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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. Case presentation: 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. Conclusion: 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract 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. Case presentation 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. Conclusion 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.

In children with hypertrophic cardiomyopathy (HCM), the genotype–phenotype association of abnormal electrocardiographic (ECG) features in the backdrop of gene positivity has not been well described. This study aimed to describe the abnormal ECG findings in children with HCM harboring who have genetic variants and determine the association with major adverse cardiac events (MACE). We retrospectively analyzed 81 variants-positive, phenotype-positive (V+P+), 66 variant-positive, phenotype-negative (V+P−), and 85 non-sarcomeric subjects. We analyzed ECG findings and clinical outcomes in the three groups of subjects. Repolarization abnormalities (ST and T wave changes) and pathologic Q waves were the most common abnormalities in variant and non-sarcomeric subjects. The V+P+ group showed higher occurrence of ST segment changes and T wave abnormalities compared to V+P− group. Independent predictors of MACE included ST segment changes (OR 3.54, CI 1.20–10.47, p = 0.022). T wave changes alone did not predict outcome (OR 2.13, CI 0.75–6.07, p = 0.157), but combined repolarization abnormalities (ST+T changes) were strong predictors of MACE (OR 5.84, CI 1.43–23.7, p = 0.014) than ST segment changes alone. Maximal wall z score by echocardiography was a predictor of MACE (OR 1.21, CI 1.07–1.37, p = 0.002). Despite the presence of significant myocardial hypertrophy (z score > 4.7), voltage criteria for LVH were much less predictive. In the non-sarcomeric group, RVH was significantly associated with MACE (OR 3.85, CI 1.08–13.73, p = 0.038). These abnormal ECG findings described on the platform of known genetic status and known myocardial hypertrophy may add incremental value to the diagnosis and surveillance of disease progression in children with HCM. Select ECG findings, particularly repolarization abnormalities, may serve as predictors of MACE in children. [ABSTRACT FROM AUTHOR]

Hypertrophic Cardiomyopathy (HCM) is an inherited myocardial disease characterised by left ventricular hypertrophy, which carries an increased risk of life-threatening arrhythmias and sudden cardiac death. The age of presentation and the underlying aetiology have a significant impact on the prognosis and quality of life of children with HCM, as childhood-onset HCM is associated with high mortality risk and poor long-term outcomes. Accurate cardiac assessment and identification of the HCM phenotype are therefore crucial to determine the diagnosis, prognostic stratification, and follow-up. Cardiac magnetic resonance (CMR) is a comprehensive evaluation tool capable of providing information on cardiac morphology and function, flow, perfusion, and tissue characterisation. CMR allows to detect subtle abnormalities in the myocardial composition and characterise the heterogeneous phenotypic expression of HCM. In particular, the detection of the degree and extent of myocardial fibrosis, using late-gadolinium enhanced sequences or parametric mapping, is unique for CMR and is of additional value in the clinical assessment and prognostic stratification of paediatric HCM patients. Additionally, childhood HCM can be progressive over time. The rate, timing, and degree of disease progression vary from one patient to the other, so close cardiac monitoring and serial follow-up throughout the life of the diagnosed patients is of paramount importance. In this review, an update of the use of CMR in childhood HCM is provided, focussing on its clinical role in diagnosis, prognosis, and serial follow-up. [ABSTRACT FROM AUTHOR]

Simple Summary: Hypertrophic cardiomyopathy (HCM) is the most common feline heart pathology, which is characterized by thickening of the ventricular walls. This disease is genetic in nature and often occurs in cats of certain breeds such as Maine Coon, Persian, Ragdoll, and Norwegian Forest. In this study, we attempted to identify the significance of determining genetic predisposition to this disease using DNA tests. We found that in homozygous cats, the disease manifests itself earlier and its progression is more severe than in heterozygous cats. Since the disease is often asymptomatic, we compared the quality of various diagnostic methods and clinical aspects for identifying HCM at an early stage. 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. [ABSTRACT FROM AUTHOR]

BackgroundSigmoid Ventricular Septum (SVS) is a type of hypertrophic cardiomyopathy characterized by a reduced angle between the basal interventricular septum and the ascending aorta, and SVS can lead to dynamic Left Ventricular Outflow Tract obstruction (LVOTO) during hypercontractile states. Patients experiencing LVOTO may manifest symptoms such as angina, syncope, etc. Radiofrequency ablation (RFA) has been utilized to treat patients with hypertrophic obstructive cardiomyopathy, but there is no reports on its use in treating LVOTO resulting from SVS. Our report describes two cases of SVS treated with endocardial ablation to improve LVOTO.Case reportCase 1: A 74-year-old female patient with angina and syncope was admitted to the hospital and diagnosed with SVS by transthoracic echocardiogram. The patient exhibited LVOTO and Systolic Anterior Motion (SAM) phenomena during the administration of the dobutamine stress test. After RFA was performed, the patient's symptoms significantly improved. Additionally, septum decreased from 16 to 13 mm after ten months, and the morphological changes associated with SVS also disappeared. Case 2: A 57-year-old female was admitted to the hospital due to recurrent chest pain after physical activity for more than four years. The transthoracic echocardiogram indicated that the patient met the diagnostic criteria for SVS, and LVOTO and SAM phenomenaoccurred following dobutamine stress test. The patient had significant improvement in symptoms after undergoing RFA treatment.ConclusionsThese two cases represent the first documented instances where dynamic LVOTO caused by SVS could be effectively managed through endocardial RFA.

