DCM markers are influenced. Results: In both type I and II diabetic mouse hearts, ERK1/2 phosphorylation level was significantly elevated. STZ treatment for 2 weeks induced similar increases in serum glucose in both WT and DKO mice. After 12 weeks of STZ treatment, DKO mice developed greater cardiac atrophy and increased levels of ANF, BNP, beta myosin heavy chain gene expression. In comparison, U0126-mediated pharmacological inhibition of ERK1/2 for 12 weeks significantly improved the cardiac function in both type I and II diabetic mouse models. Conclusion: Elevated ERK1/2 signaling contributes to the process of DCM, suggesting ERK1/2 could be therapeutic targets for the treatment of this disease.

Abstract P2036: Induced Pluripotent Stem Cell- Derived Cardiomyocytes Provide New Insights Of The Pathogenic Consequences Of The Novel Frameshift Variant (c.5769delG) In MYH7 Gene

Background: the genetic basis of hypertrophic cardiomyopathy is pleiotropic; A novel disease causing frameshift variant (c.5769delG, MYH7 ) in the beta-myosin heavy chain gene has been recently described. However, the mechanisms involved have not been adequately defined. We have used iPSC-CMs to investigate the underlying mechanisms. Methods: We have generated patient-specific iPSCs from clinically and genetically defined HCM patients carrying the pathogenic variant (c.5769delG) (n=3) and compared them to iPSCs from healthy controls (n=3). Optical mapping of calcium transients and cell action potential were performed under different stimulation conditions. iPSC-CMs contractility was recorded via widefield microscopy. Gene and protein expression analyses were performed using RT-PCR, immunoblotting and immunocytochemistry. RNA sequencing data from patients’ myocardial tissues was analyzed to validate gene expression data from iPSC-CMs. Results: HCM iPSCs-CMs showed a significant decrease in calcium release duration (i.e., time to peak) with decrease in calcium transient amplitude, compared to controls. This was associated with an accelerated contraction and a decreased contraction amplitude. Nonetheless, action potential analysis showed no significant changes. Transcriptome analysis of iPSC-CMs and patients’ myocardial tissues showed a significant down regulation of SERCA/ATP2A2 , MYH6 and KCNIP2 . Conclusion: iPSC-CMs provided new insights of the pathogenic consequences of the novel variant in MYH7 gene on calcium handling and contractility. Key words: Hypertrophic Cardiomyopathy, Disease model, MYH7 , iPSC-CMs, Calcium Handling, Contractility.

Mutation in the beta-myosin heavy chain (β-MHC) gene of adult Bangladeshi patients with hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is the most prevalent genetic cardiomyopathy characterized by sudden cardiac death. HCM is caused by the mutation in several genes that encode sarcomere proteins. Beta-Myosin Heavy Chain (β-MHC) gene is the one of the most mutated genes responsible for HCM. Studies on mutation spectrum of β-MHC gene are lacking in the Asian population including Bangladeshi patients. This study was intended to mutational analysis of β-MHC gene in Bangladeshi HCM patients. A cross-sectional study was conducted for mutation analysis of the β-MHC gene on 70 Bengali Bangladeshi HCM probands using nextgeneration sequencing at the Genetic Research Lab of Bangabandhu Sheikh Mujib Medical University. Structural and functional impact of the mutations were further analyzed by in-silico process. Thirty-nine nucleotide variants were found in both exonic (36%, n= 14) and intronic regions (64%, n=25) of β-MHC gene. We found 14 missense mutations, including the p.Glu965Lys, p.Arg941Pro, p.Lys940Met, p.Glu935Lys, and p.Met922Lys that are associated with inherited HCM. Most variants were heterozygous and one homozygous (p.Val919Leu) was found. The variant with most evidence of causing the disease was p.Glu935Lys. Among the missense variants, nine were not noted in ClinVar, dbSNP, GenomeAD databases. These unreported variants located between myosin head and tail domains might be novel mutations for Bangladeshi population. We found nine novel variants in the β-MHC gene. Findings of this research will help to developing a genetic database of HCM for early diagnosis and proper management of HCM patients in Bangladesh.

Genetic Association of Beta-Myosin Heavy-Chain Gene (MYH7) with Cardiac Dysfunction.

