Mutations In Sarcomeric Genes Research Articles

Proteomic and Functional Studies Reveal Detyrosinated Tubulin as Treatment Target in Sarcomere Mutation-Induced Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is the most common genetic heart disease. While ≈50% of patients with HCM carry a sarcomere gene mutation (sarcomere mutation-positive, HCMSMP), the genetic background is unknown in the other half of the patients (sarcomere mutation-negative, HCMSMN). Genotype-specific differences have been reported in cardiac function. Moreover, HCMSMN patients have later disease onset and a better prognosis than HCMSMP patients. To define if genotype-specific derailments at the protein level may explain the heterogeneity in disease development, we performed a proteomic analysis in cardiac tissue from a clinically well-phenotyped HCM patient group. A proteomics screen was performed in cardiac tissue from 39 HCMSMP patients, 11HCMSMN patients, and 8 nonfailing controls. Patients with HCM had obstructive cardiomyopathy with left ventricular outflow tract obstruction and diastolic dysfunction. A novel MYBPC32373insG mouse model was used to confirm functional relevance of our proteomic findings. In all HCM patient samples, we found lower levels of metabolic pathway proteins and higher levels of extracellular matrix proteins. Levels of total and detyrosinated α-tubulin were markedly higher in HCMSMP than in HCMSMN and controls. Higher tubulin detyrosination was also found in 2 unrelated MYBPC3 mouse models and its inhibition with parthenolide normalized contraction and relaxation time of isolated cardiomyocytes. Our findings indicate that microtubules and especially its detyrosination contribute to the pathomechanism of patients with HCMSMP. This is of clinical importance since it represents a potential treatment target to improve cardiac function in patients with HCMSMP, whereas a beneficial effect may be limited in patients with HCMSMN.

Cardiac and renal protective effects of 2,5-dimethylcelecoxib in angiotensin II and high-salt-induced hypertension model mice.

We reported that 2,5-dimethylcelecoxib (DM-celecoxib), a celecoxib derivative that is unable to inhibit cyclooxygenase-2, prevented cardiac remodeling induced by sarcomeric gene mutation, left ventricular pressure overload, or β-adrenergic receptor stimulation. This effect seemed to be mediated by the inhibition of the canonical Wnt/β-catenin signaling pathway, which has been suggested to play a key role in the development of chronic kidney disease and chronic heart failure. We investigated the effect of DM-celecoxib on cardiac remodeling and kidney injury in hypertension model mice induced by angiotensin II infusion in the absence or presence of high-salt load. DM-celecoxib prevented cardiac remodeling and markedly reduced urinary albumin excretion without altering blood pressure in those mice. Moreover, DM-celecoxib prevented podocyte injury, glomerulosclerosis, and interstitial fibrosis in the kidney of mice loaded with angiotensin II and high-salt load. DM-celecoxib reduced the phosphorylation level of Akt and activated glycogen synthase kinase-3, which led to the suppression of the Wnt/β-catenin signal in the heart and kidney. DM-celecoxib also reduced the expression level of snail, a key transcription factor for the epithelial-mesenchymal transition and of which gene is a target of the Wnt/β-catenin signal. Results of the current study suggested that DM-celecoxib could be beneficial for patients with hypertensive heart and kidney diseases.

Abstract 16702: Myocardial Deformation Analysis in Hypertrophic Cardiomyopathy With Sarcomere Mutations: Insights From 2,221 Patients Within the NHLBI-HCM Registry

Introduction: Hypertrophic cardiomyopathy (HCM) is caused by mutations in sarcomere genes that alter myocardial contractility and relaxation. Three-dimensional myocardial deformation analysis (3D-MDA) may elucidate left ventricular (LV) abnormalities associated with sarcomere genotype status. Hypothesis: We hypothesize that HCM patients with sarcomere mutations have changes in myocardial contractility profiles that are associated with adverse LV architectural changes. Methods: 3D-MDA was measured using validated feature-tracking software applied to 2D cine cardiac MRI studies in 2,221 genotyped patients within the NHLBI HCM Registry. Results: Baseline, cardiac MRI, and 3D MDA-derived strain characteristics stratified by sarcomere status are shown in Table 1. Sarcomere positive patients were younger, had less LV outflow tract obstruction and lower indexed LV mass, but similar LVEF and trend towards higher serum NT-proBNP levels. Maximal wall thickness, measures of diffuse myocardial fibrosis (native T1, extracellular volume fraction) were elevated with corresponding reduction in global radial strain. Global minimum principal and epicardial layer conventional strain values were higher in sarcomere positive patients. Epicardial minimum principal strain was highly correlated with indexed LV mass (r=0.42, P<0.0001), maximal wall thickness (r=0.29, P<0.0001), LVEF (r=-0.33, P<0.0001), late gadolinium enhancement (r=0.22, P<0.0001) and NT-proBNP (r=0.21, P<0.0001) levels in those with sarcomere mutations. Conclusions: Sarcomere positive HCM patients had differences in myocardial deformation strain profiles that were correlated to LV architectural changes and NT-proBNP levels despite lower indexed LV mass. More sensitive measures of contractile dysfunction may help elucidate pathophysiological mechanisms by which sarcomere mutations cause disease progression and adverse clinical outcomes in HCM.

