In vivo and in vitro study on the regulatory mechanism of XiaoChaiHu decoction on PANoptosis in sepsis-induced cardiomyopathy.

ETHNOPHARMACOLOGICAL RELEVANCE: In accordance with the tenets of traditional Chinese medicine, sepsis is categorized into three distinct syndromes: heat syndrome, blood stasis syndrome, and deficiency syndrome. Xiaochaihu decoction (XCHD) has many functions, including the capacity to protect the liver, cholagogue, antipyretic, anti-inflammatory, and anti-pathogenic microorganisms. XCHD exerts the effect of clearing heat and reconciling Shaoyang. The XCHD contains many efficacious active ingredients, yet the mechanism of sepsis-induced cardiomyopathy (SIC) remains elusive. AIM OF THE STUDY: To investigate the molecular mechanisms underlying the protective effects of XCHD against SIC using an integrated approach combining network pharmacology and molecular biology techniques. MATERIALS AND METHODS: Network pharmacology methods identified the active ingredients, target proteins, and pathways affected by XCHD in the context of SIC. We conducted in vivo experiments using mice with lipopolysaccharide-induced SIC, evaluating cardiac function through echocardiography and histology. XCHD-containing serum was analyzed to determine its principal active components using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The effects of XCHD-containing serum on SIC were further tested in vitro in LPS-treated H9c2 cardiac cells. Protein expression levels were quantified via Western blotting and enzyme-linked immunosorbent assay (ELISA). Additionally, molecular docking was performed between the active components and ZBP1, a potential target protein. Overexpression of ZBP1 in H9c2 cells allowed for a deeper exploration of its role in modulating SIC-associated gene expression. RESULTS: UPLC-MS/MS identified 31 shared XCHD and XCHD-containing serum components. These included organic acids, terpenoids, and flavonoids, which have been identified as the active components of XCHD. Our findings revealed that XCHD alleviated LPS-induced myocardial injury, improved cardiac function, and preserved cardiomyocyte morphology in mice. In vitro studies, we demonstrated that XCHD-containing serum significantly suppressed the expression of inflammatory cytokines (IL-6, IL-1ß, and TNF-α) in LPS-induced H9c2 cells. Mechanistic investigations showed that XCHD downregulated genes associated with PANoptosis, a novel cell death pathway, suggesting its protective role in sepsis-damaged hearts. Conversely, overexpression of ZBP1 abolished the protective effects of XCHD and amplified PANoptosis-related gene expression. CONCLUSIONS: Our study provides the first evidence supporting the protective effects of XCHD against SIC, both in vitro and in vivo. The underlying mechanism involves the inhibition of ZBP1-initiated PANoptosis, offering new insights into treating SIC using XCHD.

Machine learning and radiomics for ventricular tachyarrhythmia prediction in hypertrophic cardiomyopathy: insights from an MRI-based analysis.

BACKGROUND: Myocardial fibrosis is often detected in patients with hypertrophic cardiomyopathy (HCM), which causes left ventricular (LV) dysfunction and tachyarrhythmias. PURPOSE: To evaluate the potential value of a machine learning (ML) approach that uses radiomic features from late gadolinium enhancement (LGE) and cine images for the prediction of ventricular tachyarrhythmia (VT) in patients with HCM. MATERIAL AND METHODS: Hyperenhancing areas of LV myocardium on LGE images were manually segmented, and the segmentation was propagated to corresponding areas on cine images. Radiomic features were extracted using the PyRadiomics library. The least absolute shrinkage and selection operator (LASSO) method was employed for radiomic feature selection. Our model development employed the TabPFN algorithm, an adapted Prior-Data Fitted Network design. Model performance was evaluated graphically and numerically over five-repeat fivefold cross-validation. SHapley Additive exPlanations (SHAP) were employed to determine the relative importance of selected radiomic features. RESULTS: Our cohort consisted of 60 patients with HCM (73.3% male; median age = 51.5 years), among whom 17 had documented VT during the follow-up. A total of 1612 radiomic features were extracted for each patient. The LASSO algorithm led to a final selection of 18 radiomic features. The model achieved a mean area under the receiver operating characteristic curve of 0.877, demonstrating good discrimination, and a mean Brier score of 0.119, demonstrating good calibration. CONCLUSION: Radiomics-based ML models are promising for predicting VT in patients with HCM during the follow-up period. Developing predictive models as clinically useful decision-making tools may significantly improve risk assessment and prognosis.

