Mutations In Sarcomeric Genes Research Articles

Retrofitting the Heart: Explaining the Enigmatic Septal Thickening in Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy is the most common genetic cardiac disease and is characterized by left ventricular hypertrophy. Although this hypertrophy often associates with sarcomeric gene mutations, nongenetic factors also contribute to the disease, leading to diastolic dysfunction. Notably, this dysfunction manifests before hypertrophy and is linked to hypercontractility, as well as nonuniform contraction and relaxation (myofibril asynchrony) of the myocardium. Although the distribution of hypertrophy in hypertrophic cardiomyopathy can vary both between and within individuals, in most cases, it is primarily confined to the interventricular septum. The reasons for septal thickening remain largely unknown. In this article, we propose that alterations in muscle fiber geometry, present from birth, dictate the septal shape. When combined with hypercontractility and exacerbated by left ventricular outflow tract obstruction, these factors predispose the septum to an isometric type of contraction during systole, consequently constraining its mobility. This contraction, or more accurately, this focal increase in biomechanical stress, prompts the septum to adapt and undergo remodeling. Drawing a parallel, this is reminiscent of how earthquake-resistant buildings are retrofitted with vibration dampers to absorb the majority of the shock motion and load. Similarly, the heart adapts by synthesizing viscoelastic elements such as microtubules, titin, desmin, collagen, and intercalated disc components. This pronounced remodeling in the cytoskeletal structure leads to noticeable septal hypertrophy. This structural adaptation acts as a protective measure against damage by attenuating myofibril shortening while reducing cavity tension according to Laplace Law. By examining these events, we provide a coherent explanation for the septum's predisposition toward hypertrophy.

Target population for a selective cardiac myosin inhibitor in hypertrophic obstructive cardiomyopathy: Real-life estimation from the French register of hypertrophic cardiomyopathy (REMY)

BackgroundThe efficacy of current pharmacological therapies in hypertrophic cardiomyopathy is limited. A cardiac myosin inhibitor, mavacamten, has recently been approved as a first-in-class treatment for symptomatic hypertrophic obstructive cardiomyopathy. AimsTo assess the profile and burden of cardiac myosin inhibitor candidates in the hypertrophic cardiomyopathy prospective Register of hypertrophic cardiomyopathy (REMY) held by the French Society of Cardiology. MethodsData were collected at baseline and during follow-up from patients with hypertrophic cardiomyopathy enrolled in REMY by the three largest participating centres. ResultsAmong 1059 adults with hypertrophic cardiomyopathy, 461 (43.5%) had obstruction; 325 (30.7%) of these were also symptomatic, forming the “cardiac myosin inhibitor candidates” group. Baseline features of this group were: age 58±15years; male sex (n=196; 60.3%); diagnosis-to-inclusion delay 5 (1–12)years; maximum wall thickness 20±6mm; left ventricular ejection fraction 69±6%; family history of hypertrophic cardiomyopathy or sudden cardiac death (n=133; 40.9%); presence of a pathogenic sarcomere gene mutation (n=101; 31.1%); beta-blocker or verapamil treatment (n=304; 93.8%), combined with disopyramide (n=28; 8.7%); and eligibility for septal reduction therapy (n=96; 29%). At the end of a median follow-up of 66 (34–106) months, 319 (98.2%) were treated for obstruction (n=43 [13.2%] received disopyramide), 46 (14.2%) underwent septal reduction therapy and the all-cause mortality rate was 1.9/100 person-years (95% confidence interval 1.4–2.6) (46 deaths). Moreover, 41 (8.9%) patients from the initial hypertrophic obstructive cardiomyopathy group became eligible for a cardiac myosin inhibitor. ConclusionsIn this cohort of patients with hypertrophic cardiomyopathy selected from the REMY registry, one third were eligible for a cardiac myosin inhibitor.

Electrophysiological Characterization of Subclinical and Overt Hypertrophic Cardiomyopathy by Magnetic Resonance Imaging-Guided Electrocardiography