Objective·To investigate the effects of trimethylamine oxide (TMAO) on cardiac function in mice with hypertrophic cardiomyopathy (HCM) and its potential molecular mechanism.Methods·Mice with myosin heavy chain 6 (Myh6) c.1211G>A (p.R404Q+/-) point mutation were used as the animal model. According to dietary supplementation of TMAO and TMAO inhibitor iodomethylcholine (IMC), the wild type (WT) mice and HCM mice were divided into WT group, HCM group (HCM-1 group, HCM-2 group), WT+TMAO group, HCM+TMAO group and HCM+IMC group, respectively. Left ventricular fraction shortening (FS) and left ventricular posterior wall thickness (LVPW) were assessed by echocardiography in all mice. Enzyme-linked immunosorbent assay (ELISA) was used to detect the serum TMAO concentration of mice in the HCM-1 group and WT group. The regularity of myocardial cell arrangement of mice was evaluated by hematoxylin and eosin staining (HE staining). The proportion of myocardial fibrosis was evaluated by Masson staining. The activity of protein kinase A (PKA) in mouse myocardial tissue was detected by PKA kit. The expression of ryanodine receptor 2 (RyR2) and p-RyR2(S2808) in mouse myocardial tissue was detected by Western blotting.Results·The results of echocardiography showed that at 12 months of age, the FS of mice in the WT+TMAO group and HCM+TMAO group were lower than those in the corresponding WT group and HCM-1 group, respectively (P

Objectives: This retrospective observational study aimed to evaluate the correlation between visually estimated left ventricular ejection fraction (LVEF) via 2D echocardiography (ECHO) and quantitatively measured LVEF via cardiovascular magnetic resonance imaging (CMR). Methodology: The study was conducted at Aga Khan University Hospital, involving patients who underwent both 2D ECHO and CMR within a maximum interval of three months between the two studies. LVEF was visually estimated by experienced cardiologists on 2D ECHO and quantitatively calculated on CMR. Results: Among 127 patients meeting inclusion criteria, comparisons between visually estimated LVEF ranges on ECHO and LVEF on CMR consistently showed highly significant differences (p < 0.0001), with ECHO underestimating LVEF. The mean difference between visually estimated average LVEF by ECHO and calculated LVEF by CMR was 4.9 ± 7.0. Subgroup analysis revealed consistent findings across patients with coronary artery disease (CAD) and those with dilated or hypertrophic cardiomyopathy. Conclusion: Despite a significant difference, the observed discrepancy in LVEF values between visually estimated ECHO and quantitatively measured CMR remains small. Thus, visually estimated LVEF by experienced readers retains its reliability as a method for diagnosing and managing patients in routine clinical practice. [ABSTRACT FROM AUTHOR]

Background: In cats, hypertrophic cardiomyopathy (HCM) stands out as a prevailing heart disease. The mutations in the gene that encodes cardiac myosin-binding protein C (MYBPC3) have been detected in the Ragdoll and Maine Coon breeds. Objectives: HCM is believed to be hereditary in other breeds, too. Methods: Blood samples were collected for DNA extraction from 2 unaffected and 7 affected Persian breed cats with HCM. Besides accomplishing conventional polymerase chain reaction, DNA sequencing was performed. The sequence changes were utilized to detect single nucleotide polymorphisms in the MYBPC3 gene and predict amino acid substitutions based on the Acc. No. XM&lowbar;019812396.1 and comparisons with the literature on identified breed variants and control samples. Results: Although many single nucleotide polymorphisms were found in the affected and unaffected Persian cats, no causative mutation for HCM was observed. Conclusion: In this breed, HCM does not seem to be caused solely by mutations in this cardiac gene. Potential cardiac genes should be investigated to uncover other genetic reasons for this cardiac disease in the Persian cat breed. [ABSTRACT FROM AUTHOR]

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 diseasespecific 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. [ABSTRACT FROM AUTHOR]

Objective·To investigate the effects of trimethylamine oxide (TMAO) on cardiac function in mice with hypertrophic cardiomyopathy (HCM) and its potential molecular mechanism. Methods·Mice with myosin heavy chain 6 (Myh6) c.1211G>A (p. R404Q+/-) point mutation were used as the animal model. According to dietary supplementation of TMAO and TMAO inhibitor iodomethylcholine (IMC), the wild type (WT) mice and HCM mice were divided into WT group, HCM group (HCM-1 group, HCM-2 group), WT+TMAO group, HCM+TMAO group and HCM+IMC group, respectively. Left ventricular fraction shortening (FS) and left ventricular posterior wall thickness (LVPW) were assessed by echocardiography in all mice. Enzyme-linked immunosorbent assay (ELISA) was used to detect the serum TMAO concentration of mice in the HCM-1 group and WT group. The regularity of myocardial cell arrangement of mice was evaluated by hematoxylin and eosin staining (HE staining). The proportion of myocardial fibrosis was evaluated by Masson staining. The activity of protein kinase A (PKA) in mouse myocardial tissue was detected by PKA kit. The expression of ryanodine receptor 2 (RyR2) and p-RyR2(S2808) in mouse myocardial tissue was detected by Western blotting. Results·The results of echocardiography showed that at 12 months of age, the FS of mice in the WT+TMAO group and HCM+TMAO group were lower than those in the corresponding WT group and HCM-1 group, respectively (P<0.05). The LVPW of mice in the HCM+TMAO group was higher than that in the HCM-1 group, while the LVPW of mice in the HCM+IMC group was lower than that in the HCM-2 group (P<0.05). ELISA results showed that the serum TMAO concentration of mice in the HCM-1 group was higher than that in the WT mice (P<0.05). The results of HE staining and Masson staining showed that the HCM+TMAO group had a lower degree of regular arrangement of cardiomyocytes and a higher proportion of fibrosis than the HCM-1 group, while the HCM+IMC group had a higher degree of regular arrangement of cardiomyocytes and a lower proportion of fibrosis than the HCM-2 group (P<0.05). The results of PKA assay showed that the PKA activity in the myocardial tissue of mice in the WT+TMAO group and HCM+ TMAO group increased after TMAO treatment, while the PKA activity in the myocardial tissue of mice in the HCM+IMC group decreased (P<0.05). Western blotting results showed that the expression of p-RyR2(S2808) in the myocardial tissue of the WT+TMAO group and HCM+TMAO group mice increased, while it was decreased in the HCM+IMC group mice (P<0.05); however, there was no difference in RyR2 expression among the groups. Conclusion·TMAO can increase the activity of PKA and induce the phosphorylation of RyR2 at S2808, which can cause ventricular remodeling and impair cardiac function in HCM mice. [ABSTRACT FROM AUTHOR]