Impact of Aficamten on Disease and Symptom Burden in Obstructive Hypertrophic Cardiomyopathy: Results From SEQUOIA-HCM.

BACKGROUND: Aficamten is a cardiac myosin inhibitor that mitigates left ventricular outflow gradients in obstructive hypertrophic cardiomyopathy (oHCM). The clinical efficacy of aficamten across multiple outcome domains in oHCM has not been fully defined. OBJECTIVES: This responder analysis from the SEQUOIA-HCM (Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic oHCM) trial characterizes the clinical impact of aficamten. METHODS: Patients who were symptomatic of oHCM were randomized to aficamten (n = 142) or placebo (n = 140) daily for 24 weeks. Outcomes assessed included the proportion of patients with complete hemodynamic response (rest and Valsalva gradient <30 mm Hg and <50 mm Hg, respectively), relief in limiting symptoms (≥1 improvement in NYHA functional class and/or ≥10-point change in Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score), enhanced exercise capacity (≥1.5 mL/kg/min change in peak oxygen uptake), and ≥50% reduction in N-terminal pro-B-type natriuretic peptide. Eligibility for septal reduction therapy was also evaluated. RESULTS: At 24 weeks, patients treated with aficamten vs placebo showed significant improvement in limiting symptoms (71% vs 42%), were more likely to have complete hemodynamic response (68% vs 7%), demonstrated enhanced exercise capacity (47% vs 24%), and showed a decrease ≥50% in N-terminal pro-B-type natriuretic peptide (84% vs 8%) (P ≤ 0.002 for all). An improvement in ≥1 of these outcome measures was achieved in 97% of patients treated with aficamten (vs 59% placebo), including 23% on aficamten who achieved all 4 outcomes compared with none in placebo. Among 32 patients receiving aficamten and 29 patients receiving placebo who were eligible for septal reduction therapy, 28 (88%) from the aficamten group were no longer eligible at 24 weeks compared with 15 (52%) from the placebo group (P = 0.002). CONCLUSIONS: Treatment with aficamten was associated with substantial improvements across a broad range of clinically relevant efficacy measures. These results underscore the wide-ranging potential of aficamten for treatment of patients with symptomatic oHCM (Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults with oHCM [SEQUOIA-HCM]; NCT05186818).

Re-analysis of Next-generation Sequencing Data in Patients with Hypertrophic Cardiomyopathy: Contribution of Spliceogenic MYBPC3 Variants in an Italian Cohort.

Hypertrophic cardiomyopathy (HCM) is a genetic cardiac muscle disease characterized by clinical and genetic heterogeneity. Genetic testing can reveal the presence of disease-causing variants in genes encoding sarcomere proteins. However, it yields inconclusive or negative results in 40-60% of HCM cases, owing to, among other causes, technical limitations such as the inability to detect pathogenic intronic variants. Therefore, we aimed to increase the diagnostic yield of molecular analysis for HCM by improving the in-silico detection of intronic variants in MYBPC3 that may escape detection by algorithms normally used with tagged diagnostic panels. We included 142 HCM probands with negative results in Illumina TruSight Cardio panel analysis, including exonic regions of 174 cardiomyopathy genes. Raw data were re-analyzed using existing bioinformatics tools. The spliceogenic variant c.1224-80G>A was detected in three patients (2.1%), leading us to reconsider their molecular diagnosis. These patients showed late onset and mild symptoms, although no peculiar phenotypic characteristics were shared. Collectively, rare spliceogenic MYBPC3 variants may play a role in causing HCM, and their systematic detection should be performed to provide more comprehensive solutions in genetic testing using multigenic panels.