BackgroundVentricular arrhythmia in hypertrophic cardiomyopathy (HCM) relates to adverse structural change and genetic status. Cardiovascular magnetic resonance (CMR)–guided electrocardiographic imaging (ECGI) noninvasively maps cardiac structural and electrophysiological (EP) properties. ObjectivesThe purpose of this study was to establish whether in subclinical HCM (genotype [G]+ left ventricular hypertrophy [LVH]−), ECGI detects early EP abnormality, and in overt HCM, whether the EP substrate relates to genetic status (G+/G−LVH+) and structural phenotype. MethodsThis was a prospective 211-participant CMR-ECGI multicenter study of 70 G+LVH−, 104 LVH+ (51 G+/53 G−), and 37 healthy volunteers (HVs). Local activation time (AT), corrected repolarization time, corrected activation-recovery interval, spatial gradients (GAT/GRTc), and signal fractionation were derived from 1,000 epicardial sites per participant. Maximal wall thickness and scar burden were derived from CMR. A support vector machine was built to discriminate G+LVH− from HV and low-risk HCM from those with intermediate/high-risk score or nonsustained ventricular tachycardia. ResultsCompared with HV, subclinical HCM showed mean AT prolongation (P = 0.008) even with normal 12-lead electrocardiograms (ECGs) (P = 0.009), and repolarization was more spatially heterogenous (GRTc: P = 0.005) (23% had normal ECGs). Corrected activation-recovery interval was prolonged in overt vs subclinical HCM (P < 0.001). Mean AT was associated with maximal wall thickness; spatial conduction heterogeneity (GAT) and fractionation were associated with scar (all P < 0.05), and G+LVH+ had more fractionation than G−LVH+ (P = 0.002). The support vector machine discriminated subclinical HCM from HV (10-fold cross-validation accuracy 80% [95% CI: 73%-85%]) and identified patients at higher risk of sudden cardiac death (accuracy 82% [95% CI: 78%-86%]). ConclusionsIn the absence of LVH or 12-lead ECG abnormalities, HCM sarcomere gene mutation carriers express an aberrant EP phenotype detected by ECGI. In overt HCM, abnormalities occur more severely with adverse structural change and positive genetic status.

Hypertrophic cardiomyopathy in MYBPC3 carriers in aging.

Hypertrophic cardiomyopathy (HCM) is characterized by abnormal thickening of the myocardium, leading to arrhythmias, heart failure, and elevated risk of sudden cardiac death, particularly among the young. This inherited disease is predominantly caused by mutations in sarcomeric genes, among which those in the cardiac myosin binding protein-C3 (MYBPC3) gene are major contributors. HCM associated with MYBPC3 mutations usually presents in the elderly and ranges from asymptomatic to symptomatic forms, affecting numerous cardiac functions and presenting significant health risks with a spectrum of clinical manifestations. Regulation of MYBPC3 expression involves various transcriptional and translational mechanisms, yet the destiny of mutant MYBPC3 mRNA and protein in late-onset HCM remains unclear. Pathogenesis related to MYBPC3 mutations includes nonsense-mediated decay, alternative splicing, and ubiquitin-proteasome system events, leading to allelic imbalance and haploinsufficiency. Aging further exacerbates the severity of HCM in carriers of MYBPC3 mutations. Advancements in high-throughput omics techniques have identified crucial molecular events and regulatory disruptions in cardiomyocytes expressing MYBPC3 variants. This review assesses the pathogenic mechanisms that promote late-onset HCM through the lens of transcriptional, post-transcriptional, and post-translational modulation of MYBPC3, underscoring its significance in HCM across carriers. The review also evaluates the influence of aging on these processes and MYBPC3 levels during HCM pathogenesis in the elderly. While pinpointing targets for novel medical interventions to conserve cardiac function remains challenging, the emergence of personalized omics offers promising avenues for future HCM treatments, particularly for late-onset cases.

Analyzing safety and effectiveness of Mavacamten in comparison with placebo for managing hypertrophic cardiomyopathy: a systemic review and meta-analysis

BackgroundHypertrophic cardiomyopathy (HCM) is a hereditary myocardial disorder, often due to sarcomere gene mutations, characterized by the left ventricular hypertrophy. Current treatments offer symptomatic relief but lack specificity. Mavacamten, an allosteric inhibitor, has shown significant improvements in HCM patients in trials, reducing the requirement for invasive treatments. This meta-analysis assesses Mavacamten’s efficacy and safety as a targeted HCM intervention.MethodsThis study examined four randomized controlled trials comparing Mavacamten to placebo in HCM patients. Each trial had a unique primary endpoint, and secondary outcomes included improvements in NYHA-FC, eligibility for septal reduction therapy (SRT) or undergoing it, adverse events (serious and treatment-related), atrial fibrillation, and non-sustained ventricular tachycardia. Statistical analysis involved calculating risk ratios (RRs) and assessing heterogeneity.ResultsThe four included studies showed minimal risk of bias and involved 503 patients with HCM (273 Mavacamten and 230 placebo). Mavacamten significantly increased the primary endpoint (RR 2.15, 95% CI 1.20–3.86, P = 0.01) and ≥ 1 NYHA-FC class (RR 2.21, 95% CI 1.48–3.3, P = 0.0001). Mavacamten group had lower rates of SRT compared to those receiving placebo (RR, 0.30, 95% CI 0.22–0.40; P < 0.00001). No significant differences existed in rates adverse events between the Mavacamten and placebo groups.ConclusionsOur study suggests that Mavacamten may have therapeutic benefits for HCM patients, as indicated by its positive impact on certain endpoints. Further research with larger samples, longer follow-up, and comprehensive analysis is needed to understand Mavacamten’s safety and efficacy in HCM patients.