Objective·To analyze the differences and classify hypertrophic cardiomyopathy (HCM) patients and healthy controls (HC) using short-axis cine cardiac magnetic resonance (CMR) images-derived radiomics features.Methods·One hundred HCM subjects were included, and fifty HC were randomly selected at 2∶1 ratio during January 2018 to December 2021 in the Department of Cardiology, Renji Hospital, Shanghai Jiao Tong University School of Medicine. The CMR examinations were performed by experienced radiologists on these subjects. CVI 42 post-processing software was used to obtain left ventricular morphology and function measurements, including left ventricular ejection fraction (LVEF), left ventricular end-diastolic volume (LVEDV) and left ventricular end-diastolic mass (LVEDM). The 3D radiomic features of the end-diastolic myocardial region were extracted from short-axis images CMR cine. The distribution of the radiomic features in the two groups was analysed and machine learning models were constructed to classify the two groups.Results·One hundred and seven 3D radiomic features were selected and extracted. After exclusion of highly correlated features, least absolute shrinkage and selection operator (LASSO) was used, and a 5-fold cross-validation was performed. There were still 11 characteristics with non-zero coefficients. The K-best method was used to decide the top 8 features for subsequent analysis. Among them, four features were significantly different between the two groups (all P

[Display omitted] [ABSTRACT FROM AUTHOR]

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.

N-terminal cardiac myosin-binding protein C (cMyBP-C) domains (C0-C2) bind to thick (myosin) and thin (actin) filaments to coordinate contraction and relaxation of the heart. These interactions are regulated by phosphorylation of the M-domain situated between domains C1 and C2. In cardiomyopathies and heart failure, phosphorylation of cMyBP-C is significantly altered. We aimed to investigate how cMyBP-C interacts with myosin and actin. We developed complementary, high-throughput, C0-C2 FRET-based binding assays for myosin and actin to characterize the effects due to 5 HCM-linked variants or functional mutations in unphosphorylated and phosphorylated C0-C2. The assays indicated that phosphorylation decreases binding to both myosin and actin, whereas the HCM mutations in M-domain generally increase binding. The effects of mutations were greatest in phosphorylated C0-C2, and some mutations had a larger effect on actin than myosin binding. Phosphorylation also altered the spatial relationship of the probes on C0-C2 and actin. The magnitude of these structural changes was dependent on C0-C2 probe location (C0, C1, or M-domain). We conclude that binding can differ between myosin and actin due to phosphorylation or mutations. Additionally, these variables can change the mode of binding, affecting which of the interactions in cMyBP-C N-terminal domains with myosin or actin take place. The opposite effects of phosphorylation and M-domain mutations is consistent with the idea that cMyBP-C phosphorylation is critical for normal cardiac function. The precision of these assays is indicative of their usefulness in high-throughput screening of drug libraries for targeting cMyBP-C as therapy. [Display omitted] • Complementary FLT-FRET assays detect N-terminal cMyBP-C binding to myosin and actin. • FRET (binding) is reduced for myosin or actin with cMyBP-C that is phosphorylated. • HCM mutations E334K, L349R, and L352P in cMyBP-C increased myosin or actin binding. • The cMyBP-C HCM variant T59A did not alter FRET (binding) with myosin or actin. • The precision of these FLT-FRET assays makes them useful for cMyBP-C drug discovery. [ABSTRACT FROM AUTHOR]

Objective·To analyze the differences and classify hypertrophic cardiomyopathy (HCM) patients and healthy controls (HC) using short-axis cine cardiac magnetic resonance (CMR) images-derived radiomics features. Methods·One hundred HCM subjects were included, and fifty HC were randomly selected at 2∶ 1 ratio during January 2018 to December 2021 in the Department of Cardiology, Renji Hospital, Shanghai Jiao Tong University School of Medicine. The CMR examinations were performed by experienced radiologists on these subjects. CVI 42 post-processing software was used to obtain left ventricular morphology and function measurements, including left ventricular ejection fraction (LVEF), left ventricular end-diastolic volume (LVEDV) and left ventricular end-diastolic mass (LVEDM). The 3D radiomic features of the end-diastolic myocardial region were extracted from short-axis images CMR cine. The distribution of the radiomic features in the two groups was analysed and machine learning models were constructed to classify the two groups. Results·One hundred and seven 3D radiomic features were selected and extracted. After exclusion of highly correlated features, least absolute shrinkage and selection operator (LASSO) was used, and a 5-fold cross-validation was performed. There were still 11 characteristics with non-zero coefficients. The K-best method was used to decide the top 8 features for subsequent analysis. Among them, four features were significantly different between the two groups (all P<0.05). Support vector machine (SVM) and random forest (RF) models were constructed to discriminate the two groups. The results showed that the maximum area under the curve (AUC) for the single-feature model (first order grayscale: entropy) was 0.833 (95%CI 0.685‒0.968) and the maximum accuracy for the multi-feature model was 83.3% with an AUC of 0.882 (95%CI 0.705‒ 0.980). Conclusion·There are significant differences in both left ventricular function and left ventricular morphology between HCM and HC. The 3D myocardial radiomic features of the two groups are also significantly different. Although single feature is able to distinguish the two groups, the combination of multi-features show better classification performance. [ABSTRACT FROM AUTHOR]

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.

Radiomics is a new emerging field that includes extraction of metrics and quantification of so-called radiomic features from medical images. The growing importance of radiomics applied to oncology in improving diagnosis, cancer staging and grading, and improved personalized treatment, has been well established; yet, this new analysis technique has still few applications in cardiovascular imaging. Several studies have shown promising results describing how radiomics principles could improve the diagnostic accuracy of coronary computed tomography angiography (CCTA) and magnetic resonance imaging (MRI) in diagnosis, risk stratification, and follow-up of patients with coronary heart disease (CAD), ischemic heart disease (IHD), hypertrophic cardiomyopathy (HCM), hypertensive heart disease (HHD), and many other cardiovascular diseases. Such quantitative approach could be useful to overcome the main limitations of CCTA and MRI in the evaluation of cardiovascular diseases, such as readers' subjectiveness and lack of repeatability. Moreover, this new discipline could potentially overcome some technical problems, namely the need of contrast administration or invasive examinations. Despite such advantages, radiomics is still not applied in clinical routine, due to lack of standardized parameters acquisition, inconsistent radiomic methods, lack of external validation, and different knowledge and experience among the readers. The purpose of this manuscript is to provide a recent update on the status of radiomics clinical applications in cardiovascular imaging. [ABSTRACT FROM AUTHOR]

