Cardiac involvement is a major feature of RASopathies, a group of phenotypically overlapping syndromes caused by germline mutations in genes encoding components of the RAS/MAPK (mitogen-activated protein kinase) signaling pathway. In particular, Noonan syndrome (NS) is associated with a wide spectrum of cardiac pathologies ranging from congenital heart disease (CHD), present in approximately 80% of patients, to hypertrophic cardiomyopathy (HCM), observed in approximately 20% of patients. Genotype-cardiac phenotype correlations are frequently described, and they are useful indicators in predicting the prognosis concerning cardiac disease over the lifetime. The aim of this review is to clarify the molecular mechanisms underlying the development of cardiac diseases associated particularly with NS, and to discuss the main morphological and clinical characteristics of the two most frequent cardiac disorders, namely pulmonary valve stenosis (PVS) and HCM. We will also report the genotype-phenotype correlation and its implications for prognosis and treatment. Knowing the molecular mechanisms responsible for the genotype-phenotype correlation is key to developing possible targeted therapies. We will briefly address the first experiences of targeted HCM treatment using RAS/MAPK pathway inhibitors.

BACKGROUND: Dilated cardiomyopathy (DCM) is an etiologically heterogeneous group of diseases of the myocardium. With the rapid evolution in laboratory investigations, genetic background is increasingly determined including many genes with variable penetrance and expressivity. Biallelic NEXN variants are rare in humans and associated with poor prognosis: fetal and perinatal death or severe DCMs in infants.
METHODS: We describe two male infants with prenatal diagnosis of dilated cardiomyopathy with impaired ventricular contractility. One of the patients showed hydrops and polyhydramnios. Postnatally, a DCM with severely reduced systolic function was confirmed and required medical treatment. In patient 1, Whole Exome Sequencing (WES) revealed a homozygous NEXN variant: c.1156dup (p.Met386fs) while in patient 2 a custom Next Generation Sequencing (NGS) panel revealed the homozygous NEXN variant c.1579_1584delp. (Glu527_Glu528del). These NEXN variants have not been previously described. Unlike the unfavorable prognosis described for biallelic NEXN variants, we observed in both our patients a favorable clinical course over time.
CONCLUSIONS: This report might help to broaden the present knowledge regarding NEXN biallelic variants and their clinical expression. It might be worthy to consider the inclusion of the NEXN gene sequencing in the investigation of pediatric patients with DCM.

UNASSIGNED: A subcutaneous implantable cardioverter-defibrillator (S-ICD) is an alternative to a transvenous implantable cardio defibrillator (TV-ICD). An S-ICD reduces the risk of transvenous lead placement. However, further research is required to determine how S-ICDs affect patients with hypertrophic cardiomyopathy (HCM). In this study, we investigated the comparative efficacy and safety of S-ICDs versus TV-ICDs in HCM.
UNASSIGNED: On December 6th, 2023, we performed a comprehensive search of the PubMed, Embase, Scopus, and Cochrane databases to identify randomized clinical trials (RCTs) and observational studies comparing S-ICDs with TV-ICDs in HCM patients published from 2004 until 2023. No language restrictions were applied. The primary outcome was appropriate shocks (AS), with inappropriate shocks (IAS), and device-related complications considered as secondary outcomes. Odds ratios (ORs) and 95% confidence intervals (CIs) were pooled using a random effects model. The ROBINS-I tool was used to assess the risk of bias of the studies.
UNASSIGNED: The search yielded 1,114 records. Seven studies comprising 4,347 HCM patients were included, of whom 3,325 (76.0%) had TV-ICDs, and 1,022 (22.6%) had S-ICDs. There were 2,564 males (58.9%). The age range was from 39.1 to 49.4 years. Compared with the TV-ICD group, the S-ICD cohort had a significantly lower incidence of device-related complications (OR 0.52; 95% CI: 0.30-0.89; P=0.02; I2=4%). Contrastingly, there were no statistically significant differences in the occurrences of AS (OR 0.49; 95% CI: 0.22-1.08; P=0.08; I2=75%) and IAS (OR 1.03; 95% CI: 0.57-1.84; P=0.93; I2=65%) between the two device modalities. In the analysis of the overall risk of bias in the studies, we found 42% of them with several, 28% with moderate, and 14% with low risk of bias.
UNASSIGNED: In HCM patients, S-ICDs were associated with a lower incidence of device-associated problems than TV-ICDs. AS and IAS incidence rates were similar between groups. These findings may assist clinicians in determining the most suitable device for treating patients with HCM.

