Genetic Cardiomyopathy Research Articles

Abstract 12547: Obesity as Risk Factor for Malignant Ventricular Arrhythmias in Phospholamban Cardiomyopathy

Introduction: The pathogenic phospholamban (PLN) p.Arg14del mutation can cause severe arrhythmogenic cardiomyopathy. However, disease penetrance and clinical course are heterogenous and can differ largely between affected individuals. The impact of external factors - such as lifestyle - on the clinical course has not been studied yet. Hypothesis: We hypothesized that obese PLN mutation carriers have worse clinical outcomes, characterized by a higher burden of malignant ventricular arrhythmias (MVA). Methods: PLN p.Arg14del mutation carriers from the Dutch PLN registry with available follow-up (FU) data were included. MVA was defined as either sustained ventricular tachycardia, ventricular fibrillation, appropriate implantable cardioverter defibrillator intervention or (aborted) cardiac arrest. Patients were categorized into three groups based on their body mass index (BMI): normal weight (BMI 18.5 - 24.9 kg/m 2 ), overweight (25.0 - 29.9 kg/m 2 ) and obese (BMI > 30.0 kg/m 2 ). Mutation carriers with a BMI < 18.5 kg/m 2 or MVA at baseline were excluded. Results: A total of 179 PLN mutation carriers were included in this analysis: 105 (58.7%) normal weight, 59 (33.0%) overweight, 15 (8.4%) obese. The obese group had the highest percentage of MVA (26.7%), followed by the overweight (13.6%) and normal weight (4.8%) groups, as shown in the Kaplan-Meier curve (log-rank 0.016). Continuous BMI was significantly correlated with the incidence of MVA during FU: hazard ratio 1.15 [1.04 - 1.27; p=0.006] per 1-unit increase of BMI, adjusted for age, sex and comorbidities (hypertension, type 2 diabetes mellitus, dyslipidemia, coronary heart disease). Additionally, BMI value predicted MVA with an area under the curve of 0.73 [0.63 - 0.84; p=0.002]. Conclusions: In PLN p.Arg14del mutation carriers, high BMI values and obesity are associated with higher incidence of MVA. This suggests a potential role for lifestyle intervention in the management of this genetic cardiomyopathy.

Dilated Cardiomyopathy in Children: Early Detection and Treatment.

Cardiomyopathy is segregated into primary and secondary categories, leading to different phenotypes, including dilated, hypertrophic, and restrictive patterns. Dilated cardiomyopathy (DCM) is a mixed bag of heart diseases with the unique features of cardiac dilatation and subnormal to poor myocardial contractility. Dilated cardiomyopathy in the pediatric age group is generally characterized by unobstructed, dilated, and contracting left ventricular chamber defects and is associated with heart failure. Other causes include genetic juvenile-onset cardiomyopathy, drug-induced cardiomyopathy, stress-induced cardiomyopathy, hemochromatosis, endocrine causes (thyroid disorder and pheochromocytoma), autoimmune diseases, and nutritional deficiencies (selenium and thiamine). It is characterized by thinning of the left ventricle, a dilated left ventricle or biventricular dilatation, left ventricular systolic dysfunction, left ventricular diastolic dysfunction, global hypokinesia, and cardiomegaly (seen on a chest X-ray). Decreased cardiac output leads to fatigue, cachexia, narrow pulse pressure, dicrotic pulse/hypokinetic pulse, dyspnea, cool extremities, decreased blood supply to the brain (cognitive dysfunction), and reduced blood supply to the kidney (renal failure). Left ventricular diastolic dysfunction can result in dyspnea, orthopnea, and paroxysmal nocturnal dyspnea. Cardiomyopathy can also occur with or without left ventricular dysfunction, as in left ventricular non-compaction cardiomyopathy (LVNC), which is a rare heart disease occurring due to two (likely) pathogenic nonsense mutations: DSG2-p.S363X and TBX20-p.D278X. The study of familial forms of LVNC is helpful for risk prediction and genetic counseling of relatives. Right ventricular chamber failure can be identified on the electrocardiogram as sinus tachycardia and non-specific ST/T changes. The complications include arrhythmia (atrial fibrillation) and thromboembolism (left ventricular mural thrombosis). It is of utmost importance in the field of heart transplantation as the definitive treatment of the disease. Heart transplantation is now an acceptable treatment option for patients with dilated cardiomyopathy. This short review highlights different methods for the detection and diagnosis of dilated cardiomyopathy and the treatment modalities available for the same.