Abstract 16683: Profiling Cardiac Inflammation and Molecular Changes During the Transition of Hypertrophic to Dilated Cardiomyopathy

Introduction: Hypertrophic cardiomyopathy (HCM) is a disease caused primarily by sarcomere gene mutations [like myosin-binding protein C3 ( MYBPC3 )], with several distinct phenotypes. Tissue-level inflammation has been reported in human HCM, tissue-specific neutrophil subsets, and their dysregulation cause inflammatory myopathies, and neutrophil extracellular traps (NETs) are associated with cardiac fibrosis in aged rodents. However, the mechanism(s) responsible for the broad phenotypic variability and changes observed over time transitioning from HCM to dilated cardiomyopathy (DCM) has not yet been elucidated. Objective: To determine the cardiac inflammatory signature of HCM and transition from HCM to DCM and its relationship to fibrosis and ventricular remodeling in an established MYBPC3 ( cMyBP-C t/t ) mouse model. Method and Results: Mixed-gender cMyBP-C +/+ (WT) and mutant mice ( cMyBP-C t/t ) underwent echocardiography and were euthanized at one, two and three months of age (n=8) and blood and hearts were harvested. Echocardiography and histopathology examination confirmed significant heart dysfunction and tissue remodeling in cMyBP-C t/t mice showing cardiac hypertrophy at one month of age (Left ventricular (LV) posterior wall systole 1.20 ±0.39 vs 1.51±0.49 and LV posterior wall diastole 0.96 ±0.22 vs 1.38 ±0.36 mm; * p<0.05 ), and DCM phenotype (LV internal diameter systole 2.40 ±0.41 vs 3.67 ±0.25 and LV internal diameter diastole 3.44 ±0.29 vs 4.30 ±0.39 mm; * p<0.05 ) along with myofibrillar loss and increased cardiac fibrosis at three months. Interestingly, LV dysfunction and hypertrophy resulted in a time-dependent increase in the activation of coagulation, as measured by plasma microvesicle tissue factor activity, thrombin antithrombin, and D-dimer. In silico analysis of RNA-Seq data from 3-months old cMyBP-C t/t mice heart revealed key genes and pathways associated with HCM, DCM, tissue remodeling, renin-angiotensin-aldosterone signaling, fibrosis, apoptosis, NETosis, and inflammation. Conclusions: The transition from HCM to a DCM phenotype involves proinflammatory and profibrotic signaling. Therapies directed at tissue-specific inflammation and NETs may be a novel and impactful strategy for HCM.

Non-compaction cardiomyopathy: genetic and clinical features, 5-years outcomes

Abstract Presence of morphological sign as a left ventricular non-compaction (LVNC) only, without supporting clinical criteria, does not determine diagnosis of non-compaction cardiomyopathy (NCCM). Objective To study of the spectrum of NCCM-associated genes, analysis of phenotype-genotype correlations and predictors of life-threatening ventricular tachyarrhythmia (ltVTA), myocardial fibrosis, and adverse outcome. Methods Of 93 pts with identified (Echo/MRI) morphological criteria for LVNC (follow-up median 5,1 years), 60 unrelated pts were included in the study (aged 38.5±13.8 years; 33/55% male; LVEF 42.1±12.9%) with clinical confirmed NCCM (presence any one obligate criteria): family history, neuromuscular disorder, abnormal 12-lead ECG, arrhythmia, HF or thromboembolism (Figure). Genetic testing by NGS (174 genes) was performed; all variants considered as pathogenic (PV) and likely pathogenic (LPV) were confirmed by a Sanger sequencing. Baseline and follow-up data (ECG, HM, Echo, MRI, device interrogation) were collected. Combined adverse outcomes (HF death; SCD; LVAD; HTx; and ltVTA: VT/VF, successful resuscitation, ICD shock) were accepted as composite endpoint. Results PV and LPV were detected in 33 (55%) pts. The most common variants were identified in sarcomere genes – TTNtv, MYBPC3, and MYH7 (47.4%); ion channel genes – 18.2%; digenic mutations were found in 21.6% pts. Gene positivity was associated with systolic dysfunction (LVEF≤49%); the highest risk of low LVEF revealed for digenic carriers (OR 38; 95% CI 4.74–305; p=0.0001). According to CATREG analysis, predictive model was built (R=0,80; R2=0,65; F=10,1; p=0,0001); the presence of disease-causing PV/LPV (β=0.46; F=15.2; p=0,0001) along with low LVEF (β=−0.28; F= 5.96; p=0,018), fibrosis (β=0.21; F= 3.05; p=0,037), wide QRS (β=0.22; F= 4.11; p=0,011) were identified as independent predictors of adverse outcomes. As a result of ROC analysis, independent predictors of ltVTA were determined: fibrosis (nLGE≥2: AUC 0.824; 95% CI: 0.716–0.931; p=0.0001; sen 69%, spe 79%), systolic dysfunction (LVEF≤39%: AUC 0.832; 95% CI: 0.720–0.943; p=0.0001; sen 85%, spe 70%) and nsVT (HR≥150 bmp: AUC 0.829; 95% CI: 0.719–0.940; p=0.0001; sen 76%, spe 83%). According to ROC curves analysis, independent markers of myocardial fibrosis (LGE) were found: nsVT (HR≥150 bpm: AUC 0.766; 95% CI: 0.635–0.897; sen 80%, spe 77%); QRS fragmentation (nQRSfr≥4 leads ECG: AUC 0.822; 95% CI: 0.706–0.938; sen 76%, spe 92%); QTc duration (QTc≥450 ms: AUC 0.828; 95% CI: 0.722–0.935; sen 80%, spe 72%) and native MRI T1-relaxation (T1≥1086 ms: AUC 0.752; 95% CI: 0.626–0.879; sen 70%, spe 70%). Conclusion This results show a basically genetic causing NCCM with predominant mutations in sarcomere genes. As per predictive model, the strongest predictor of poor outcome was gene positivity. Identifying the genetic cause allows risk stratification and management optimization with counseling NCCM pts and their relatives. Study design Funding Acknowledgement Type of funding source: None

Arrhythmic phenotypes in patients with left ventricular non-compaction cardiomyopathy

Abstract Background Identification of pts with left ventricular non-compaction cardiomyopathy (NCCM) at high risk of life-threatening arrhythmic events is focused on clinical and instrumental criteria. The genetic component is not taken into account when deciding on a strategy for preventive measures. Purpose To analyze life-threatening arrhythmic events in pts with the arrhythmic variant of NCCM and to identify genetic factors that may increase the risk of life-threatening arrhythmic events. Methods The study included 159 pts, among whom 58 had malignant ventricular arrhythmias (mean age 43.54±11.95 years, 34/24/58.6% male). The NCCM criteria were confirmed using Echocardiography and CMR. Mutation search was carried out by the next generation sequencing (NGS) in 21 pts with nonsustained ventricular tachycardia (NVT). Results During the follow-up period (median follow-up of 36 months), life-threatening arrhythmic events (documented sustained VT, SCD with successful resuscitation and CD implantation, SCD) were registered in 29 pts (50%), and 10 pts had CD implanted. As a result of sequencing, 23.8% (5 out of 21) of pts with NVT revealed rare genetic variants with uncertain clinical significance (VUS) in 3 genes encoding ion channel proteins: KCNQ1, KCNH2 (9.5%), RYR2 (9.5%). In 9 (42.9%) pts, 10 identified mutations were localized in the genes responsible for the synthesis of sarcomeric proteins: MYBPC3 (23.8%), MYH7 (23.8%). 12 genetic variants were found in overlapping phenotypes between NCCM, ARVC and DCM: PKP2, DSP, PLN, TRPM4 (14.3%), RBM20, LDB3 (9.5%), DPP6, DTNA, NEXN in 11 (52.4%) pts. In this group of pts, the most common (81.8% of cases) were life-threatening arrhythmic events that required surgical intervention: 6 pts were implanted with CD for primary prevention of SCD, two pts - CRT-D, two pts with systolic dysfunction were performed with OHT and one patient was implanted with the Accucinch transcatheter direct mitral valve annuloplasty system. In pts with mutations in sarcomeric protein genes, CD was implanted in 4.7% of cases, and in 14.3% of pts with mutations in ion channel genes (p<0.01). Conclusion The presence of mutations in genes that control the functioning of ion channels in complex overlapping genotypes is an additional risk factor for ventricular arrhythmias in patients with NCCM. Determining the genetic component opens up new opportunities for personalizing the risk stratification of pts with NCCM. Funding Acknowledgement Type of funding source: None