The challenge of risk stratification in hypertrophic cardiomyopathy: clinical, genetic and imaging insights from a quaternary referral centre

Abstract Background Hypertrophic cardiomyopathy (HCM) is the commonest genetic cardiomyopathy and may result in sudden cardiac death (SCD). Clinical risk stratification scores are utilised to estimate SCD risk and determine potential utility of a primary prevention implantable cardioverter defibrillator (ICD). Methods Patients with a confirmed diagnosis of HCM from a quaternary HCM service were defined according to clinical characteristics, genetic profiles and cardiac imaging results. European Risk-SCD score and American Heart Association / American College of Cardiology (AHA/ACC) Score were calculated. The primary outcome was cardiac arrest. Results 380 patients with HCM were followed up for a median of 6.4 years. 18 patients (4.7%) experienced cardiac arrest, with predictive factors being younger age (37.2 vs 54.4 years, p=0.0041), unexplained syncope (33.3% vs 9.4%, p=0.007), non-sustained ventricular tachycardia (50.0% vs 12.7%, p&amp;lt;0.0001), increased septal thickness (21.5 vs 17.5mm, p=0.0003), and presence of a sarcomeric gene mutation (100.0% vs 65.8%, p=0.038). The Risk-SCD and AHA/ACC scores had poor agreement (kappa coefficient 0.38). Risk-SCD score had poor sensitivity (44.4%), classifying 55.6% of patients with cardiac arrest as low-risk but was highly specific (93.7%). AHA/ACC risk score did not discriminate between groups significantly. 20 patients (5.3%) died, with most &amp;gt;60-year-olds having a non-cardiac cause of death (p=0.0223). Conclusion This study highlights limited (38%) agreement between the Risk-SCD and AHA/ACC scores. Most cardiac arrests occurred in ostensibly low or medium-risk patients under both scores. Appropriate ICD selection remains challenging. Utilising newer markers such as cardiac MRI and genetic findings may assist future risk refinement.

Assessment of Myocardial Work in sarcomere gene mutation carriers and overt hypertrophic cardiomyopathy

Abstract Introduction Hypertrophic cardiomyopathy (HCM) is a common genetic heart disease defined by unexplained hypertrophy and often characterized by diastolic and systolic dysfunction. In recent studies, HCM patients were found to have impaired left ventricular (LV) myocardial work (MW), a more load-independent parameter compared to global longitudinal strain (GLS). MW was never studied in sarcomere mutation carriers. Aim To compare MW between sarcomere mutation carriers, healthy controls and overt HCM. Methods A single centre study with a case-control design. The study population comprised 3 groups: overt HCM patients with a likely pathogenic/pathogenic sarcomere gene variant (n=51), carriers (n=51) and age and sex matched (to the carriers) healthy controls (n=32). All participants (pts) underwent a transthoracic echocardiogram including myocardial deformation analysis to calculate global longitudinal strain (GLS) and MW. MW was calculated from same-day non-invasive blood pressure evaluation. Global work index (GWI), Global constructive work (GCW), Global work efficiency (GWE) and Global wasted work (GWW) were obtained. Results GWI (1695mmHg% vs 1869mmHg%, p=0.001) and GCW (1993mmHg% vs 2244mmHg%, p&amp;lt;0.001) were lower in sarcomere mutation carriers compared to controls. LVEF and GLS were similar between the two groups (p=0.233). HCM pts were older (p&amp;lt;0.001), less likely female (p=0.01) and had a higher prevalence of cardiovascular (Cv) comorbidities, including hypertension (p&amp;lt;0.001), compared with sarcomere gene mutation carriers. Global work index (GWI) (1209mmHg%vs1695mmHg%), global constructive work (1456mmHg% vs 1993mmHg%, p&amp;lt;0.001) and global work efficiency (GWE) (89% vs 95%, p&amp;lt;0.001) were significantly lower in overt HCM compared with sarcomere mutation carriers. GWW was higher (117mmHg% vs 95mmHg%, p=0.006) in overt HCM. Conclusion In this study, we show for the first time that MW indexes were significantly worse in sarcomere gene mutation carriers compared to controls. GLS and MW indexes were also significantly different between overt HCM and sarcomere gene mutation carriers. These data suggest that MW is more sensitive to early changes than GLS and could play a major role in the evaluation and follow-up of sarcomere mutation carriers.

Abstract 14463: Beyond Sarcomere Mutations Plakophilin-2 and Familial Hypertrophic Cardiomyopathy

Background: Hypertrophic cardiomyopathy (HCM) is a genetically heterogeneous disorder with diverse clinical presentation, course and outcomes. It is commonly caused by mutations in sarcomeric genes. Non-sarcomeric gene mutations have been associated with HCM in certain metabolic and storage diseases. Pathogenic mutations in plakophilin-2 (PKP2) gene have been associated with enhanced desmosomal protein degradation and linked to arrhythmogenic right ventricular cardiomyopathy (ARVC), Brugada syndrome and dilated cardiomyopathy. We report an association between PKP2 gene mutation and familial HCM. Case presentation: A 65-year-old man with family history of HCM (maternal grandfather, 2 aunts and an uncle) presented with dyspnea on exertion (NYHA class II-III) and pedal edema. Echo showed severe LVH, mid-cavitary obstruction and LV apical aneurysm. Cardiac MRI confirmed findings (Figure:A and B) and additionally showed significant late gadolinium enhancement (Figure:C and D, &gt;20% of LV myocardium). Extended ambulatory heart monitor detected frequent runs on non-sustained ventricular tachycardia. A primary prevention ICD was implanted. Genetic testing identified a pathogenic mutation [c.1237C&gt;T (p.Arg413*)] in exon 5 of PKP2 gene resulting in premature translational stop signal and disrupted desmosomal protein plakophilin-2. Family screening (Figure:E) identified a sister with positive results who also had non-obstructive HCM (Figure:E). Discussion: We present a family with typical presentations of HCM and no phenotypic evidence of ARVC. This novel observation provides evidence for pleiotropic model of complex genotype-phenotype interactions through nonlinear networks. Further evidence would be needed to understand potential molecular basis of hypertrophic signaling in PKP2 gene mutation.

Abstract 16516: CMR-ECG Imaging in Hypertrophic Cardiomyopathy Detects Electrophysiological Abnormalities Before Hypertrophy or ECG Changes

INTRODUCTION: In hypertrophic cardiomyopathy (HCM), ventricular arrhythmia associates with severity of LVH and scar, and presence vs absence of a sarcomeric gene mutation (G+LVH+ vs G-LVH+). Also, ECG changes in subclinical HCM (G+LVH-) signal increased risk of phenotype progression. HYPOTHESES: ECG Imaging (ECGI) can detect: i) subtle electrophysiological (EP) abnormalities in subclinical HCM (pre-LVH). ii) EP abnormalities related to genetic status (G+ vs G-LVH+) and structural changes (late gadolinium enhancement [LGE], max. wall thickness [MWT]) in overt disease. METHODS: 200 participant multicenter study: 70 G+LVH-, 51 G+LVH+, 53 G-LVH+ and 26 healthy volunteers (HV) underwent 12-lead ECG (to detect abnormal Q-waves, repolarization changes, LVH criteria) and CMR-ECGI computing epicardial unipolar electrograms (UEGs) to derive: activation time (AT), activation-recovery intervals (ARIc), spatial gradients (activation: G AT , repolarisation: G RT ) and fractionation. RESULTS: Compared to HV, G+LVH- had prolongation of AT (40.3±7.3 vs 35.4±6.1 ms p=0.003) and steeper G RT (mean: 1.12±0.27 vs 1.00±0.23 ms/mm p=0.042, max: 11.7±2.8 vs 10.0±1.9 ms/mm p=0.005). AT was prolonged even in G+LVH- with a normal 12-lead ECG (p&lt;0.004). Compared to G+LVH-, G+LVH+ had similar AT but a more prolonged ARIc (275±29 vs 245±26 ms p&lt;0.001). Compared to G-LVH+, G+LVH+ had similar MWT and LGE, but more signal fractionation (0.02±0.02 vs 0.01±0.03% UEGs with ≥2 deflections p=0.002). In overt HCM (all LVH+), MWT associated with AT ( r s 0.25 p=0.011) while LGE burden associated with G AT ( r s=0.27 p=0.006) and fractionation ( r s=0.22 p=0.025). CONCLUSION: Cardiac activation prolongation and repolarization abnormalities occur in subclinical HCM (before hypertrophy). Activation is prolonged even in subclinical HCM with normal 12-lead ECG. In overt HCM, ECGI abnormalities track adverse structural changes and reveal greater fractionation in those with a sarcomeric mutation.

