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Pubblicazioni recenti - dilated cardiomyopathy
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Titin-related Cardiomyopathy: Is it a Distinct Disease?
Curr Cardiol Rep2022 Jun;():. doi: 10.1007/s11886-022-01726-0.
Santiago Celine F, Huttner Inken G, Fatkin Diane,
Abstract
PURPOSE OF REVIEW:
Truncating TTN variants (TTNtv) are the most common genetic cause of dilated cardiomyopathy (DCM), but the underlying mechanisms are incompletely understood and effective therapeutic strategies are lacking. Here we review recent data that shed new light on the functional consequences of TTNtv and how these effects may vary with mutation location.
RECENT FINDINGS:
Whether TTNtv act by haploinsufficiency or dominant negative effects has been hotly debated. New evidence now implicates both mechanisms in TTNtv-related DCM, showing reduced titin content and persistent truncated titin that may be incorporated into protein aggregates. The extent to which aggregate formation and protein quality control defects differ with TTNtv location and contribute to contractile dysfunction is unresolved. TTNtv-associated DCM has a complex etiology that involves varying combinations of wild-type titin deficiency and dominant negative effects of truncated mutant titin. Therapeutic strategies to improve protein handling may be beneficial in some cases.
© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
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DIAGNOSIS AND MANAGEMENT OF SUSPECTED CONGESTIVE HEART FAILURE SECONDARY TO DILATED CARDIOMYOPATHY IN A SAND TIGER SHARK () WITH ESTABLISHMENT OF PRELIMINARY NORMAL ECHOCARDIOGRAPHIC INDICES.
J Zoo Wildl Med2022 Jun;53(2):363-372. doi: 10.1638/2021-0127.
Hyatt Michael W, Gerlach Trevor J,
Abstract
Elasmobranch cardiac anatomy and physiology has been well described; however, there is a dearth of information regarding cardiac disease. In support of a clinical case of suspected congestive heart failure in a 22-yr-old male sand tiger shark (), a study was undertaken to identify feasible echocardiographic imaging planes and preliminary indices for this species. Eleven echocardiograms were performed on six apparently healthy sand tiger sharks. Echocardiographic parameters are presented using descriptive statistics, including mean, median, standard deviation (SD), minimum and maximum values. These data were utilized for the diagnosis and clinical management of the affected shark. The shark initially presented with increased respiratory effort, dependent, peripheral edema, and anemia. Echocardiography revealed atrial, ventricular, and sinus venosus dilation. As congestive heart failure secondary to dilated cardiomyopathy was strongly suspected, therapy was initiated with oral benazepril and torsemide, and later pimobendan. After a year of therapy, clinical signs resolved. Cardiac size and function improved on echocardiography with a reduction in sinus venosus dilation, maximum and minimum atrial and ventricular inner diameters, and an increase in atrial and ventricular fractional shortening. Cardiac disease in elasmobranchs may be underdiagnosed, so it may be necessary to develop standardized ultrasound techniques and cardiac measurements for each species of elasmobranch managed within zoos and aquaria.
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A case of congenital fiber-type disproportion syndrome presenting dilated cardiomyopathy with ACTA1 mutation.
Mol Genet Genomic Med2022 Jun;():e2008. doi: 10.1002/mgg3.2008.
Matsumoto Ayumi, Tsuda Hidetoshi, Furui Sadahiro, Kawada-Nagashima Masako, Anzai Tatsuya, Seki Mitsuru, Watanabe Kazuhisa, Muramatsu Kazuhiro, Osaka Hitoshi, Iwamoto Sadahiko, Nishino Ichizo, Yamagata Takanori,
Abstract
BACKGROUND:
Actin, alpha, skeletal muscle 1 (ACTA1) is one of the causative genes of nemaline myopathy (NM) and congenital fiber-type disproportion (CFTD). CFTD is characterized by type 1 fiber atrophy and distinguished from NM in the absence of rods. Eight patients with CFTD, including one patient with dilated cardiomyopathy (DCM), have previously been reported. Herein, we report the case of a 10-year-old boy presenting with CFTD and DCM.
