Exploring the etiology of dilated cardiomyopathy using Mendelian randomization.

Background: Observational clinical studies suggest an association between dilated cardiomyopathy (DCM) and various factors including titin, cardiac troponin I (CTnI), desmocollin-2, the perinatal period, alcoholism, Behçet's disease, systemic lupus erythematosus, hyperthyroidism and thyrotoxicosis, hypothyroidism, carnitine metabolic disorder, and renal insufficiency. The causal nature of these associations remains uncertain. This study aims to explore these correlations using the Mendelian randomization (MR) approach. Objective: To investigate the etiology of DCM through Mendelian randomization analysis. Methods: Data mining was conducted in genome-wide association study databases, focusing on variant target proteins (titin, CTnI, desmocollin-2), the perinatal period, alcoholism, Behçet's disease, systemic lupus erythematosus, hyperthyroidism and thyrotoxicosis, hypothyroidism, carnitine metabolic disorder, and renal insufficiency, with DCM as the outcome. The analysis employed various regression models, namely, the inverse-variance weighted (IVW), MR-Egger, simple mode, weighted median, and weighted mode methods. Results: The IVW results showed a correlation between titin protein and DCM, identifying titin as a protective factor [OR = 0.856, 95% CI (0.744-0.985), P = 0.030]. CTnI protein correlated with DCM, marking it as a risk factor [OR = 1.204, 95% CI (1.010-1.436), P = 0.040]. Desmocollin-2 also correlated with DCM and was recognized as a risk factor [OR = 1.309, 95% CI (1.085-1.579), P = 0.005]. However, no causal relationship was found between the perinatal period, alcoholism, Behçet's disease, systemic lupus erythematosus, hyperthyroidism and thyrotoxicosis, hypothyroidism, carnitine metabolic disorder, renal insufficiency, and DCM (P > 0.05). The MR-Egger intercept test indicated no pleiotropy (P > 0.05), affirming the effectiveness of Mendelian randomization in causal inference. Conclusion: Titin, CTnI, and desmocollin-2 proteins were identified as independent risk factors for DCM. Contrasting with previous observational studies, no causal relationship was observed between DCM and the perinatal period, alcoholism, Behçet's disease, systemic lupus erythematosus, hyperthyroidism and thyrotoxicosis, hypothyroidism, carnitine metabolic disorder, or renal insufficiency.

Biallelic NEXN variants and fetal onset dilated cardiomyopathy: two independent case reports and revision of literature.

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.

Differences in T cell-associated serum markers between ischemic cardiomyopathy and dilated cardiomyopathy.

Background: Ischemic cardiomyopathy (ICM) and dilated cardiomyopathy (DCM) have similar clinical manifestations but differ in pathogenesis. We aimed to identify T cell-associated serum markers that can be used to distinguish between ICM and DCM. Methods: We identified differentially expressed genes (DEGs) with transcriptome sequencing data in GSE116250, and then conducted enrichment analysis of DEGs in the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. Protein-protein interaction (PPI) networks were used to analyze the relationship between T cells-related genes and identify hub genes. Enzyme-linked immunosorbent assay (ELISA) kits were used to detect T cell-associated proteins in serum, and receiver operating characteristic (ROC) curves were used to evaluate the diagnostic efficacy of these serum markers. Results: Using the limma package and Venn plots, we found that the non-failing donors (NFD) and DCM groups shared many of the same DEGs and DEGs-enriched functions compared to the ICM group, which were involved in T cell activation and differentiation, among other functions. Subsequently, the immune cell score showed no difference between NFD and DCM, but they were significantly different from ICM patients in CD8 T cells CD4 T cells memory resting and activated, T cells follicular helper, and M1 macrophage. After analyzing T cell-associated DEGs, it was found that 4 DEGs encoding secreted proteins were highly expressed in the ICM group compared with the NFD and DCM groups, namely chemokine (C-C motif) ligand 21 (CCL21), interleukin (IL)-1ß, lymphocyte-activation gene 3 (LAG3), and vascular cell adhesion molecule-1 (VCAM-1). Importantly, the serum levels of CCL21, IL-1ß, LAG3, and VCAM-1 in ICM patients were all significantly higher than those in DCM patients. The ROC curves showed that the area under the curve (AUC) values of serum CCL21, IL-1ß, LAG3, and VCAM-1 were 0.775, 0.868, 0.934, and 0.903, respectively. Conclusions: We have identified four T cell-associated serum markers, CCL21, IL-1ß, LAG3, and VCAM-1, as potential diagnostic serum markers that differentiate ICM from DCM.