Abstract 12408: Response to Mavacamten by Sarcomere Gene Mutation Status in EXPLORER-HCM

Background: Mavacamten is a small molecule inhibitor of cardiac myosin that was developed based on insights into the molecular basis of hypertrophic cardiomyopathy (HCM). In the phase 3 EXPLORER-HCM trial (NCT03470545), patients showed consistent benefit in the primary endpoint with mavacamten treatment vs placebo while subgroup analysis of patients with pathogenic or likely pathogenic variants in a broad panel of HCM-related genes, revealed a slightly more favorable response. However, it is unknown how patients specifically with sarcomere gene variants responded. Aims: To assess the effect of HCM-specific sarcomere gene variants on response to mavacamten. Methods: Sequencing using a 60 gene panel (Invitae) was optional in EXPLORER-HCM. In this exploratory analysis, responses to mavacamten vs placebo for the primary, secondary, and exploratory endpoints were analysed. Patients were grouped based on sarcomere gene variant status (positive for pathogenic/likely pathogenic/variants of uncertain significance [SARC+], negative [SARC–]) or no sequencing). Analyses were adjusted for clinically relevant variables. Results: Of 190/251 patients sequenced, 73 were SARC+ (mavacamten, n = 33; placebo, n = 40), 117 were SARC– (mavacamten, n = 57; placebo, n = 60) and 61 had no panel sequencing (mavacamten, n = 33; placebo, n = 28). Mavacamten treatment showed a favorable response for the primary endpoint vs placebo, for SARC+ (odds ratio [OR], 4.43 [95% CI, 1.56-12.58]), and for SARC– (OR, 2.52 [95% CI, 0.99-6.42]) ( Figure ). Improvements with mavacamten vs placebo were observed in both SARC+ and SARC– subgroups for change from baseline to week 30 in post-exercise left ventricular outflow tract gradient, and peak oxygen consumption, and in New York Heart Association class. Conclusions: In this exploratory subgroup analysis, mavacamten treatment benefit was observed both in patients with and without sarcomere gene variants.

MDM2 Regulation of HIF Signaling Causes Microvascular Dysfunction in Hypertrophic Cardiomyopathy.

Microvasculature dysfunction is a common finding in pathologic remodeling of the heart and is thought to play an important role in the pathogenesis of hypertrophic cardiomyopathy (HCM), a disease caused by sarcomere gene mutations. We hypothesized that microvascular dysfunction in HCM was secondary to abnormal microvascular growth and could occur independent of ventricular hypertrophy. We used multimodality imaging methods to track the temporality of microvascular dysfunction in HCM mouse models harboring mutations in the sarcomere genes Mybpc3 (cardiac myosin binding protein C3) or Myh6 (myosin heavy chain 6). We performed complementary molecular methods to assess protein quantity, interactions, and post-translational modifications to identify mechanisms regulating this response. We manipulated select molecular pathways in vivo using both genetic and pharmacological methods to validate these mechanisms. We found that microvascular dysfunction in our HCM models occurred secondary to reduced myocardial capillary growth during the early postnatal time period and could occur before the onset of myocardial hypertrophy. We discovered that the E3 ubiquitin protein ligase MDM2 (murine double minute 2) dynamically regulates the protein stability of both HIF1α (hypoxia-inducible factor 1 alpha) and HIF2α (hypoxia-inducible factor 2 alpha)/EPAS1 (endothelial PAS domain protein 1) through canonical and noncanonical mechanisms. The resulting HIF imbalance leads to reduced proangiogenic gene expression during a key period of myocardial capillary growth. Reducing MDM2 protein levels by genetic or pharmacological methods normalized HIF protein levels and prevented the development of microvascular dysfunction in both HCM models. Our results show that sarcomere mutations induce cardiomyocyte MDM2 signaling during the earliest stages of disease, and this leads to long-term changes in the myocardial microenvironment.

ERRγ agonist under mechanical stretching manifests hypertrophic cardiomyopathy phenotypes of engineered cardiac tissue through maturation

Engineered cardiac tissue (ECT) using human induced pluripotent stem cell-derived cardiomyocytes is a promising tool for modeling heart disease. However, tissue immaturity makes robust disease modeling difficult. Here, we established a method for modeling hypertrophic cardiomyopathy (HCM) malignant (MYH7 R719Q) and nonmalignant (MYBPC3 G115∗) pathogenic sarcomere gene mutations by accelerating ECT maturation using an ERRγ agonist, T112, and mechanical stretching. ECTs treated with T112 under 10% elongation stimulation exhibited more organized and mature characteristics. Whereas matured ECTs with the MYH7 R719Q mutation showed broad HCM phenotypes, including hypertrophy, hypercontraction, diastolic dysfunction, myofibril misalignment, fibrotic change, and glycolytic activation, matured MYBPC3 G115∗ ECTs displayed limited phenotypes, which were primarily observed only under our new maturation protocol (i.e., hypertrophy). Altogether, ERRγ activation combined with mechanical stimulation enhanced ECT maturation, leading to a more accurate manifestation of HCM phenotypes, including non-cardiomyocyte activation, consistent with clinical observations.