Cardiac dysfunction accelerates the risk of heart failure, and its pathogenesis involves a complex interaction between genetic and environmental factors. Variations in myosin affect contractile abilities of cardiomyocytes and cause structural and functional abnormalities in myocardium. The study aims to find the association of MYH7 rs121913642 (c.1594 T>C) and rs121913645 (c.667G>A) variants with cardiac dysfunction in the Punjabi Pakistani population. Patients with heart failure (n = 232) and healthy controls (n = 205) were enrolled in this study. MYH7 variant genotyping was performed using tetra ARMS-PCR. MYH7 rs121913642 TC genotype was significantly more prevalent in the patient group (p < 0.001). However, MYH7 rs121913645 genotype frequencies were not significantly different between the patient and control groups (p < 0.666). Regression analysis also revealed that the rs121913642 C allele increases the risk of cardiac failure by ~2 [OR:1.98, CI: 1.31–2.98, p < 0.001] in comparison to the T allele. High levels of the cardiac enzymes cardiac troponin I (cTnI) and CK-MB were observed in patients. There was also an increase in total cholesterol, LDL cholesterol, and uric acid in patients compared to the healthy control group (p < 0.001). In conclusion, the MYH7 gene variant rs121913642 is genetically associated with cardiac dysfunction and involved in the pathogenesis of HF.

Új lehetőség a szisztolés szívelégtelenség (HFrEF) kezelésében: omecamtiv-mecarbil

Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiovascular disorder worldwide which exhibits considerable genetic heterogeneity. Widespread utilization of next-generation sequencing (NGS) in HCM has uncovered substantial genetic variation and highlighted the importance of a standardized approach to variant interpretation. According to this, accurate and consistent interpretation of sequence variants is essential for effective clinical care for individuals and their families with HCM. With this regard, the 2015 guidelines from the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) were widely applicable, but several elements lacked specificity for given genes or diseases. The latter guideline was adapted for the most frequent causative HCM gene, the beta myosin heavy chain gene (MYH7) by the ClinGen (Clinical Genome Resource) expert panel, the Inherited Cardiomyopathy Expert Panel. Due to the adaptation, the guideline became gene-specific, with general considerations which are widely adaptable for most of the causative genes in HCM. Based on the modified guideline, web-based interpretation algorithms have been developed which integrate data from population databases and define pathogenicity of different variants independent of the observer, therefore aiding standardized clinical interpretation of genetic testing. The latter approach serves as a basis for recommendation for genetic testing in the recent ACC/AHA HCM guideline published in 2020. The current review is meant to compile the latest advances in HCM genetic testing in clinical practice, while bringing into focus some of the ongoing challenges clinical geneticists are still facing. Although nowadays the interpretation of genetic findings is two steps closer to a more accurate approach due to gene adaptation and automatization, the multitude of putative causative genes have been once again reduced to the 8 sarcomere genes, a backward step.

Genetic diagnosis in hypertrophic cardiomyopathy: two steps forward, one step back

Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiovascular disorder worldwide which exhibits considerable genetic heterogeneity. Widespread utilization of next-generation sequencing (NGS) in HCM has uncovered substantial genetic variation and highlighted the importance of a standardized approach to variant interpretation. According to this, accurate and consistent interpretation of sequence variants is essential for effective clinical care for individuals and their families with HCM. With this regard, the 2015 guidelines from the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) were widely applicable, but several elements lacked specificity for given genes or diseases. The latter guideline was adapted for the most frequent causative HCM gene, the beta myosin heavy chain gene (MYH7) by the ClinGen (Clinical Genome Resource) expert panel, the Inherited Cardiomyopathy Expert Panel. Due to the adaptation, the guideline became gene-specific, with general considerations which are widely adaptable for most of the causative genes in HCM. Based on the modified guideline, web-based interpretation algorithms have been developed which integrate data from population databases and define pathogenicity of different variants independent of the observer, therefore aiding standardized clinical interpretation of genetic testing. The latter approach serves as a basis for recommendation for genetic testing in the recent ACC/AHA HCM guideline published in 2020. The current review is meant to compile the latest advances in HCM genetic testing in clinical practice, while bringing into focus some of the ongoing challenges clinical geneticists are still facing. Although nowadays the interpretation of genetic findings is two steps closer to a more accurate approach due to gene adaptation and automatization, the multitude of putative causative genes have been once again reduced to the 8 sarcomere genes, a backward step.

Screening of MYH7 gene mutation sites in hypertrophic cardiomyopathy and its significance.