Hypertrophic cardiomyopathy and left ventricular non-compaction: Distinct diseases or variant phenotypes of a single condition?

Hypertrophic cardiomyopathy (HCM) is a genetically determined myocardial disease characterized by an increased thickness of the left ventricle (LV) wall that cannot be solely attributed to abnormal loading conditions. HCM may present with an intraventricular or LV outflow tract obstruction, diastolic dysfunction, myocardial fibrosis and/or ventricular arrhythmias. Differentiating HCM from other diseases associated with LV hypertrophy, such as hypertension, aortic stenosis, or LV non-compaction (LVNC), can at times be challenging. LVNC is defined by excessive LV trabeculation and deep recesses between trabeculae, often accompanied by increased LV myocardial mass. Previous studies indicate that the LVNC phenotype may be observed in up to 5% of the general population; however, in most cases, it is a benign finding with no impact on clinical outcomes. Nevertheless, LVNC can occasionally lead to LV systolic dysfunction, manifesting as a phenotype of dilated or non-dilated left ventricular cardiomyopathy, with an increased risk of thrombus formation and arterial embolism. In extreme cases, where LVNC is associated with a very thickened LV wall, it can even mimic HCM. There is growing evidence of an overlap between HCM and LVNC, including similar genetic mutations and clinical presentations. This raises the question of whether HCM and LVNC represent different phenotypes of the same disease or are, in fact, two distinct entities.

Desmoplakin CSM models unravel mechanisms regulating the binding to intermediate filaments and putative therapeutics for cardiocutaneous diseases.

Arrhythmogenic cardiomyopathy (AC) is a common cause of sudden cardiac arrest and death in young adults. It can be induced by different types of mutations throughout the desmoplakin gene including the R2834H mutation in the extreme carboxyterminus tail of desmoplakin (DP CT) which remains structurally uncharacterized and poorly understood. Here, we have created 3D models of DP CT which show the structural effects of AC-inducing mutations as well as the implications of post-translational modifications (PTMs). Our results suggest that, in absence of PTMs, positively charged wildtype DP CT likely folds back onto negatively-charged plectin repeat 14 of nearby plakin repeat domain C (PRD C) contributing to the recruitment of intermediate filaments (IFs). When phosphorylated and methylated, negatively-charged wildtype DP CT would then fold back onto positively-charged plectin repeat 17 of PRD C, promoting the repulsion of intermediate filaments. However, by preventing PTMs, the R2834H mutation would lead to the formation of a cytoplasmic mutant desmoplakin with a constitutively positive DP CT tail that would be aberrantly recruited by cytoplasmic IFs instead of desmosomes, potentially weakening cell-cell contacts and promoting AC. Virtual screening of FDA-approved drug libraries identified several promising drug candidates for the treatment of cardiocutaneous diseases through drug repurposing.

Anaesthetic Management of Right Inguinal Hernioplasty With Hemiorchidectomy in a High-Risk Dilated Cardiomyopathy Patient.

This case report details the successful anaesthetic management of a 65-year-old male with severe dilated cardiomyopathy, coronary artery disease, and extensive cardiovascular risk factors scheduled for elective right inguinal hernioplasty with hemiorchidectomy. The anaesthetic approach, including regional nerve blocks (ilioinguinal, iliohypogastric, genital branch of genitofemoral) and transversus abdominis plane block, successfully minimised cardiac stress and maintained hemodynamic stability throughout the procedure.

Contemporary characteristics, outcomes and novel risk score for Takotsubo cardiomyopathy: a national inpatient sample analysis.