BackgroundPrompt interventions prevent adverse events (AE) in hypertrophic cardiomyopathy (HCM). We evaluated the pattern and the predictive role of feature tracking (FT)-cardiac magnetic resonance (CMR) imaging parameters in an HCM population with a normal left ventricular ejection fraction (LVEF) and a low fibrosis burden.MethodsThe CMR and clinical data of 170 patients, consisting of 142 HCM (45 ± 15.7 years, 62.7% male) and 28 healthy (42.2 ± 11.26 years, 50% male) subjects, who were enrolled from 2015 to 2020, were evaluated. HCM patients had a normal LVEF with a late gadolinium enhancement (LGE) percentage below 15%. Between-group differences were described, and the potent predictors of AE were determined. A P-value below 0.05 was considered significant.ResultsLV global longitudinal, circumferential, and radial strains (GLS, GCS, and GRS, respectively) and the LV myocardial mass index (MMI) were different between the healthy and HCM cases (all Ps

With the advent of next-generation whole genome sequencing, many variants of uncertain significance (VUS) have been identified in individuals suffering from inheritable hypertrophic cardiomyopathy (HCM). Unfortunately, this classification of a genetic variant results in ambiguity in interpretation, risk stratification, and clinical practice. Here, we aim to review some basic science methods to gain a more accurate characterization of VUS in HCM. Currently, many genomic data-based computational methods have been developed and validated against each other to provide a robust set of resources for researchers. With the continual improvement in computing speed and accuracy, in silico molecular dynamic simulations can also be applied in mutational studies and provide valuable mechanistic insights. In addition, high throughput in vitro screening can provide more biologically meaningful insights into the structural and functional effects of VUS. Lastly, multi-level mathematical modeling can predict how the mutations could cause clinically significant organ-level dysfunction. We discuss emerging technologies that will aid in better VUS characterization and offer a possible basic science workflow for exploring the pathogenicity of VUS in HCM. Although the focus of this mini review was on HCM, these basic science methods can be applied to research in dilated cardiomyopathy (DCM), restrictive cardiomyopathy (RCM), arrhythmogenic cardiomyopathy (ACM), or other genetic cardiomyopathies.

Hypertrophic cardiomyopathy (HCM) is the most prevalent genetically inherited cardiomyopathy that follows an autosomal dominant inheritance pattern. The majority of HCM cases can be attributed to mutation of the MYBPC3 gene, which encodes cMyBP-C, a crucial structural protein of the cardiac muscle. The manifestation of HCM's morphological, histological, and clinical symptoms is subject to the complex interplay of various determinants, including genetic mutation and environmental factors. Approximately half of MYBPC3 mutations give rise to truncated protein products, while the remaining mutations cause insertion/deletion, frameshift, or missense mutations of single amino acids. In addition, the onset of HCM may be attributed to disturbances in the protein and transcript quality control systems, namely, the ubiquitin–proteasome system and nonsense-mediated RNA dysfunctions. The aforementioned genetic modifications, which appear to be associated with unfavorable lifelong outcomes and are largely influenced by the type of mutation, exhibit a unique array of clinical manifestations ranging from asymptomatic to arrhythmic syncope and even sudden cardiac death. Although the current understanding of the MYBPC3 mutation does not comprehensively explain the varied phenotypic manifestations witnessed in patients with HCM, patients with pathogenic MYBPC3 mutations can exhibit an array of clinical manifestations ranging from asymptomatic to advanced heart failure and sudden cardiac death, leading to a higher rate of adverse clinical outcomes. This review focuses on MYBPC3 mutation and its characteristics as a prognostic determinant for disease onset and related clinical consequences in HCM. [ABSTRACT FROM AUTHOR]

Purpose of Review: In this review, we will overview the baseline and longitudinal imaging modalities utilized in the care of patients with hypertrophic cardiomyopathy (HCM) with a focus on echocardiography and cardiac magnetic resonance (CMR) imaging, especially in the new era of cardiac myosin inhibitors (CMIs). Recent Findings: Traditional therapies for hypertrophic cardiomyopathy (HCM) have been well established for decades. Attempts to investigate new drug therapy in HCM resulted in neutral clinical trials, until the discovery of cardiac myosin inhibitors (CMIs). The introduction of this new class of small oral molecules which target the hypercontractility resulting from excessive actin-myosin cross-bridging at the sarcomere level is the first therapeutic option which directly addresses the underlying pathophysiology of HCM. While imaging has always played a central role in HCM diagnosis and management, CMIs introduced a new paradigm in the use of imaging to evaluate and monitor patients with HCM. Summary: Echocardiography and cardiac magnetic resonance imaging (CMR) are the central modalities in the care of patients with HCM, but their roles and our understanding of their strengths and limitations are evolving as newer therapeutics are being investigated in clinical trials and in daily practice. In this review, we will focus the recent CMI trials and discuss the role of baseline and longitudinal imaging with echocardiography and CMR in the care of patients with HCM in the era of CMIs. [ABSTRACT FROM AUTHOR]

Hypertrophic cardiomyopathy (HCM) is an inherited myocardial disease with the presence of left ventricular hypertrophy (LVH). The disease is characterized by high locus, allelic and phenotypic heterogeneity, even among members of the same family. The list of confirmed and potentially relevant genes implicating the disease is constantly increasing, with novel genes frequently reported. Heterozygous alterations in the five main sarcomeric genes (MYBPC3, MYH7, TNNT2, TNNI3, and MYL2) are estimated to account for more than half of confirmed cases. The genetic discoveries of recent years have shed more light on the molecular pathogenic mechanisms of HCM, contributing to substantial advances in the diagnosis of the disease. Genetic testing applying next-generation sequencing (NGS) technologies and early diagnosis prior to the clinical manifestation of the disease among family members demonstrate an important improvement in the field. [ABSTRACT FROM AUTHOR]