The challenge of risk stratification in hypertrophic cardiomyopathy: Clinical, genetic and imaging insights from a quaternary referral centre

BackgroundHypertrophic cardiomyopathy (HCM) is the commonest genetic cardiomyopathy and may result in sudden cardiac death (SCD). Clinical risk stratification scores are utilised to estimate SCD risk and determine potential utility of a primary prevention implantable cardioverter defibrillator (ICD). MethodsPatients with a confirmed diagnosis of HCM from a quaternary HCM service were defined according to clinical characteristics, genetic profiles and cardiac imaging results. European Risk-SCD score and American Heart Association / American College of Cardiology (AHA/ACC) Score were calculated. The primary outcome was cardiac arrest. Results380 patients with HCM were followed up for a median of 6.4 years. 18 patients (4.7%) experienced cardiac arrest, with predictive factors being younger age (37.2 vs 54.4 years, p = 0.0041), unexplained syncope (33.3% vs 9.4%, p = 0.007), non-sustained ventricular tachycardia (50.0% vs 12.7%, p < 0.0001), increased septal thickness (21.5 vs 17.5 mm, p = 0.0003), and presence of a sarcomeric gene mutation (100.0% vs 65.8%, p = 0.038). The Risk-SCD and AHA/ACC scores had poor agreement (kappa coefficient 0.38). Risk-SCD score had poor sensitivity (44.4%), classifying 55.6% of patients with cardiac arrest as low-risk but was highly specific (93.7%). AHA/ACC risk score did not discriminate between groups significantly. 20 patients (5.3%) died, with most >60-year-olds having a non-cardiac cause of death (p = 0.0223). ConclusionThis study highlights limited (38%) agreement between the Risk-SCD and AHA/ACC scores. Most cardiac arrests occurred in ostensibly low or medium-risk patients under both scores. Appropriate ICD selection remains challenging. Incorporating newer risk markers such as HCM genotyping and myocardial fibrosis quantification by cardiac MRI may assist future risk refinement.

RAF1 mutation leading to hypertrophic cardiomyopathy in a Chinese family with a history of sudden cardiac death: A diagnostic insight into Noonan syndrome.

Hypertrophic cardiomyopathy (HCM) is predominantly caused by mutations in sarcomeric genes. However, a subset of cases is attributed to genetic disorders unrelated to sarcomeric genes, such as Noonan syndrome (NS) and other RASopathies. In this study, we present a family with a history of sudden cardiac death (SCD) and focus on two adults with syndromic left ventricular hypertrophy (LVH). Clinical evaluations, including echocardiography, were conducted to assess cardiac manifestations. Whole-exome sequencing was performed to identify potential genetic variants underlying syndromic LVH in the study participants. Whole-exome sequencing revealed a missense variant in the RAF1 gene, c.782C>T (p.Pro261Leu). This variant confirmed the diagnosis of NS in the affected individuals. The findings of this study underscore the importance of family history investigation and genetic testing in diagnosing syndromic LVH. By identifying the underlying genetic cause, clinicians can better understand the etiology of RAS-HCM and its association with SCD in young adults.

The cardioprotective potential of melatonin on cardiac hypertrophy: A mechanistic overview

Cardiac hypertrophy (CH) is an increment of muscle mass to maintain the heart regular operations. A physiological cardiac hypertrophy due to exercise or other normal physiological process is characterized by normal contractile function and structural framework of heart tissue. In contrast, pathological hypertrophy occurs in response to increased pressure or volume overload from several cardiovascular diseases including hypertension, valvular diseases, cardiac infarction and heart failure. It is of major concern as it is one of the leading causes of death worldwide. Despite much progress in this field there is a scope for understanding of the molecular mechanisms of this condition. In this review, various types of cardiac hypertrophy and their intricate physio-pathological mechanisms have been discussed. In addition, the genetic mutations in sarcomere genes and oxidative stress are also closely linked to hypertrophic cardiomyopathy. Although several drugs against cardiac hypertrophy have been used, it appears that melatonin, due to its high bioavailability and low side effects, is a better candidate than the conventional medicine for treatment of hypertrophic cardiomyopathy. Melatonin, a hormone and a potent antioxidant, is secreted mainly from the pineal gland, but it is also synthesized from different peripheral tissues including the heart. This molecule can regulate a myriad of cellular functions. It can protect against cardiac hypertrophy via reducing oxidative stress, elevating Cu-Mn SOD via controlling several cell signalling pathways of Akt/mTOR, ROR-α and NLRP3 cascades. Melatonin also mitigates cardiac hypertrophy by suppressing pro-inflammatory cytokines including TNF-α and TGF-β and cardiac hypertrophy markers like β-MHC, ANP, BNP, LDH. This review focuses on the molecular mechanisms of cardiac hypertrophy and the defensive role of melatonin on it. We propose melatoninas a propitious adjunct for the treatment of cardiac hypertrophy.