BACKGROUND: Takotsubo cardiomyopathy (TC) is an established differential diagnosis of myocardial infarction with non-obstructive coronaries with significant interest but limited data on prognostication. We reviewed the characteristics and in-hospital outcomes and developed a novel risk score for TC. METHODS: Using the National Inpatient Sample data from 2016 to 2020, we identified adult patients (≥18 years) with acute coronary syndrome (ACS) and TC. We divided the cohort into ACS with and without TC and retrieved baseline data. Multivariable regression analysis was conducted to identify factors associated with TC diagnosis and adverse outcomes, leading to the development of a risk-scoring system. RESULTS: Among 7 219 004 adult ACS admissions, 78 214 (1.0%) were diagnosed with TC, with a mean age of 68.2 years, 64 526 (82.5%) being female and 5475 (7.0%, compared with 8.4% for other ACS) in-hospital mortality events. Factors significantly associated with TC were female sex (OR 6.78 (95% CI 6.47 to 7.09), p<0.001) and chronic heart failure (OR 1.60 (95% CI 1.54 to 1.66), p<0.001). A novel risk score was developed, including the following parameters: male sex, age >70 years, non-white race, hypertension, hyperlipidemia, history of coronary artery bypass grafting, history of percutaneous coronary intervention, cardiac arrhythmias, renal failure, cardiogenic shock and vasopressor use. The area under curves for in-hospital mortality was 0.716 in the derivation and 0.725 in the validation cohorts. CONCLUSIONS: TC remains a high-risk diagnosis in a minority of ACS cases, with mortality rates similar to other ACS causes. Our novel risk score offers a valuable tool for risk stratification in patients with TC, but external validation is needed to confirm its utility.

Metabolomics: Implication in cardiovascular research and diseases.

Cellular metabolism influences all aspects of cellular function and is crucial for overall organismal health. Metabolic disorders related to cardiovascular health can lead to cardiovascular diseases (CVDs). Moreover, associated comorbidities may also damage cardiovascular metabolism, exacerbating CVD and perpetuating a vicious cycle. Given the prominent role of metabolic alterations in CVD, metabolomics has emerged as an imperative technique enabling a comprehensive assessment of metabolites and metabolic architecture within the body. Metabolite profile and metabolic pathways help to deepen and broaden our understanding of complex genomic landscape and pathophysiology of CVD. Here in this review, we aim to overview the experimental and clinical applications of metabolomics in pathogenesis, diagnosis, prognosis, and management of various CVD plus future perspectives and limitations.

Stress Echocardiography for Assessment of Diastolic Function.

PURPOSE OF REVIEW: Diastolic dysfunction is an important, though often underappreciated, cause for exertional dyspnea. Echocardiography enables noninvasive evaluation of diastolic function and filling pressure, but images acquired at rest may be insensitive for detection of exertional abnormalities. This review focuses on stress echocardiography to assess diastolic function, including traditional and novel techniques, with emphasis on specific patient sub-groups in whom this testing may be valuable. RECENT FINDINGS: Emerging data informs patient selection for diastolic stress testing. Further, increasing literature provides considerations for performance and interpretation of diastolic metrics relevant to patients with heart failure with preserved ejection fraction, hypertrophic cardiomyopathy, athletes, and those with microvascular coronary dysfunction. Methods, such as speckle-tracking and multi-modality imaging, provide additional and complementary information for non-invasive diastolic assessment. This review serves as a guide to optimally utilize existing and novel techniques of stress echocardiography for diastolic assessment across a broad range of patients.

Recurrent atrial flutter after radiofrequency ablation for atrial fibrillation in a patient with hypertrophic obstructive cardiomyopathy undergoing repetitive transcoronary ablation of septal hypertrophy.