Inherited cardiomyopathies are a prevalent cause of heart failure and sudden cardiac death. Both hypertrophic (HCM) and dilated cardiomyopathy (DCM) are genetically heterogeneous and typically present with an autosomal dominant mode of transmission. Whole exome sequencing and autozygosity mapping was carried out in eight un-related probands from consanguineous Middle Eastern families presenting with HCM/DCM followed by bioinformatic and co-segregation analysis to predict the potential pathogenicity of candidate variants. We identified homozygous missense variants in TNNI3K, DSP, and RBCK1 linked with a dilated phenotype, in NRAP linked with a mixed phenotype of dilated/hypertrophic, and in KLHL24 linked with a mixed phenotype of dilated/hypertrophic and non-compaction features. Co-segregation analysis in family members confirmed autosomal recessive inheritance presenting in early childhood/early adulthood. Our findings add to the mutational spectrum of recessive cardiomyopathies, supporting inclusion of KLHL24, NRAP and RBCK1 as disease-causing genes. We also provide evidence for novel (recessive) modes of inheritance of a well-established gene TNNI3K and expand our knowledge of the clinical heterogeneity of cardiomyopathies. A greater understanding of the genetic causes of recessive cardiomyopathies has major implications for diagnosis and screening, particularly in underrepresented populations, such as those of the Middle East. [ABSTRACT FROM AUTHOR]

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. 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. 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. 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. • Hypertrophic cardiomyopathy (hcm) patients have low overall mortality rate. • Expected survival rates in our hcm probands did not differ from its reference population. • Despite no gender differences in phenotype severity were identified among hcm probands, women did present a diagnosis delay and worse mortality outcomes. [ABSTRACT FROM AUTHOR]

Left ventricular (LV) apical aneurysms in hypertrophic cardiomyopathy (HCM) are a recognized risk marker for adverse cardiovascular events. There is variable practice among clinicians and discordance between international guidelines regarding treatment recommendations and prognostication for this important phenotype. The authors sought to describe the morphology, clinical course, and risk of adverse events in a large single-center cohort of HCM patients with LV apical aneurysms. This study analyzed 160 HCM patients with an LV apical aneurysm who were evaluated in our dedicated HCM clinic between January 1997 and April 2021. Mean age was 59.1 ± 13.6 years, and 71% of these patients were male. Mean aneurysm size was 1.77 ± 1.04 cm. Over 6.2 ± 4.8 years, 14 (9%) patients had a sudden cardiac death (SCD) event, including appropriate therapy from an implantable cardioverter-defibrillator (ICD) or resuscitation from cardiac arrest (annualized event rate 1.77%/y), 39 (24%) had either a thromboembolic stroke or apical thrombus formation (2.9%/y), and 14 (9%) developed LV systolic dysfunction with an ejection fraction (EF) <50% (1.28%/y). HRs for SCD, stroke or thrombus, and EF <50% per 1-cm increase in aneurysm size were 1.69 (P = 0.007), 1.60 (P = 0.0002), and 1.63 (P = 0.01), respectively. Aneurysm size ≥2 cm was associated with a 5-year SCD rate of 9.7%, compared with 2.9% for aneurysm size <2 cm (log-rank P = 0.037). This subgroup also had higher risk of stroke/thrombus formation (HR: 2.20; P = 0.002), with an annualized event rate of 2.7%/year. A total of 39 (24%) patients reached the combined end point of SCD, stroke, or LV dysfunction (2.12%/y) with an HR of 1.47/cm increase in aneurysm size (P = 0.003) and an HR of 2.22 for patients with aneurysm size ≥2 cm (P = 0.02). Increasing aneurysm size confers poorer prognosis. Aneurysm size ≥2 cm should alert potential consideration for prophylactic anticoagulation and primary prevention ICDs. [Display omitted] [ABSTRACT FROM AUTHOR]

Hypertrophic cardiomyopathy (HCM) is a monogenic disease with autosomal dominant inheritance. Genotype–phenotype relationships are complex, with variable penetrance even within the same family. The involvement of other modulating genetic and environmental factors is unknown. We aimed to analyze the HCM in monozygotic twins, carriers of the same founder pathogenic variant MYBPC3 p.G263*. The relationship was verified using the PowerPlex 16 HS System kit. Phenotypic differences and environmental differences (overloading conditions, coexistence and location, lifestyle, sport, and intensity) were analyzed. Three pairs of twins genetically identical for all markers and carriers of MYBPC3 G263* were identified. No environmental differences were identified. One of the 89-year-old twins had symptomatic severe obstructive HCM that required septal ablation, while her twin has remained asymptomatic with mild phenotype >80 years. A 49-year-old twin had a severe phenotype of obstructive HCM and pending myectomy, while his twin had a mild asymptomatic phenotype. In the last pair of twins, one presented a much larger left ventricular hypertrophy than his identical twin. In summary, we present three pairs of HCM twin patients sharing not only the genetic cause of the inherited disease but the entire genetic background. Despite identical genetic information and the absence of other known clinical, environmental, or lifestyle differences, the severity of the HCM phenotype is strikingly different. These unexplained differences should prompt the study of other unknown modulating factors, either epigenetic or environmental. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Male and female patients with hypertrophic cardiomyopathy (HCM) differ in physiologic characteristics and hemodynamics. Little is known about gender-related differences in left atrial (LA) strain and exercise capacity. The aim of this study was to assess the gender-related differences in the relationship between exercise capacity and cardiac function including LA function in patients with HCM., Methods: Five hundred and thirty-two patients with HCM undergoing exercise stress echocardiography and cardiopulmonary exercise testing (CPET) were prospectively recruited between October 2015 and April 2019 as part of a cohort study in a quaternary referral center. To reduce potential confounding factors, propensity score (PS) matching was performed in 420 patients. LA strain mechanics were evaluated using speckle-tracking echocardiography., Results: The majority of patients were male, comprising 58% of the total. Female HCM patients were older (54±14 vs . 50±15 years, P=0.002). After PS matching, percent-predicted peak VO 2 was similar between the genders (67.5%±20.7% vs . 65.8%±21.8%, P=0.41), even though female HCM patients had lower peak VO 2 (17.7±5.9 vs . 24.1±8.3 mL/kg/min, P<0.001). Left ventricular (LV) diastolic function was worse for female HCM patients. This is shown by worse E/e' ratio (15.0±5.9 vs . 12.9±6.4, P<0.001) and larger LA volume in respect to LV (0.88±0.35 vs . 0.74±0.31, P<0.001), compared with male HCM patients. The gender-related differences in LA reservoir strain were more evident for patients aged 60 years and older (27.5%±8.8% vs . 30.9%±9.1%, P=0.03). LA reservoir strain was found to have a significant association with exercise capacity in both male and female HCM patients (for females, β=0.27, P=0.001; for males, β=0.27, P<0.001), independent of LV diastolic dysfunction and stroke volume., Conclusions: Gender-related differences in LA reservoir strain were increasingly evident for older HCM patients aged 60 years and older. LA reservoir strain was an independent determinant of percent-predicted peak VO 2 in male and female patients, underpinning the importance of LA function in determining exercise capacity in HCM., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cdt.amegroups.com/article/view/10.21037/cdt-24-147/coif). N.G.S. receives consulting fees from Bristol-Myers Squibb. M.Y.D. receives consulting fees from Cytokinetics, Inc. and Bristol-Myers Squibb. The other authors have no conflicts of interest to declare., (2024 Cardiovascular Diagnosis and Therapy. All rights reserved.)

