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1.
Cells ; 13(9)2024 Apr 26.
Article in English | MEDLINE | ID: mdl-38727290

ABSTRACT

Dilated cardiomyopathy (DCM) is the most common cause of heart failure, with a complex aetiology involving multiple cell types. We aimed to detect cell-specific transcriptomic alterations in DCM through analysis that leveraged recent advancements in single-cell analytical tools. Single-cell RNA sequencing (scRNA-seq) data from human DCM cardiac tissue were subjected to an updated bioinformatic workflow in which unsupervised clustering was paired with reference label transfer to more comprehensively annotate the dataset. Differential gene expression was detected primarily in the cardiac fibroblast population. Bulk RNA sequencing was performed on an independent cohort of human cardiac tissue and compared with scRNA-seq gene alterations to generate a stratified list of higher-confidence, fibroblast-specific expression candidates for further validation. Concordant gene dysregulation was confirmed in TGFß-induced fibroblasts. Functional assessment of gene candidates showed that AEBP1 may play a significant role in fibroblast activation. This unbiased approach enabled improved resolution of cardiac cell-type-specific transcriptomic alterations in DCM.


Subject(s)
Cardiomyopathy, Dilated , Fibroblasts , Sequence Analysis, RNA , Single-Cell Analysis , Transcriptome , Humans , Cardiomyopathy, Dilated/genetics , Cardiomyopathy, Dilated/pathology , Cardiomyopathy, Dilated/metabolism , Fibroblasts/metabolism , Single-Cell Analysis/methods , Transcriptome/genetics , Sequence Analysis, RNA/methods , Myocardium/metabolism , Myocardium/pathology , Gene Expression Profiling
2.
Medicine (Baltimore) ; 103(19): e37889, 2024 May 10.
Article in English | MEDLINE | ID: mdl-38728483

ABSTRACT

RATIONALE: Anesthesia management of patients with dilated cardiomyopathy (DCM) has always been a challenge for anesthesiologists. Eighty percent of patients with DCM have heart failure as the first symptom, which may be accompanied by arrhythmias, thromboembolism, etc. Thrombosis is a significant contributing factor to adverse cardiovascular and cerebrovascular events, and its risk is severely underestimated in the anesthetic management of DCM. PATIENT CONCERNS: We present a case of a 54-year-old hypersensitive female patient with dilated cardiomyopathy and purpura who underwent an interventional thrombectomy under general anesthesia following a lower limb thromboembolism. DIAGNOSIS: Patient underwent an interventional thrombectomy under general anesthesia, with in situ thrombosis occurring during the surgery. INTERVENTIONS: After maintaining stable hemodynamics, proceed with the intervention to retrieve the embolus. OUTCOME: Patients in the advanced DCM developed acute thrombosis twice during embolization. LESSONS: This case discusses the causes of intraoperative thrombosis and summarizes and reflects on the anesthesia management of this case, which has always been one of the difficult points for anesthesiologists to master. In the anesthesia management of DCM patients, it is also necessary to maintain hemodynamic stability, enhance perioperative coagulation management, use anticoagulants rationally, and avoid the occurrence of thrombotic events.


Subject(s)
Anesthesia, General , Cardiomyopathy, Dilated , Femoral Artery , Thrombectomy , Humans , Female , Middle Aged , Cardiomyopathy, Dilated/complications , Cardiomyopathy, Dilated/surgery , Thrombectomy/methods , Femoral Artery/surgery , Anesthesia, General/methods , Thromboembolism/etiology
4.
J Am Coll Cardiol ; 83(19): 1841-1851, 2024 May 14.
Article in English | MEDLINE | ID: mdl-38719365

ABSTRACT

BACKGROUND: Nondilated left ventricular cardiomyopathy (NDLVC) has been recently differentiated from dilated cardiomyopathy (DCM). A comprehensive characterization of these 2 entities using cardiac magnetic resonance (CMR) and genetic testing has never been performed. OBJECTIVES: This study sought to provide a thorough characterization and assess clinical outcomes in a large multicenter cohort of patients with DCM and NDLVC. METHODS: A total of 462 patients with DCM (227) or NDLVC (235) with CMR data from 4 different referral centers were retrospectively analyzed. The study endpoint was a composite of sudden cardiac death or major ventricular arrhythmias. RESULTS: In comparison to DCM, NDLVC had a higher prevalence of pathogenic or likely pathogenic variants of arrhythmogenic genes (40% vs 23%; P < 0.001), higher left ventricular (LV) systolic function (LV ejection fraction: 51% ± 12% vs 36% ± 15%; P < 0.001) and higher prevalence of free-wall late gadolinium enhancement (LGE) (27% vs 14%; P < 0.001). Conversely, DCM showed higher prevalence of pathogenic or likely pathogenic variants of nonarrhythmogenic genes (23% vs 12%; P = 0.002) and septal LGE (45% vs 32%; P = 0.004). Over a median follow-up of 81 months (Q1-Q3: 40-132 months), the study outcome occurred in 98 (21%) patients. LGE with septal location (HR: 1.929; 95% CI: 1.033-3.601; P = 0.039) was independently associated with the risk of sudden cardiac death or major ventricular arrhythmias together with LV dilatation, older age, advanced NYHA functional class, frequent ventricular ectopic activity, and nonsustained ventricular tachycardia. CONCLUSIONS: In a multicenter cohort of patients with DCM and NDLVC, septal LGE together with LV dilatation, age, advanced disease, and frequent and repetitive ventricular arrhythmias were powerful predictors of major arrhythmic events.