Background:There have been few reports of mutations in the beta-myosin heavy chain (MYH7) gene in hypertrophic cardiomyopathy (HCM), which is associated with sudden cardiac death caused by HCM. This study aimed to screen the mutation sites in the sarcomeric gene MYH7 in Chinese patients with HCM. We also planned to analyze the pathogenicity of the mutation site as well as its significance in clinical and forensic medicine.Methods:From January 2006 to June 2017, autopsy cases were collected from the Department of Pathology, the Affiliated Hospital of Qingdao University. The experiment was to detect MYH7 gene status in formalin-fixed paraffin-embedded tissues from 18 independent autopsy cases who suffered HCM related sudden death (fatal HCM) and 20 cases without cardiomyopathy. Common mutation exon fragments of MYH7 gene were amplified by polymerase chain reaction. The end-of-deoxygenation method and gene cloning method were further performed to analyze the mutation sites. Homologous comparison among mutant sites was conducted using BLAST online database.Results:The 1336th nucleotide of MYH7 gene at exon 14 was converted from T to G in one HCM case, resulting in the conversion of threonine (Thr) at position 446 to proline (Pro). In another case, the 1402th nucleotide at exon 14 was converted from T to C, resulting in the conversion of phenylalanine (Phe) at position 468 to leucine (Leu). Homologous comparison results showed that the two amino acid residues of Thr446 and Phe468 are highly conserved among different species.Conclusions:Our results showed fatal HCM harbored mutations of Thr446Pro and Phe468Leu in the MYH7 gene. It is significant for clinical and forensic medicine to further explore the functions and detailed mechanisms of these mutations.

Effects of the loss of estrogen on the heart's hypertrophic response to chronic left ventricle volume overload in rats.

Aortic valve regurgitation (AR) can result in heart failure from chronic overloading of the left ventricle (LV). Little is known of the role of estrogens in the LV responses to this condition. The aim of the study was to compare LV remodeling in female rats with severe AR in absence of estrogens by ovariectomy (Ovx). In a first study, we investigated over 6 months the development of hypertrophy in four groups of female Wistar rats: AR or sham-operated (sham) and Ovx or not. Ovx reduced normal heart growth. As expected, volume overload (VO) from AR resulted in significant LV dilation (42% and 32% increase LV end-diastolic diameter in intact and Ovx groups vs. their respective sham group; p < 0.0001). LV weight was also significantly and similarly increased in both AR groups (non-Ovx and Ovx). Increase in stroke volume or cardiac output and loss of systolic function were similar between AR intact and AR Ovx groups compared to sham. We then investigated what were the effects of 17beta-estradiol (E2; 0.03 mg/kg/day) treatment on the parameters studied in Ovx rats. Ovx reduced uterus weight by 85% and E2 treatment restored up to 65% of the normal weight. E2 also helped normalize heart size to normal values. On the other hand, it did not influence the extent of the hypertrophic response to AR. In fact, E2 treatment further reduced LV hypertrophy in AR Ovx rats (41% over Sham Ovx + E2). Systolic and diastolic functions parameters in AR Ovx + E2 were similar to intact AR animals. Ovx in sham rats had a significant effect on the LV gene expression of several hypertrophy markers. Atrial natriuretic peptide (Nppa) gene expression was reduced by Ovx in sham-operated females whereas brain natriuretic peptide (Nppb) expression was increased. Alpha (Myh6) and beta (Myh7) myosin heavy chain genes were also significantly modulated by Ovx in sham females. In AR rats, LV expression of both Nppa and Nppb genes were increased as expected. Ovx further increased it of AR rats for Nppa and did the opposite for Nppb. Interestingly, AR in Ovx rats had only minimal effects on Myh6 and Myh7 genes whereas they were modulated as expected for intact AR animals. In summary, loss of estrogens by Ovx in AR rats was not accompanied by a worsening of hypertrophy or cardiac function. Normal cardiac growth was reduced by Ovx in sham females but not the hypertrophic response to AR. On the other hand, Ovx had important effects on LV gene expression both in sham and AR female rats.

Genotypic and Phenotypic Correlation Regarding Expression Level of Myosin Heavy Chain (Myh7) Gene Polymorphisms in Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy (HCM), where it can be seen as unexplained left ventricular hypertrophy, is the most common inherited cardiac disorder. This condition is a major cause of sudden death. The clinical phenotype is heterogeneous, and mutations in a number of sarcomeric contractile protein genes are responsible for causing HCM, which is usually inherited as an autosomal dominant trait. The mode of inheritance can differ from those of HCM caused by mutations in sarcomere genes. Detailed clinical evaluation and mutation analysis are, therefore, important in providing an accurate diagnosis in order to enable genetic counseling, prognostic evaluation and appropriate clinical management. This Review summarizes current knowledge on the genetics regarding beta myosin heavy chain gene (MYH7), disease mechanisms, and correlations between phenotype and genotype in patients with HCM.

Effects of increased myocardial tissue concentration of myristic, palmitic and palmitoleic acids on the course of cardiac atrophy of the failing heart unloaded by heterotopic transplantation.

The present experiments were performed to evaluate if increased heart tissue concentration of fatty acids, specifically myristic, palmitic and palmitoleic acids that are believed to promote physiological heart growth, can attenuate the progression of unloading-induced cardiac atrophy in rats with healthy and failing hearts. Heterotopic abdominal heart transplantation (HT(x)) was used as a model for heart unloading. Cardiac atrophy was assessed from the ratio of the native- to-transplanted heart weight (HW). The degree of cardiac atrophy after HT(x) was determined on days 7, 14, 21 and 28 after HT(x) in recipients of either healthy or failing hearts. HT(x) of healthy hearts resulted in 23+/-3, 46+/-3, 48+/-4 and 46+/-4 % HW loss at the four time-points. HT(x) of the failing heart resulted in even greater HW losses, of 46+/-4, 58+/-3, 66+/-2 and 68+/-4 %, respectively (P<0.05). Activation of "fetal gene cardiac program" (e.g. beta myosin heavy chain gene expression) and "genes reflecting cardiac remodeling" (e.g. atrial natriuretic peptide gene expression) after HT(x) was greater in failing than in healthy hearts (P<0.05 each time). Exposure to isocaloric high sugar diet caused significant increases in fatty acid concentrations in healthy and in failing hearts. However, these increases were not associated with any change in the course of cardiac atrophy, similarly in healthy and post-HT(x) failing hearts. We conclude that increasing heart tissue concentrations of the fatty acids allegedly involved in heart growth does not attenuate the unloading-induced cardiac atrophy.

Hypoxia favors myosin heavy chain beta gene expression in an Hif-1alpha-dependent manner

The potentiation of the naturally limited regenerative capacity of the heart is dependent on an understanding of the mechanisms that are activated in response to pathological conditions such as hypoxia. Under these conditions, the expression of genes suggested to support cardiomyocyte survival and heart adaptation is triggered. Particularly important are changes in the expression of myosin heavy chain (MHC) isoforms. We propose here that alterations in the expression profiles of MHC genes are induced in response to hypoxia and are primarily mediated by hypoxia inducible factor (HIF). In in vitro models of mouse embryonic stem cell-derived cardiomyocytes, we showed that hypoxia (1% O2) or the pharmacological stabilization of HIFs significantly increased MHCbeta (Myh7) gene expression. The key role of HIF-1alpha is supported by the absence of these effects in HIF-1alpha-deficient cells, even in the presence of HIF-2alpha. Interestingly, ChIP analysis did not confirm the direct interaction of HIF-1alpha with putative HIF response elements predicted in the MHCalpha and beta encoding DNA region. Further analyses showed the significant effect of the mTOR signaling inhibitor rapamycin in inducing Myh7 expression and a hypoxia-triggered reduction in the levels of antisense RNA transcripts associated with the Myh7 gene locus. Overall, the recognized and important role of HIF in the regulation of heart regenerative processes could be highly significant for the development of novel therapeutic interventions in heart failure.

Modified Low-Dose Triiodo-L-thyronine Therapy Safely Improves Function Following Myocardial Ischemia-Reperfusion Injury