Non-obstructive hypertrophic cardiomyopathy, or apical hypertrophic cardiomyopathy (ApHCM), also referred to as Yamaguchi syndrome, is a type of hypertrophic cardiomyopathy (HCM) characterized by significant thickening of the left ventricular apex without blockage in the left ventricular outflow tract. It is a very rare variant of HCM. Patients with non-obstructive HCM often experience symptoms such as chest pain, palpitations, shortness of breath, and syncope, which may resemble those seen in various cardiovascular and non-cardiac conditions. Yamaguchi syndrome presents as a challenging yet manageable condition in the ED. Early recognition, accurate diagnosis, and appropriate management are crucial for better outcomes. We report a case of a young female who presented to the ED with breathlessness and chest pain. The ECG findings suggested acute coronary syndrome (ACS), but echocardiography and cardiac biomarkers indicated otherwise, leading to the diagnosis of Yamaguchi Syndrome., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Shinde et al.)

Patients with hypertrophic cardiomyopathy (HCM) mostly experience minimal symptoms throughout their lifetime, and some individuals have an increased risk of ventricular arrhythmias and sudden cardiac death (SCD). How to identify patients with a higher risk of ventricular arrythmias and SCD is the priority in HCM research. The American College of Cardiology/American Heart Association (ACC/AHA) and the European Society of Cardiology (ESC) both recommend the use of risk algorithms to identify patients at high risk of ventricular arrhythmias, to be selected for implantation of implantable cardioverters/defibrillators (ICDs) for primary prevention of SCD, although major discrepancies exist. The present SCD risk scoring systems cannot accurately identify early-stage HCM patients with modest structural remodeling and mild disease manifestations. Unfortunately, SCD events could occur in young asymptomatic HCM patients and even as initial symptoms, prompting the determination of new risk factors for SCD. This review summarizes the studies based on patients' surgical specimens, transgenic animals, and patient-derived induced pluripotent stem cells (hiPSCs) to explore the possible molecular mechanism of ventricular arrhythmia and SCD. Ion channel remodeling, Ca2+ homeostasis abnormalities, and increased myofilament Ca2+ sensitivity may contribute to changes in action potential duration (APD), reentry circuit formation, and trigger activities, such as early aferdepolarization (EAD) or delayed afterdepolarization (DAD), leading to ventricular arrhythmia in HCM. Besides the ICD implantation, novel drugs represented by the late sodium current channel inhibitor and myosin inhibitor also shed light on the prevention of HCM-related arrhythmias. The ideal prevention strategy of SCD in early-stage HCM patients needs to be combined with gene screening, hiPSC-CM testing, machine learning, and advanced ECG studies, thus achieving individualized SCD prevention.

Hypertrophic cardiomyopathy (HCM) is the most prevalent genetically inherited cardiomyopathy that follows an autosomal dominant inheritance pattern. The majority of HCM cases can be attributed to mutation of the MYBPC3 gene, which encodes cMyBP-C, a crucial structural protein of the cardiac muscle. The manifestation of HCM’s morphological, histological, and clinical symptoms is subject to the complex interplay of various determinants, including genetic mutation and environmental factors. Approximately half of MYBPC3 mutations give rise to truncated protein products, while the remaining mutations cause insertion/deletion, frameshift, or missense mutations of single amino acids. In addition, the onset of HCM may be attributed to disturbances in the protein and transcript quality control systems, namely, the ubiquitin–proteasome system and nonsense-mediated RNA dysfunctions. The aforementioned genetic modifications, which appear to be associated with unfavorable lifelong outcomes and are largely influenced by the type of mutation, exhibit a unique array of clinical manifestations ranging from asymptomatic to arrhythmic syncope and even sudden cardiac death. Although the current understanding of the MYBPC3 mutation does not comprehensively explain the varied phenotypic manifestations witnessed in patients with HCM, patients with pathogenic MYBPC3 mutations can exhibit an array of clinical manifestations ranging from asymptomatic to advanced heart failure and sudden cardiac death, leading to a higher rate of adverse clinical outcomes. This review focuses on MYBPC3 mutation and its characteristics as a prognostic determinant for disease onset and related clinical consequences in HCM.

Cardiac magnetic resonance (CMR) has been recently implemented in clinical practice to refine the daunting task of establishing the risk of sudden cardiac death (SCD) in patients with hypertrophic cardiomyopathy (HCM). We present an exemplificative case highlighting the practical clinical utility of this imaging modality in a 24-year-old man newly diagnosed with an apical HCM. CMR was essential in unmasking a high risk of SCD, which appeared low-intermediate after traditional risk assessment. A discussion examines the essential role of CMR in guiding the patient’s therapy and underlines the added value of CMR, including novel and potential CMR parameters, compared to traditional imaging assessment for SCD risk stratification.

Abstract Background Hypertrophic cardiomyopathy (HCM) related myocardial vascular remodelling may lead to the reduction of myocardial blood supply and a subsequent progressive loss of cardiac function. This process has been difficult to observe and thus their connection remains unclear. Here we used non-invasive myocardial blood flow sensitive CMR to show an impairment of resting myocardial perfusion in a mouse model of naturally occurring HCM. Methods We used a mouse model (DBA/2 J; D2 mouse strain) that spontaneously carries variants in the two most susceptible HCM genes—Mybpc3 and Myh7 and bears the key features of human HCM. The C57BL/6 J (B6) was used as a reference strain. Mice with either B6 or D2 backgrounds (male: n = 4, female: n = 4) underwent cine-CMR for functional assessment at 9.4 T. Left ventricular (LV) wall thickness was measured in end diastolic phase by cine-CMR. Quantitative myocardial perfusion maps (male: n = 5, female: n = 5 in each group) were acquired from arterial spin labelling (cine ASL-CMR) at rest. Myocardial perfusion values were measured by delineating different regions of interest based on the LV segmentation model in the mid ventricle of the LV myocardium. Directly after the CMR, the mouse hearts were removed for histological assessments to confirm the incidence of myocardial interstitial fibrosis (n = 8 in each group) and small vessel remodelling such as vessel density (n = 6 in each group) and perivascular fibrosis (n = 8 in each group). Results LV hypertrophy was more pronounced in D2 than in B6 mice (male: D2 LV wall thickness = 1.3 ± 0.1 mm vs B6 LV wall thickness = 1.0 ± 0.0 mm, p

Wildfires pose a major health risk for humans, wildlife, and domestic animals. We previously discovered pathophysiologic parallels between domestic cats with naturally occurring smoke inhalation and thermal burn injuries and human beings with similar injuries; these were characterized by transient myocardial thickening, cardiac troponin I elevation and formation of intracardiac thrombosis. While the underlying mechanisms remain unclear, results from murine models suggest that platelet priming and activation may contribute to a global hypercoagulable state and thrombosis. Herein, we evaluated and compared the degree of platelet activation, platelet response to physiologic agonists and levels of platelet-derived microvesicles (PDMV) in 29 cats with naturally occurring wildfire thermal injuries (WF), 21 clinically healthy cats with subclinical hypertrophic cardiomyopathy (HCM) and 11 healthy cats without HCM (CC). We also quantified and compared circulating PDMVs in WF cats to CC cats. In addition, we examined the association between thrombotic events, severity of burn injuries, myocardial changes, and the degree of platelet activation in cats exposed to wildfires. Flow cytometric detection of platelet surface P-selectin expression showed that WF cats had increased platelet response to adenosine diphosphate (ADP) and thrombin compared to the two control groups indicating the presence of primed platelets in circulation. In addition, cats in the WF group had increased circulating levels of PDMV, characterized by increased phosphatidylserine on the external leaflet. Cats in the WF group with documented intracardiac thrombosis had elevated platelet activation and platelet priming in the presence of ADP. While high dose arachidonic acid (AA) mostly resulted in platelet inhibition, persistent response to AA was noted among cats in the WF group with intracardiac thrombosis. Univariate and multiple logistic regression analyses demonstrated that increased platelet response to AA was independently associated with thrombotic events. This is the first study reporting the significant association between platelet priming and intracardiac thrombosis in domestic cats with naturally occurring wildfire-related injuries and smoke inhalation. Further studies are required to delineate additional mechanisms between inflammation and thrombosis, especially regarding platelet primers and the cyclooxygenase pathway.One Sentence SummaryPlatelet activation and shedding of platelet-derived microvesicles due to platelet priming is present following naturally occurring wildfire smoke exposure and thermal burn injuries in a population of domestic cats.

Objective: We aimed to study the long-term association of LV mass index (LVMI) and myocardial fibrosis with ventricular arrhythmia (VA) in a population of patients with confirmed hypertrophic cardiomyopathy (HCM) using cardiac magnetic resonance imaging (CMR). Methods: We retrospectively analyzed the data in consecutive HCM patients confirmed on CMR referred to an HCM clinic between January 2008 and October 2018. Patients were followed up yearly following diagnosis. Baseline demographics, risk factors and clinical outcomes from cardiac monitoring and an implanted cardioverter defibrillator (ICD) were analyzed for association of LVMI and LV late gadolinium enhancement (LVLGE) with VA. Patients were then allocated to one of two groups according to the presence of VA (Group A) or absence of VA (Group B) during the follow-up period. The transthoracic echocardiogram (TTE) and CMR parameters were compared between the two groups. Results: A total of 247 patients with confirmed HCM (age 56.2 ± 16.6, male = 71%) were studied over the follow-up period of 7 ± 3.3 years (95% CI = 6.6–7.4 years). LVMI derived from CMR was higher in Group A (91.1 ± 28.1 g/m2 vs. 78.8 ± 28.3 g/m2, p = 0.003) when compared to Group B. LVLGE was higher in Group A (7.3 ± 6.3% vs. 4.7 ± 4.3%, p = 0.001) when compared to Group B. Multivariable Cox regression analysis showed LVMI (hazard ratio (HR) = 1.02, 95% CI = 1.001–1.03, p = 0.03) and LVLGE (HR = 1.04, 95% CI = 1.001–1.08, p = 0.04) to be independent predictors for VA. Receiver operative curves showed higher LVMI and LVLGE with a cut-off of 85 g/m2 and 6%, respectively, to be associated with VA. Conclusions: LVMI and LVLGE are strongly associated with VA over long-term follow-up. LVMI requires more thorough studies to consider it as a risk stratification tool in patients with HCM.