UNASSIGNED: Hypertrophic cardiomyopathy (HCM), identified as a primary cause of sudden cardiac death (SCD), intertwines with pulmonary hypertension (PH) to amplify cardiovascular morbidity. This complex synergy poses significant therapeutic challenges due to the absence of drugs specifically targeting their concurrent manifestation. This study seeks to unravel the molecular intricacies linking HCM and PH, aiming to lay the groundwork for targeted therapeutic interventions.
UNASSIGNED: Through the analysis of gene expression profiles from datasets GSE36961 (HCM) and GSE113439 (PH) within the public data repository of Gene Expression Omnibus (GEO), this research systematically identified differentially expressed genes (DEGs), conducted extensive functional annotations, and constructed detailed protein-protein interaction (PPI) networks to uncover crucial hub genes. Further, co-expression analyses, alongside drug prediction and molecular docking simulations, were employed to pinpoint potential therapeutic agents that could ameliorate the combined pathology of HCM and PH.
UNASSIGNED: Our comprehensive analysis unearthed 79 DEGs shared between HCM and PH, highlighting fourteen as pivotal hub genes. Validation across three additional datasets (GSE35229, GSE32453, and GSE53408) from GEO accentuated secreted phosphoprotein 1 (SPP1) as a key gene of interest. Remarkably, the study identified tacrolimus, ponatinib, bosutinib, dasatinib, doxorubicin, and zanubrutinib as promising drugs for addressing the dual challenge of HCM and PH.
UNASSIGNED: The findings of this investigation shed light on the genetic underpinnings of HCM and PH\'s simultaneous occurrence, emphasizing the central role of SPP1 in their pathogenesis. The identification of six candidate drugs offers a hopeful vista for future therapeutic strategies targeting this complex cardiovascular interplay, marking a significant stride towards mitigating the compounded morbidity of HCM and PH. Future mechanistic and clinical studies are warranted for the investigation of this potential target and therapeutics.

Hypertrophic cardiomyopathy (HCM), which is associated with thickening of the left ventricular wall, is one of the most common heart pathologies in cats. This disease has a hereditary etiology and is primarily related to mutations in the MYBPC3 and MYH7 genes. This study aims to determine the effect of the presence of heterozygosity or homozygosity for the p. A31P mutation (c.91G>C) in the MYBPC3 gene in cats (Maine Coon) of different ages referring to the HCM severity and development, and to compare echocardiographic data and various clinical aspects for the most objective detection of disease in cats of different breeds. The incidence of HCM was 59% of the 103 cases of heart disease in cats in this study. In 23 cats diagnosed with HCM, cats heterozygous for the mutation accounted for 34%, and homozygous cats accounted for 26%. Cats homozygous for this mutation had moderate to severe HCM, suggesting an association with high penetrance of HCM and a significant risk of cardiac death in this group. The penetrance of the heterozygous type was lower than that of the homozygous genotype. This study also indicates that HCM has some age-related penetrance. The disease did not occur in the study group of cats aged up to 1 year, whereas at the age of 7 and older, the percentage of animals diagnosed with HCM was the highest and amounted to 44.3% of the total number of studied cats with HCM.