METHODS:
We performed exome sequencing and analyzed the effect of Met327Lys mutations on cultured C2C12 muscle cells compared with that seen in the wild type (WT, ACTA1) and previously identified Asp294Val mutations associated with a severe phenotype of CFTD without cardiomyopathy.
RESULTS:
Exome sequencing revealed a de novo mutation, c.980?T?>?A, p.(Met327Lys), in ACTA1 (NM_001100.4). C2C12 cells transfected with the WT plasmid expressed ACTA1 in the nucleus and cytoplasm. Cells with the Asp294Val mutant showed needle-like structures in the cytoplasm, whereas the expression of the Met327Lys mutant resulted in few aggregations but many apoptotic cells.
CONCLUSION:
Apoptosis induced in Met327Lys-transfected muscle cells supports the pathogenicity of the mutation and can be implicated as one of the histopathological features associated with CFTD, as in NM.
© 2022 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.
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Targeted Analysis of circRNA Expression in Patient Samples by Lexo-circSeq.
Front Mol Biosci2022 ;9():875805. doi: 10.3389/fmolb.2022.875805.
Naarmann-de Vries Isabel S, Eschenbach Jessica, Schudy Sarah, Meder Benjamin, Dieterich Christoph,
Abstract
Recently, circular RNAs (circRNAs) have been extensively studied in animals and plants. circRNAs are generated by backsplicing from the same linear transcripts that are canonically spliced to produce, for example, mature mRNAs. circRNAs exhibit tissue-specific expression and are potentially involved in many diseases, among them cardiovascular diseases. The comprehensive analysis of circRNA expression patterns across larger patient cohorts requires a streamlined and cost-effective workflow designed to meet small input requirements. In this article, we present Lexo-circSeq, a targeted RNA sequencing approach that can profile up to 110 circRNAs and their corresponding linear transcripts in one experiment. We established Lexo-circSeq employing total human heart RNA and show that our protocol can detect depletion of a specific circRNA in hiPSC-derived cardiomyocytes. Finally, Lexo-circSeq was applied to biopsies from patients diagnosed with dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM), respectively. Interestingly, our results indicate that circular-to-linear-ratios for circSLC8A1 and circRBM33 are deregulated in cardiomyopathy.
Copyright © 2022 Naarmann-de Vries, Eschenbach, Schudy, Meder and Dieterich.
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Construction of Immune-Related ceRNA Network in Dilated Cardiomyopathy: Based on Sex Differences.
Front Genet2022 ;13():882324. doi: 10.3389/fgene.2022.882324.
Liu Chang, Liu Jian, Wu Daihong, Luo Shaoling, Li Weijie, Chen Lushan, Liu Zhen, Yu Bingbo,
Abstract
Immune targeted therapy has become an attractive therapeutic approach for patients with dilated cardiomyopathy (DCM) recently. Genetic predisposition and gender play a critical role in immune-related responses of DCM. This study aimed to perform a bioinformatics analysis of molecular differences between male and female samples and identify immune-related ceRNA network in DCM. The gene expression microarray and clinical features dataset of GSE19303 was downloaded from the GEO. The raw data were preprocessed, followed by identification of differentially expressed genes (DEGs) between male and female DCM samples. Crucial functions and pathway enrichment analysis of DEGs were investigated through GO analysis and KEGG pathway analysis, respectively. A lncRNA-miRNA-mRNA network was constructed and a central module was extracted from the ceRNA network. Compared with the female group, the male group benefits more from IA/IgG immunotherapy. Male patients of DCM had a significant positive correlation with the abundance of inflammatory cells (B cells, memory B cells, CD8 Tem cells, and NK cells). Sex difference DEGs had a widespread impact on the signaling transduction, transcriptional regulation, and metabolism in DCM. Subsequently, we constructed an immune-related ceRNA network based on sex differences in DCM, including five lncRNAs, six miRNAs, and 29 mRNAs. Furthermore, we extracted a central module from the ceRNA network, including two lncRNAs (XIST and LINC00632), three miRNAs (miR-1-3p, miR-17-5p, and miR-22-3p), and six mRNAs (CBL, CXCL12, ESR1, IGF1R, IL6ST, and STC1). Among these DEGs, CBL, CXCL12, and IL6ST expression was considered to be associated with inflammatory cell infiltration in DCM. The identified ceRNA network and their enriched pathways may provide genetic insights into the phenotypic diversity of female and male patients with DCM and may provide a basis for development of sex-related individualization of immunotherapy.