Titin Cardiomyopathy Associated With Refractory Ventricular Tachycardia: A Case Report.

Cardiomyopathy is defined as structural and functional myocardial abnormality not attributed to ischemic, valvular, hypertensive, or congenital cardiac causes. The main phenotypes of cardiomyopathy include hypertrophic, dilated, non-dilated left ventricular, restrictive, arrhythmogenic right ventricular, Takotsubo, and left ventricular noncompaction cardiomyopathies. A significant proportion of dilated cardiomyopathy (DCM) cases represents patients with genetic mutations, most commonly titin gene truncating variants (TTNtv). It has been shown that TTNtv mutation contributes to the development of certain types of DCM such as alcohol, chemotherapy, and peripartum. We present a case of DCM where genetic workup revealed TTNtv without other contributing factors. The course was complicated by multiple ventricular tachycardias (VTs) refractory to medical management, despite treatment with amiodarone, sotalol, dofetilide, mexiletine, and propranolol. Interestingly, endocardial mapping failed to delineate the substrate of tachycardia. This report underscores the importance of genetic testing in DCM and highlights the potential association of titin cardiomyopathy with refractory VTs, possibly of epicardial origin.

Feasibility and reproducibility of cardiovascular magnetic resonance-feature tracking for quantitative right atrial function in dilated cardiomyopathy patients.

Background: The importance of right heart assessment in dilated cardiomyopathy (DCM) is increasingly recognized. The development of cardiovascular magnetic resonance-feature tracking (CMR-FT) has provided a novel approach to quantify myocardial deformation and evaluate cardiac function. In this study, we aimed to evaluate the feasibility and reproducibility of CMR-FT for the quantitative derivation of right atrial (RA) strain and strain rate (SR) in patients with DCM. Methods: A total of 68 DCM patients (84% male; aged 50.6±13.2 years) and 58 healthy controls (81% male; aged 48.4±11.2 years) were retrospectively enrolled from September 2018 to August 2022 at the First Affiliated Hospital of Zhejiang Chinese Medical University and Shenzhen Clinical Medical College of Guangzhou University of Chinese Medicine. RA reservoir, conduit, and booster strain (εs, εe, and εa) and peak positive, peak early negative, and peak late negative SR (SRs, SRe, and SRa) were measured using CMR-FT and compared between 2 groups using Student's t-test. Intra- and inter-observer reproducibility was evaluated using intraclass correlation coefficients (ICC) and Bland-Altman plots. Results: Compared to healthy controls, DCM patients showed significantly lower RA strain (εs: 19.7%±9.0% vs. 44.4%±9.7%; εe: 7.9%±5.3% vs. 25.8%±8.6%; εa: 11.8%±6.2% vs. 18.6%±5.1%, all P<0.001) and SR (SRs: 1.17±0.48 vs. 1.92±0.62 s-1; SRe: -0.85±0.56 vs. -1.94±0.63 s-1; SRa: -1.39±0.71 vs. -2.01±0.65 s-1, all P<0.001). There was no significant difference in RA maximum volume index between the 2 groups. Simple linear regression analysis demonstrated a significant correlation between N-terminal B-type natriuretic peptide (NT-proBNP), RA emptying fraction passive (RAEF passive), and RA εe [(NT-proBNP and εe): r=-0.48, P<0.001, 95% confidence interval (CI): -0.64 to -0.26; and (RAEF passive and εe): r=0.41, P=0.001, 95% CI: 0.22 to 0.56, respectively] in DCM patients. Intra- and inter-observer reproducibility was excellent (all ICCs >0.85) for RA deformation measurements. Conclusions: CMR-FT is a promising, noninvasive approach for the quantitative assessment of RA phasic function in patients with DCM. DCM patients exhibit impaired RA reservoir, conduit, and booster pump function prior to visible RA enlargement.