Gene-echocardiography: refining genotype-phenotype correlations in hypertrophic cardiomyopathy.

This study aims to clarify the association between hypertrophic patterns and genetic variants in hypertrophic cardiomyopathy (HCM) patients, contributing to the advancement of personalized management strategies for HCM. A comprehensive evaluation of genetic mutations was conducted in 392 HCM-affected families using Whole Exome Sequencing. Concurrently, relevant echocardiographic data from these individuals were collected. Our study revealed an increased susceptibility to enhanced septal and interventricular septal thickness in HCM patients harbouring gene mutations compared with those without. Mid-septal hypertrophy was found to be associated predominantly with myosin binding protein C3 (MYBPC3) variants, while a higher septum-to-posterior wall ratio correlated with myosin heavy chain 7 (MYH7) variants. Mutations in MYH7, MYBPC3, and other sarcomeric or myofilament genes (troponin I3 [TNNI3], tropomyosin 1 [TPM1], and troponin T2 [TNNT2]) showed a relationship with increased hypertrophy in the anterior wall, interventricular septum, and lateral wall of the left ventricle. In contrast, alpha kinase 3 (ALPK3)-associated hypertrophy chiefly presented in the apical region, while hypertrophy related to titin (TTN) and obscurin (OBSCN) mutations exhibited a uniform distribution across the myocardium. Hypertrophic patterns varied with the type and category of gene mutations, offering valuable diagnostic insights. Our findings underscore a strong link between hypertrophic patterns and genetic variants in HCM, providing a foundation for more accurate genetic testing and personalized management of HCM patients. The novel concept of 'gene-echocardiography' may enhance the precision and efficiency of genetic counselling and testing in HCM.

Abstract P2046: The Role Of A Novel Alpha-crystallin B Chain Variant In Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is a common inherited cardiovascular disorder affecting 1 in 500 people in the general population. Characterized by asymmetric left ventricular hypertrophy, cardiomyocyte disarray and cardiac fibrosis, HCM is a highly complex disease with heterogenous clinical presentation. While mutations in sarcomere genes can account for a substantial proportion of familial cases, 40-50% of HCM patients do not carry such sarcomere variants and the causal mutations for their diseases remain elusive. Recently, we identified a novel variant of the alpha-crystallin B chain (CRYAB R123W ) in a pair of homozygotic twins who developed concordant HCM phenotypes that manifested over a nearly identical time course. Yet, how CRYAB R123W promotes HCM phenotype remains unclear. Here, we generated mice carrying the Cryab R123W -knockin allele and demonstrated that hearts from these animals exhibit increased maximal elastance, reduced diastolic function and are more susceptible to ventricular tachycardia with programmed stimulation. Upon transverse aortic constriction, mice carrying the Cryab R123W allele developed pathogenic left ventricular hypertrophy with substantial cardiac fibrosis and progressively decreased ejection fraction. In contrast to another well-characterized CRYAB variant (R120G) which induced Desmin aggregation, no evidence of protein aggregation was observed in hearts expressing CRYAB R123W despite its potent effect on driving cellular hypertrophy. Unexpectedly, CRYAB R123W appears to enhance calcium signaling by promoting nuclear localization of NFAT through direct interaction with calcineurin. Studies on isolated adult cardiomyocytes reveal altered fractional shortening, calcium dyshomeostasis, prolonged action potential duration, and T-wave alternans. Crossing of CRYAB R123W mice with a mybpc3 knock-in model of HCM did not potentiate pathological hypertrophy in compound heterozygotes, indicating that the pathological mechanisms in this model are independent of the sarcomere. Thus, our data establish the Cryab R123W allele as a novel genetic model of HCM that potentially unveils additional sarcomere-independent mechanisms of cardiac pathological hypertrophy and sudden cardiac death.

Hypertrophic Cardiomyopathy: Genetic Foundations, Outcomes, Interconnections, and Their Modifiers.

Hypertrophic cardiomyopathy (HCM) is the most prevalent heritable cardiomyopathy. HCM is considered to be caused by mutations in cardiac sarcomeric protein genes. Recent research suggests that the genetic foundation of HCM is much more complex than originally postulated. The clinical presentations of HCM are very variable. Some mutation carriers remain asymptomatic, while others develop severe HCM, terminal heart failure, or sudden cardiac death. Heterogeneity regarding both genetic mutations and the clinical course of HCM hinders the establishment of universal genotype-phenotype correlations. However, some trends have been identified. The presence of a mutation in some genes encoding sarcomeric proteins is associated with earlier HCM onset, more severe left ventricular hypertrophy, and worse clinical outcomes. There is a diversity in the mechanisms implicated in the pathogenesis of HCM. They may be classified into groups, but they are interrelated. The lack of known supplementary elements that control the progression of HCM indicates that molecular mechanisms that exist between genotype and clinical presentations may be crucial. Secondary molecular changes in pathways implicated in HCM pathogenesis, post-translational protein modifications, and epigenetic factors affect HCM phenotypes. Cardiac loading conditions, exercise, hypertension, diet, alcohol consumption, microbial infection, obstructive sleep apnea, obesity, and environmental factors are non-molecular aspects that change the HCM phenotype. Many mechanisms are implicated in the course of HCM. They are mostly interconnected and contribute to some extent to final outcomes.

Systolic anterior motion of the anterior mitral valve leaflet begins in subclinical hypertrophic cardiomyopathy.

Anterior mitral valve leaflet (AMVL) elongation is detectable in overt and subclinical hypertrophic cardiomyopathy (HCM). We sought to investigate the dynamic motion of the aorto-mitral apparatus to understand the behaviour of the AMVL and the mechanisms of left ventricular outflow tract obstruction (LVOTO) predisposition in HCM. Cardiovascular magnetic resonance imaging using a 1.5 Tesla scanner was performed on 36 HCM sarcomere gene mutation carriers without left ventricular hypertrophy (G+LVH-), 31 HCM patients with preserved ejection fraction carrying a pathogenic sarcomere gene mutation (G+LVH+), and 53 age-, sex-, and body surface area-matched healthy volunteers. Dynamic excursion of the aorto-mitral apparatus was assessed semi-automatically on breath-held three-chamber cine steady-state free precession images. Four pre-defined regions of interest (ROIs) were tracked: ROIPMVL: hinge point of the posterior mitral valve leaflet; ROITRIG: intertrigonal mitral annulus; ROIAMVL: AMVL tip; and ROIAAO: anterior aortic annulus. Compared with controls, normalized two-dimensional displacement-vs.-time plots in G+LVH- revealed subtle but significant systolic anterior motion (SAM) of the AMVL (P < 0.0001) and reduced longitudinal excursion of ROIAAO (P = 0.014) and ROIPMVL (P = 0.048). In overt and subclinical HCM, excursion of the ROITRIG/AMVL/PMVL was positively associated with the burden of left ventricular fibrosis (P < 0.028). As expected, SAM was observed in G+LVH+ together with reduced longitudinal excursion of ROITRIG (P = 0.049) and ROIAAO (P = 0.008). Dyskinesia of the aorto-mitral apparatus, including SAM of the elongated AMVL, is detectable in subclinical HCM before the development of LVH or left atrial enlargement. These data have the potential to improve our understanding of early phenotype development and LVOTO predisposition in HCM.

The Definition of Sarcomeric and Non-Sarcomeric Gene Mutations in Hypertrophic Cardiomyopathy Patients: A Multicenter Diagnostic Study Across Türkiye.

Hypertrophic cardiomyopathy is a common genetic heart disease and up to 40%-60% of patients have mutations in cardiac sarcomere protein genes. This genetic diagnosis study aimed to detect pathogenic or likely pathogenic sarcomeric and non-sarcomeric gene mutations and to confirm a final molecular diagnosis in patients diagnosed with hypertrophic cardiomyopathy. A total of 392 patients with hypertrophic cardiomyopathy were included in this nationwide multicenter study conducted at 23 centers across Türkiye. All samples were analyzed with a 17-gene hypertrophic cardiomyopathy panel using next-generation sequencing technology. The gene panel includes ACTC1, DES, FLNC, GLA, LAMP2, MYBPC3, MYH7, MYL2, MYL3, PLN, PRKAG2, PTPN11, TNNC1, TNNI3, TNNT2, TPM1, and TTR genes. The next-generation sequencing panel identified positive genetic variants (variants of unknown significance, likely pathogenic or pathogenic) in 12 genes for 121 of 392 samples, including sarcomeric gene mutations in 30.4% (119/392) of samples tested, galactosidase alpha variants in 0.5% (2/392) of samples and TTR variant in 0.025% (1/392). The likely pathogenic or pathogenic variants identified in 69 (57.0%) of 121 positive samples yielded a confirmed molecular diagnosis. The diagnostic yield was 17.1% (15.8% for hypertrophic cardiomyopathy variants) for hypertrophic cardiomyopathy and hypertrophic cardiomyopathy phenocopies and 0.5% for Fabry disease. Our study showed that the distribution of genetic mutations, the prevalence of Fabry disease, and TTR amyloidosis in the Turkish population diagnosed with hypertrophic cardiomyopathy were similar to the other populations, but the percentage of sarcomeric gene mutations was slightly lower.