Subject(s)
Cardiomyopathy, Dilated , Magnetic Resonance Imaging, Cine , Humans , Male , Female , Cardiomyopathy, Dilated/diagnostic imaging , Cardiomyopathy, Dilated/physiopathology , Middle Aged , Retrospective Studies , Magnetic Resonance Imaging, Cine/methods , Adult , Aged , Death, Sudden, Cardiac/epidemiology , Death, Sudden, Cardiac/etiology , Follow-Up Studies
5.
Front Immunol ; 15: 1327372, 2024.
Article in English | MEDLINE | ID: mdl-38736889

ABSTRACT

Introduction: Growing evidence from animal models indicates that the myocardium hosts a population of B cells that play a role in the development of cardiomyopathy. However, there is minimal data on human myocardial B cells in the context of cardiomyopathy. Methods: We integrated single-cell and single-nuclei datasets from 45 healthy human hearts, 70 hearts with dilated cardiomyopathy (DCM), and 8 hearts with arrhythmogenic right ventricular cardiomyopathy (ARVC). Interactions between B cells and other cell types were investigated using the CellChat Package. Differential gene expression analysis comparing B cells across conditions was performed using DESeq2. Pathway analysis was performed using Ingenuity, KEGG, and GO pathways analysis. Results: We identified 1,100 B cells, including naive B cells and plasma cells. Cells showed an extensive network of interactions within the healthy myocardium that included outgoing signaling to macrophages, T cells, endothelial cells, and pericytes, and incoming signaling from endothelial cells, pericytes, and fibroblasts. This niche relied on ECM-receptor, contact, and paracrine interactions; and changed significantly in the context of cardiomyopathy, displaying disease-specific features. Differential gene expression analysis showed that in the context of DCM both naive and plasma B cells upregulated several pathways related to immune activation, including upregulation of oxidative phosphorylation, upregulation of leukocyte extravasation, and, in naive B cells, antigen presentation. Discussion: The human myocardium contains naive B cells and plasma cells, integrated into a diverse and dynamic niche that has distinctive features in healthy, DCM, and ARVC. Naive myocardial-associated B cells likely contribute to the pathogenesis of human DCM.


Subject(s)
Arrhythmogenic Right Ventricular Dysplasia , B-Lymphocytes , Cardiomyopathy, Dilated , Myocardium , Humans , Cardiomyopathy, Dilated/immunology , Cardiomyopathy, Dilated/genetics , Arrhythmogenic Right Ventricular Dysplasia/genetics , Arrhythmogenic Right Ventricular Dysplasia/metabolism , B-Lymphocytes/immunology , B-Lymphocytes/metabolism , Myocardium/metabolism , Myocardium/immunology , Myocardium/pathology , Male , Female , Cell Communication/immunology , Gene Expression Profiling , Middle Aged , Adult , Transcriptome , Gene Expression Regulation
6.
Genome Biol ; 25(1): 135, 2024 May 23.
Article in English | MEDLINE | ID: mdl-38783323

ABSTRACT

BACKGROUND: Dilated cardiomyopathy (DCM) is one of the most common causes of heart failure. Multiple identified mutations in nexilin (NEXN) have been suggested to be linked with severe DCM. However, the exact association between multiple mutations of Nexn and DCM remains unclear. Moreover, it is critical for the development of precise and effective therapeutics in treatments of DCM. RESULTS: In our study, Nexn global knockout mice and mice carrying human equivalent G645del mutation are studied using functional gene rescue assays. AAV-mediated gene delivery is conducted through systemic intravenous injections at the neonatal stage. Heart tissues are analyzed by immunoblots, and functions are assessed by echocardiography. Here, we identify functional components of Nexilin and demonstrate that exogenous introduction could rescue the cardiac function and extend the lifespan of Nexn knockout mouse models. Similar therapeutic effects are also obtained in G645del mice, providing a promising intervention for future clinical therapeutics. CONCLUSIONS: In summary, we demonstrated that a single injection of AAV-Nexn was capable to restore the functions of cardiomyocytes and extended the lifespan of Nexn knockout and G645del mice. Our study represented a long-term gene replacement therapy for DCM that potentially covers all forms of loss-of-function mutations in NEXN.