DCM-Spheroid Morphs Express PADs and Citrullinated Cytoskeletal Proteins.

During investigating the role of peptidylarginine deiminase (PAD) enzymes in dilated cardiomyopathy (DCM), we observed unique spheroid formation in DCM-myofibroblasts that distinguished them from normal cardiac myofibroblasts. The present study aimed to assess the presence of PADs, the extracellular matrix (ECM), and citrullination in DCM spheroids using immunofluorescence staining and imaging techniques. The results revealed that spheroids derived from DCM-myofibroblasts displayed a more distinctive, tightly packed structure compared with those derived from human cardiac fibroblasts. DCM spheroids showed abundant protein expression of the PAD 2, 3, and 4 enzymes. Notably, increased Ki67 protein expression was associated with increased proliferation in DCM spheroids. Cytoskeletal proteins such as Col-1A, vimentin, α-SMA, and F-actin were highly abundant in DCM spheroids. Furthermore, DCM spheroids contained citrullinated cytoskeletal proteins, mainly citrullinated vimentin and citrullinated fibronectin. These observations supported the occurrence of PAD-mediated citrullination of ECM proteins in DCM spheroids. Collectively, these findings describe the distinctive features of DCM spheroids, representing the cellular characteristics of DCM myofibroblasts. Therefore, DCM spheroids can serve as an in vitro model for further investigations of disease morphology and therapeutic efficacy.

Titin: roles in cardiac function and diseases.

The giant protein titin is an essential component of muscle sarcomeres. A single titin molecule spans half a sarcomere and mediates diverse functions along its length by virtue of its unique domains. The A-band of titin functions as a molecular blueprint that defines the length of the thick filaments, the I-band constitutes a molecular spring that determines cell-based passive stiffness, and various domains, including the Z-disk, I-band, and M-line, serve as scaffolds for stretch-sensing signaling pathways that mediate mechanotransduction. This review aims to discuss recent insights into titin's functional roles and their relationship to cardiac function. The role of titin in heart diseases, such as dilated cardiomyopathy and heart failure with preserved ejection fraction, as well as its potential as a therapeutic target, is also discussed.

Left bundle branch block-induced dilated cardiomyopathy: Definitions, pathophysiology, and therapy.

Left bundle branch block (LBBB) is a frequent finding in patients with heart failure (HF), particularly in those with dilated cardiomyopathy (DCM). LBBB has been commonly described as a consequence of DCM development. However, a total recovery of left ventricular (LV) function after cardiac resynchronization therapy (CRT), observed in patients with LBBB and DCM, has led to increasing acknowledgement of LBBB-induced dilated cardiomyopathy (LBBB-iDCM) as a specific pathological entity. Its recognition has important clinical implications, as LBBB-iDCM patients may benefit from an early CRT strategy rather than medical HF therapy only. At present, there are no definitive diagnostic criteria enabling the universal identification of LBBB-iDCM, and no defined therapeutic approach in this subgroup of patients. This review compiles the main findings about LBBB-iDCM pathophysiology and the current proposed diagnostic criteria and therapeutic approach.

Heart in Disguise: Unmasking a Novel Gene Deletion in Dilated Cardiomyopathy.

Dilated cardiomyopathy (DCM) is an underrecognized condition with a myriad of etiologies, but it is often labeled idiopathic. However, genetic mutations are emerging as a more common cause of idiopathic DCM than previously believed. Herein, we present a case of a previously healthy 45-year-old woman who presented with three weeks of exertional dyspnea and orthopnea. An echocardiogram showed DCM with severely reduced systolic function and diastolic dysfunction. She was extensively worked up for potential etiologies of her heart failure which included HIV testing, parasite smear, viral serologies, autoimmune testing, cardiac MRI for infiltrative diseases, and coronary catheterization. She was ultimately tested for genetic mutations which revealed a 49-51 exon deletion of the dystrophin (Duchenne muscular dystrophy (DMD)) gene. This case highlights the guideline-based evaluation and management of new-onset heart failure in a healthy 45-year-old female without known predisposing risk factors or family history. It also sheds light on the expansive genetic etiologies that have only recently been identified in those with idiopathic cardiomyopathy. Further research is crucial to improve our understanding of genetic associations of cardiomyopathy.