Prognostic Prediction of Genotype vs Phenotype in Genetic Cardiomyopathies

BackgroundDiverse genetic backgrounds often lead to phenotypic heterogeneity in cardiomyopathies (CMPs). Previous genotype-phenotype studies have primarily focused on the analysis of a single phenotype, and the diagnostic and prognostic features of the CMP genotype across different phenotypic expressions remain poorly understood. ObjectivesWe sought to define differences in outcome prediction when stratifying patients based on phenotype at presentation compared with genotype in a large cohort of patients with CMPs and positive genetic testing. MethodsDilated cardiomyopathy (DCM), arrhythmogenic right ventricular cardiomyopathy, left-dominant arrhythmogenic cardiomyopathy, and biventricular arrhythmogenic cardiomyopathy were examined in this study. A total of 281 patients (80% DCM) with pathogenic or likely pathogenic variants were included. The primary and secondary outcomes were: 1) all-cause mortality (D)/heart transplant (HT); 2) sudden cardiac death/major ventricular arrhythmias (SCD/MVA); and 3) heart failure–related death (DHF)/HT/left ventricular assist device implantation (LVAD). ResultsSurvival analysis revealed that SCD/MVA events occurred more frequently in patients without a DCM phenotype and in carriers of DSP, PKP2, LMNA, and FLNC variants. However, after adjustment for age and sex, genotype-based classification, but not phenotype-based classification, was predictive of SCD/MVA. LMNA showed the worst trends in terms of D/HT and DHF/HT/LVAD. ConclusionsGenotypes were associated with significant phenotypic heterogeneity in genetic cardiomyopathies. Nevertheless, in our study, genotypic-based classification showed higher precision in predicting the outcome of patients with CMP than phenotype-based classification. These findings add to our current understanding of inherited CMPs and contribute to the risk stratification of patients with positive genetic testing.

EP News: Basic and Translational.

Laws et al (Circ Res 2022;130:1698, PMID 35617362) provided a timely and comprehensive review on the prevalence of genetic cardiomyopathies with arrhythmias as the first presentation. While ventricular arrhythmias are well-recognized as presentation for arrhythmogenic cardiomyopathy in the right ventricle, the scope of arrhythmogenic cardiomyopathy has broadened to include those with dominant left ventricular involvement, usually with a phenotype of dilated cardiomyopathy. In addition, careful evaluation for genetic cardiomyopathy is warranted for patients presenting with frequent premature ventricular contractions, conduction system disease, and early-onset atrial fibrillation, in which most detected genes are in the cardiomyopathy panels.

Recurrent acute myocarditis: An under-recognized clinical entity associated with the later diagnosis of a genetic arrhythmogenic cardiomyopathy.

Myocardial inflammation has been consistently associated with genetic arrhythmogenic cardiomyopathy (ACM) and it has been hypothesized that episodes mimicking acute myocarditis (AM) could represent early inflammatory phases of the disease. We evaluated the temporal association between recurrent acute myocarditis (RAM) episodes and the later diagnosis of a genetic ACM. Between January 2012 and December 2021, patients with RAM and no previous cardiomyopathy were included (Recurrent Acute Myocarditis Registry, NCT04589156). A follow-up visit including clinical evaluation, resting and stress electrocardiogram, cardiac magnetic resonance imaging, and genetic testing was carried out. Endpoints of the study was the incidence of both ACM diagnosis criteria and ACM genetic mutation at the end of follow-up. Twenty-one patients with RAM were included and follow-up was completed in 19/21 patients (90%). At the end of follow-up, 3.3 ± 2.9 years after the last AM episode, 14/21 (67%) patients with an ACM phenotype (biventricular: 10/14, 71%; left ventricular: 4/14, 29%) underwent genetic testing. A pathogenic or likely pathogenic mutation was found in 8/14 patients (57%), 5/8 in the Desmoplakin gene, 2/8 in the Plakophillin-2 gene, and 1/8 in the Titin gene. Family history of cardiomyopathy or early sudden cardiac death had a positive predictive value of 88% for the presence of an underlying genetic mutation in patients with RAM. RAM is a rare entity associated with the latter diagnosis of an ACM genetic mutation in more than a third of the cases. In those patients, RAM episodes represent early inflammatory phases of the disease. Including RAM episodes in ACM diagnosis criteria might allow early diagnosis and potential therapeutic interventions.

Targeting GPCRs to treat cardiac fibrosis.

Cardiac fibrosis occurs ubiquitously in ischemic heart failure, genetic cardiomyopathies, diabetes mellitus, and aging. It triggers myocardial stiffness, which impairs cardiac function, ultimately progressing to end-stage heart failure and increased mortality. Although several targets for anti-fibrotic therapies have been identified, including TGF-β and receptor tyrosine kinase, there is currently no FDA-approved drug specifically targeting cardiac fibrosis. G protein-coupled receptors (GPCRs) are integral, multipass membrane-bound receptors that exhibit diverse and cell-specific expression, offering novel and unrealized therapeutic targets for cardiac fibrosis. This review highlights the emerging roles of several GPCRs and briefly explores their downstream pathways that are crucial in cardiac fibrosis. We will not only provide an overview of the GPCRs expressed on cardiac fibroblasts that are directly involved in myofibroblast activation but also describe those GPCRs which contribute to cardiac fibrosis via indirect crosstalk mechanisms. We also discuss the challenges of identifying novel effective therapies for cardiac fibrosis and offer strategies to circumvent these challenges.

Clinical role of genetic testing for overlapping between Brugada syndrome and arrhythmogenic right ventricular cardiomyopathy

Abstract Background/Introduction Brugada syndrome (BrS) and arrhythmogenic right ventricular cardiomyopathy (ARVC) are inherited arrhythmias that may predispose to sudden cardiac arrest. Although its pathogenetic mechanisms differ, overlapping features between BrS and ARVC have been demonstrated previously. However, it remains to be determined whether genetic testing for ARVC-related gene is needed in patients with BrS. Purpose This study is aimed to analyze genetic profiles of BrS patients using next generation sequencing (NGS) based multigene panel including ARVC related genes. Methods Patients who were confirmed as BrS or clinically suspected as BrS with type 2 or 3 Brugada pattern electrocardiography were studied. Genetic testing using NGS panels (Illumina Inc., San Diego, CA, USA) included 30 genetic variants associated with inherited arrhythmia and genetic cardiomyopathy. Results Among the total 119 patients from BrS registry, 63 patients were confirmed as BrS and 56 patients were clinically suspected as BrS without fulfilling diagnostic criteria. One-hundred-fourteen patients (95.8%) were male, and mean age of onset was 43.6 year-old. Genetic variants were identified in 25 of 42 patients who received genetic testing. Six out of 25 patients (24.0%) showed ARVC-related genotypes (2 PKP2, 1 DSG2, 1 TMEM43, 1 JUP, and 1 DSP) (Figure 1 and Table 1). None of the patients showed structural or electrocardiographic features that fulfill diagnostic criteria of ARVC. It is notable that ARVC-related genotypes were mostly frequently accounted for BrS patients, following SCN5A and SCN10A. Conclusion In the clinic setting, ARVC-related genetic variants were identified in significant proportion of BrS patients, supporting that genetic testing of ARVC-overlapping is needed. This study suggests that follow-up including imaging study should be considered in BrS patients with ARVC-related genotypes to monitor disease progression as ARVC. Funding Acknowledgement Type of funding sources: None.

Prognostic prediction of genotype versus phenotype in genetic cardiomyopathies

Abstract Background In cardiomyopathies (CMPs), the diverse genetic background often leads to phenotypic heterogeneity. Currently, genotype-phenotype studies are founded on clinical phenotype-based classification of CMPs, contributing possible biases due to the exclusion of specific and unascertained phenotypic expressions of CMP genes. Purpose We sought to define differences in outcome when stratifying patients based on phenotype at presentation compared with genotype in a large cohort of CMP patients with positive genetic testing. Methods In this study, we included the whole spectrum of non-hypertrophic CMP phenotypes, genetically determined: dilated cardiomyopathy (DCM), arrhythmogenic right ventricular cardiomyopathy (ARVC), left ventricular arrhythmogenic cardiomyopathy (ALVC) and biventricular ARVC (BiV). The primary and secondary outcomes were: 1) all-cause mortality/heart transplant (D/HT); 2) heart failure-related death/heart transplant/left ventricular assist device implantation (DHF/HT/VAD); and 3) sudden cardiac death/life-threatening ventricular arrhythmias (SCD/MVA). Results Two hundred and eighty-one patients (80% DCM) carrying pathogenic or likely pathogenic variants were included in this study. The phenotype was classified as DCM, ARVC, ALVC and BiV according to current consensus criteria. The median follow-up was 188 months. Variants in titin (TTN; 34%) and sarcomeric genes (SARC; 22%) were the most frequent genotypes and almost invariably associated with a DCM phenotype. DSP, LMNA and FLNC displayed more heterogeneous phenotypic presentations, including DCM, ARVC, ALVC, BiV. At survival analysis, the arrhythmic outcome occurred more frequently in patients without a DCM phenotype and in carriers of DSP, PKP2, LMNA and FLNC variants. However, after adjustment for age and sex, the genotype-based classification but not the phenotype-based classification was predictive of the arrhythmic outcome. LMNA showed the worst trend in term of D/HT and DHF/HT/LVAD. Conclusions In genetic cardiomyopathies, genotype is associated with significant phenotypic heterogeneity. Nevertheless, in our study, the genotypic-based classification showed higher precision in predicting CMP patients' outcome in respect to the phenotype-based classification. These findings add to the current understanding of inherited CMPs and may implement the risk stratification of patients with positive genetic testing. Funding Acknowledgement Type of funding sources: None.

Association between obesity and hypertrophic cardiomyopathy phenotype, validation in a latin american cohort

Abstract Objectives Hypertrophic Cardiomyopathy (HCM) is the most common genetic cardiomyopathy. The influence of obesity on the disease phenotype is not well established. A recent publication sought to answer this gap. Our objective is to assess the relationship of a obesity on the phenotype of our cohort and compare it to the published literature. Methods We performed a retrospective observational study of consecutive patients diagnosed with HCM at a single center in Argentina. We included 1331 patients between March 1993 and December 2021. We excluded patients <18 years of age, metabolic diseases & syndromes and patients who were lost on follow up. We defined Obesity as a body mass index ≥30 kg/m2. Results 1168 patients had available data for analysis. 54 (10.4%) patients were obese. Mean age was 54±28 years and 33 (61%) were male. Average maximal left ventricular wall thickness (LVWT) in this group was 20 mm ± 5 mm. When comparing obese vs non-obese patients we found no statistically significant differences for gender, age, family history of HCM, family history of sudden death (SD), previous VF/VT/NSVT, ESC low, intermediate or high risk for SD groups, fibrosis, apical aneurism, LV diameter, maximum LVWT, high risk genetic mutation, abnormal BP response to exercise, device implant, septal alcohol ablation, reduced EF on follow up, nor death/HF/Stroke/AICD appropriate therapy/AF development. We did find that obese patients had less unexplained syncope (6% vs 13%, OR 0.43, p=0.03), had more frequently an NYHA > III/IV (15.3% vs 8.9%, OR 1.8, p=0,03), a trend to having less frequently a LVWT >30 mm (3.5% vs 8.1%, OR 0.41, p=0.07) but more frequently had systolic anterior motion of the mitral valve on echocardiography (45% vs 34%, OR 1.58, p=0.04). We noted a trend to being more frequently indicated LV myectomy (9.2% vs 5%, OR 1.9, p=0,07) and significantly having elevated ultrasensitive troponin I (7.8% vs 3.7%, OR 2.2, p=0,04). Conclusions We found that obese patients from our cohort, as described in other series, had more advanced symptoms. In our set of obese patients they were more frequently sent to myectomy rather than alcohol septal ablation as described in other series. AF was not more prevalent among our obese patients and maximum wall thickness and fibrosis were not higher either. We did find that obese patients had more frequently elevated biomarkers. As HCM is so frequent it is important to characterize cohorts and compare data. Funding Acknowledgement Type of funding sources: None.

Proteomics profiling reveals signaling pathways associated with major adverse cardiovascular events in patients with hypertrophic cardiomyopathy

Abstract Background Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiomyopathy affecting 1 in 200–500 people in the US. It is characterized by a diverse clinical course, and only a subset of patients with HCM experience major adverse cardiovascular events (MACE) such as arrhythmias (e.g., ventricular tachycardia/fibrillation [VT/VF], atrial fibrillation [AF]), stroke, and heart failure. However, the molecular mechanisms underlying the presence of MACE in HCM are still not well understood. Purpose Our aim was to reveal signaling pathways associated with prior MACE in patients with HCM by applying plasma proteomics profiling. Methods We conducted a multicenter case-control study of patients with HCM comparing those with and without a prior history of MACE. We performed plasma proteomics profiling of 5032 proteins. We defined prior MACE as a composite outcome of sustained VT/VF, AF, stroke/transient ischemic attack, left ventricular ejection fraction ≤50%, New York Heart Association functional class ≥2 symptoms, resuscitated cardiac arrest, or appropriate implantable cardioverter defibrillator therapy. We applied the random forest method to derive a proteomics-based discrimination model developed in patients enrolled at one institution (training set) and externally validated the model on patients enrolled at another institution (test set). We then performed pathway analysis of proteins differentially regulated in patients with prior MACE. Pathways with a false discovery rate (FDR) <0.05 with at least 5 associated proteins were declared positive. Results A total of 396 patients were included, with 278 in the training set and 118 in the test set. In this cohort, 251 (63%) patients had prior MACE (171 in the training set and 80 in the test set). Using the proteomics-based model derived from the training set, the area under the receiver operating characteristic curve was 0.81 (95% CI 0.73–0.88) in the test set (Figure 1). There were 632 differentially expressed proteins (univariable p<0.05). Pathway analysis identified significantly dysregulated pathways in patients with prior MACE (Figure 2). This included both pathways known to be associated with MACE (e.g., TGF-β [FDR=0.03]) and novel pathways (e.g., Ras-MAPK [FDR=0.01] and its upstream PI3K-Akt [FDR=7.7x10–7] pathways). Pathways involved in cellular metabolism/proliferation (e.g., HIF 1 [FDR=0.01] and Wnt [FDR=0.04] pathways) and inflammation (e.g., complement and coagulation cascades [FDR=2.7x10–21], cytokine-cytokine receptor interaction [FDR=8.1x10–16]) were also significantly dysregulated. Conclusions Our study in patients with HCM reveals that those with a prior history of MACE have a distinctive plasma proteomics profile. We further identified both previously known and novel pathways dysregulated in this subset with a more severe form of HCM. Our findings may aid in development of targeted therapies for the prevention of MACE in HCM. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): R01 HL157216

A Unique Association of Left Ventricular Noncompaction With Rheumatic Heart Disease

Left ventricular noncompaction cardiomyopathy (LVNC) is a type of primary genetic cardiomyopathy, which occurs during embryogenesis by the arrest in the ventricular myocardium compaction. LVNC is characterized by prominent wall trabeculations and intertrabecular recesses that communicate with the ventricular cavity. There are 2 types of cardiomyopathy: the first one is associated with other primary cardiac structural abnormalities like malfunctional cardiac valves as mentioned in the case report below and the second type is in which there are no other associated cardiac structural abnormalities also called isolated LV noncompaction cardiomyopathy. We report an association of severe rheumatic mitral valve disease and LV noncompaction with significantly reduced ejection fraction which is rare.

Genotype-phenotype Correlates in Arrhythmogenic Cardiomyopathies.

The definition of arrhythmogenic cardiomyopathy (ACM) has expanded beyond desmosomal arrhythmogenic right ventricular cardiomyopathy (ARVC) to include other genetic cardiomyopathies with a significant arrhythmia burden. Emerging data on genotype-phenotype correlations has led recent consensus guidelines to urge genetic testing as a critical component of not only diagnosis but also management of ACM. Plakophilin-2 (PKP2) ARVC/ACM is most likely to meet ARVC Task Force Criteria with right sided involvement and ventricular arrhythmias, while desmoplakin (DSP) ACM may have a normal electrocardiogram (ECG) and has a subepicardial LV scar pattern. Extra-desmosomal ACM including ACM associated with transmembrane protein 43 and phospholamban variants may have characteristic ECG patterns and biventricular cardiomyopathy. Lamin A/C and SCN5A cardiomyopathy often have heart block on ECG with DCM, but are distinct from DCM in that they have significantly elevated arrhythmic risk. Newer genes, especially filamin-C (FLNC) also may have distinct imaging scar patterns, arrhythmia risk, and risk predictors. Recognition of these key differences have implications for clinical management and reinforce the importance of genetic testing in the diagnosis and the emerging opportunities for genotype-specific management of ACM patients.

Identification and functional characterization of BICD2 as a candidate disease gene in an consanguineous family with dilated cardiomyopathy

BackgroundFamilial dilated cardiomyopathy (DCM) is a genetic cardiomyopathy that is associated with reduced left ventricle function or systolic function. Fifty-one DCM-causative genes have been reported, most of which are inherited in an autosomal dominant manner. However, recessive DCM-causative gene is rarely observed.MethodsWhole-exome sequencing (WES) was performed in a consanguineous family with DCM to identify candidate variants. Sanger sequencing was utilized to confirm the variant. We then checked the DCM candidate gene in 210 sporadic DCM cases. We next explored BICD2 function in both embryonic and adult bicd2-knockout zebrafish models. In vivo cardiac function of bicd2-knockout fish was detected by echocardiography and RNA-seq.ResultsWe identified an autosomal recessive and evolutionarily conserved missense variant, NM_001003800.1:c.2429G > A, in BICD2, which segregated with the disease phenotype in a consanguineous family with DCM. Furthermore, we confirmed the presence of BICD2 variants in 3 sporadic cases. Knockout of bicd2 resulted in partial embryonic lethality in homozygotes, suggesting a vital role for bicd2 in embryogenesis. Heart dilation and decreased ejection fraction, cardiac output and stroke volume were observed in bicd2-knockout zebrafish, suggesting a phenotype similar to human DCM. Furthermore, RNA-seq confirmed a larger transcriptome shift in in bicd2 homozygotes than in heterozygotes. Gene set enrichment analysis of bicd2-deficient fish showed the enrichment of altered gene expression in cardiac pathways and mitochondrial energy metabolism.ConclusionsOur study first shows that BICD2 is a novel candidate gene associated with familial DCM, and our findings will facilitate further insights into the molecular pathological mechanisms of DCM.

Myosins and MyomiR Network in Patients with Obstructive Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiomyopathy. The molecular mechanisms determining HCM phenotypes are incompletely understood. Myocardial biopsies were obtained from a group of patients with obstructive HCM (n = 23) selected for surgical myectomy and from 9 unused donor hearts (controls). A subset of tissue-abundant myectomy samples from HCM (n = 10) and controls (n = 6) was submitted to laser-capture microdissection to isolate cardiomyocytes. We investigated the relationship among clinical phenotype, cardiac myosin proteins (MyHC6, MyHC7, and MyHC7b) measured by optimized label-free mass spectrometry, the relative genes (MYH7, MYH7B and MYLC2), and the MyomiR network (myosin-encoded microRNA (miRs) and long-noncoding RNAs (Mhrt)) measured using RNA sequencing and RT-qPCR. MyHC6 was lower in HCM vs. controls, whilst MyHC7, MyHC7b, and MyLC2 were comparable. MYH7, MYH7B, and MYLC2 were higher in HCM whilst MYH6, miR-208a, miR-208b, miR-499 were comparable in HCM and controls. These results are compatible with defective transcription by active genes in HCM. Mhrt and two miR-499-target genes, SOX6 and PTBP3, were upregulated in HCM. The presence of HCM-associated mutations correlated with PTBP3 in myectomies and with SOX6 in cardiomyocytes. Additionally, iPSC-derived cardiomyocytes, transiently transfected with either miR-208a or miR-499, demonstrated a time-dependent relationship between MyomiRs and myosin genes. The transfection end-stage pattern was at least in part similar to findings in HCM myectomies. These data support uncoupling between myosin protein/genes and a modulatory role for the myosin/MyomiR network in the HCM myocardium, possibly contributing to phenotypic diversity and providing putative therapeutic targets.

Genetic cardiomyopathies and clinical implications in heart transplant recipients: An opportunity for missed diagnoses

Over half of patients (50.8%) who require cardiac transplantation (HTx) suffer from dilated cardiomyopathy (DCM), including patients with hypertrophic cardiomyopathy (HCM), restrictive cardiomyopathy (RCM), arrhythmogenic cardiomyopathy (ACM) and left ventricular non-compaction (LVNC).1 Up to 40% of DCM cases have a monogenic etiology but are likely underdiagnosed.2,3 For example, in a study of patients presenting for cardiac catheterization, 4.5% carried a pathogenic/likely pathogenic mutation for a cardiovascular monogenic disorder, but only 35% of those patients had previously been diagnosed with the genetic cause of their disease; importantly, none of the DCM patients harboring a pathogenic/likely pathogenic mutation had been given a diagnosis of familial cardiomyopathy.

Genetic profile and genotype-phenotype correlations in hypertrophic cardiomyopathy presenting during childhood

Genetic cardiomyopathy (CM) is a rare disease in childhood. Risk factors for outcomes remain poorly described. Our study aimed to analyse clinical and genetical aspects in a pediatric hypertrophic cardiomyopathy (HMC) population and to establish genotype-phenotype correlations. A retrospective study of all patients with “idiopathic” HCM diagnosed in southeast France, before the age of 18 years was performed. All data (clinic, echocardiography, genetic testing) were retrospectively collected. Patients who did not have complete genetic testing according to current scientific development had another DNA blood sample during the study to complete the testing. Genetic tests were considered positive if the variant found was classified as pathogenic, likely pathogenic or variant of uncertain significance. Thirty-three patients were diagnosed with “idiopathic” HCM. Median age at diagnosis was 6.8 years old [0.3–12.1]. Genetic testing was positive in 21 cases (63.6%). Patients with an identified mutation had more visceral impact (38% vs. 8%, P = 0.009), a higher rate of implantable cardiac defibrillator (24% vs. none, P = 0.025) and more frequent heart transplant (19% vs. none, P = 0.025). In our population with paediatric HCM, a positive genetic testing is associated with a worse clinical course. Those data have to be corroborated with larger-scale studies.

Assessment of the Diagnostic Yield of Combined Cardiomyopathy and Arrhythmia Genetic Testing

Genetic testing can guide management of both cardiomyopathies and arrhythmias, but cost, yield, and uncertain results can be barriers to its use. It is unknown whether combined disease testing can improve diagnostic yield and clinical utility for patients with a suspected genetic cardiomyopathy or arrhythmia. To evaluate the diagnostic yield and clinical management implications of combined cardiomyopathy and arrhythmia genetic testing through a no-charge, sponsored program for patients with a suspected genetic cardiomyopathy or arrhythmia. This cohort study involved a retrospective review of DNA sequencing results for cardiomyopathy- and arrhythmia-associated genes. The study included 4782 patients with a suspected genetic cardiomyopathy or arrhythmia who were referred for genetic testing by 1203 clinicians; all patients participated in a no-charge, sponsored genetic testing program for cases of suspected genetic cardiomyopathy and arrhythmia at a single testing site from July 12, 2019, through July 9, 2020. Positive gene findings from combined cardiomyopathy and arrhythmia testing were compared with findings from smaller subtype-specific gene panels and clinician-provided diagnoses. Among 4782 patients (mean [SD] age, 40.5 [21.3] years; 2551 male [53.3%]) who received genetic testing, 39 patients (0.8%) were Ashkenazi Jewish, 113 (2.4%) were Asian, 571 (11.9%) were Black or African American, 375 (7.8%) were Hispanic, 2866 (59.9%) were White, 240 (5.0%) were of multiple races and/or ethnicities, 138 (2.9%) were of other races and/or ethnicities, and 440 (9.2%) were of unknown race and/or ethnicity. A positive result (molecular diagnosis) was confirmed in 954 of 4782 patients (19.9%). Of those, 630 patients with positive results (66.0%) had the potential to inform clinical management associated with adverse clinical outcomes, increased arrhythmia risk, or targeted therapies. Combined cardiomyopathy and arrhythmia gene panel testing identified clinically relevant variants for 1 in 5 patients suspected of having a genetic cardiomyopathy or arrhythmia. If only patients with a high suspicion of genetic cardiomyopathy or arrhythmia had been tested, at least 137 positive results (14.4%) would have been missed. If testing had been restricted to panels associated with the clinician-provided diagnostic indications, 75 of 689 positive results (10.9%) would have been missed; 27 of 75 findings (36.0%) gained through combined testing involved a cardiomyopathy indication with an arrhythmia genetic finding or vice versa. Cascade testing of family members yielded 402 of 958 positive results (42.0%). Overall, 2446 of 4782 patients (51.2%) had only variants of uncertain significance. Patients referred for arrhythmogenic cardiomyopathy had the lowest rate of variants of uncertain significance (81 of 176 patients [46.0%]), and patients referred for catecholaminergic polymorphic ventricular tachycardia had the highest rate (48 of 76 patients [63.2%]). In this study, comprehensive genetic testing for cardiomyopathies and arrhythmias revealed diagnoses that would have been missed by disease-specific testing. In addition, comprehensive testing provided diagnostic and prognostic information that could have potentially changed management and monitoring strategies for patients and their family members. These results suggest that this improved diagnostic yield may outweigh the burden of uncertain results.

Abstract GS101: Myosin Binding Protein H-like Competes With Cardiac Myosin Binding Protein-c To Prolong Atrial Contraction

Myosin binding protein-H like (MyBP-HL) has recently been identified as a novel component of myofilaments in the cardiac atria. Loss of MyBP-HL is associated with dilated cardiomyopathy and arrhythmia in humans and mice. MyBP-HL is highly homologous to cardiac myosin binding protein-C (cMyBP-C), which has been studied in the context of genetic cardiomyopathy. Prior work using mouse atrial tissue lysates established MyBP-HL and cMyBP-C bind competitively and maintain a stoichiometric ratio compared to myosin heavy chain. We now confirm this competitive binding using neonatal rat ventricular cardiomyocytes (NRVMs) transfected with mouse Mybphl . Using confocal microscopy with internal controls, we found a linear, inverse relationshib between myosin binding protein levels with NRVMs with high levels of MyBP-HL expression showing a reduction in cMyBP-C levels compared to untransfected NRVMs that only express cMyBP-C. While we show that these two myosin binding proteins bind comparatively with each other, the functional consequences are unclear. We performed force-calcium measurements of permeabilized single atrial cardiomyocytes and found that loss of MyBP-HL does not significantly alter the calcium sensitivity of force development, or the specific force generated by isometric contraction. Because cMyBP-C is a known regulator of crossbridge sliding velocity, we evaluated contraction and relaxation kinetics of Mybphl single-myofibrils from WT and Mybphl homozygous null mice. Atrial myofibrils lacking Mybphl showed a significantly faster rate and shorter duration of their linear phase of relaxation, which is governed by the off-rate of myosin from actin. This suggests that extra cMyBP-C in the atria can hasten myofibril relaxation. In healthy atria with MyBP-HL replacing approximately half the cMyBP-C, the slow phase of relaxation is prolonged. While the physiological importance of this is not explored, it provides a mechanism by which loss of function mutations in MYBPHL cause contractile dysfunction.

Specific alterations of regional myocardial work in strength-trained athletes using anabolic androgenic steroids compared to athletes with genetic hypertrophic cardiomyopathy

BackgroundStrength-trained athletes using anabolic androgenic steroids (AAS) have left ventricular (LV) hypertrophy and myocardial fibrosis that can lead to sudden cardiac death. A similar feature was described in athletes with hypertrophic cardiomyopathy (HCM), which complicates the diagnosis for clinicians. In this context, we aimed to compare the LV function of the 2 populations by measuring global and regional strain and myocardial work using speckle-tracking imaging. MethodsTwenty-four strength-trained asymptomatic athletes using AAS (AAS-Athletes), 22 athletes diagnosed with HCM (HCM-Athletes), and 20 healthy control athletes (Ctrl-Athletes) underwent a resting echocardiography to assess LV function. We evaluated LV global and regional strains and myocardial work, with an evaluation of the constructive work (CW), wasted work, and work efficiency (WE). ResultsCompared to Ctrl-Athletes, both AAS-Athletes and HCM-Athletes had a thicker interventricular septum, with majored values in HCM-Athletes. LV strain was reduced in AAS-Athletes and even more in HCM-Athletes. Consequently, global WE was significantly diminished in both AAS and HCM-Athletes (93% ± 2% in Ctrl-Athletes, 90% ± 4% in AAS-Athletes, and 90% ± 5% in HCM-Athletes (mean ± SD); p < 0.05). Constructive work and WE regional analysis showed specific alterations, with the basal septal segments preferentially affected in AAS-Athletes, and both septal and apical segments affected in HCM-Athletes. ConclusionThe regional evaluation of myocardial work reported specific alterations of the major LV hypertrophy induced by the regular use of AAS compared to the LV hypertrophy due to HCM. This finding could help clinicians to differentiate between these 2 forms of pathological hypertrophy.

The potential of CRISPR-Cas9 prime editing for cardiovascular disease research and therapy.

The ability to edit any genomic sequence has led to a better understanding of gene function and holds promise for the development of therapies for genetic diseases. This review describes prime editing - the latest CRISPR-Cas9 genome editing technology. Prime editing enables precise and accurate genome editing in terminally differentiated, postmitotic cells like cardiomyocytes, paving the way for therapeutic applications for genetic cardiomyopathies. Prime editing has been used to precisely insert up to 40 bases, create deletions up to 80 base pairs, and can perform all 12 possible transition and transversion base mutations with lower indels and off-target effects than other genome editing methods. The development of several software tools has simplified the experimental design and led to increased efficiency of the process. Improvements in methods for in-vivo delivery of the prime editing components should enable this technology to be used to edit the genome in patients. Prime editing has the potential to revolutionize the future of biomedical research and transform cardiovascular medicine. Improved understanding of the prime editing process and developments in agent design, efficacy and delivery will benefit scientists and patients and could be an effective way to cure cardiovascular diseases.