Subject(s)
Cardiomyopathy, Dilated , Genetic Therapy , Mice, Knockout , Animals , Cardiomyopathy, Dilated/genetics , Cardiomyopathy, Dilated/therapy , Mice , Humans , Dependovirus/genetics , Myocytes, Cardiac/metabolism , Disease Models, Animal , Mutation , Genetic Vectors/administration & dosage , Gene Transfer Techniques
7.
Biomolecules ; 14(5)2024 Apr 27.
Article in English | MEDLINE | ID: mdl-38785931

ABSTRACT

Dilated cardiomyopathy (DCM) encompasses various acquired or genetic diseases sharing a common phenotype. The understanding of pathogenetic mechanisms and the determination of the functional effects of each etiology may allow for tailoring different therapeutic strategies. MicroRNAs (miRNAs) have emerged as key regulators in cardiovascular diseases, including DCM. However, their specific roles in different DCM etiologies remain elusive. Here, we applied mRNA-seq and miRNA-seq to identify the gene and miRNA signature from myocardial biopsies from four patients with DCM caused by volume overload (VCM) and four with ischemic DCM (ICM). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were used for differentially expressed genes (DEGs). The miRNA-mRNA interactions were identified by Pearson correlation analysis and miRNA target-prediction programs. mRNA-seq and miRNA-seq were validated by qRT-PCR and miRNA-mRNA interactions were validated by luciferase assays. We found 112 mRNAs and five miRNAs dysregulated in VCM vs. ICM. DEGs were positively enriched for pathways related to the extracellular matrix (ECM), mitochondrial respiration, cardiac muscle contraction, and fatty acid metabolism in VCM vs. ICM and negatively enriched for immune-response-related pathways, JAK-STAT, and NF-kappa B signaling. We identified four pairs of negatively correlated miRNA-mRNA: miR-218-5p-DDX6, miR-218-5p-TTC39C, miR-218-5p-SEMA4A, and miR-494-3p-SGMS2. Our study revealed novel miRNA-mRNA interaction networks and signaling pathways for VCM and ICM, providing novel insights into the development of these DCM etiologies.


Subject(s)
Cardiomyopathy, Dilated , MicroRNAs , RNA, Messenger , Humans , Cardiomyopathy, Dilated/genetics , Cardiomyopathy, Dilated/metabolism , Cardiomyopathy, Dilated/pathology , MicroRNAs/genetics , MicroRNAs/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , Gene Regulatory Networks , Male , Gene Expression Profiling , Gene Expression Regulation , Middle Aged , Female
8.
Channels (Austin) ; 18(1): 2355121, 2024 Dec.
Article in English | MEDLINE | ID: mdl-38762910

ABSTRACT

L-type calcium channels (LTCCs), the major portal for Ca2+ entry into cardiomyocytes, are essential for excitation-contraction coupling and thus play a central role in regulating overall cardiac function. LTCC function is finely tuned by multiple signaling pathways and accessory proteins. Leucine-rich repeat-containing protein 10 (LRRC10) is a little studied cardiomyocyte-specific protein recently identified as a modulator of LTCCs. LRRC10 exerts a remarkable effect on LTCC function, more than doubling L-type Ca2+ current (ICa,L) amplitude in a heterologous expression system by altering the gating of the channels without changing their surface membrane expression. Genetic ablation of LRRC10 expression in mouse and zebrafish hearts leads to a significant reduction in ICa,L density and a slowly progressive dilated cardiomyopathy in mice. Rare sequence variants of LRRC10 have been identified in dilated cardiomyopathy and sudden unexplained nocturnal cardiac death syndrome, but these variants have not been clearly linked to disease. Nevertheless, the DCM-associated variant, I195T, converted LRRC10 from a ICa,L potentiator to a ICa,L suppressor, thus illustrating the wide dynamic range of LRRC10-mediated ICa,L regulation. This review focuses on the contemporary knowledge of LTCC modulation by LRRC10 and discusses potential directions for future investigations.


Subject(s)
Calcium Channels, L-Type , Animals , Calcium Channels, L-Type/metabolism , Calcium Channels, L-Type/genetics , Humans , Myocytes, Cardiac/metabolism , Cardiomyopathy, Dilated/metabolism , Cardiomyopathy, Dilated/genetics , Membrane Proteins/metabolism , Membrane Proteins/genetics
9.
J Am Coll Cardiol ; 83(22): 2214-2232, 2024 Jun 04.
Article in English | MEDLINE | ID: mdl-38811098

ABSTRACT

Arrhythmias frequently accompany heart failure and left ventricular dysfunction. Tachycardias, atrial fibrillation, and premature ventricular contractions can induce a reversible form of dilated cardiomyopathy (CM) known as arrhythmia-induced CM (AiCM). The intriguing question is why certain individuals are more susceptible to AiCM, despite similar arrhythmia burdens. The primary challenge is determining the extent of arrhythmias' contribution to left ventricular systolic dysfunction. AiCM should be considered in patients with a mean heart rate of >100 beats/min, atrial fibrillation, or a PVC burden of >10%. Confirmation of AiCM occurs when CM reverses upon eliminating the responsible arrhythmia. Therapy choice depends on the specific arrhythmia, patient comorbidities, and preferences. After left ventricular function is restored, ongoing follow-up is essential if an abnormal myocardial substrate persists. Accurate diagnosis and treatment of AiCM have the potential to enhance patients' quality of life, improve clinical outcomes, and reduce hospital admissions and overall health care costs.