Background: We have shown that thyroid hormones (THs) are cardioprotective and can be potentially used as safe therapeutic agents for diabetic cardiomyopathy and permanent infarction. However, no reliable, clinically translatable protocol exists for TH treatment of myocardial ischemia-reperfusion (IR) injury. We hypothesized that modified low-dose triiodo-L-thyronine (T3) therapy would confer safe therapeutic benefits against IR injury.Methods: Adult female rats underwent left coronary artery ligation for 60 min or sham surgeries. At 2 months following surgery and T3 treatment (described below), the rats were subjected to functional, morphological, and molecular examination.Results: Following surgery, the rats were treated with T3 (8 μg/kg/day) or vehicle in drinking water ad libitum following IR for 2 months. Oral T3 significantly improved left ventricular (LV) contractility, relaxation, and relaxation time constant, and decreased beta-myosin heavy chain gene expression. As it takes rats ~6 h post-surgery to begin drinking water, we then investigated whether modified T3 dosing initiated immediately upon reperfusion confers additional improvement. We injected an intraperitoneal bolus of T3 (12 μg/kg) upon reperfusion, along with low-dose oral T3 (4.5 μg/kg/day) in drinking water for 2 months. Continuous T3 therapy (bolus + low-dose oral) enhanced LV contractility compared with oral T3 alone. Relaxation parameters were also improved compared to vehicle. Importantly, these were accomplished without significant increases in hypertrophy, serum free T3 levels, or blood pressure.Conclusions: This is the first study to provide a safe cardiac therapeutic window and optimized, clinically translatable treatment-monitoring protocol for myocardial IR using commercially available and inexpensive T3. Low-dose oral T3 therapy supplemented with bolus treatment initiated upon reperfusion is safer and more efficacious.

Generation of induced pluripotent stem cells (iPSCs) from a hypertrophic cardiomyopathy patient with the pathogenic variant p.Val698Ala in beta-myosin heavy chain (MYH7) gene

Induced pluripotent stem cells (iPSCs) were generated from peripheral blood mononuclear cells (PBMCs) isolated from the whole blood of a 43-year-old male with hypertrophic cardiomyopathy (HCM) who carries the pathogenic variant p.Val698Ala in beta-myosin heavy chain (MYH7). Patient-derived PBMCs were reprogrammed using non-integrative episomal vectors containing reprogramming factors OCT4, SOX2, LIN28, KLF4 and L-MYC. iPSCs were shown to express pluripotent markers, have trilineage differentiation potential, carry the pathogenic MYH7 variant p.Val698Ala, have a normal karyotype and no longer carry the episomal reprogramming vector. This line is useful for studying the link between variants in MYH7 and the pathogenesis of HCM.

The structural effects of mutations can aid in differential phenotype prediction of beta-myosin heavy chain (Myosin-7) missense variants.

High-throughput sequencing platforms are increasingly used to screen patients with genetic disease for pathogenic mutations, but prediction of the effects of mutations remains challenging. Previously we developed SAAPdap (Single Amino Acid Polymorphism Data Analysis Pipeline) and SAAPpred (Single Amino Acid Polymorphism Predictor) that use a combination of rule-based structural measures to predict whether a missense genetic variant is pathogenic. Here we investigate whether the same methodology can be used to develop a differential phenotype predictor, which, once a mutation has been predicted as pathogenic, is able to distinguish between phenotypes-in this case the two major clinical phenotypes (hypertrophic cardiomyopathy, HCM and dilated cardiomyopathy, DCM) associated with mutations in the beta-myosin heavy chain (MYH7) gene product (Myosin-7). A random forest predictor trained on rule-based structural analyses together with structural clustering data gave a Matthews' correlation coefficient (MCC) of 0.53 (accuracy, 75%). A post hoc removal of machine learning models that performed particularly badly, increased the performance (MCC = 0.61, Acc = 79%). This proof of concept suggests that methods used for pathogenicity prediction can be extended for use in differential phenotype prediction. Analyses were implemented in Perl and C and used the Java-based Weka machine learning environment. Please contact the authors for availability. andrew@bioinf.org.uk or andrew.martin@ucl.ac.uk Supplementary data are available at Bioinformatics online.

Carfilzomib-induced cardiotoxicity mitigated by dexrazoxane through inhibition of hypertrophic gene expression and oxidative stress in rats