UNASSIGNED: Sudden cardiac death (SCD) represents the most severe complication of hypertrophic cardiomyopathy (HCM). The risk stratification of SCD in patients with HCM remains a subject of ongoing debate, and the utility of left atrial (LA) and left ventricular (LV) myocardial strain for risk stratification of also SCD remains uncertain. Through use of feature-tracking cardiac magnetic resonance (FT-CMR), this study aimed to investigate the attenuation of LA and LV strain in HCM and to assess their predictive value in SCD.
UNASSIGNED: This retrospective and cross-sectional study included patients with HCM who underwent 3.0 T cardiac magnetic resonance (CMR) at a single institution. Feature-tracking strain analysis was conducted to obtain the strain rate (SR) and LV strain and to evaluate LV function. LA strain was measured during different functional phases including left atrial reservoir strain (LARS), LA conduit strain (LACS), and LA booster strain. All patients were categorized into high- and low-risk groups for SCD as defined by the 2020 American Heart Association/American College HCM implantable cardioverter defibrillator class of recommendation algorithm. Comparison between the two groups was conducted using the independent samples t test and the nonparametric rank sum test. Multivariate logistic regression analysis was performed to further identify the factors influencing SCD risk in HCM.
UNASSIGNED: Compared with those in the low-risk group, patients in the high-risk group had lower left ventricular ejection fraction (LVEF), LV stroke volume index (LVSVI), and LA stroke volume index (LASVI) but a higher LV end-systolic volume index (LVESVI), LV maximum wall thickness, and late gadolinium enhancement (LGE) (P<0.001). LV strain, SR, and LA strain all showed significant differences between the high- and low-risk groups (LARS: P=0.04; LACS: P=0.02; all other P values <0.001). The LV global circumferential strain (LVGCS) had a strong negative correlation with LVEF in patients with HCM (r=-0.76; P<0.001). Multivariate analysis showed that LV global radial strain (LVGRS) and LARS could be used for categorizing the patients into the high-risk group [LVGRS: odds ratio (OR) =0.69; 95% confidence interval (CI): 0.55-0.87, P<0.001; LARS: OR =1.39; 95% CI: 1.02-1.90, P=0.03]. The combined LVGRS-LARS model exhibited a superior diagnostic value for high risk of SCD [area under the curve (AUC) =0.95; 95% CI: 0.90-1.00; P<0.001] compared to LARS alone (AUC =0.63; 95% CI: 0.51-0.76; P=0.04).
UNASSIGNED: LA and LV strain measured by FT-CMR can accurately identify those patients with HCM at a high risk of SCD. This approach may prove considerably value in guiding early therapeutic intervention with implantable cardioverter-defibrillators (ICDs) to prevent adverse clinical outcomes.

UNASSIGNED: Sarcomeric hypertrophic cardiomyopathy (HCM) must be differentiated from phenotypically similar conditions because clinical management and prognosis may greatly differ. Patients with unexplained left ventricular hypertrophy require an early, confirmed genetic diagnosis through diagnostic or predictive genetic testing. We tested the feasibility and practicality of the application of a 17-gene next-generation sequencing (NGS) panel to detect the most common genetic causes of HCM and HCM phenocopies, including treatable phenocopies, and report detection rates. Identification of transthyretin cardiac amyloidosis (ATTR-CA) and Fabry disease (FD) is essential because of the availability of disease-specific therapy. Early initiation of these treatments may lead to better clinical outcomes.
UNASSIGNED: In this international, multicenter, cross-sectional pilot study, peripheral dried blood spot samples from patients of cardiology clinics with an unexplained increased left ventricular wall thickness (LVWT) of ≥13 mm in one or more left ventricular myocardial segments (measured by imaging methods) were analyzed at a central laboratory. NGS included the detection of known splice regions and flanking regions of 17 genes using the Illumina NextSeq 500 and NovaSeq 6000 sequencing systems.
UNASSIGNED: Samples for NGS screening were collected between May 2019 and October 2020 at cardiology clinics in Colombia, Brazil, Mexico, Turkey, Israel, and Saudi Arabia. Out of 535 samples, 128 (23.9%) samples tested positive for pathogenic/likely pathogenic genetic variants associated with HCM or HCM phenocopies with double pathogenic/likely pathogenic variants detected in four samples. Among the 132 (24.7%) detected variants, 115 (21.5%) variants were associated with HCM and 17 (3.2%) variants with HCM phenocopies. Variants in MYH7 (n=60, 11.2%) and MYBPC3 (n=41, 7.7%) were the most common HCM variants. The HCM phenocopy variants included variants in the TTR (n=7, 1.3%) and GLA (n=2, 0.4%) genes. The mean (standard deviation) ages of patients with HCM or HCM phenocopy variants, including TTR and GLA variants, were 42.8 (17.9), 54.6 (17.0), and 69.0 (1.4) years, respectively.
UNASSIGNED: The overall diagnostic yield of 24.7% indicates that the screening strategy effectively identified the most common forms of HCM and HCM phenocopies among geographically dispersed patients. The results underscore the importance of including ATTR-CA (TTR variants) and FD (GLA variants), which are treatable disorders, in the differential diagnosis of patients with increased LVWT of unknown etiology.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is believed to have low overall mortality rate, that could be influenced by gender, particularly among probands. We aimed to evaluate the survival rates and possible gender differences in a homogeneous cohort of HCM proband patients, referred for genetic testing, from the same geographical area, without differences in medical care access nor clinical referral pathways.
METHODS: we compared the mortality rates of a cohort of consecutive HCM probands referred for genetic testing (2000-2022), from a Spanish region (xxx1) with a centralized genetic testing pathway, with its control reference population by Ederer II method. Gender differences were analyzed.
RESULTS: Among the 649 HCM probands included in this study, there were significantly more men than women (61.3% vs 38.7, p < 0.05), with an earlier diagnosis (53.5 vs 61.1 years old, p < 0.05). Clinical evolution or arrhythmogenic HCM profile did no show no significant gender differences. Mean follow up was 9,8 years ±6,6 SD (9,9 ± 7 vs 9,6 ± 6,1, p = 0.59). No statistically significant differences in observed mortality, expected survival and excess mortality were found in the general HCM proband cohort. However, we found a significant excess mortality in female probands with HCM. No additional differences in analysis by genetic status were identified.
CONCLUSIONS: Expected survival in our HCM probands did not differ from its reference population. However, despite no gender differences in phenotype severity were identified, proband HCM women did present a diagnosis delay and worse mortality outcomes.