De Novo p.Asp3368Gly Variant of Dystrophin Gene Associated with X-Linked Dilated Cardiomyopathy and Skeletal Myopathy: Clinical Features and In Silico Analysis.

Dystrophin (DMD) gene mutations are associated with skeletal muscle diseases such as Duchenne and Becker Muscular Dystrophy (BMD) and X-linked dilated cardiomyopathy (XL-DCM). To investigate the molecular basis of DCM in a 37-year-old woman. Clinical and genetic investigations were performed. Genetic testing was performed with whole exome sequencing (WES) using the Illumina platform. According to the standard protocol, a variant found by WES was confirmed in all available members of the family by bi-directional capillary Sanger resequencing. The effect of the variant was investigated by using an in silico prediction of pathogenicity. The index case was a 37-year-old woman diagnosed with DCM at the age of 33. A germline heterozygous A>G transversion at nucleotide 10103 in the DMD gene, leading to an aspartic acid-glycine substitution at the amino acid 3368 of the DMD protein (c.10103A>G p.Asp3368Gly), was identified and confirmed by PCR-based Sanger sequencing of the exon 70. In silico prediction suggests that this variant could have a deleterious impact on protein structure and functionality (CADD = 30). The genetic analysis was extended to the first-degree relatives of the proband (mother, father, and sister) and because of the absence of the variant in both parents, the p.Asp3368Gly substitution was considered as occurring de novo. Then, the direct sequencing analysis of her 8-year-old son identified as hemizygous for the same variant. The young patient did not present any signs or symptoms attributable to DCM, but reported asthenia and presented with bilateral calf hypertrophy at clinical examination. Laboratory testing revealed increased levels of creatinine kinase (maximum value of 19,000 IU/L). We report an early presentation of dilated cardiomyopathy in a 33-year-old woman due to a de novo pathogenic variant of the dystrophin (DMD) gene (p.Asp3368Gly). Genetic identification of this variant allowed an early diagnosis of a skeletal muscle disease in her son.

The Characteristics and Outcomes of Nonhospitalized Patients With Heart Failure in Saudi Arabia: A Contemporary Single-Center Study.

Background Contemporary data on patients with heart failure (HF) in Saudi Arabia is limited. Methods This was a retrospective study of patients who were followed in the HF Clinic at our center after January 1, 2022. The study end date was August 31, 2023. Patients who were alive and followed for <6 months were excluded. We reported the clinical characteristics, utilization of established therapies for HF, proportion of potential candidates for ancillary HF treatments, and rates of HF events and mortality. Results A total of 202 patients met the study criteria. The mean age was 56.0 ± 15.2 years. The median follow-up from the initial visit to the study end date was 47 months (interquartile range {IQR}: 29-58 months). Coronary artery disease (CAD) was the cause of HF in 85 (42%) patients. At their latest visit, 103 (51%) patients had diabetes, 82 (41%) were obese, and 134 (66%) received quadruple therapy. Iron deficiency was present in 143 (71%) patients during follow-up. At their latest visit, moderate-to-severe or severe functional mitral regurgitation (MR) and hyperkalemia were present in 15 (7%) and 20 (10%) patients, respectively. The combined annual rate of HF hospitalization and emergency visits for HF was 20%. At least one hospitalization for HF within a year before the study end date occurred in 19 (9%) patients. The annual all-cause mortality was 1.8%. Conclusion This contemporary cohort of outpatients with HF was relatively young and had a high prevalence of diabetes, obesity, and iron deficiency. An estimate of potential candidates for iron replacement, transcatheter repair of the mitral valve, novel potassium binders, and the implantation of the pulmonary artery pressure monitor was among the first reported regionally. All-cause mortality was low, yet the burden of HF-related events was significant.

