Objectives The aim of this study was to describe the clinical profile associated with triple sarcomere gene mutations in a large hypertrophic cardiomyopathy (HCM) cohort. Background In patients with ...HCM, double or compound sarcomere gene mutation heterozygosity might be associated with earlier disease onset and more severe outcome. The occurrence of triple mutations has not been reported. Methods A total of 488 unrelated index HCM patients underwent screening for myofilament gene mutations by direct deoxyribonucleic acid sequencing of 8 genes, including myosin binding protein C ( MYBPC3 ), beta-myosin heavy chain ( MYH7) , regulatory and essential light chains (MYL2, MYL3), troponin-T (TNNT2), troponin-I ( TNNI3 ), alpha-tropomyosin (TPM1), and actin (ACTC). Results Of the 488 index patients, 4 (0.8%) harbored triple mutations, as follows: MYH7 -R869H, MYBPC3 -E258K, and TNNI3 -A86fs in a 32-year-old woman; MYH7 -R723C, MYH7 -E1455X, and MYBPC3 -E165D in a 46-year old man; MYH7 -R869H, MYBPC3 -K1065fs, and MYBPC3 -P371R in a 45-year old woman; and MYH7 -R1079Q, MYBPC3 -Q969X, and MYBPC3 -R668H in a 50-year old woman. One had a history of resuscitated cardiac arrest, and 3 had significant risk factors for sudden cardiac death, prompting the insertion of an implantable cardioverter-defibrillator in all, with appropriate shocks in 2 patients. Moreover, 3 of 4 patients had a severe phenotype with progression to end-stage HCM by the fourth decade, requiring cardiac transplantation (n = 1) or biventricular pacing (n = 2). The fourth patient, however, had clinically mild disease. Conclusions Hypertrophic cardiomyopathy caused by triple sarcomere gene mutations was rare but conferred a remarkably increased risk of end-stage progression and ventricular arrhythmias, supporting an association between multiple sarcomere defects and adverse outcome. Comprehensive genetic testing might provide important insights to risk stratification and potentially indicate the need for differential surveillance strategies based on genotype.
Sudden cardiac death (SCD) in the young is a rare but tragic consequence of a number of genetic cardiovascular disorders. The care of survivors of cardiac arrest and families affected by SCD seeks to ...prevent further SCD events through family screening.
The aim of this article is to review the genetic basis of SCD in the young and outline the clinical aspects of caring for families affected by SCD.
Inherited cardiomyopathies and primary arrhythmia syndromes are important causes of SCD in young people. Over the past 30 years, there has been an explosion of knowledge regarding the underlying genetic mechanisms of these disorders and dramatic advances in genetic testing technologies. Family screening with thorough multidisciplinary clinical assessment and genetic testing allows for the initiation of preventive strategies in high-risk relatives and ultimately a reduction in SCD events.
MicroRNAs (miRNAs) regulate post-transcriptional gene expression during development and disease. We have determined the miRNA expression levels of early- and end-stage hypertrophic cardiomyopathy ...(HCM) in a severe, transgenic mouse model of the disease. Five miRNAs were differentially expressed at an early stage of HCM development. Time-course analysis revealed that decreased expression of miR-1 and miR-133a commences at a pre-disease stage, and precedes upregulation of target genes causal of cardiac hypertrophy and extracellular matrix remodelling, suggesting a role for miR-1 and miR-133a in early disease development. At end-stage HCM, 16 miRNA are dysregulated to form an expression profile resembling that of other forms of cardiac hypertrophy, suggesting common responses. Analysis of the mRNA transcriptome revealed that miRNAs potentially target 15.7% upregulated and 4.8% downregulated mRNAs at end-stage HCM, and regulate mRNAs associated with cardiac hypertrophy and electrophysiology, calcium signalling, fibrosis, and the TGF-β signalling pathway. Collectively, these results define the miRNA expression signatures during development and progression of severe HCM and highlight critical miRNA regulated gene networks that are involved in disease pathogenesis.
Recently, the implantable cardioverter-defibrillator (ICD) has been promoted for prevention of sudden death in hypertrophic cardiomyopathy (HCM). However, the effectiveness and appropriate selection ...of patients for this therapy is incompletely resolved.
To study the relationship between clinical risk profile and incidence and efficacy of ICD intervention in HCM.
Multicenter registry study of ICDs implanted between 1986 and 2003 in 506 unrelated patients with HCM. Patients were judged to be at high risk for sudden death; had received ICDs; underwent evaluation at 42 referral and nonreferral institutions in the United States, Europe, and Australia; and had a mean follow-up of 3.7 (SD, 2.8) years. Measured risk factors for sudden death included family history of sudden death, massive left ventricular hypertrophy, nonsustained ventricular tachycardia on Holter monitoring, and unexplained prior syncope.
Appropriate ICD intervention terminating ventricular tachycardia or fibrillation.
The 506 patients were predominately young (mean age, 42 SD, 17 years) at implantation, and most (439 87%) had no or only mildly limiting symptoms. ICD interventions appropriately terminated ventricular tachycardia/fibrillation in 103 patients (20%). Intervention rates were 10.6% per year for secondary prevention after cardiac arrest (5-year cumulative probability, 39% SD, 5%), and 3.6% per year for primary prevention (5-year probability, 17% SD, 2%). Time to first appropriate discharge was up to 10 years, with a 27% (SD, 7%) probability 5 years or more after implantation. For primary prevention, 18 of the 51 patients with appropriate ICD interventions (35%) had undergone implantation for only a single risk factor; likelihood of appropriate discharge was similar in patients with 1, 2, or 3 or more risk markers (3.83, 2.65, and 4.82 per 100 person-years, respectively; P = .77). The single sudden death due to an arrhythmia (in the absence of advanced heart failure) resulted from ICD malfunction. ICD complications included inappropriate shocks in 136 patients (27%).
In a high-risk HCM cohort, ICD interventions for life-threatening ventricular tachyarrhythmias were frequent and highly effective in restoring normal rhythm. An important proportion of ICD discharges occurred in primary prevention patients who had undergone implantation for a single risk factor. Therefore, a single marker of high risk for sudden death may be sufficient to justify consideration for prophylactic defibrillator implantation in selected patients with HCM.
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an arrhythmia syndrome characterized by adrenaline induced ventricular tachycardia. The primary genetic aetiologies underlying CPVT are ...either autosomal dominant or autosomal recessive inheritance, resulting from heterozygous mutations in cardiac ryanodine receptor (RYR2) and homozygous mutations in cardiac calsequestrin-2 (CASQ2), respectively. Recently, a large family with autosomal dominant CPVT due to a heterozygous mutation in CASQ2, p.Lys180Arg, was reported. This resource is the first induced pluripotent stem cell line generated from a patient with autosomal dominant CPVT due to a heterozygous mutation in CASQ2. Induced pluripotent stem cells were generated from the whole blood of a 40-year-old woman with severe CPVT who is heterozygous for the p.Lys180Arg CASQ2 mutation. Induced pluripotent stem cell (iPSC) characterization confirmed expression of pluripotency makers, trilineage differentiation potential, and the absence of exogenous pluripotency vector expression.
Abstract Hypertrophic cardiomyopathy (HCM) is the most common inherited primary myocardial disorder. HCM is characterized by interstitial fibrosis and excessive accumulation of extracellular matrix ...(ECM) proteins. Fibrosis in HCM has been associated with impaired cardiac function and heart failure, and has been considered a key substrate for ventricular arrhythmias and sudden death. The molecular triggers underpinning ECM production are not well established. We have previously developed a double-mutant mouse model of HCM that recapitulates the phenotype seen in humans with multiple mutations, including earlier onset of the disease, progression to a dilated phenotype, severe heart failure and premature mortality. The present study investigated the expression of ECM-encoding genes in severe HCM and heart failure. Significant upregulation of structural Fn1 , regulatory Mmp14 , Timp1 , Serpin3A , SerpinE1 , SerpineE2 , Tgfβ1 , and Tgfβ2 ; and matricellular Ccn2 , Postn , Spp1 , Thbs1 , Thbs4 , and Tnc was evident from the early, pre-phenotype stage. Non-myocytes expressed ECM genes at higher levels than cardiomyocytes in normal and diseased hearts. Synchronous increase of secreted CCN2 and TIMP1 plasma levels and decrease of MMP3 levels were observed in end-stage disease. CCN2 protein expression was increased from early disease in double-mutant hearts and played an important role in ECM responses. It was a powerful modulator of ECM regulatory ( Timp1 and SerpinE1 ) and matricellular protein-encoding ( Spp1 , Thbs1 , Thbs4 and Tnc ) gene expression in cardiomyocytes when added exogenously in vitro . Modulation of CCN2 (CTGF, connective tissue growth factor) and associated early ECM changes may represent a new therapeutic target in the treatment and prevention of heart failure in HCM.
Familial hypertrophic cardiomyopathy (FHC) patients are advised to avoid strenuous exercise due to increased risk of arrhythmias. Mice expressing the human FHC-causing mutation R403Q in the myosin ...heavy chain gene (MYH6) recapitulate the human phenotype, including cytoskeletal disarray and increased arrhythmia susceptibility. Following in vivo administration of isoproterenol, mutant mice exhibited tachyarrhythmias, poor recovery and fatigue. Arrhythmias were attenuated with the β-blocker atenolol and protein kinase A inhibitor PKI. Mutant cardiac myocytes had significantly prolonged action potentials and triggered automaticity due to reduced repolarization reserve and connexin 43 expression. Isoproterenol shortened cycle length, and escalated electrical instability. Surprisingly isoproterenol did not increase Ca
1.2 current. We found alterations in Ca
1.2-β1 adrenergic receptor colocalization assessed using super-resolution nanoscopy, and increased Ca
1.2 phosphorylation in mutant hearts. Our results reveal for the first time that altered ion channel expression, co-localization and β-adrenergic receptor signaling associated with myocyte disarray contribute to electrical instability in the R403Q mutant heart.
ObjectiveTo codesign an online support intervention for families after sudden cardiac death (SCD) in the young (<35 years).DesignCodesign of an SCD family intervention by stakeholder focus ...groups.SettingFamilies and healthcare professionals with experience in SCD in the young.ParticipantsSemistructured online focus groups were held with key stakeholders, that is, family members who had experienced young SCD, healthcare professionals and researchers based in New South Wales, Australia. Guided discussions were used to develop an online support intervention. Thematic analysis of discussions and iterative feedback on draft materials guided content development.ResultsFour focus groups were held (4–6 participants per group, 12 unique participants). Stakeholder involvement facilitated development of high-level ideas and priority issues. Creative content and materials were developed based on user preference for stories, narratives and information reflecting everyday experience of families navigating the legal and medical processes surrounding SCD, normalising and supporting grief responses in the context of family relationships and fostering hope. Emphasis on accessibility led to the overarching need for digital information and online engagement. These insights allowed development of an online intervention—COPE-SCD: A COmmunity suPporting familiEs after Sudden Cardiac Death—which includes a website and online support programme.ConclusionUsing codesign with stakeholders we have developed a support intervention that addresses the needs of SCD families and aims to fill a large gap in existing healthcare. We will evaluate COPE-SCD to determine whether this is an effective intervention for support of families following a young SCD.
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