Subject(s)
Arrhythmias, Cardiac , Humans , Arrhythmias, Cardiac/etiology , Arrhythmias, Cardiac/therapy , Arrhythmias, Cardiac/physiopathology , Cardiomyopathies/etiology , Cardiomyopathies/therapy , Cardiomyopathies/physiopathology , Cardiomyopathies/diagnosis , Cardiomyopathy, Dilated/therapy , Cardiomyopathy, Dilated/physiopathology , Cardiomyopathy, Dilated/etiology
10.
Zhongguo Zhong Yao Za Zhi ; 49(7): 1956-1965, 2024 Apr.
Article in Chinese | MEDLINE | ID: mdl-38812208

ABSTRACT

The latent structure model and association rules analysis were employed to explore the compatibility rules of prescriptions for heart failure of dilated cardiomyopathy, with a view to providing theoretical support for the clinical treatment of this disease based on syndrome differentiation and the formulation of guidelines. The articles about the treatment of heart failure of dilated cardiomyopathy were retrieved from CNKI, Wanfang, VIP, and SinoMed. The database was established in Microsoft Excel 2019. Lantern 5.0 and Rstudio were used to analyze the latent structure and association rules of Chinese medicine with the frequency greater than 4.00%. Furthermore, the frequency structure model was used to mine the rules of prescriptions for heart failure of dilated cardiomyopathy. The study included 175 traditional Chinese medicine(TCM) prescriptions, involving 128 Chinese medicines, with the cumulative frequency of 1 847. High-frequency medicines included Astragali Radix, Salviae Miltiorrhizae Radix et Rhizoma, Poria, Cinnamomi Ramulus, Glycyrrhizae Radix et Rhizoma, with the main effects of tonifying, activating blood, resolving stasis, and releasing exterior. A total of 17 hidden variables, 34 hidden categories, and 6 comprehensive cluster models, along with 15 core prescriptions, were obtained. According to the prescriptions, the patients mainly had the syndromes of heart-Yang and Qi deficiency, Qi deficiency and blood stasis, heart-kidney Yang deficiency or Qi-Yin deficiency. Fifty-four strong association rules were obtained through association rule analysis. The highest degree of support was observed for the combination of Salviae Miltiorrhizae Radix et Rhizoma-Astragali Radix, while the highest degree of confidence was found for the combination of Salviae Miltiorrhizae Radix et Rhizoma-Cinnamomi Ramulus-Ophiopogonis Radix-Astragali Radix. The heart failure of dilated cardiomyopathy, characterized by internal deficiency and excess manifestations, is attributed to deficiency, stasis, and water. These factors are closely associated with the heart, lung, and spleen. The treatment should follow the principle of invigorating Qi and warming Yang, and meanwhile the method of activating blood and resolve stasis or moving Qi and promoting urination can be adopted according to the specific syndrome of patients.


Subject(s)
Cardiomyopathy, Dilated , Drugs, Chinese Herbal , Heart Failure , Cardiomyopathy, Dilated/drug therapy , Cardiomyopathy, Dilated/physiopathology , Humans , Drugs, Chinese Herbal/therapeutic use , Drugs, Chinese Herbal/chemistry , Heart Failure/drug therapy , Heart Failure/physiopathology , Medicine, Chinese Traditional , Drug Prescriptions/statistics & numerical data
11.
J Gen Physiol ; 156(6)2024 Jun 03.
Article in English | MEDLINE | ID: mdl-38709176

ABSTRACT

Dilated cardiomyopathy (DCM) is a condition characterized by impaired cardiac function, due to myocardial hypo-contractility, and is associated with point mutations in ß-cardiac myosin, the molecular motor that powers cardiac contraction. Myocardial function can be modulated through sequestration of myosin motors into an auto-inhibited "super-relaxed" state (SRX), which may be further stabilized by a structural state known as the "interacting heads motif" (IHM). Here, we sought to determine whether hypo-contractility of DCM myocardium results from reduced function of individual myosin molecules or from decreased myosin availability to interact with actin due to increased IHM/SRX stabilization. We used an established DCM myosin mutation, E525K, and characterized the biochemical and mechanical activity of wild-type and mutant human ß-cardiac myosin constructs that differed in the length of their coiled-coil tail, which dictates their ability to form the IHM/SRX state. We found that short-tailed myosin constructs exhibited low IHM/SRX content, elevated actin-activated ATPase activity, and fast velocities in unloaded motility assays. Conversely, longer-tailed constructs exhibited higher IHM/SRX content and reduced actomyosin ATPase and velocity. Our modeling suggests that reduced velocities may be attributed to IHM/SRX-dependent sequestration of myosin heads. Interestingly, longer-tailed E525K mutants showed no apparent impact on velocity or actomyosin ATPase at low ionic strength but stabilized IHM/SRX state at higher ionic strength. Therefore, the hypo-contractility observed in DCM may be attributable to reduced myosin head availability caused by enhanced IHM/SRX stability in E525K mutants.


Subject(s)
Cardiac Myosins , Cardiomyopathy, Dilated , Ventricular Myosins , Animals , Humans , Actins/metabolism , Actins/genetics , Cardiomyopathy, Dilated/genetics , Cardiomyopathy, Dilated/metabolism , Cardiomyopathy, Dilated/physiopathology , Mutation , Myocardial Contraction/physiology , Ventricular Myosins/genetics , Ventricular Myosins/metabolism , Cardiac Myosins/genetics , Cardiac Myosins/metabolism
12.
BMC Cardiovasc Disord ; 24(1): 282, 2024 May 29.
Article in English | MEDLINE | ID: mdl-38811883

ABSTRACT

Sudden cardiac death (SCD) is a major public health issue worldwide. In the young (< 40 years of age), genetic cardiomyopathies and viral myocarditis, sometimes in combination, are the most frequent, but underestimated, causes of SCD. Molecular autopsy is essential for prevention. Several studies have shown an association between genetic cardiomyopathies and viral myocarditis, which is probably underestimated due to insufficient post-mortem investigations. We report on four autopsy cases illustrating the pathogenesis of these combined pathologies. In two cases, a genetic hypertrophic cardiomyopathy was diagnosed in combination with Herpes Virus Type 6 (HHV6) and/or Parvovirus-B19 (PVB19) in the heart. In the third case, autopsy revealed a dilated cardiomyopathy and virological analyses revealed acute myocarditis caused by three viruses: PVB19, HHV6 and Epstein-Barr virus. Genetic analyses revealed a mutation in the gene coding for desmin. The fourth case illustrated a channelopathy and a PVB19/HHV6 coinfection. Our four cases illustrate the highly probable deleterious role of cardiotropic viruses in the occurrence of SCD in subjects with genetic cardiomyopathies. We discuss the pathogenetic link between viral myocarditis and genetic cardiomyopathy. Molecular autopsy is essential in prevention of these SCD, and a close collaboration between cardiologists, pathologists, microbiologists and geneticians is mandatory.


Subject(s)
Autopsy , Death, Sudden, Cardiac , Herpesvirus 6, Human , Myocarditis , Parvovirus B19, Human , Humans , Myocarditis/virology , Myocarditis/pathology , Myocarditis/genetics , Death, Sudden, Cardiac/etiology , Death, Sudden, Cardiac/pathology , Death, Sudden, Cardiac/prevention & control , Male , Adult , Female , Herpesvirus 6, Human/genetics , Herpesvirus 6, Human/isolation & purification , Parvovirus B19, Human/genetics , Cardiomyopathy, Dilated/genetics , Cardiomyopathy, Dilated/virology , Cardiomyopathy, Dilated/pathology , Roseolovirus Infections/complications , Roseolovirus Infections/virology , Roseolovirus Infections/diagnosis , Roseolovirus Infections/pathology , Cardiomyopathy, Hypertrophic/genetics , Cardiomyopathy, Hypertrophic/pathology , Parvoviridae Infections/complications , Young Adult , Genetic Predisposition to Disease , Fatal Outcome , Epstein-Barr Virus Infections/complications , Herpesvirus 4, Human/genetics , Coinfection , Cause of Death , Mutation , Middle Aged
13.
Int J Mol Sci ; 25(10)2024 May 13.
Article in English | MEDLINE | ID: mdl-38791328

ABSTRACT

Inherited muscular diseases (MDs) are genetic degenerative disorders typically caused by mutations in a single gene that affect striated muscle and result in progressive weakness and wasting in affected individuals. Cardiac muscle can also be involved with some variability that depends on the genetic basis of the MD (Muscular Dystrophy) phenotype. Heart involvement can manifest with two main clinical pictures: left ventricular systolic dysfunction with evolution towards dilated cardiomyopathy and refractory heart failure, or the presence of conduction system defects and serious life-threatening ventricular arrhythmias. The two pictures can coexist. In these cases, heart transplantation (HTx) is considered the most appropriate option in patients who are not responders to the optimized standard therapeutic protocols. However, cardiac transplant is still considered a relative contraindication in patients with inherited muscle disorders and end-stage cardiomyopathies. High operative risk related to muscle impairment and potential graft involvement secondary to the underlying myopathy have been the two main reasons implicated in the generalized reluctance to consider cardiac transplant as a viable option. We report an overview of cardiac involvement in MDs and its possible association with the underlying molecular defect, as well as a systematic review of HTx outcomes in patients with MD-related end-stage dilated cardiomyopathy, published so far in the literature.