Myosin binding protein C (MyBPC) is a multi-domain protein with each region having a distinct functional role in muscle contraction. The central domains of MyBPC have often been overlooked due to their unclear roles. However, recent research shows promise in understanding their potential structural and regulatory functions. Understanding the central region of MyBPC is important because it may have specialized function that can be used as drug targets or for disease-specific therapies. In this review, we provide a brief overview of the evolution of our understanding of the central domains of MyBPC in regard to its domain structures, arrangement and dynamics, interaction partners, hypothesized functions, disease-causing mutations, and post-translational modifications. We highlight key research studies that have helped advance our understanding of the central region. Lastly, we discuss gaps in our current understanding and potential avenues to further research and discovery.

UNASSIGNED: Discriminating hypertrophic cardiomyopathy (HCM) and hypertensive heart disease (HHD) is challenging, because both are characterized by left ventricular hypertrophy (LVH). Radiomics might be effective to differentiate HHD from HCM. Therefore, this study aimed to investigate discriminators and build discrimination models between HHD and HCM using multiparametric cardiac magnetic resonance (CMR) findings and radiomics score (radscore) derived from late gadolinium enhancement (LGE) and cine images.
UNASSIGNED: In this single center, retrospective study, 421 HCM patients [median and interquartile range (IQR), 50.0 (38.0-59.0) years; male, 70.5%] from January 2017 to September 2021 and 200 HHD patients [median and IQR, 44.5 (35.0-57.0) years; male, 88.5%] from September 2015 to July 2022 were consecutively included and randomly stratified into a training group and a validation group at a ratio of 6:4. Multiparametric CMR findings were obtained using cvi42 software and radiomics features using Python software. After dimensional reduction, the radscore was calculated by summing the remaining radiomics features weighted by their coefficients. Multiparametric CMR findings and radscore that were statistically significant in univariate logistic regression were used to build combined discrimination models via multivariate logistic regression.
UNASSIGNED: After multivariate logistic regression, the maximal left ventricular end diastolic wall thickness (LVEDWT), left ventricular ejection fraction (LVEF), presence of LGE, cine radscore and LGE radscore were identified as significant characteristics and used to build a combined discrimination model. This model achieved an area under the receiver operator characteristic curve (AUC) of 0.979 (0.968-0.990) in the training group and 0.981 (0.967-0.995) in the validation group, significantly better than the model using multiparametric CMR findings alone (P<0.001).
UNASSIGNED: Radiomics features derived from cardiac cine and LGE images can effectively discriminate HHD from HCM.