Introduction: Septal myectomy for obstructive hypertrophic cardiomyopathy (HCM) is associated with conduction block; however, the electrophysiological characteristics of conduction block have not been well characterized. The aim of study was to assess the feasibility and safety of His bundle pacing (HBP) and left bundle branch area pacing (LBBAP) in patients with septal myectomy‐associated conduction block. Methods and Results: Patients with HCM and indications for pacing or cardiac resynchronization therapy after septal myectomy were included. Electrophysiological mapping was performed to identify the site of block. The success rates and pacing characteristics of HBP and LBBAP were also recorded. The echocardiographic data and complications were documented and tracked during follow‐up. Ten patients with atrioventricular block (AVB) or left bundle branch block (LBBB) post‐myectomy were included in the study. The site of block was infranodal in the nine patients with AVB. HBP failed due to the lack of distal His bundle capture (N = 7) or LBBB correction (N = 3). LBBAP was successful in nine patients and failed in one. QRS duration narrowed from 163.3 ± 16.6 ms after surgery to 123.6 ± 15.8 ms during LBBAP (p <.001). The mean depth of the leads was 13.3 ± 4.0 mm (range from 10 to 20 mm). At a mean follow‐up of 5.3 ± 3.9 months, pacing parameters and left ventricular ejection fraction remained stable. Conclusions: Electrophysiological mapping revealed that the site of block was infra‐Hisian and not correctable with HBP in patients with HCM post‐myectomy. LBBAP appears to be a more feasible physiological strategy for these patients. [ABSTRACT FROM AUTHOR]

Aims Hypertrophic cardiomyopathy (HCM) is characterized by cardiomyocyte hypertrophy and disarray, and myocardial stiffness due to interstitial fibrosis, which result in impaired left ventricular filling and diastolic dysfunction. The latter manifests as exercise intolerance, angina, and dyspnoea. There is currently no specific treatment for improving diastolic function in HCM. Here, we investigated whether myeloperoxidase (MPO) is expressed in cardiomyocytes and provides a novel therapeutic target for alleviating diastolic dysfunction in HCM. Methods and results Human cardiomyocytes derived from control-induced pluripotent stem cells (iPSC-CMs) were shown to express MPO, with MPO levels being increased in iPSC-CMs generated from two HCM patients harbouring sarcomeric mutations in the MYBPC3 and MYH7 genes. The presence of cardiomyocyte MPO was associated with higher chlorination and peroxidation activity, increased levels of 3-chlorotyrosine-modified cardiac myosin binding protein-C (MYBPC3), attenuated phosphorylation of MYBPC3 at Ser-282, perturbed calcium signalling, and impaired cardiomyocyte relaxation. Interestingly, treatment with the MPO inhibitor, AZD5904, reduced 3-chlorotyrosine-modified MYBPC3 levels, restored MYBPC3 phosphorylation, and alleviated the calcium signalling and relaxation defects. Finally, we found that MPO protein was expressed in healthy adult murine and human cardiomyocytes, and MPO levels were increased in diseased hearts with left ventricular hypertrophy. Conclusion This study demonstrates that MPO inhibition alleviates the relaxation defect in hypertrophic iPSC-CMs through MYBPC3 phosphorylation. These findings highlight cardiomyocyte MPO as a novel therapeutic target for improving myocardial relaxation associated with HCM, a treatment strategy which can be readily investigated in the clinical setting, given that MPO inhibitors are already available for clinical testing. [ABSTRACT FROM AUTHOR]

Objective·To evaluate the relation between body mass index (BMI) and left ventricular structure and function in patients with hypertrophic cardiomyopathy (HCM) through cardiovascular magnetic resonance (CMR). Methods·Twenty-two healthy people (control group) and 92 consecutive patients with HCM (HCM group) who received treatment in the Department of Cardiology of Renji Hospital, Shanghai Jiao Tong University School of Medicine were included from January 2016 to December 2020, and all participants completed CMR examination under the scrutiny of cardiologists and radiologists. Patients with HCM were grouped according to BMI index: the normal BMI subgroup (BMI<24.00 kg/m²), the overweight subgroup (24.00 kg/m² ≤BMI<28.00 kg/m²) and the obesity subgroup (BMI≥28.00 kg/m²). The structural and functional indexes of CMR between the HCM group and the control group and among the three HCM subgroups were compared, including left ventricular end-diastolic volume (LVEDV), left ventricular end-systolic volume (LVESV), left ventricular ejection fraction (LVEF), left ventricular mass index (LVMI) and global longitudinal strain (GLS). The relationship between BMI and GLS was explored by stepwise linear analysis. Results·The HCM group had higher LVEF (P=0.001), higher LVMI (P=0.000) and lower GLS (P=0.000) compared with the control group. LVEDV increased (both P=0.000) and GLS decreased (P=0.005, P=0.000) in the overweight and the obesity subgroup compared with the normal BMI subgroup. In the stepwise linear regression, it suggested that BMI in patients with HCM was associated with decreased GLS independently after being adjusted for age (β=-0.431, P=0.000). Conclusion·BMI is negatively correlated with the left ventricular structure and function in patients with HCM. Losing weight to keep BMI in normal range may help to improve left ventricular function and clinical prognosis. [ABSTRACT FROM AUTHOR]

Inherited cardiomyopathies are a prevalent cause of heart failure and sudden cardiac death. Both hypertrophic (HCM) and dilated cardiomyopathy (DCM) are genetically heterogeneous and typically present with an autosomal dominant mode of transmission. Whole exome sequencing and autozygosity mapping was carried out in eight un-related probands from consanguineous Middle Eastern families presenting with HCM/DCM followed by bioinformatic and co-segregation analysis to predict the potential pathogenicity of candidate variants. We identified homozygous missense variants in TNNI3K, DSP, and RBCK1 linked with a dilated phenotype, in NRAP linked with a mixed phenotype of dilated/hypertrophic, and in KLHL24 linked with a mixed phenotype of dilated/hypertrophic and non-compaction features. Co-segregation analysis in family members confirmed autosomal recessive inheritance presenting in early childhood/early adulthood. Our findings add to the mutational spectrum of recessive cardiomyopathies, supporting inclusion of KLHL24, NRAP and RBCK1 as disease-causing genes. We also provide evidence for novel (recessive) modes of inheritance of a well-established gene TNNI3K and expand our knowledge of the clinical heterogeneity of cardiomyopathies. A greater understanding of the genetic causes of recessive cardiomyopathies has major implications for diagnosis and screening, particularly in underrepresented populations, such as those of the Middle East.