Subject(s)
Cardiomyopathy, Dilated , Heart Transplantation , Muscular Dystrophies , Humans , Cardiomyopathy, Dilated/surgery , Heart Transplantation/methods , Muscular Dystrophies/complications
14.
J Gen Physiol ; 156(6)2024 Jun 03.
Article in English | MEDLINE | ID: mdl-38727632

ABSTRACT

JGP study (Duno-Miranda et al. https://doi.org/10.1085/jgp.202313522) shows that a mutation linked to dilated cardiomyopathy stabilizes ß-cardiac myosin in its autoinhibited, super-relaxed state.


Subject(s)
Mutation , Humans , Cardiomyopathy, Dilated/genetics , Cardiomyopathy, Dilated/metabolism , Animals
15.
Korean J Radiol ; 25(6): 540-549, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38807335

ABSTRACT

OBJECTIVE: This study investigated the feasibility and prognostic relevance of threshold-based quantification of myocardial delayed enhancement (MDE) on CT in patients with nonischemic dilated cardiomyopathy (NIDCM). MATERIALS AND METHODS: Forty-three patients with NIDCM (59.3 ± 17.1 years; 21 male) were included in the study and underwent cardiac CT and MRI. MDE was quantified manually and with a threshold-based quantification method using cutoffs of 2, 3, and 4 standard deviations (SDs) on three sets of CT images (100 kVp, 120 kVp, and 70 keV). Interobserver agreement in MDE quantification was assessed using the intraclass correlation coefficient (ICC). Agreement between CT and MRI was evaluated using the Bland-Altman method and the concordance correlation coefficient (CCC). Patients were followed up for the subsequent occurrence of the primary composite outcome, including cardiac death, heart transplantation, heart failure hospitalization, or appropriate use of an implantable cardioverter-defibrillator. The Kaplan-Meier method was used to estimate event-free survival according to MDE levels. RESULTS: Late gadolinium enhancement (LGE) was observed in 29 patients (67%, 29/43), and the mean LGE found with the 5-SD threshold was 4.1% ± 3.6%. The 4-SD threshold on 70-keV CT showed excellent interobserver agreement (ICC = 0.810) and the highest concordance with MRI (CCC = 0.803). This method also yielded the smallest bias with the narrowest range of 95% limits of agreement compared to MRI (bias, -0.119%; 95% limits of agreement, -4.216% to 3.978%). During a median follow-up of 1625 days (interquartile range, 712-1430 days), 10 patients (23%, 10/43) experienced the primary composite outcome. Event-free survival significantly differed between risk subgroups divided by the optimal MDE cutoff of 4.3% (log-rank P = 0.005). CONCLUSION: The 4-SD threshold on 70-keV monochromatic CT yielded results comparable to those of MRI for quantifying MDE as a marker of myocardial fibrosis, which showed prognostic value in patients with NIDCM.


Subject(s)
Cardiomyopathy, Dilated , Contrast Media , Feasibility Studies , Fibrosis , Magnetic Resonance Imaging , Tomography, X-Ray Computed , Humans , Male , Cardiomyopathy, Dilated/diagnostic imaging , Female , Middle Aged , Prognosis , Tomography, X-Ray Computed/methods , Fibrosis/diagnostic imaging , Magnetic Resonance Imaging/methods , Myocardium/pathology , Adult , Aged
16.
Sci Rep ; 14(1): 11980, 2024 05 25.
Article in English | MEDLINE | ID: mdl-38796549

ABSTRACT

Pathogenic BAG5 variants recently linked to dilated cardiomyopathy (DCM) prompt further investigation into phenotypic, mutational, and pathomechanistic aspects. We explored the clinical and molecular characteristics of DCM associated with BAG5 variants, uncovering the consistently severe manifestations of the disease and its impact on the endoplasmic reticulum (ER) stress response. The analysis involved three siblings affected by DCM and arrhythmia, along with their four unaffected siblings, their unaffected father, and their mother who exhibited arrhythmia. The parents were consanguineous. Exome and Sanger sequencing identified a novel BAG5 variant, c.444_445delGA (p.Lys149AsnfsTer6), homozygous in affected siblings and heterozygous in parents and unaffected siblings. We generated heterozygous and homozygous Bag5 point mutant knock-in (KI) mice and evaluated cardiac pathophysiology under stress conditions, including tunicamycin (TN) administration. Bag5-/- mice displayed no abnormalities up to 12 months old and showed no anomalies during an exercise stress test. However, following TN injection, Bag5-/- mice exhibited significantly reduced left ventricular fractional shortening (LVFS) and ejection fraction (LVEF). Their cardiac tissues exhibited a notable increase in apoptotic cells, despite non-distinctive changes in CHOP and GRP78 levels. Interestingly, only Bag5 KI male mice demonstrated arrhythmia, which was more pronounced in Bag5-/- than in Bag5+/-males. Here, our study reveals a novel BAG5 mutation causing DCM by impairing the ER stress response, with observed sex-specific arrhythmia differences.