INTRODUCTION: We described the clinical characteristics of a patient with hypertrophic obstructive cardiomyopathy (HOCM) who had undergone transcoronary ablation of septal hypertrophy (TASH) twice and developed atrial flutter after radiofrequency ablation for atrial fibrillation (AF) due to pulmonary vein reconnection. This case of HOCM is unique because of its complex complications and multiple complex atrial arrhythmias. The treatment of HOCM was successful and the postoperative follow-up results was good. METHODS AND RESULTS: A 71-year-oldfemale, developed exertional dyspnea with palpitations 12 years ago, with a valid diagnosis of HOCM according to the echocardiography which showed an absolute increase in the interventricular septum thickness (22.8 mm). She underwent two rounds of TASH and only the second round was successful. During a visit due to recurrent palpitations, the patient was diagnosed with AF based on electrocardiographic examination. Circumferential pulmonary vein isolation (CPVI) was performed to treat AF. However, the recurrence of atrial flutter was detected on her electrocardiograms (ECGs) three years after the operation. Since the patient had an interstitial lung injury, there were relative contraindications for antiarrhythmic drugs. Due to restrictive use of antiarrhythmic drugs and continuous palpitation, the patient agreed to receive a second radiofrequency ablation. Left-sided macroreentrant circuits were identified via high-density mapping and successful ablation was performed at the isthmus. CONCLUSIONS: Performing catheter ablation and TASH respectively in patients with HOCM associated with AF would be tricky. But taking such a comprehensive and respective clinical treatment would be beneficial to patients in the long term.

The many faces of SCN5A pathogenic variants: from channelopathy to cardiomyopathy.

The SCN5A gene encodes the alpha subunit of the cardiac sodium channel, which plays a fundamental role in the generation and propagation of the action potential in the heart muscle. During the past years our knowledge concerning the function of the cardiac sodium channel and the diseases caused by mutations of the SCN5A gene has grown. Although initially SCN5A pathogenic variants were mainly associated with channelopathies, increasing recent evidence suggests an association with structural heart disease in the form of heart muscle disease. The pathways leading to a cardiomyopathic phenotype remain unclear and require further elucidation. The aim of the present review is to provide a concise summary regarding the mechanisms through which SCN5A pathogenic variants result in heart disease, focusing in cardiomyopathy, highlighting along the way the complex role of the SCN5A gene at the intersection of cardiac excitability and contraction networks.

History and Perspective of LAMP-2 Deficiency (Danon Disease).

Danon disease, an X-linked dominant vacuolar cardiomyopathy and skeletal myopathy, is caused by a primary deficiency of lysosome-associated membrane protein-2 (LAMP-2). This disease is one of the autophagy-related muscle diseases. Male patients present with the triad of cardiomyopathy, myopathy, and intellectual disability, while female patients present with cardiomyopathy. The disease's leading cause of death is heart failure, and its prognostic factor is cardiomyopathy. Pathologically, the disease is characterized by the appearance of unique autophagic vacuoles with sarcolemmal features (AVSFs). Twenty-six families have been found to have this disease in Japan. It has been over 40 years since the first report of this disease by Danon et al. and over 20 years since the identification of the causative gene, LAMP2, by Nishino et al. Although the pathogenetic mechanism of Danon disease remains unestablished, the first clinical trials using AAV vectors have finally begun in recent years. The development of novel therapies is expected in the future.

The D75N and P161S Mutations in the C0-C2 Fragment of cMyBP-C Associated with Hypertrophic Cardiomyopathy Disturb the Thin Filament Activation, Nucleotide Exchange in Myosin, and Actin-Myosin Interaction.