Copyright © 2022 Liu, Liu, Wu, Luo, Li, Chen, Liu and Yu.
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Transcriptomic Analysis of Dysregulated Genes of the nDNA-mtDNA Axis in a Mouse Model of Dilated Cardiomyopathy.
Front Genet2022 ;13():921610. doi: 10.3389/fgene.2022.921610.
Ziemann Mark, Wu Wei, Deng Xiu-Ling, Du Xiao-Jun,
Abstract
Mitochondrial dysfunction is implicated in the development of cardiomyopathy and heart failure. Transcription of mitochondrial DNA (mtDNA) encoded genes and subsequent protein synthesis are tightly regulated by nuclear DNA (nDNA) encoded proteins forming the nDNA-mtDNA axis. The scale of abnormalities in this axis in dilated cardiomyopathy (DCM) is unclear. We previously demonstrated, in a mouse DCM model with cardiac Mst1 overexpression, extensive downregulation of mitochondrial genes and mitochondrial dysfunction. Using the pre-acquired transcriptome sequencing database, we studied expression of gene sets of the nDNA-mtDNA axis. Using RNA-sequencing data from DCM hearts of mice at early and severe disease stages, transcriptome was performed for dysregulated nDNA-encoded gene sets that govern mtDNA transcription and protein synthesis. To validate gene data, expression of a panel of proteins was determined by immunoblotting. Relative to littermate controls, DCM hearts showed significant downregulation of all mtDNA encoded mRNAs, as well as mtDNA transcriptional activators. Downregulation was also evident for gene sets of mt-rRNA processing, aminoacyl-tRNA synthases, and mitoribosome subunits for protein synthesis. Multiple downregulated genes belong to mitochondrial protein-importing machinery indicating compromised importing of proteins for mtDNA transcription and translation. Diverse changes were genes of mtRNA-binding proteins that govern maturation and stability of mtDNA-derived RNAs. Expression of mtDNA replicome genes was largely unchanged. These changes were similarly observed in mouse hearts at early and severe stages of DCM. Transcriptome revealed in our DCM model dysregulation of multiple gene sets of the nDNA-mtDNA axis, that is, expected to interfere with mtDNA transcription and protein synthesis. Dysfunction of the nDNA-mtDNA axis might contribute to mitochondrial dysfunction and ultimately development of DCM.
Copyright © 2022 Ziemann, Wu, Deng and Du.
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Transcriptome analysis uncovers the autophagy-mediated regulatory patterns of the immune microenvironment in dilated cardiomyopathy.
J Cell Mol Med2022 Jun;():. doi: 10.1111/jcmm.17455.
Sun Shuo, Lu Jiangting, Lai Chaojie, Feng Zhaojin, Sheng Xia, Liu Xianglan, Wang Yao, Huang Chengchen, Shen Zhida, Lv Qingbo, Fu Guosheng, Shang Min,
Abstract
The relationship between autophagy and immunity has been well studied. However, little is known about the role of autophagy in the immune microenvironment during the progression of dilated cardiomyopathy (DCM). Therefore, this study aims to uncover the effect of autophagy on the immune microenvironment in the context of DCM. By investigating the autophagy gene expression differences between healthy donors and DCM samples, 23 dysregulated autophagy genes were identified. Using a series of bioinformatics methods, 13 DCM-related autophagy genes were screened and used to construct a risk prediction model, which can well distinguish DCM and healthy samples. Then, the connections between autophagy and immune responses including infiltrated immunocytes, immune reaction gene-sets and human leukocyte antigen (HLA) genes were systematically evaluated. In addition, two autophagy-mediated expression patterns in DCM were determined via the unsupervised consensus clustering analysis, and the immune characteristics of different patterns were revealed. In conclusion, our study revealed the strong effect of autophagy on the DCM immune microenvironment and provided new insights to understand the pathogenesis and treatment of DCM.
© 2022 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.
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Enalapril and Enalaprilat Pharmacokinetics in Children with Heart Failure Due to Dilated Cardiomyopathy and Congestive Heart Failure after Administration of an Orodispersible Enalapril Minitablet (LENA-Studies).
Pharmaceutics2022 May;14(6):. doi: 1163.
Laeer Stephanie, Cawello Willi, Burckhardt Bjoern B, Ablonczy László, Bajcetic Milica, Breur Johannes M P J, Dalinghaus Michiel, Male Christoph, de Wildt Saskia N, Breitkreutz Jörg, Faisal Muhammed, Keatley-Clarke Anne, Klingmann Ingrid, Lagler Florian B,
Abstract
Angiotensin-converting enzyme inhibitors (ACEI), such as enalapril, are a cornerstone of treatment for pediatric heart failure which is still used off-label. Using a novel age-appropriate formulation of enalapril orodispersible minitablets (ODMTs), phase II/III open-label, multicenter pharmacokinetic (PK) bridging studies were performed in pediatric patients with heart failure due to dilated cardiomyopathy (DCM) and congenital heart disease (CHD) in five participating European countries. Children were treated for 8 weeks with ODMTs according to an age-appropriate dosing schedule. The primary objective was to describe PK parameters (area under the curve (AUC), maximal concentration (Cmax), time to reach maximal concentration (t-max)) of enalapril and its active metabolite enalaprilat. Of 102 patients, 89 patients ( = 26, DCM; = 63 CHD) were included in the primary PK endpoint analysis. Rate and extent of enalapril and its active metabolite enalaprilat were described and etiology and age could be identified as potential PK modifying factors. The dosing schedule appeared to be tolerated well and did not result in any significant drug-related serious adverse events. The PK analysis and the lack of severe safety events supports the applied age-appropriate dosing schedule for the enalapril ODMTs.
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Compound Heterozygous Variants in a Patient with Dilated Cardiomyopathy Led to an Aberrant ?-Dystroglycan Pattern.
Int J Mol Sci2022 Jun;23(12):. doi: 6685.
Gaertner Anna, Burr Lidia, Klauke Baerbel, Brodehl Andreas, Laser Kai Thorsten, Klingel Karin, Tiesmeier Jens, Schulz Uwe, Knyphausen Edzard Zu, Gummert Jan, Milting Hendrik,
Abstract
Fukutin encoded by is a ribitol 5-phosphate transferase involved in glycosylation of ?-dystroglycan. It is known that mutations in affect the glycosylation of ?-dystroglycan, leading to a dystroglycanopathy. Dystroglycanopathies are a group of syndromes with a broad clinical spectrum including dilated cardiomyopathy and muscular dystrophy. In this study, we reported the case of a patient with muscular dystrophy, early onset dilated cardiomyopathy, and elevated creatine kinase levels who was a carrier of the compound heterozygous variants p.Ser299Arg and p.Asn442Ser in . Our work showed that compound heterozygous mutations in lead to a loss of fully glycosylated ?-dystroglycan and result in cardiomyopathy and end-stage heart failure at a young age.
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Ferulic Acid, Pterostilbene, and Tyrosol Protect the Heart from ER-Stress-Induced Injury by Activating SIRT1-Dependent Deacetylation of eIF2?.
Int J Mol Sci2022 Jun;23(12):. doi: 6628.
Monceaux Kévin, Gressette Mélanie, Karoui Ahmed, Pires Da Silva Julie, Piquereau Jérôme, Ventura-Clapier Renée, Garnier Anne, Mericskay Mathias, Lemaire Christophe,
Abstract
Disturbances in Endoplasmic Reticulum (ER) homeostasis induce ER stress, which has been involved in the development and progression of various heart diseases, including arrhythmias, cardiac hypertrophy, ischemic heart diseases, dilated cardiomyopathy, and heart failure. A mild-to-moderate ER stress is considered beneficial and adaptative for heart functioning by engaging the pro-survival unfolded protein response (UPR) to restore normal ER function. By contrast, a severe or prolonged ER stress is detrimental by promoting cardiomyocyte apoptosis through hyperactivation of the UPR pathways. Previously, we have demonstrated that the NAD-dependent deacetylase SIRT1 is cardioprotective in response to severe ER stress by regulating the PERK pathway of the UPR, suggesting that activation of SIRT1 could protect against ER-stress-induced cardiac damage. The purpose of this study was to identify natural molecules able to alleviate ER stress and inhibit cardiomyocyte cell death through SIRT1 activation. Several phenolic compounds, abundant in vegetables, fruits, cereals, wine, and tea, were reported to stimulate the deacetylase activity of SIRT1. Here, we evaluated the cardioprotective effect of ten of these phenolic compounds against severe ER stress using cardiomyoblast cells and mice. Among the molecules tested, we showed that ferulic acid, pterostilbene, and tyrosol significantly protect cardiomyocytes and mice heart from cardiac alterations induced by severe ER stress. By studying the mechanisms involved, we showed that the activation of the PERK/eIF2?/ATF4/CHOP pathway of the UPR was reduced by ferulic acid, pterostilbene, and tyrosol under ER stress conditions, leading to a reduction in cardiomyocyte apoptosis. The protection afforded by these phenolic compounds was not directly related to their antioxidant activity but rather to their ability to increase SIRT1-mediated deacetylation of eIF2?. Taken together, our results suggest that ferulic acid, pterostilbene, and tyrosol are promising molecules to activate SIRT1 to protect the heart from the adverse effects of ER stress.
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Exploring the Potential of Symmetric Exon Deletion to Treat Non-Ischemic Dilated Cardiomyopathy by Removing Frameshift Mutations in .
Genes (Basel)2022 Jun;13(6):. doi: 1093.
Rodriguez-Polo Ignacio, Behr Rüdiger,
Abstract
Non-ischemic dilated cardiomyopathy (DCM) is one of the most frequent pathologies requiring cardiac transplants. Even though the etiology of this disease is complex, frameshift mutations in the giant sarcomeric protein Titin could explain up to 25% of the familial and 18% of the sporadic cases of DCM. Many studies have shown the potential of genome editing using CRISPR/Cas9 to correct truncating mutations in sarcomeric proteins and have established the grounds for myoediting. However, these therapies are still in an immature state, with only few studies showing an efficient treatment of cardiac diseases. This publication hypothesizes that the Titin ()-specific gene structure allows the application of myoediting approaches in a broad range of locations to reframe TTNtvvariants and to treat DCM patients. Additionally, to pave the way for the generation of efficient myoediting approaches for DCM, we screened and selected promising target locations in . We conceptually explored the deletion of symmetric exons as a therapeutic approach to restore 's reading frame in cases of frameshift mutations. We identified a set of 94 potential candidate exons of that we consider particularly suitable for this therapeutic deletion. With this study, we aim to contribute to the development of new therapies to efficiently treat titinopathies and other diseases caused by mutations in genes encoding proteins with modular structures, e.g., Obscurin.
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The Role of Circulating Collagen Turnover Biomarkers and Late Gadolinium Enhancement in Patients with Non-Ischemic Dilated Cardiomyopathy.
Diagnostics (Basel)2022 Jun;12(6):. doi: 1435.
Revnic Radu, Cojan-Minzat Bianca Olivia, Zlibut Alexandru, Orzan Rares-Ilie, Agoston Renata, Muresan Ioana Danuta, Horvat Dalma, Cionca Carmen, Chis Bogdan, Agoston-Coldea Lucia,
Abstract
BACKGROUND:
Myocardial scarring is a primary pathogenetic process in nonischemic dilated cardiomyopathy (NIDCM) that is responsible for progressive cardiac remodeling and heart failure, severely impacting the survival of these patients. Although several collagen turnover biomarkers have been associated with myocardial fibrosis, their clinical utility is still limited. Late gadolinium enhancement (LGE) determined by cardiac magnetic resonance imaging (CMR) has become a feasible method to detect myocardial replacement fibrosis. We sought to evaluate the association between collagen turnover biomarkers and replacement myocardial scarring by CMR and, also, to test their ability to predict outcome in conjunction with LGE in patients with NIDCM.
METHOD:
We conducted a prospective study on 194 patients (48.7 ± 14.3 years of age; 74% male gender) with NIDCM. The inclusion criteria were similar to those for the definition of NIDCM, performed exclusively by CMR: (1) LV dilation with an LV end-diastolic volume (LVEDV) of over 97 mL/m; (2) global LV dysfunction, expressed as a decreased LVEF of under 45%. CMR was used to determine the presence and extent of LGE. Several collagen turnover biomarkers were determined at diagnosis, comprising galectin-3 (Gal3), procollagen type I carboxy-terminal pro-peptide (PICP) and N-terminal pro-peptide of procollagen type III (PIIINP). A composite outcome (all-cause mortality, ventricular tachyarrhythmias, heart failure hospitalization) was ascertained over a median of 26 months.
RESULTS:
Gal3, PICP and PIIINP were considerably increased in those with LGE+ ( < 0.001), also being directly correlated with LGE mass (r = 0.42; r = 0.44; r = 0.31; all < 0.001). Receiver operating characteristic (ROC) analysis revealed a significant ability to diagnose LGE, with an area under the ROC of 0.816 for Gal3, 0.705 for PICP, and 0.757 for PIIINP (all < 0.0001). Kaplan-Meier analysis showed that at a threshold of >13.8 ng/dL for Gal3 and >97 ng/dL for PICP, they were able to significantly predict outcome (HR = 2.66, < 0.001; HR = 1.93, < 0.002). Of all patients, 17% ( = 33) reached the outcome. In multivariate analysis, after adjustment for covariates, only LGE+ and Gal3+ remained independent predictors for outcome ( = 0.008; = 0.04). Nonetheless, collagen turnover biomarkers were closely related to HF severity, providing incremental predictive value for severely decreased LVEF of under 30% in patients with NIDCM, beyond that with LGE alone.
CONCLUSIONS:
In patients with NIDCM, circulating collagen turnover biomarkers such as Gal3, PICP and PIIINP are closely related to the presence and extent of LGE and can significantly predict cardiovascular outcome. The joint use of LGE with Gal3 and PICP significantly improved outcome prediction.
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Myogenic Determination and Differentiation of Chicken Bone Marrow-Derived Mesenchymal Stem Cells under Different Inductive Agents.
Animals (Basel)2022 Jun;12(12):. doi: 1531.
Zhou Zhen, Zhao Changbin, Cai Bolin, Ma Manting, Kong Shaofen, Zhang Jing, Zhang Xiquan, Nie Qinghua,
Abstract
Poultry plays an important role in the meat consumer market and is significant to further understanding the potential mechanism of muscle development in the broiler. Bone marrow-derived mesenchymal stem cells (BM-MSCs) can provide critical insight into muscle development due to their multi-lineage differentiation potential. To our knowledge, chicken BM-MSCs demonstrate limited myogenic differentiation potential under the treatment with dexamethasone (DXMS) and hydrocortisone (HC). 5-azacytidine (5-Aza), a DNA demethylating agent, which has been widely used in the myogenic differentiation of BM-MSCs in other species. There is no previous report that applies 5-Aza to myogenic-induced differentiation of chicken BM-MSCs. In this study, we evaluated the myogenic determination and differentiation effect of BM-MSCs under different inductive agents. BM-MSCs showed better differentiation potential under the 5-Aza-treatment. Transcriptome sequence analysis identified 2402 differentially expressed DEGs including 28 muscle-related genes after 5-Aza-treatment. The DEGs were significantly enriched in Gene Ontology database terms, including in the cell plasma membrane, molecular binding, and cell cycle and differentiation. KEGG pathway analysis revealed that DEGs were enriched in myogenic differentiation-associated pathways containing the PI3K-Akt signaling pathway, the TGF-? signaling pathway, Arrhythmogenic right ventricular cardiomyopathy, dilated cardiomyopathy, and hypertrophic cardiomyopathy, which suggested that BM-MSCs differentiated into a muscle-like phenotype under 5-Aza-treatment. Although BM-MSCs have not formed myotubes in our study, it is worthy of further study. In summary, our study lays the foundation for constructing a myogenic determination and differentiation model in chicken BM-MSCs.
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Clinical characterization and natural history of chemotherapy-induced dilated cardiomyopathy.
ESC Heart Fail2022 Jun;():. doi: 10.1002/ehf2.14045.
Lalario Andrea, Del Mestre Eva, Lo Casto Michele, Nuzzi Vincenzo, Manca Paolo, Bromage Daniel I, Barbati Giulia, Merlo Marco, Sinagra Gianfranco, Cannatà Antonio,
Abstract
AIMS:
Chemotherapy-induced dilated cardiomyopathy (CI-DCM) is a well-recognized phenotype of non-ischemic dilated cardiomyopathy (DCM), characterized by poor outcomes. However, a detailed comparison between idiopathic DCM (iDCM) and CI-DCM is still lacking.
METHODS AND RESULTS:
All consecutive DCM patients enrolled in the Trieste Muscle Heart Disease Registry were analysed. CI-DCM and iDCM were defined according to current recommendations. The primary study outcome measure was all-mortality death and secondary outcomes were a) a composite of cardiovascular death/heart-transplantation/ventricular-assist-device implantation, and b) major ventricular arrhythmias. The study included 551 patients (499 iDCM and 52 CI-DCM). At enrolment, compared with iDCM, CI-DCM patients were older (51 ± 14 years vs. 58 ± 3 years, respectively, P
CONCLUSIONS:
In a well-selected DCM cohort, patients with a chemotherapy-induced aetiology had a higher incidence of all-cause mortality compared with iDCM. Conversely, the incidence of life-threatening ventricular arrhythmic events was higher among patients with iDCM.
© 2022 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.
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Efficacy and Safety of a Combined Aerobic, Strength and Flexibility Exercise Training Program in Patients with Implantable Cardiac Devices.
J Cardiovasc Dev Dis2022 Jun;9(6):. doi: 182.
Squeo Maria Rosaria, Di Giacinto Barbara, Perrone Marco Alfonso, Santini Massimo, Sette Maria Luisa, Fabrizi Emanuele, Vaquer Antonia, Parisi Attilio, Spataro Antonio, Biffi Alessandro,
Abstract
: The "FIDE Project" (Fitness Implantable DEvice) was organized by the Institute of Sports Medicine and Science and the World Society of Arrhythmias with the aim of demonstrating the usefulness of exercise training in improving functional capacity in patients with implantable cardiac devices. : Thirty sedentary patients were selected for the project (25 males and 5 females), with a mean age of 73 ± 5 years (range 44-94 years). Twenty-five were implanted with a Pacemaker (PM) and five with an Implantable Cardioverter Defibrillator (ICD). Atrial fibrillation/atrial flutter was present in ten (34%) patients, post-ischemic dilated cardiomyopathy in five (17.2%), sick sinus syndrome in six (20,7%), complete atrium-ventricular block in six (20.7%), hypertrophic cardiomyopathy in one (3.4%) and recurrent syncope in one (3.4%). The baseline assessment comprised cardiovascular examination, resting and stress ECG, cardiopulmonary exercise testing (V ?O2peak), strength assessment of different muscle groups, and a flexibility test. The same measurements were repeated after 15-20 consecutive training sessions, over a 2-month period. The exercise prescription was set to 70-80% of HRR (Heart rate reserve) and to 50-70% of 1RM (1-repetition maximum, muscular force). The training protocol consisted of two training sessions per week performed in our institute, 90 min for each (warm-up, aerobic phase, strength phase and stretching) and one or more at home autonomously. : The cardiopulmonary testing after the training period documents a significant improvement in V ?O2peak (15 ± 4 mL/kg/min vs. 17 ± 4; = 0.001) and in work load (87 ± 30 watts vs. 108 ± 37; = 0.001). Additionally, strength capacity significantly increased after the cardiac rehabilitation program, (quadriceps: 21 ± 18 kg vs. 29 ± 16 kg, = 0.00003). Flexibility tests show a positive trend, but without statistical significance (sit-and-reach test: -19 ± 11 cm vs. -15 ± 11.7 cm; back-scratch test: -19 ± 11.6 cm vs. -15 ± 10 cm; lateral flexibility right -44 ± 1.4 cm vs. -43 ± 9.5 cm; left -43 ± 5 vs. -45 ± 8.7 cm). : A brief period of combined aerobic, strength and flexibility exercise training (FIDE project) proved to be effective and safe in improving functional capacity in patients with cardiac implantable devices.
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A Comprehensive Outlook on Dilated Cardiomyopathy (DCM): State-Of-The-Art Developments with Special Emphasis on OMICS-Based Approaches.
J Cardiovasc Dev Dis2022 Jun;9(6):. doi: 174.
Sarohi Vivek, Srivastava Shriya, Basak Trayambak,
Abstract
Dilated cardiomyopathy (DCM) remains an enigmatic cardiovascular disease (CVD) condition characterized by contractile dysfunction of the myocardium due to dilation of the ventricles. DCM is one of the major forms of CVD contributing to heart failure. Dilation of the left or both ventricles with systolic dysfunction, not explained by known causes, is a hallmark of DCM. Progression of DCM leads to heart failure. Genetic and various other factors greatly contribute to the development of DCM, but the etiology has still remained elusive in a large number of cases. A significant number of studies have been carried out to identify the genetic causes of DCM. These candidate-gene studies revealed that mutations in the genes of the fibrous, cytoskeletal, and sarcomeric proteins of cardiomyocytes result in the development of DCM. However, a significant proportion of DCM patients are idiopathic in nature. In this review, we holistically described the symptoms, causes (in adults and newborns), genetic basis, and mechanistic progression of DCM. Further, we also summarized the state-of-the-art diagnosis, available biomarkers, treatments, and ongoing clinical trials of potential drug regimens. DCM-mediated heart failure is on the rise worldwide including in India. The discovery of biomarkers with a better prognostic value is the need of the hour for better management of DCM-mediated heart failure patients. With the advent of next-generation omics-based technologies, it is now possible to probe systems-level alterations in DCM patients pertaining to the identification of novel proteomic and lipidomic biomarkers. Here, we also highlight the onset of a systems-level study in Indian DCM patients by applying state-of-the-art mass-spectrometry-based "clinical proteomics" and "clinical lipidomics".
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Tricuspid Valve Prolapse: An Uncommon Pathology Revealed by TEE.
Methodist Debakey Cardiovasc J2022 ;18(3):87-88. doi: 10.14797/mdcvj.1095.
Lewandowski David, Nabi Faisal,
Abstract
A 73-year-old male with a history of dilated cardiomyopathy and paroxysmal atrial fibrillation underwent transthoracic echocardiography (TTE) to evaluate for endocarditis due to fever and gram-positive cocci in chains on blood cultures. TTE revealed a 3 × 8 mm mass on the ventricular aspect of the tricuspid valve ( ). Subsequent transesophageal echocardiography (TEE) showed that the mass in question was actually myxomatous degeneration of the tricuspid valve (TV) and redundant chordae with significant valve prolapse. shows the prolapsing TV leaflets at the same level as the mitral valve. and show the valve at the level of the annulus in early systole and then prolapsing 8 mm in mid-late systole, respectively. Tricuspid valve prolapse (TVP) is uncommon, and one study of 118,000 patients reported an incidence of 0.3%. Since diagnostic parameters are not clearly defined, diagnosis is often determined subjectively. One objective criteria, > 2 mm atrial displacement of the TV leaflets in the TEE parasternal short-axis view, is noted to have high diagnostic accuracy. TVP is commonly associated with mitral valve prolapse. Patients with TVP have more severe tricuspid regurgitation and right-sided chamber enlargement compared to patients with no TVP. Due to the lack of significant tricuspid regurgitation in this case, the patient was reassured, and no further intervention was recommended.
Copyright: © 2022 The Author(s).
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Single-nucleus profiling of human dilated and hypertrophic cardiomyopathy.
Nature2022 Jun;():. doi: 10.1038/s41586-022-04817-8.
Chaffin Mark, Papangeli Irinna, Simonson Bridget, Akkad Amer-Denis, