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Hypertrophic cardiomyopathy (HCM) progressing to end-stage heart failure and heart transplantation (HT) is a rare clinical scenario with an insufficiently explored genetic background. In this single-center retrospective cohort study, we aimed to characterize the genetic spectrum, variants of HCM adverse remodeling, and aspects of molecular pathogenesis of this subgroup. The study included 14 patients (9 females), among whom 10 developed a dilated/hypokinetic phenotype and 4 a restrictive phenotype. In 13 patients (93%), at least one pathogenic or likely pathogenic genetic variant was identified. Dilated remodeling/hypokinesis was associated with loss-of-function variants in Show less

Heart failure (HF) as the terminal stage of various cardiac diseases, its underlying molecular mechanisms still remain elusive. Emerging evidence have implicated long noncoding RNAs (lncRNAs) play a multifaceted role in the progression of cardiac hypertrophy and HF. Here, it is identified that a lncRNA forkhead box O6, opposite strand (Foxo6os) is significantly downregulated in murine HF model induced using transverse aortic constriction (TAC). Knockdown of Foxo6os accelerates cardiomyocyte hypertrophy, reflects as elevated expression of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and myosin heavy chain 7 (MYH7). Conversely, Foxo6os overexpression can improve cardiac function and alleviate adverse cardiac remodeling. Mechanistically, Foxo6os directly interacts with myosin-binding protein-C (MYBPC3), which then recruits protein kinase C alpha (PKC-α) to facilitate MYBPC3 phosphorylation, resulting in maintaining myocardial contractility and postponing HF progression. Therefore, these findings underscore the critical role of Foxo6os in preserving cardiomyocyte contractile function, suggesting a potential for Foxo6os as a novel therapeutic target of HF. Show less

Hypertrophic cardiomyopathy (HCM) is often characterized by augmented cardiac contractility, which frequently remains undetectable in its early stages. Emerging evidence suggests that hypercontractility is linked to mitochondrial defects that develop early in HCM progression. However, imaging markers for identifying these early alterations in myocardial function are lacking. We used cardiac magnetic resonance feature tracking (CMR-FT) to assess myocardial strain in a Show less

An estimated 1 in 500 people live with hypertrophic cardiomyopathy (HCM), a disease for which genetic diagnosis can identify family members at risk, and increasingly guide therapy. Mutations in the myosin binding protein C3 ( We developed a scaled multidimensional mapping strategy to evaluate the functional impact of variants across a critical domain of MYBPC3. We incorporate saturation base editing at the native Our multidimensional mapping strategy enabled high-resolution functional analysis of This work provides a platform for extending genome engineering in iPSCs to multiplexed assays of variant effects across diverse disease-relevant cellular phenotypes, enhancing the understanding of variant pathogenicity and uncovering novel biological mechanisms that could inform therapeutic strategies. Show less

Familial hypertrophic cardiomyopathy (HCM) is the most common genetic cardiovascular disease (CVD). Related mutations contributing to hypercontractility and poor relaxation in HCM are not completely understood. This study aimed to explore and verify a novel variant of cardiac myosin-binding protein C (cMyBP-C, encoded by MYBPC3) in an HCM family. Clinical information and cardiac parameters were collected in the pedigree. Genomic DNA was extracted from peripheral blood and second-generation sequencing technology was used to investigate the proband and his family members. Subsequent sequence analysis was performed with DNAMAN software. The cardiac expression levels of MYBPC3 mRNA and cMyBP-C protein were assessed using RT-qPCR and Western blot analysis, respectively. Typical interventricular septal thickening was detected in all four HCM patients without left ventricular outflow tract obstruction. The c.1042₁₀₄₃insCGGCA mutation in MYBPC3 was verified in the proband and family members. In silico analysis of the mutation revealed that c.1042₁₀₄₃insCGGCA led to a shift in the sequence of nucleotides, creating a premature stop codon at the new reading frame. RT-qPCR analysis of MYBPC3 mRNA revealed a marked reduction in HCM heart compared to the normal controls (P < 0.05). Consistently, Western blot analysis showed significantly reduced expression of cMyBP-C in the pedigree in comparison with the controls (P < 0.05). The novel c.1042₁₀₄₃insCGGCA MYBPC3 mutation is a genetic basis for HCM due to c-MyBP-C haploinsufficiency. Show less

Mutations in cardiac myosin-binding protein C (cMyBP-C) are a leading cause of hypertrophic cardiomyopathy (HCM). Although most cMyBP-C mutations produce truncated proteins and cause HCM via haploinsufficiency, the mechanisms by which missense mutations result in disease remain poorly understood. Here, we have evaluated three mutations in immunoglobulin-like domains C1 (P161S, Y237S) and C2 (P371R), predicted to be pathogenic for HCM, assessing their effects on cMyBP-C actin-binding function, protein thermal stability, and residue mobility. Using a fluorescence lifetime-based actin-binding assay, we found that N-terminal mutants P161S, Y237S, and P371R enhanced C0-C2 interactions with actin in both unphosphorylated and phosphorylated states, suggesting that the mutations strengthen actin binding and make the binding resistant to phosphorylation-mediated regulation. Differential scanning calorimetry revealed that mutants exhibit destabilized thermal melting profiles with reduced unfolding temperature, energy, and cooperativity. Molecular dynamics simulations indicated that these mutations induce allosteric effects, increasing fluctuations of unstructured loops in C1 or C2 that contain key actin-binding residues. These alterations in protein stability and residue mobility may promote domains to visit binding-competent conformations more frequently, reduce the energetic cost of complex formation, and/or expose actin-interacting interfaces, thereby enhancing C0-C2 binding and contributing to HCM pathogenesis. Show less

Heart failure (HF) is a serious cardiovascular condition resulting from abnormalities in multiple biological processes, affecting over 64 million people worldwide. We sought to expand our understanding of the genetic basis of HF and more specific NICM subtype in the East Asian populations and evaluate the biological pathways underlying subclinical left ventricular dysfunction. We conducted a meta-analysis of genome-wide association studies (GWAS) for all-cause HF in the East Asian populations (N cases ~ 13,385) and a more precise definition of nonischemic cardiomyopathy (NICM) subtype in multi-ancestry populations (N cases~3,603). We identified a low-frequency East-Asian enriched coding variant near MYBPC3 and a NICM specific locus. Follow up analyses demonstrated male-specific HF association at the MYBPC3 locus, and highlighted SVIL as a candidate causal gene for NICM. Moreover, we demonstrated that SVIL deficiency aggravated cardiomyocyte hypertrophy, apoptosis and impaired cell viability in phenylephrine (PE)-treated H9C2 cells. In addition, the gene expression level of B-type natriuretic peptide (BNP) which was deemed as a hallmark for HF was further elevated by SVIL silencing in PE-stimulated H9C2 cells. RNA-sequencing analysis of H9C2 cells revealed that the function of SVIL might be mediated through pathways relevant to regulation and differentiation of heart muscle. These results enhance our understanding of the genetic architecture of HF in the East Asian populations, and provide important insight into the biological pathways underlying NICM and sex-specific relevance of the MYBPC3 locus that warrants further replication in another datasets. Show less

Heart failure is a complex trait, influenced by environmental and genetic factors, affecting over 30 million individuals worldwide. Here we report common-variant and rare-variant association studies of all-cause heart failure and examine how different classes of genetic variation impact its heritability. We identify 176 common-variant risk loci at genome-wide significance in 2,358,556 individuals and cluster these signals into five broad modules based on pleiotropic associations with anthropomorphic traits/obesity, blood pressure/renal function, atherosclerosis/lipids, immune activity and arrhythmias. In parallel, we uncover exome-wide significant associations for heart failure and rare predicted loss-of-function variants in TTN, MYBPC3, FLNC and BAG3 using exome sequencing of 376,334 individuals. We find that total burden heritability of rare coding variants is highly concentrated in a small set of Mendelian cardiomyopathy genes, while common-variant heritability is diffusely spread throughout the genome. Finally, we show that common-variant background modifies heart failure risk among carriers of rare pathogenic truncating variants in TTN. Together, these findings discern genetic links between dysregulated metabolism and heart failure and highlight a polygenic component to heart failure not captured by current clinical genetic testing. Show less

Left ventricular hypertrophy (LVH) refers to the pathological thickening of the myocardial wall and is strongly associated with several adverse cardiac outcomes and sudden cardiac death. While the biomechanical drivers of LVH are well established, growing evidence points to a critical role for cardiac and systemic metabolism in modulating hypertrophic remodeling and disease pathogenesis. Despite the efficiency of fatty acid oxidation (FAO), LVH hearts preferentially increase glucose uptake and catabolism to drive glycolysis and oxidative phosphorylation (OXPHOS). The development of therapies to increase and enhance LFCA FAO is underway, with promising results. However, the mechanisms of systemic metabolic states and LCFA dynamics in the context of cardiac hypertrophy remain incompletely understood. Further, it is unknown to what extent cardiac metabolism is influenced by whole-body energy balance and lipid profiles, despite the common occurrence of lipotoxicity in LVH. In this study, we measured whole-body and cellular respiration along with analysis of lipid and glycogen stores in a mouse model of LVH. We found that loss of the cardiac-specific gene, Show less

Hypertrophic cardiomyopathy (HCM)-associated mutations in sarcomeric proteins lead to the disruption of the actin-myosin interaction and its calcium regulation and cause myocardial hypercontractility. About half of such mutations are found in the Show less

Cardiomyopathy (CM) is a heterogeneous group of diseases characterized by structural and functional changes in the heart, with the exact cause often remaining unknown. CM can arise from both inherited and acquired metabolic disturbances. Alterations in energy production and substrate utilization impair the heart's contractile function and limit its ability to respond to stress. Given the complexity and dynamic nature of CM, as well as the multiple etiologies involved, we reviewed metabolomic studies employing high-throughput platforms to understand how metabolic pathways shift across CM subtypes and how these perturbations may inform clinical translation. Several recurring disruptions emerge across CM with alterations in amino acid metabolism (valine, leucine, methionine, tryptophan, tyrosine); mitochondrial redox imbalance (NAD/NADH shifts, niacinamide, acylcarnitines); and oxidative stress as central hallmarks. Each subtype, however, displays a different emphasis. For instance, hypertrophic CM is characterized by nucleotide remodeling, particularly in cases involving Show less

Hypertrophic cardiomyopathy (HCM) is often caused by pathogenic or likely pathogenic variants, of which 30-50 % involve a variant in the gene encoding cardiac myosin-binding protein-C (MYBPC3). We generated human induced pluripotent stem cell lines from five individuals from two families carrying a pathogenic Dutch MYBPC3 founder variant: c.2373insG (n = 2) and c.2827C > T (n = 3), with highly variable disease expression. Peripheral blood mononuclear cells were reprogrammed using episomal plasmids. All cell lines express pluripotent markers, exhibit a normal karyotype, and could differentiate into derivatives of each germ layers in vitro. These cell lines can serve as disease model to investigate HCM pathogenesis. Show less

Models for estimating the risk of sudden cardiac death (SCD) in pediatric hypertrophic cardiomyopathy (HCM) used in our setting do not consider some parameters of routine clinical practice. The objective was to identify non-classical risk factors and evaluate their prognostic value. Retrospective observational study, including patients with isolated HCM 0-18 years old, evaluating clinical, genetic, and imaging variables. The risk of SCD or major arrhythmic cardiac events (MACEs) was estimated according to the three most widely used European models (HCM Risk-SCD, European Society of Cardiology [ESC] algorithm, and HCM Risk-Kids), analyzing their predictive capacity by adding genotyping and advanced cardiac imaging parameters. The sample included 77 patients followed up for 5.25 years. Ten (13%) experienced a MACE. We found that MACE was significantly associated with myocardial deformation and positive genotype status, and associated, although not significantly, to late gadolinium enhancement (LGE) in cardiac MRI (P = .062). Events were more frequent (hazard ratio = 18.5; P = .006) and occurred earlier (P = .022) in association with variants in genes other than MYBPC3. The inclusion of "genotype other than MYBPC3" and "presence of LGE" improved the predictive capacity of the models for the high-risk (C-statistic 0.94 vs 0.84 with HCM Risk-SCD; 0.88 vs 0.74 with ESC algorithm; 0.90 vs 0.80 with HCM Risk-Kids) and intermediate-risk categories (C-statistic 0.88 vs 0.51 with HCM Risk-SCD; 0.85 vs 0.64 with ESC algorithm; 0.84 vs 0.51 with HCM Risk-Kids). The predictive capacity of European risk models improves by incorporating the variables "genotype other than MYBPC3" and "presence of LGE", although larger studies are required to validate their prognostic value. Show less

Apical hypertrophic cardiomyopathy (HCM) is a rare variant of HCM, often considered to have a benign prognosis. This study aimed to compare the clinical characteristics and genetic predisposition of apical HCM with non-apical HCM. We included 195 patients with HCM who underwent next-generation sequencing at two tertiary centres in South Korea (2017-2024). The primary outcome was a composite of lethal arrhythmic events (LAE), including death, ventricular arrhythmia, implantable cardioverter defibrillator (ICD) implantation and appropriate ICD shock. Secondary outcomes included major adverse cardiovascular events (MACE), such as new-onset atrial fibrillation, ischaemic stroke, heart failure hospitalisation, septal reduction therapy or heart transplant. Of the 195 patients, 67 (34.4%) had apical HCM. Patients with apical HCM were older at diagnosis and had lower maximal left ventricular wall thickness compared with non-apical HCM. Disease-causing variants were less frequent in apical HCM (20.9% vs 46.9%, p<0.001). Although apical HCM is associated with less hypertrophy and lower genetic yield, it is not entirely benign. The presence of disease-causing variants is an important predictor of arrhythmic risk, underscoring the value of genetic testing in all HCM patients, regardless of phenotype. Show less

A woman in her 50s with known MYBPC3-associated obstructive hypertrophic cardiomyopathy was evaluated for septal reduction therapy. The electrocardiogram, echocardiogram, and cardiac magnetic resonance found several features inconsistent with the diagnosis. Targeted screening confirmed adult-onset Fabry disease. Enzyme replacement therapy was started. Show less

The highly conserved long non-coding RNA (lncRNA) MIR505HG has been primarily recognized as a precursor for microRNAs (miR)-424 and miR-503. However, studies have since demonstrated that MIR503HG has distinct functions from its associated miRNAs, playing important roles in cell proliferation, invasion, apoptosis, and differentiation. While these miRNAs are known to influence cardiomyocyte differentiation, the specific role of MIR503HG in heart development remains unexplored. We seek to determine how MIR503HG deletion impacts ventricular chamber development and to identify underlying molecular mechanisms. To study the role of the lncRNA in vivo, we generated a functional MIR503HG knockout mouse model (MIR503HG-/-) using a synthetic polyadenylation signal to terminate MIR503HG transcription without affecting miR-424/503 expression. We performed morphological analyses on embryonic and adult hearts using microCT along with cardiac functional analysis via transthoracic echocardiography. We further apply single-nuclei RNA sequencing (snRNA-seq) on adult hearts to identify potential molecular mechanisms underlying the observed phenotypes. Functional deletion of MIR503HG alone was associated with reduced compact myocardium thickness and increased trabecular myocardium in the left ventricle (LV) at embryonic day 17.5 compared to wild-type mice, indicating a LV non-compaction (LVNC) phenotype. Moreover, adult MIR503HG-/- mutant hearts showed increased trabecular complexity, impaired LV relaxation, and mitral valve regurgitation. SnRNA-seq further revealed altered expression of several genes associated with cardiomyocyte function and LVNC, including Actc1, Mib1, Mybpc3, and Myh7. Lastly, Notch1 activity was also significantly increased in mutant hearts which has been previously associated with LVNC. MIR503HG plays a role in ventricular chamber development, and its deletion leads to an LVNC phenotype independent of the miRNA cluster within its locus, highlighting its importance in cardiac development and disease. We further suggest that abnormal Notch1 activity may underpin the LVNC phenotype presented. Show less

The constant monitoring of the population's diet and assessment of occupational exposure and environmental impacts are the key to determining health risks and understanding the factors contributing to potential abnormalities in developing lifestyle diseases. Extensive long-term lifestyle monitoring studies can provide data on population health risks, including the most common cardiovascular diseases like hypertension. This paper presents research recommendations for future researchers and doctors to improve the diagnosis of hypertension and targeted, personalised treatment. The research proposal includes a lifestyle study, a diagnostic panel with new biomarkers, and an environmental exposure assessment of men working in the metallurgical industry. New developments and improved interventions are constantly being sought, including new biomarkers with high diagnostic utility for cardiovascular diseases like hypertension. This should enable early diagnosis, and consequently allow for appropriate and, most importantly, personalised therapy, and prevent an increase in CVD deaths. Only the effective diagnosis, treatment, and monitoring of hypertension can reduce the risk of developing diseases associated with hypertension. I propose that several new parameters (NO, cfDNA, MPO, PCSK9, MyBPC3, microRNA, TAS, Pb, and Cd) with prognostic and/or predictive potential should be included in screening to confirm the need for the extensive testing of middle-aged men by healthcare professionals due to the risk of hypertension. Show less

During the ejection phase of the cardiac cycle, left ventricular (LV) cardiac myocytes undergo loaded shortening and generate power. However, few studies have measured sarcomere shortening during loaded contractions. Here, we simultaneously monitored muscle length (ML) and sarcomere length (SL) during isotonic contractions in rodent permeabilized LV cardiac myocyte preparations. In permeabilized cardiac myocyte preparations from rats, we found that ML and SL traces were closely matched, as SL velocities were within ∼77% of ML velocities during half-maximal Ca2+ activations. We next tested whether cardiac myosin binding protein-C (cMyBP-C) regulates loaded shortening and power output by modulating cross-bridge availability. We characterized force-velocity and power-load relationships in wildtype (WT) and cMyBP-C deficient (Mybpc3-/-) mouse permeabilized cardiac myocyte preparations, at both the ML and SL level, before and after treatment with the small molecule myosin inhibitor, mavacamten. We found that SL traces closely matched ML traces in both WT and Mybpc3-/- cardiac myocytes. However, Mybpc3-/- cardiac myocytes exhibited disproportionately high sarcomere shortening velocities at high loads. Interestingly, in Mybpc3-/- cardiac myocytes, 0.5 µM mavacamten slowed SL-loaded shortening across the force-velocity curve and normalized SL shortening velocity at high loads. Overall, these results suggest that cMyBP-C moderates sarcomere-loaded shortening, especially at high loads, at least in part, by modulating cross-bridge availability. Show less

Inherited arrhythmias and cardiomyopathies are a group of potentially lethal genetic cardiac disorders which are often passed down through generations and pose risks to several family members. While individually rare, these conditions are collectively common and pose significant challenges for clinical management given their variable severity, age of onset, and response to treatments. Earlier genetic analyses revealed crucial insights into the main genetic culprits of these disorders, such as Show less

BackgroundGenome-wide association studies (GWAS) have identified numerous genetic variants associated with Alzheimer's disease (AD), but their functional implications remain unclear. Transcriptome-wide association studies (TWAS) offer enhanced statistical power by analyzing genetic associations at the gene level rather than at the variant level, enabling assessment of how genetically-regulated gene expression influences AD risk. However, previous AD-TWAS have been limited by small expression quantitative trait loci (eQTL) reference datasets or reliance on AD-by-proxy phenotypes.ObjectiveTo perform the most powerful AD-TWAS to date using summary statistics from the largest available brain and blood Show less

Mutations in the sarcomere protein, particularly in cardiac myosin binding protein C gene ( We used multi-omics approaches and super-resolution imaging to explore the effects of MyBPC3 P459fs mutation on humans and cells. HCM patients carrying MyBPC3 P459fs mutation (MyBPC3-P459fs HCMs) and healthy controls (HCs) were evaluated for myocardial function using both conventional and advanced echocardiography. In parallel, H9C2 myocardial cells infected with either MyBPC3 P459fs mutation (P459fs cells) or its wild type (WT cells) were investigated for myocardial fiber formation and the potential pathways behind this using super-resolution imaging and metabolomics and proteomics. First, conventional and advanced echocardiography showed that MyBPC3-P459fs HCMs exhibited left ventricular diastolic and systolic dysfunction. Subsequently, super-resolution imaging indicated that P459fs cells formed fewer and shorter myocardial fibers in the cytoplasm compared to WT cells. Moreover, our metabolomic and proteomic data suggested several key components of mitochondrial membrane integrity, myocardial remodeling, myocardial energy metabolism, oxidative stress, inflammation, and actin binding capacity were significantly altered in response to P459fs mutation. This investigation indicated myocardial dysfunction and myocardial fiber disarray in clinical HCMs with MyBPC3 P459fs mutation and added potential pathways underlying this. These findings provided a link between the observed structural and functional disorders in MyBPC3 P459fs mutation and its onset of HCM pathogenesis and might have a significant translational contribution to effective treatment in HCM patients with MyBPC3 P459fs mutation. Show less

Cardiomyopathy (CM) is associated with atrial remodeling and atrial fibrillation (AF), often complicating rhythm management. Ventricular dysfunction contributes to AF through pressure and volume overload, while AF worsens ventricular function via tachycardia and irregular activation. Evidence suggests catheter ablation improves outcomes in CM patients, though success is influenced by the extent of atrial and ventricular remodeling. Patients undergoing their first catheter ablation for AF were divided into hypertrophic (HCM), ischemic (ICM), non-ischemic (NICM), and no-CM groups. Pre-ablation late-gadolinium enhancement cardiac magnetic imaging (LGE-MRI) was used to assess left atrial (LA) fibrosis burden and anatomical distribution. Patients were followed prospectively for arrhythmia recurrence. A total of 552 patients, 39 HCM (69% obstructive), 39 ICM, 115 with NICM, and 359 without CM were included between January 2015 and December 2022. LA fibrosis was significantly higher in patients with CM (19.1 ± 7.5% vs. 16.5 ± 6.9%; P = 0.01). HCM and ICM had the greatest LA fibrosis among the different CM subtypes (21.3 ± 8.7% and 21.9 ± 9.1%, respectively). There was no significant difference in the regional distribution of fibrosis among the various groups. AF recurrence was observed in 321 (58.2%) after 456 (175-1204) days. Multivariate analysis revealed that compared to no CM, HCM was associated with a three-fold increase in AF recurrence (HR = 3.07, 95% CI 2.06-4.58, P < 0.001), followed by ICM (HR 1.61, 95%, CI 0.95-2.72; P = 0.07) and NICM (HR of 1.53, 95% CI 1.14-2.06; P = 0.05). LA fibrosis and volume index were independently associated with recurrence (HR = 1.03, 95% CI 1.01-1.06, P = 0.01 and HR = 1.02, 95% CI 1.01-1.03, P = 0.01). Genetic testing revealed key distinctions between HCM and NICM, with MYBPC3 and MYH7 as prominent genes in HCM and a heterogeneous genetic basis in NICM. Hypertrophic cardiomyopathy is associated with the highest risk of AF recurrence followed by ischemic and non-ischemic cardiomyopathy after catheter ablation. LA fibrosis regional patterns did not differ between cardiomyopathy types, while overall fibrosis and volume predicted recurrence. Show less

Phenotypic heterogeneity is apparent among individuals with putative monogenic disease, such as familial hypertrophic cardiomyopathy. Genome sequencing (GS) allows interrogation of the full spectrum of inborn genetic variation in an individual and RNA profiling provides a snapshot of the cardiac-specific pathogenic effects on gene expression. Identify candidate genetic modifiers of hypertrophic cardiomyopathy phenotype. We performed GS of 48 individuals with variants in GS identified the Evaluation of the whole genome, even in the case of alleged monogenic disease, leads to important new insights. The identified variants, regions, and genes are candidates to modify disease presentation in cardiomyopathy. Show less

Hypertrophic cardiomyopathy (HCM) affects approximately 600,000 people in the United States. Loss-of-function mutations in Myosin Binding Protein C3, MYBPC3, are the most common genetic cause of HCM, with the majority of mutations resulting in haploinsufficiency. To restore cardiac MYBPC3, we use an adeno-associated virus (AAV9) vector and engineer an optimized expression cassette with a minimal promoter and cis-regulatory elements (TN-201) to enhance packaging efficiency and cardiomyocyte expression. Rather than simply preventing cardiac dysfunction preclinically, we demonstrate in a symptomatic MYBPC3-deficient murine model the ability of AAV gene therapy to reverse cardiac hypertrophy and systolic dysfunction, improve diastolic dysfunction, and prolong survival. Dose-ranging efficacy studies exhibit restoration of wild-type MYBPC3 protein levels and saturation of cardiac improvement at the clinically relevant dose of 3E13 vg/kg, outperforming a previously published construct. These findings suggest that TN-201 may offer therapeutic benefits in MYBPC3-associated cardiomyopathy, pending further validation in clinical settings. Show less

Human ventriculum myosin (βmys) powers contraction sometimes in complex with myosin binding protein C (MYBPC3). The latter regulates βmys activity and impacts cardiac function. Single residue variants (SRVs) change protein sequence in βmys or MYBPC3 causing inheritable heart diseases by affecting the βmys/MYBPC3 complex. Muscle genetics encode instructions for contraction informing native protein construction, functional integration, and inheritable disease impairment. A digital model decodes these instructions and evolves by processing new information content from diverse data modalities using a human partner-driven virtuous cycle optimization. A general neural-network contraction model characterizes SRV impacts on human health. It rationalizes phenotype and pathogenicity assignment given the SRVs characteristics and, in this sense, decodes βmys/MYBPC3 complex genetics and implicitly captures ventricular muscle functionality. When an SRV modified domain locates to an inter-protein contact in βmys/MYBPC3 it affects complex coordination. Domains involved, one in βmys and the other in MYBPC3, form coordinated domains (co-domains). Bilateral co-domains imply potential for their SRV modification probabilities to respond jointly to a common perturbation revealing location. Human genetic diversity from the serial founder effect is the common systemic perturbation coupling co-domains subsequently mapped by a method called 2-dimensional correlation genetics (2D-CG). Interpreting general neural-network contraction model output involves 2D-CG co-domain mapping providing structural insights with natural language expression. It aligns machine-learned intelligence from the neural network model with human provided structural insight from the 2D-CG map, and other data from the literature, to form a neural-symbolic hybrid model integrating genetic and protein-interaction data into a nascent digital twin. The process forms a template for combining new information content from diverse data modalities into an evolving digital model. This nascent digital twin interprets SRV implications for disease mechanism discovery. Show less

To investigate the clinical features and mutational spectrum underlying hypertrophic cardiomyopathy (HCM) in São Miguel Island (Azores, Portugal), we analyzed 37 adult patients (12 sporadic, 25 familial) with positive genetic tests. Seven disease-causing variants were identified, being two novels, in three sarcomeric genes (MYH7, TNNT2, and MYBPC3) and one non-sarcomeric gene (ALPK3). The novel variants, classified as likely pathogenic (LP), involved large multi-exon deletions in MYBPC3 (exons 26-32 and 28-33). These deletions were found in heterozygosity in two young males who remained clinically stable, though early onset may predict a more severe prognosis. Segregation analysis in a consanguineous family revealed two new genotypes: a digenic heterozygous for MYH7:c.1750G>C (p.Gly584Arg; P) and TNNT2:c.842A>T (p.Asn281Ile; LP) variants, and a homozygous for the TNNT2 variant. The 70-year-old homozygous patient remained stable and without arrhythmic events, challenging the belief that homozygous variants have a worse prognosis. This study is the first molecular and clinical analysis of HCM in the Azores. Show less

Patients with cardiomyopathies are a heterogeneous group of patients who experience high morbidity and mortality. Early cardiac assessment and intervention with access to genetic counselling in a multidisciplinary Cardiomyopathy Clinic may improve outcomes and prevent progression to advanced heart failure. Our prospective cohort study was conducted at a multidisciplinary Cardiomyopathy Clinic with 421 patients enrolled (42.5% female, median age 58 years), including 224 patients with dilated cardiomyopathy (DCM, 42.9% female, median age 57 years), 72 with hypertrophic cardiomyopathy (HCM, 43.1% female, median age 60 years), 79 with infiltrative cardiomyopathy (65.8% female, median age 70 years) and 46 who were stage A/at risk for genetic cardiomyopathy (54.3% female, median age 36 years). Patients were seen in follow-up at a median of 18 months. A pathogenic/likely pathogenic variant was identified in 28.5% of the total cohort, including 33.3% of the DCM cohort (28% TTN mutations) and 34.1% of the HCM cohort (60% MYBPC3 and 20% MYH7) who underwent genetic testing. The use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers/angiotensin receptor neprilysin inhibitor (48.3-69.5% of total cohort, P < 0.001), β-blockers (58.4-72.4%, P < 0.001), mineralocorticoid receptor antagonists (33.9-41.4%, P = 0.0014) and sodium/glucose cotransporter-2 inhibitors (5.3-27.9%, P < 0.001) all increased at follow-up. Precision-based therapies were also implemented, including tafamidis for transthyretin amyloidosis (n = 21), enzyme replacement therapy for Fabry disease (n = 14) and mavacamten (n = 4) for HCM. Optimization of medications and devices resulted in improvements in left ventricular ejection fraction (LVEF) from 27% to 43% at follow-up for DCM patients with reduced LVEF at baseline (P < 0.001) and reduction in left ventricular mass index (LVMI) from 156 g/m Our study demonstrates that a multidisciplinary cardiomyopathy clinic can improve the clinical profiles of patients with diverse genetic cardiomyopathies. Show less