Novel FHL1 mutation variant identified in a patient with nonobstructive hypertrophic cardiomyopathy and myopathy \u2013 a case report

BackgroundHypertrophic cardiomyopathy (HCM) is a genetic disorder mostly caused by sarcomeric gene mutations, but almost 10% of cases are attributed to inherited metabolic and neuromuscular disorders. First described in 2008 in an American-Italian family with scapuloperoneal myopathy, FHL1 gene encodes four-and-a-half LIM domains 1 proteins which are involved in sarcomere formation, assembly and biomechanical stress sensing both in cardiac and skeletal muscle, and its mutations are responsible for a large spectrum of neuromuscular disorders (mostly myopathies) and cardiac disease, represented by HCM, either isolated, or in conjunction with neurologic and skeletal muscle impairment. We thereby report a novel mutation variant in FHL1 structure, associated with HCM and type 6 Emery-Dreifuss muscular dystrophy (EDMD).Case presentationWe describe the case of a 40 year old male patient, who was referred to our department for evaluation in the setting of NYHA II heart failure symptoms and was found to have HCM. The elevated muscular enzymes raised the suspicion of a neuromuscular disease. Rigid low spine and wasting of deltoidus, supraspinatus, infraspinatus and calf muscles were described by the neurological examination. Electromyography and muscle biopsy found evidence of chronic myopathy. Diagnosis work-up was completed by next-generation sequencing genetic testing which found a likely pathogenic mutation in the FHL1 gene (c.157-1G > A, hemizygous) involved in the development of X-linked EDMD type 6.ConclusionThis case report highlights the importance of multimodality diagnostic approach in a patient with a neuromuscular disorder and associated hypertrophic cardiomyopathy by identifying a novel mutation variant in FHL1 gene. Raising awareness of non-sarcomeric gene mutations which can lead to HCM is fundamental, because of diagnostic and clinical risk stratification challenges.

Preventative therapeutic approaches for hypertrophic cardiomyopathy.

Sarcomeric gene mutations are associated with the development of hypertrophic cardiomyopathy (HCM). Current drug therapeutics for HCM patients are effective in relieving symptoms, but do not prevent or reverse disease progression. Moreover, due to heterogeneity in the clinical manifestations of the disease, patients experience variable outcomes in response to therapeutics. Mechanistically, alterations in calcium handling, sarcomeric disorganization, energy metabolism and contractility participate in HCM disease progression. While some similarities exist, each mutation appears to lead to mutation‐specific pathophysiology. Furthermore, these alterations may precede or proceed development of the pathology. This review assesses the efficacy of HCM therapeutics from studies performed in animal models of HCM and human clinical trials. Evidence suggests that a preventative rather than corrective therapeutic approach may be more efficacious in the treatment of HCM. In addition, a clear understanding of mutation‐specific mechanisms may assist in informing the most effective therapeutic mode of action.

Molecular Basis of Inflammation in the Pathogenesis of Cardiomyopathies.

Cardiomyopathies (CMPs) represent a diverse group of heart muscle diseases, grouped into specific morphological and functional phenotypes. CMPs are associated with mutations in sarcomeric and non-sarcomeric genes, with several suspected epigenetic and environmental mechanisms involved in determining penetrance and expressivity. The understanding of the underlying molecular mechanisms of myocardial diseases is fundamental to achieving a proper management and treatment of these disorders. Among these, inflammation seems to play an important role in the pathogenesis of CMPs. The aim of the present study is to review the current knowledge on the role of inflammation and the immune system activation in the pathogenesis of CMPs and to identify potential molecular targets for a tailored anti-inflammatory treatment.