Carfilzomib (CFZ) is an inhibitor of proteasome that is generally used in the treatment of multiple myeloma but due to its cardiotoxicity clinical use may be limited. Dexrazoxane (DZR), an inhibitor of topoisomerase-II, prevents cardiac damage by reducing the formation of reactive oxygen species and hypertrophic gene expression. This study evaluated the protective effect of DZR on CFZ-induced cardiotoxicity. Thirty-two male Albino rats were randomly divided into four groups (n = 8). Group I received DMSO, Group II received CFZ (4 mg/kg, intraperitoneally [i.p.]) twice weekly up to day 16, Group III received DZR (20 mg/kg, i.p.) for 16 days and CFZ twice weekly for 16, Group IV received DZR (40 mg/kg, i.p.) for 16 days and CFZ twice weekly for 16. CFZ-induced cardiotoxicity was assessed by hematological, biochemical, mRNA expression, oxidative stress and histopathological studies. CFZ-induced significant changes have been observed in blood parameters including red blood cells, white blood cells, hemoglobin and hematocrit concentrations which were associated with increase in cardiac enzymes markers like creatine kinase (CK), CK-MB and lactate dehydrogenase. Treatment with DZR reversed the hematological statistics and the biochemical markers of CFZ-induced cardiotoxicity. Furthermore, DZR also attenuated the effects of CFZ-induced toxic effect on redox markers such as malondialdehyde and reduced glutathione. Above findings were further confirmed by beta-myosin heavy chain (β-MHC) and alpha-MHC (α-MHC) gene expression. Histopathological reports suggested that DZR ameliorates CFZ-induced changes in cardiac cellular architecture in rats. These results confirm that DZR protects heart from CFZ-induced cardiotoxicity.

Abstract 20016: Genetic Anticipation in Familial Hypertrophic Cardiomyopathy

Introduction: To identify HCM at the earliest time possible, estimating the onset of disease based on diagnostic criteria is vital in timing the initiation of screening and interventions. Hypothesis: Clinic observations indicate an early diagnose of HCM in second generation of most affected families. From the pedigrees with or without mutations in beta-myosin heavy chain gene (MYH7) affected in two or more generations with hypertrophic cardiomyopathy (HCM), ages and maximal wall thickness (MWT) of left ventricles at diagnosis were evaluated to investigate the potential genetic anticipation in patients with familiar HCM (FHCM). Methods: 56 individuals from 25 families were analyzed. Linear mixed effects models were adopted to prevent misinterpretation resulting from the cohort effect. Published data containing 9 sarcomere mutations (181 individuals in 52 families) also were extracted. Results: MYH7 mutations were detected in 9 of the 25 probands, The median age of HCM diagnosis was 24 in the younger generation and 55 in the older (p &lt; 0.001). In the parametric model, the estimated change in the expected age at diagnosis for the entire cohort was 25.8 years (p &lt;0.001). Statistically significant earlier ages at diagnoses were also observed within subgroups of MYH7+ and MYH7- mutations, and probands older and younger than 30 years old. Although the estimated change in MWT at diagnosis for the entire cohort was only 2.161 mm (p =0.212), the subgroup of probands in the younger generation aged less than 30 years had 10.393 mm (p=0.018) thicker MWT and showed a significant reverse correlation with age. Analysis of published data also supports these findings. Conclusions: Genetic anticipation was observed in patients with FHCM. FHCM is prone to be diagnosed at an earlier age in younger generations. Patients who are younger with relatives affected by HCM, especially those who are diagnosed before 30 years of age, should continue to be tracked to offer appropriate screening modalities as earlier as possible.

GW26-e1369 Noval Arg1114Cys, Glu1142Lys mutations in beta myosin heavy chain gene in Chinese pedigrees with familial hypertrophic cardiomyopathy

GW26-e1369 Noval Arg1114Cys, Glu1142Lys mutations in beta myosin heavy chain gene in Chinese pedigrees with familial hypertrophic cardiomyopathy

GW26-e2376 Genetic anticipation in familial hypertrophic cardiomyopathy

From the pedigrees of families with or without mutations in beta-myosin heavy chain gene (MYH7) afflicted in two or more generations with hypertrophic cardiomyopathy (HCM), age and maximal wall thickness (MWT) of left ventricle at diagnoses were evaluated to investigate the patterns of inheritance

A rare mutation in MYH7 gene occurs with overlapping phenotype

Mutations in the beta-myosin heavy chain gene (MYH7) cause different muscle disorders. The specific molecular pathobiological processes that cause these different phenotypes remains unexplained. We describe three members of a family with an autosomal dominant mutation in the distal rod of MYH7 [c.5401G> A (p.Glu1801Lys)] displaying a complex phenotype characterized by Laing Distal Myopathy like phenotype, left ventricular non compaction cardiomyopathy and Fiber Type Disproportion picture at muscle biopsy. We suggest that this overlapping presentation confirm the phenotypic variability of MYH7 myopathy and may be helpful to improve the genotype phenotype correlation.