Dilated Cardiomyopathy and Nail-Patella Syndrome: A Case Report.

Nail-patella syndrome (NPS) is a rare genetic disorder with multiple skeletal deformities and a variety of extra-skeletal involvements. We present a 17-year-old male with a clinical tetrad of skeletal abnormalities, multiple bony deformities, advanced renal failure, hypothyroidism, and dilated cardiomyopathy. A clinical diagnosis of NPS was made, supported by radiographic findings, and corroborated by compatible renal biopsy results. There are very few published reports describing the association of dilated cardiomyopathy with this syndrome. A high index of suspicion is needed to make this diagnosis, given myriads of multi-systemic manifestations.

Management of Hypertensive Emergency in the Setting of Primary Aldosteronism Complicated by Heart Failure With Reduced Ejection Fraction.

We present a case of a 49-year-old man with a past medical history of uncontrolled hypertension and alcohol use disorder presently in sustained remission who presented to the ED with shortness of breath. He was admitted for the management of hypertensive emergency and hypokalemia and was later found to have primary aldosteronism complicated by heart failure with reduced ejection fraction. The patient's treatment-resistant hypertension as well as hypokalemia, which was refractory to repletion, resolved with mineralocorticoid-receptor-antagonist pharmacotherapy. After a single oral dose of spironolactone 25 mg, the patient's mean arterial pressure decreased by approximately 26.5%. Spironolactone 25 mg was continued twice daily not only as the mainstay treatment for primary aldosteronism but also to optimize guideline-directed medical therapy for the treatment of heart failure with reduced ejection fraction.

The application of radiology for dilated cardiomyopathy diagnosis, treatment, and prognosis prediction: a bibliometric analysis.

Background: Radiology plays a highly crucial role in the diagnosis, treatment, and prognosis prediction of dilated cardiomyopathy (DCM). Related research has increased rapidly over the past few years, but systematic analyses are lacking. This study thus aimed to provide a reference for further research by analyzing the knowledge field, development trends, and research hotspots of radiology in DCM using bibliometric methods. Methods: Articles on the radiology of DCM published between 2002 and 2021 in the Web of Science Core Collection database (WoSCCd) were searched and analyzed. Data were retrieved and analyzed using CiteSpace V, VOSviewer, and Scimago Graphic software, and included the name, research institution, and nationality of authors; journals of publication; and the number of citations. Results: A total of 4,257 articles were identified on radiology of DCM from WoSCCd. The number of articles published in this field has grown steadily from 2002 to 2021 and is expected to reach 392 annually by 2024. According to subfields, the number of papers published in cardiac magnetic resonance field increased steadily. The authors from the United States published the most (1,364 articles, 32.04%) articles. The author with the most articles published was Bax JJ (54 articles, 1.27%) from Leiden University Medical Center. The most cited article was titled "2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure", with 138 citations. Citation-based clustering showed that arrhythmogenic cardiomyopathy, T1 mapping, and endomyocardial biopsy are the current hots pots for research in DCM radiology. The most frequently occurring keyword was "dilated cardiomyopathy". The keyword-based clusters mainly included "late gadolinium enhancement", "congestive heart failure", "cardiovascular magnetic resonance", "sudden cardiac death", "ventricular arrhythmia", and "cardiac resynchronization therapy". Conclusions: The United States and Northern Europe are the most influential countries in research on DCM radiology, with many leading distinguished research institutions. The current research hots pots are myocardial fibrosis, risk stratification of ventricular arrhythmia, the prognosis of cardiac resynchronization therapy (CRT) treatment, and subtype classification of DCM.

Heartache in a Bottle: Understanding Alcoholic Cardiomyopathy.

Alcoholic cardiomyopathy (ACM) is a cardiac ailment marked by impaired contraction and dilation of one or both ventricles of the heart. The extent of daily alcohol intake and duration of alcohol abuse are linked to the development of ACM, although the exact thresholds and timeline for alcohol misuse to induce heart dysfunction remain uncertain. Thus, the objective of this systematic review is to comprehensively evaluate the existing knowledge on the specific disease entity, particularly in light of the ongoing issue of alcohol misuse, with the intention of determining if recent advancements and discoveries have significantly altered the understanding of this condition compared to the past century. This systematic review involved a literature search that was conducted on PubMed to identify suitable and appropriate literature for the study. The inclusion criteria encompassed articles that focused on ACM or the relationship between alcohol abuse and cardiac dysfunction, involved human subjects or relevant animal models, were written in the English language, and were published within the last 10 years. The exclusion criteria included duplicates, case reports, letters, editorials, and reviews not specifically addressing ACM. As a result, a total of 18 articles were included in this systematic review. The risk of bias was assessed through the use of the Cochrane risk-of-bias tool for clinical trials. The findings of this systematic review indicated that the likelihood of ACM occurrence significantly rose when the consumption of over 80 g of alcohol per day occurred for at least five years. The systematic review further revealed that ACM is associated with various detrimental changes in the cellular, structural, and histological aspects of the heart muscles, even though the specific clinical and histological characteristics of ACM have yet to be established. In individuals with an extensive history of excessive alcohol abuse, the diagnosis of ACM was reached through the exclusion of other potential causes of the condition. The fundamental approach to treatment lies in abstaining from alcohol. It is crucial to manage symptoms in individuals with secondary heart failure and address any related complications.

Analysis of the role of glucose metabolism-related genes in dilated cardiomyopathy based on bioinformatics.

Background: Dilated cardiomyopathy (DCM) is a prevalent condition with diverse etiologies, including viral infection, autoimmune response, and genetic factors. Despite the crucial role of energy metabolism in cardiac function, therapeutic targets for key genes in DCM's energy metabolism remain scarce. Methods: Our study employed the GSE79962 and GSE42955 datasets from the Gene Expression Omnibus (GEO) database for myocardial tissue sample collection and target gene identification via differential gene expression screening. Using various R packages, GSEA software, and the STRING database, we conducted data analysis, gene set enrichment, and protein-protein interaction predictions. The least absolute shrinkage and selection operator (LASSO) and Support Vector Machine (SVM) algorithms aided in feature gene selection, while the predictive model's efficiency was evaluated via the receiver operating characteristic (ROC) curve analysis. We used the non-negative matrix factorization (NMF) method for molecular typing and the cell-type identification by estimating relative subsets of RNA transcripts (CIBERSORT) algorithm for predicting immune cell infiltration. Results: The DLAT and LDHA genes may regulate the immune microenvironment of DCM by influencing activated dendritic cells, activated mast cells, and M0 macrophages, respectively. The BPGM, DLAT, PGM2, ADH1A, ADH1C, LDHA, and PFKM genes may regulate m6A methylation in DCM by affecting the ZC3H13, ALKBH5, RBMX, HNRNPC, METTL3, and YTHDC1 genes. Further regulatory mechanism analysis suggested that PFKM, DLAT, PKLR, PGM2, LDHA, BPGM, ADH1A, and ADH1C could be involved in the development of cardiomyopathy by regulating the Toll-like receptor signaling pathway. Conclusions: PFKM, DLAT, PKLR, PGM2, LDHA, BPGM, ADH1A, and ADH1C may serve as potential targets for guiding the diagnosis, treatment, and follow-up of DCM.

Basic science methods for the characterization of variants of uncertain significance in hypertrophic cardiomyopathy.

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.

A Rare Case of Coexisting Mutation in Desmin and Thioredoxin Reductase 2 Genes Causing Dilated Cardiomyopathy.

Desmin (DES) maintains the overall structure of cardiomyocytes and cytoskeletal organization within striated muscle cells. Mitochondrial thioredoxin reductase 2 (TXNRD-2) is essential for mitochondrial oxygen radical scavenging. We describe a rare case of dilated cardiomyopathy (DCM) in an 18-year-old female with a heterozygous mutation involving both DES and TXNRD-2 genes.

Severe Disseminated Intravascular Coagulopathy Associated With Biventricular Massive Mural Thrombi in Newly Diagnosed Non-ischemic Cardiomyopathy.

Hemostatic system abnormalities have been previously associated with congestive heart failure (CHF). Here, we report a rare case of disseminated intravascular coagulopathy (DIC) in the setting of non-ischemic cardiomyopathy with right atrial and biventricular thrombus. We present a 55-year-old female with a past medical history of bronchial asthma who presented with a six-day history of bilateral leg swelling and dry cough. Her physical examination on admission was significant for signs of biventricular heart failure. Initial workup was significant for elevated pro-brain natriuretic peptide (ProBNP), elevated transaminases, marked thrombocytopenia (19,000/mcL), and coagulopathy with international normalized ratio (INR) of 2.5 and D-dimer of 15,585 ng/mL. Transthoracic echocardiogram (TTE) showed a large mobile right atrial thrombus protruding into the right ventricle and a more adherent left ventricular (LV) thrombus with severely reduced biventricular contractility. Pan CT was done and was significant for multifocal multilobar pulmonary emboli. A lower limb venous duplex was done and revealed extensive bilateral lower limb deep venous thrombosis (DVT). This rare case demonstrates an unusual association between DIC with non-ischemic cardiomyopathy, biventricular thrombus, extensive deep vein thrombosis, and pulmonary embolism (PE). In comparison, there are multiple prior reports for DIC with CHF and LV thrombus. However, our case differs from prior reports in terms of the presence of right atrial and biventricular thrombus. The patient received antibiotics, diuretics, and cryoprecipitate in the setting of persistent low fibrinogen levels. The patient underwent Interventional radiology-guided thrombectomy for extensive pulmonary emboli followed by inferior vena cava (IVC) filter insertion, resulting in the resolution of the right atrial thrombus and extensive decrease of the pulmonary emboli burden. The patient was then given apixaban after normalization of the platelet count and fibrinogen level. Hypercoagulability workup was inconclusive. The patient was then discharged after improvement of symptoms. Early recognition of DIC and cardiac thrombi in patients with new-onset heart failure is crucial for the implementation of the correct management by thrombectomy, optimizing heart failure medications, and anticoagulation to achieve better outcomes.

Mechanism of angiotensin-converting enzyme inhibitors in the treatment of dilated cardiomyopathy based on a protein interaction network and molecular docking.

Background: Dilated cardiomyopathy (DCM) is a severe manifestation or intermediate stage of cardiovascular disease progression with a significantly poor prognosis. Based on a protein interaction network and molecular docking, the present study determined the genes and mechanism of action of angiotensin-converting enzyme inhibitors (ACEIs) in the treatment of DCM, providing a direction for future studies on ACEI drugs for DCM. Methods: This is a retrospective study. DCM samples and healthy controls were downloaded from the GSE42955 dataset, and the targets of the potential active ingredients were obtained from PubChem. Hub genes in ACEIs were analyzed by constructing network models and a protein-protein interaction (PPI) network using the STRING database and Cytoscape software. Molecular docking was performed using Autodock vina software. Results: Twelve DCM samples and five control samples were finally included. A total of 62 intersected genes were obtained by intersecting the differentially expressed genes with six ACEI target genes. PPI analysis identified 15 intersecting hub genes from these 62 genes. Enrichment analysis showed that the hub genes were associated with T helper type 17 (Th17) cell differentiation as well as the nuclear factor kappa-B (NF-kappa B), interleukin 17 (IL-17), mitogen-activated protein kinase (MAPK), tumor necrosis factor (TNF), phosphatidylinositol 3 kinase (PI3K)/protein kinase B (AKT) (PI3K-Akt), and Toll-like receptor signaling pathways. Molecular docking indicated that the compound Benazepril to produce favorable interactions with TNF proteins with a relatively higher score (-8.3). Conclusions: This study primarily revealed that the preventive and curative effects of ACEI treatment on DCM could be realized through multiple targets and pathways, and its mechanism of action is related to genes such as TNF, vascular endothelial growth factor A (VEGFA), interleukin 6 (IL6), C-C motif chemokine ligand 2 (CCL2), Cyclin D1 (CCND1), and AKT serine/threonine kinase 1 (AKT1), with immune- and inflammation-related signaling pathways involvement.