Lifelong Clinical Impact of the Presence of Sarcomere Gene Mutation in Japanese Patients With Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is mainly caused by mutations in sarcomere genes. Regarding the clinical implications of genetic information, little is known about the lifelong clinical effect of sarcomere mutations in Japanese HCM patients. We studied 211 consecutive Japanese patients with HCM who had agreed to genetic testing between 2003 and 2013. Genetic analyses were performed by direct DNA sequencing in the 6 common sarcomere genes (MYH7,MYBPC3,TNNT2,TNNI3,TPM1,ACTC). Through variant filtering, 21 mutations were identified in 67 patients. After excluding 8 patients whose variants were determined as having uncertain significance, finally 203 patients (130 men, age at study entry: 61.8±14.1 years) were investigated for clinical presentation and course. At the time of study entry, patients with mutations were younger, had more frequent non-sustained ventricular tachycardia, had greater interventricular wall thickness, were more frequently in the dilated phase and less frequently had apical HCM. Through their lifetimes, a total of 98 HCM-related morbid events occurred in 72 patients. Survival analysis revealed that patients with sarcomere gene mutations experienced those morbid events significantly more frequently, and this tendency was more prominent for lethal arrhythmic events. In our HCM cohort, patients with sarcomere gene mutations had poorer lifelong outcome. Genetic information is considered important for better management of HCM.

Abstract MP100: Scalable Functional Classification of Heart Failure-associated Genetic Variants in Cardiac Troponin T

Sarcomere gene mutations are the most common inheritable risk factor for heart failure, a disease with high morbidity and mortality, yet the pathogenicity of a large proportion of sarcomere gene variants remains unknown. The knowledge of which and how sarcomere gene variants result in heart failure would provide valuable prognostic and diagnostic information for individuals harboring sarcomere gene variants. Here, we developed a transgenic human cardiomyocyte model that enables scalable delivery of genetic variants in cardiac troponin T (cTnT; encoded by TNNT2 ), empowering high-throughput analysis of variant-specific sarcomere function. Using this model, in conjunction with CRISPR-derived isogenic standards and biomimetic cardiac tissues, we demonstrate that hypertrophic cardiomyopathy (HCM) variants in TNNT2 evoke elevated cardiac tissue contractile function, while dilated cardiomyopathy (DCM) variants produce decreased contractile function. RNA-seq revealed a transcriptional network that correlates with contractile function and identified NPPB expression as a molecular signature of contraction. Through the development of a cellular NPPB reporter, we functionally screen a panel of 51 TNNT2 variants, and provide molecular and tissue-level evidence for the functional reclassification of TNNT2 “variants of unknown significance” to pathogenic, and “pathogenic” variants to benign. Finally, adaption of this cellular reporter to assess variant calcium sensitivity, together with analysis of myofilament-localized calcium transients, demonstrates a parallel between contractile function and calcium sensitivity in human cardiomyocytes. This study establishes a new tool to study sarcomere genetic variants at scale, reclassifies the pathogenicity of previously-identified TNNT2 variants, and provides new insights into the cellular pathogenesis of human heart failure.

A novel homozygous TPM1 mutation in familial pediatric hypertrophic cardiomyopathy and in silico screening of potential targeting drugs.

Familial hypertrophic cardiomyopathy (HCM) is the most common genetic cardiac disease. While sarcomeric gene mutations explain many HCM cases, the genetic basis of about half of HCM cases remains elusive. Here we aimed to identify the gene causing HCM in a non-consanguineous Saudi Arabian family with affected family members and a history of sudden death. The impact of the identified mutation on protein structure and potential drug targets were evaluated in silico. Triplets (two HCM subjects and one patent ductus arteriosus (PDA) case) and unaffected parents were screened by targeted next-generation sequencing (NGS) for 181 candidate cardiomyopathy genes. In silico structural and functional analyses, including protein modeling, structure prediction, drug screening, drug binding, and dynamic simulations were performed to explore the potential pathogenicity of the variant and to identify candidate drugs. A homozygous missense mutation in exon 1 of TMP1 (assembly GRCh37-chr15: 63340781; G>A) was identified in the triplets [two HCM and one patent ductus arteriosus (PDA)] that substituted glycine for arginine at codon 3 (p.Gly3Arg). The parents were heterozygous for the variant. The mutation was predicted to cause a significant and deleterious change in the TPM1 protein structure that slightly affected drug binding, stability, and conformation. In addition, we identified several putative TPM1-targeting drugs through structure-based in silico screening. TPM1 mutations are a common cause of HCM and other congenital heart defects. To date, TPM1 has not been associated with isolated PDA; to our knowledge, this is the first report of the homozygous missense variation p.Gly3Arg in TPM1 associated with familial autosomal recessive pediatric HCM and PDA. The identified candidate TPM1 inhibitors warrant further prospective investigation.

Distal Arthrogryposis and Lethal Congenital Contracture Syndrome - An Overview.

Distal arthrogryposis (DA) is a skeletal muscle disorder which can be classified under a broader term as Arthrogryposis multiplex contractures. DA is characterized by the presence of joint contractures at various parts of the body, particularly in distal extremities. It is identified as an autosomal dominant and a rare X-linked recessive disorder associated with increased connective tissue formation around joints in such way that immobilizes muscle movement causing deformities. DA is again classified into various types since it manifests as a range of conditions representing different etiologies. Myopathy is one of the most commonly listed etiologies of DA. The mutations in sarcomeric protein-encoding genes lead to decreased sarcomere integrity, which is often associated with this disorder. Also, skeletal disorders are often associated with cardiac disorders. Some studies mention the presence of cardiomyopathy in patients with skeletal dysfunction. Therefore, it is hypothesized that the congenitally mutated protein that causes DA can also lead to cardiomyopathy. In this review, we will summarize the different forms of DA and their clinical features, along with gene mutations responsible for causing DA in its different forms. We will also examine reports that list mutations also known to cause heart disorders in the presence of DA.

Mitochondrial Energetics and Ca2+-Activated ATPase in Obstructive Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is the most common genetic disease of the myocardium associated to mutations in sarcomeric genes, but the link between genotype and phenotype remains poorly understood. Magnetic resonance spectroscopy studies have demonstrated impaired cardiac energetics in patients with HCM, and altered mitochondria were described in biopsies, but little is known about possible perturbations of mitochondrial function and adenosine triphosphate (ATP) production/consumption. The aim of this study was to investigate possible abnormalities in mitochondrial enzymes generating/scavenging reactive oxygen species, and changes in the Ca2+-activated ATPases in myocardial tissue from patients with obstructive HCM undergoing surgical myectomy compared to unused donor hearts (CTRL). Methods and Results: Both the amount and activity of mitochondrial Complex I (nicotinamide adenine dinucleotide -reduced form, NADH, dehydrogenase) were upregulated in HCM vs. CTRL, whilst the activity of Complex V (ATP synthase) was not reduced and ATP levels were significantly higher in HCM vs. CTRL. Antioxidant Mn-activated superoxide dismutase (SOD2) and (m)-aconitase activities were increased in HCM vs. CTRL. The Cu/Zn-activated superoxide dismutase (SOD1) amount and mtDNA copy number were unaltered in HCM. Total Ca2+-activated ATPase activity and absolute amount were not different HCM vs. CTRL, but the ratio between ATPase sarcoplasmic/endoplasmic reticulum Ca2+ transporting type 2 (ATP2A2) and type 1 (ATP2A1), ATP2A2/ATP2A1, was increased in HCM in favor of the slow isoform (ATP2A2). Conclusion: HCM is characterized by mitochondrial Complex I hyperactivity and preserved Ca2+-activated ATPase activity with a partial switch towards slow ATP2A2. This data may give insight into the abnormal cellular energetics observed in HCM cardiomyopathy but other studies would need to be performed to confirm the observations described here.

MYH7B variants cause hypertrophic cardiomyopathy by activating the CaMK-signaling pathway.

Hypertrophic cardiomyopathy (HCM) is a common genetic disease, predominantly caused by mutations in cardiac sarcomere genes; however, whether MYH7B causes HCM is not known. In this study, 549 unrelated patients with HCM and 500 healthy-controls were screened using targeted sequencing and whole exome sequencing together. We observed seven variants in MYH7B causing HCM in 8/549 patients, which accounted for 1.46% of HCM cases. Of these seven variants, three likely pathogenic variants in MYH7B co-segregating with 5 HCM patients were identified in three HCM pedigrees without other HCM-associated variants. Myh7b knockout rats were generated and cardiac functions were detected by Millar pressure-volume catheterization and echocardiography. Spontaneous HCM phenotypes, cellular disarray and cardiac fibrosis were observed in both Myh7b+/-/Myh7b-/- rats. Transcriptome sequencing showed that calcium is the key mediator of cardiac hypertrophy in Myh7b knockout. Subsequent analysis confirmed over-activation of CaMK-signaling pathway in cardiomyocytes of Myh7b-/- rats. Furthermore, MYH7B expression in human and rat hearts was identified and microRNA-208a and microRNA-499 levels are unchanged in HCM patients and Myh7b+/-/Myh7b-/- rats. This study is the first to identifyMYH7B variants as cause of HCM, which account for 1.46% of pathogenesisin HCM patients. Activation of CaMK-signaling pathway may be involved in its pathophysiology.

Sarcomeric Gene Variants and Their Role with Left Ventricular Dysfunction in Background of Coronary Artery Disease.

Cardiovascular diseases are one of the leading causes of death in developing countries, generally originating as coronary artery disease (CAD) or hypertension. In later stages, many CAD patients develop left ventricle dysfunction (LVD). Left ventricular ejection fraction (LVEF) is the most prevalent prognostic factor in CAD patients. LVD is a complex multifactorial condition in which the left ventricle of the heart becomes functionally impaired. Various genetic studies have correlated LVD with dilated cardiomyopathy (DCM). In recent years, enormous progress has been made in identifying the genetic causes of cardiac diseases, which has further led to a greater understanding of molecular mechanisms underlying each disease. This progress has increased the probability of establishing a specific genetic diagnosis, and thus providing new opportunities for practitioners, patients, and families to utilize this genetic information. A large number of mutations in sarcomeric genes have been discovered in cardiomyopathies. In this review, we will explore the role of the sarcomeric genes in LVD in CAD patients, which is a major cause of cardiac failure and results in heart failure.

Apical Hypertrophic Cardiomyopathy: The Variant Less Known.

Hypertrophic cardiomyopathy (HCM) is an umbrella term for a heterogeneous heart muscle disease that was historically (and still is) defined by the detection of left ventricular (LV) hypertrophy (LVH) in the absence of abnormal cardiac loading conditions. Long after this morphological definition was established, the genetic basis of HCM was discovered, and we now know it is predominantly caused by autosomal dominant mutations in sarcomeric protein genes.1 Several patterns of LVH have been described in HCM: asymmetric septal (here referred to as “classic” HCM), concentric, reverse septal, neutral, and apical (ApHCM),2 as well as other, rarer LVH variants such as isolated lateral LVH and isolated inferoseptal LVH. Distinguishing between morphological HCM subtypes has conferred little in terms of personalized management strategies, with one distinctive exception: ApHCM. Compared with classic HCM, ApHCM is more sporadic, sarcomere mutations are detected less frequently, there is more atrial fibrillation (AF) and sudden cardiac death (SCD) risk factors differ. No authoritative ApHCM‐specific recommendations to guide diagnosis, family screening, and patient risk stratification currently exist. First described in Japan in 1976,2 ApHCM is exemplified by “giant” negative precordial T‐waves on electrocardiography and by “spadelike” configuration of its LV cavity in end diastole.3 This review summarizes the epidemiology, clinical expression, genetics, and prognosis of ApHCM, while also highlighting knowledge gaps

Hypertrophic Cardiomyopathy: Diverse Pathophysiology Revealed by Genetic Research, Toward Future Therapy.

Hypertrophic cardiomyopathy (HCM) is an intractable disease that causes heart failure mainly due to unexplained severe cardiac hypertrophy and diastolic dysfunction. HCM, which occurs in 0.2% of the general population, is the most common cause of sudden cardiac death in young people. HCM has been studied extensively using molecular genetic approaches. Genes encoding cardiac β-myosin heavy chain, cardiac myosin-binding protein C, and troponin complex, which were originally identified as causative genes, were subsequently reported to be frequently implicated in HCM. Indeed, HCM has been considered a disease of sarcomere gene mutations. However, fewer than half of patients with HCM have mutations in sarcomere genes. The others have been documented to have mutations in cardiac proteins in various other locations, including the Z disc, sarcoplasmic reticulum, plasma membrane, nucleus, and mitochondria. Next-generation sequencing makes it possible to detect mutations at high throughput, and it has become increasingly common to identify multiple cardiomyopathy-causing gene mutations in a single HCM patient. Elucidating how mutations in different genes contribute to the disease pathophysiology will be a challenge. In studies using animal models, sarcomere mutations generally tend to increase myocardial Ca2+ sensitivity, and some mutations increase the activity of myosin ATPase. Clinical trials of drugs to treat HCM are ongoing, and further new therapies based on pathophysiological analyses of the causative genes are eagerly anticipated.

Clinical Classification of Arrhythmogenic Right Ventricular Cardiomyopathy

Introduction: Commonly accepted clinical classification of arrhythmogenic right ventricular cardiomyopathy (ARVC) is still not developed. Objective: To study the clinical forms of ARVC. Methods: Fifty-four patients (38.7 ± 14.1 years, 42.6% men) with ARVC. Follow-up period: 21 (6–60) months. All patients underwent electrocardiography, 24 h-Holter monitoring, echocardiography, and DNA diagnostic. Magnetic resonance imaging was performed in 49 patients. Results: According to the features of clinical course of ARVC, 4 clinical forms were identified. (I) Latent arrhythmic form (n = 27) – frequent premature ventricular contractions and/or nonsustained ventricular tachycardia (VT) in the absence of sustained VT and syncope; characterized by absence of fatal arrhythmic events. (II) Manifested arrhythmic form (n = 11) – sustained VT/ventricular fibrillation; the high incidence of appropriate implantation of cardioverter-defibrillator (ICD) interventions (75%) registered. (III) ARVC with progressive chronic heart failure (CHF, n = 8) as the main manifestation of the disease; incidence of appropriate ICD interventions was 50%, mortality rate due to CHF was 25%. (IV) Combination of ARVC with left ventricular noncompaction (n = 8); characterized by mutations in desmosomal or sarcomere genes, aggressive ventricular arrhythmias, appropriate ICD interventions in 100% patients. Described 4 clinical forms are stable in time, do not transform into each other, and they are genetically determined. Conclusions: The described clinical forms of ARVC are determined by a combination of genetic and environmental factors and do not transform into each other. The proposed classification could be used in clinical practice to determine the range of diagnostic and therapeutic measures and to assess the prognosis of the disease in a particular patient.

Left ventricular hypertrophy: The tip of the iceberg

In the current European Guidelines, hypertrophic cardiomyopathy (HCM) is defined as a wall thickness (WT) ≥ 15 mm. Its epidemiology is presented as such: 40-60% sarcomeric protein gene mutations, 25–30% unknown and 5–10% genetic and non-genetic causes. However, clinical practice does not necessarily confirm these values. We sought to describe the panel of LVWT and final aetiologic diagnoses among patients referred for assessment of LVWT ≥ 12 mm. Consecutive patients referred to our tertiary centre since January 2017 for the assessment of LVWT ≥ 12 mm were retrospectively included. Patients presenting with severe aortic stenosis ( n = 107) were excluded. 121 patients were included in the final analysis. Personal and familial history were collected for all patients and each patient underwent a complete physical examination, electrocardiogram and transthoracic echocardiography. Additional assessments were carried out based on the results of this first screening. Median LVWT was 15 mm (IQR 14 – 17). Final aetiologies were distributed as follows: 38 (31%) amyloidosis, 26 (21%) post-hypertensive, 35 (29%) sarcomeric, 4 (3%) other diagnoses and 18 (16%) undetermined. Among patients diagnosed with amyloidosis, 4 (11%) were inherited TTR, 8 (21%) wild-type TTR, 13 (34%) TTR of undetermined type, 11 (29%) light chain and 2 (6%) AA or apoA2 amyloidosis. Among patients diagnosed with sarcomeric HCMs, 4 (11%) were carriers of a mutation. 43 patients (36%) had a maximal LVWT between 12 and 15 mm. 11 (26%) of them had cardiac amyloidosis, 4 (9%) sarcomeric HCM, 17 (40%) undetermined LVH, 11 (26%) post-hypertensive HCM and 2 (5%) other aetiologies. Meaningful diagnoses of HCMs, such as cardiac amyloidosis (26%) and sarcomeric HCM (9%), could be made in the 12 to 15 mm range of LVWT. Overall, sarcomeric HCM does not seem to be the main aetiology and the true prevalence of cardiac amyloidosis seems to be underestimated.