About half of the mutations that lead to hypertrophic cardiomyopathy (HCM) occur in the MYBPC3 gene. However, the molecular mechanisms of pathogenicity of point mutations in cardiac myosin-binding protein C (cMyBP-C) remain poorly understood. In this study, we examined the effects of the D75N and P161S substitutions in the C0 and C1 domains of cMyBP-C on the structural and functional properties of the C0-C1-m-C2 fragment (C0-C2). Differential scanning calorimetry revealed that these mutations disorder the tertiary structure of the C0-C2 molecule. Functionally, the D75N mutation reduced the maximum sliding velocity of regulated thin filaments in an in vitro motility assay, while the P161S mutation increased it. Both mutations significantly reduced the calcium sensitivity of the actin-myosin interaction and impaired thin filament activation by cross-bridges. D75N and P161S C0-C2 fragments substantially decreased the sliding velocity of the F-actin-tropomyosin filament. ADP dose-dependently reduced filament sliding velocity in the presence of WT and P161S fragments, but the velocity remained unchanged with the D75N fragment. We suppose that the D75N mutation alters nucleotide exchange kinetics by decreasing ADP affinity to the ATPase pocket and slowing the myosin cycle. Our molecular dynamics simulations mean that the D75N mutation affects myosin S1 function. Both mutations impair cardiac contractility by disrupting thin filament activation. The results offer new insights into the HCM pathogenesis caused by missense mutations in N-terminal domains of cMyBP-C, highlighting the distinct effects of D75N and P161S mutations on cardiac contractile function.

Detection of Fibroadipose Tissue Infiltration with Cardiac Computed Tomography: A Case of Arrhythmogenic Cardiomyopathy.

In the evaluation of cardiomyopathies, cardiac computed tomography (CCT) is predominantly used for assessing congenital or acquired coronary artery diseases as a potential etiology underlying the observed myocardial abnormalities. However, its utility is expected to expand. We present a case of an asymptomatic patient with claustrophobia who sought medical attention due to frequent ventricular beats. The resting electrocardiogram revealed repolarization abnormalities characterized by flattened T-waves in the lateral leads and low QRS voltages in the peripheral leads, whereas transthoracic echocardiography was normal. CCT accurately identified hypodense areas indicative of fibrofatty infiltration within the inferolateral and anterior walls of the left ventricle. Furthermore, late iodine contrast-phase imaging revealed subepicardial late enhancement striae in the same regions. These imaging findings were pivotal in establishing a diagnosis of left-dominant arrhythmogenic cardiomyopathy. This clinical vignette underscores the potential of CCT in tissue characterization, particularly when cardiac magnetic resonance imaging is contraindicated or unavailable.

ST-segment elevation in V1-4 in takotsubo cardiomyopathy with ventricular septal perforation: A case report and literature review.

Background: Takotsubo cardiomyopathy (TCM) is a nonischemic cardiomyopathy characterized by chest pain, typically manifesting transient left ventricular (LV) apical akinesis, and ischemic electrocardiographic changes, mimicking acute coronary syndrome (ACS). Although ventricular septal perforation (VSP) is a rare complication of TCM, it is potentially life-threatening if left untreated. Whether the conventional electrocardiographic criteria for TCM are beneficial, even in patients of TCM with VSP, remains unclear. Case presentation: An 87-year-old woman was admitted for worsening dyspnea. Elevated serum cardiac enzyme levels, LV dysfunction on echocardiography, and ST-segment elevation in leads V1-4 on electrocardiogram were initially suggestive of ACS. An emergency coronary angiography revealed 90 % focal stenosis of the mid-portion of the right coronary artery (RCA) with Thrombolysis in Myocardial Infarction flow grade 2. However, left ventriculography revealed LV apical ballooning with a coexisting left-to-right shunting, which was beyond single RCA distributions, leading to a final diagnosis of TCM with VSP. Repeat echocardiography confirmed VSP and right ventricular involvement with severe pulmonary hypertension. Following successful percutaneous coronary intervention with a drug-eluting stent for RCA stenosis, the patient was managed with medical treatment without surgical intervention. Eventually, VSP and associated pulmonary hypertension markedly improved along with the normalization of the patient's cardiac structure and function. The patient's clinical course was uneventful at the 1-year follow-up. Conclusions: Herein, we describe the case of TCM with VSP that we successfully managed with medical treatments. Our case highlights the significance of elucidating this rare complication of TCM, pitfalls of the conventional electrocardiographic diagnostic criteria for TCM, and potential of this unique electrocardiographic pattern for identifying TCM-associated VSP.