Subject(s)
Arrhythmias, Cardiac , Cardiomyopathy, Dilated , Endoplasmic Reticulum Chaperone BiP , Endoplasmic Reticulum Stress , Animals , Cardiomyopathy, Dilated/genetics , Endoplasmic Reticulum Stress/genetics , Humans , Arrhythmias, Cardiac/genetics , Male , Female , Mice , Pedigree , Mice, Knockout , Adult , Apoptosis/genetics , Mutation
17.
Sci China Life Sci ; 67(6): 1155-1169, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38811441

ABSTRACT

CFIRL is a long noncoding RNA (lncRNA), we previously identified as the most significantly upregulated lncRNA in the failing hearts of patients with dilated cardiomyopathy (DCM). In this study, we determined the function of CFIRL and its role in DCM. Real-time polymerase chain reaction and in situ hybridization assays revealed that CFIRL was primarily localized in the nucleus of cardiac fibroblasts and robustly increased in failing hearts. Global knockdown or fibroblast-specific knockout of CFIRL attenuated transverse aortic constriction (TAC)-induced cardiac dysfunction and fibrosis in vivo. Overexpression of CFIRL in vitro promoted fibroblast proliferation and aggravated angiotensin II-induced differentiation to myofibroblasts. CFIRL knockdown attenuated these effects. Mechanistically, RNA pull-down assay and gene expression profiling revealed that CFIRL recruited ENO1, a newly identified noncanonical transcriptional factor, to activate IL-6 transcription. IL-6 exerted a paracrine effect on cardiomyocytes to promote cardiac hypertrophy, which can be prevented by CFIRL knockdown. These findings uncover the critical role of CFIRL, a fibroblast-associated lncRNA, in heart failure by facilitating crosstalk between fibroblasts and cardiomyocytes. CFIRL knockdown might be a potent strategy to prevent cardiac remodeling in heart failure, particularly in DCM.


Subject(s)
Cardiomyopathy, Dilated , Fibroblasts , Fibrosis , Myocytes, Cardiac , RNA, Long Noncoding , RNA, Long Noncoding/genetics , RNA, Long Noncoding/metabolism , Cardiomyopathy, Dilated/genetics , Cardiomyopathy, Dilated/metabolism , Animals , Fibroblasts/metabolism , Male , Humans , Myocytes, Cardiac/metabolism , Mice , Cell Proliferation , Interleukin-6/metabolism , Interleukin-6/genetics , Mice, Inbred C57BL , Myocardium/metabolism , Myocardium/pathology , Myofibroblasts/metabolism , Heart Failure/genetics , Heart Failure/metabolism , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Cell Differentiation , Gene Knockdown Techniques
18.
PLoS Genet ; 20(5): e1011279, 2024 May.
Article in English | MEDLINE | ID: mdl-38748723

ABSTRACT

The leiomodin (Lmod) family of actin-binding proteins play a critical role in muscle function, highlighted by the fact that mutations in all three family members (LMOD1-3) result in human myopathies. Mutations in the cardiac predominant isoform, LMOD2 lead to severe neonatal dilated cardiomyopathy. Most of the disease-causing mutations in the LMOD gene family are nonsense, or frameshift, mutations predicted to result in expression of truncated proteins. However, in nearly all cases of disease, little to no LMOD protein is expressed. We show here that nonsense-mediated mRNA decay, a cellular mechanism which eliminates mRNAs with premature termination codons, underlies loss of mutant protein from two independent LMOD2 disease-causing mutations. Furthermore, we generated steric-blocking oligonucleotides that obstruct deposition of the exon junction complex, preventing nonsense-mediated mRNA decay of mutant LMOD2 transcripts, thereby restoring mutant protein expression. Our investigation lays the initial groundwork for potential therapeutic intervention in LMOD-linked myopathies.


Subject(s)
Codon, Nonsense , Nonsense Mediated mRNA Decay , Humans , Cardiomyopathy, Dilated/genetics , Cardiomyopathy, Dilated/metabolism , Codon, Nonsense/genetics , Microfilament Proteins/genetics , Microfilament Proteins/metabolism , Muscle Proteins/genetics , Muscle Proteins/metabolism , Mutation , Nonsense Mediated mRNA Decay/genetics , RNA, Messenger/genetics , RNA, Messenger/metabolism
19.
Zhonghua Xin Xue Guan Bing Za Zhi ; 52(4): 384-390, 2024 Apr 24.
Article in Chinese | MEDLINE | ID: mdl-38644253

ABSTRACT

Objective: To investigate the risk factors and long-term prognosis of major adverse cardiovascular events(MACEs) in patients with dilated cardiomyopathy (DCM). Methods: This study was a single-center retrospective cohort study. Clinical information from 300 patients with DCM hospitalized in Peking Union Medical College Hospital from April 2013 to April 2023 was collected. Based on echocardiography results, the patients were divided into two groups: isolated DCM and DCM with left ventricular non-compaction cardiomyopathy (LVNC). The MACEs, including major heart failure events, severe ventricular arrhythmias, and cardiovascular death, were recorded by outpatient or telephone follow-up. Univariate and multivariate Cox proportional hazard regression models were used to analyze the risk factors affecting the prognosis of patients with DCM. Kaplan-Meier curve and log-rank were used for survival analysis to compare the difference in the incidence of cardiovascular events between the two groups. Results: The included 300 DCM patients were (47.8±16.8) years old, with 197 males (65.7%), of which 237 (79.0%) were isolated DCM and 63 (21.0%) were DCM with LVNC. The follow-up time was 4.0 (1.9, 6.2) years. A total of 142 (47.3%) MACEs occurred, including 117 (39.0%) major heart failure events, 20 (6.7%) severe ventricular arrhythmia events, and 53 (17.7%) cardiovascular death events. Multivariate Cox proportional hazard regression analysis showed that increased left ventricular end-diastolic diameter (HR=1.21, 95%CI: 1.01-1.44, P=0.042), moderate or severe mitral regurgitation (HR=1.71, 95%CI: 1.19-2.47, P=0.004), increased ln (N-terminal pro-B-type natriuretic peptide) (HR=1.30, 95%CI: 1.10-1.54, P=0.002) were independent risk factors for dverse cardiovascular events in DCM patients, and angiotensin-converting enzyme inhibitor (ACEI)/angiotensin receptor blocker (ARB)/angiotensin receptor neprilysin inhibitor (ARNI) treatment (HR=0.45, 95%CI: 0.26-0.78, P=0.004) was independent protective factor. Kaplan-Meier survival analysis found no significant difference in the risk of MACEs between isolated DCM and DCM with LVNC (P=0.22). Similarly, there were no significant differences in the incidence of major heart failure, severe ventricular arrhythmia, and cardiovascular death between the two groups (all P>0.05). Conclusion: An increase in left ventricular end-diastolic diameter, moderate or severe mitral regurgitation, elevated N-terminal pro-B-type natriuretic peptide, and non use of ACEI/ARB/ARNI are independent predictors of cardiovascular events in DCM patients. There was no significant risk of MACEs in patients with isolated DCM and DCM with LVNC, and suggested that LVNC may be a unique phenotype and should be accurately managed in combination with genetic background.


Subject(s)
Cardiomyopathy, Dilated , Humans , Cardiomyopathy, Dilated/complications , Retrospective Studies , Male , Risk Factors , Middle Aged , Prognosis , Female , Heart Failure/epidemiology , Proportional Hazards Models , Adult
20.
BMC Pediatr ; 24(1): 251, 2024 Apr 11.
Article in English | MEDLINE | ID: mdl-38605385

ABSTRACT

BACKGROUND: Dilated cardiomyopathy (DCMP) is characterized by the enlargement and weakening of the heart and is a major cause of heart failure in children. Infection and nutritional deficiencies are culprits for DCMP. Zinc is an important nutrient for human health due to its anti-oxidant effect that protects cell against oxidative damage. This case-control study aimed to investigate the relationship between dietary intake of zinc and selenium and the risk of DCMP in pediatric patients. METHODS: A total of 36 DCMP patients and 72 matched controls were recruited, and their dietary intakes were assessed via a validated food frequency questionnaire. We used chi-square and sample T-test for qualitative and quantitative variables, respectively. Logistic regression analysis was applied to assess the relationship between selenium and zinc intake with the risk of DCMP. RESULTS: After fully adjusting for confounding factors, analyses showed that selenium (OR = 0.19, CI = 0.057-0.069, P trend < 0.011) and zinc (OR = 0.12, CI = 0.035-0.046, P trend < 0.002) intake were strongly associated with 81% and 88% lower risk of pediatric DCMP, respectively. CONCLUSIONS: This study highlights the protective role of adequate dietary intake of selenium and zinc in decreasing the risk of DCMP in children. Malnutrition may exacerbate the condition and addressing these micronutrient deficiencies may improve the cardiac function. Further studies are recommended to detect the underlying mechanisms and dietary recommendations for DCMP prevention.


Subject(s)
Cardiomyopathy, Dilated , Malnutrition , Selenium , Humans , Child , Selenium/analysis , Case-Control Studies , Cardiomyopathy, Dilated/etiology , Deoxycytidine Monophosphate , Zinc , Malnutrition/complications
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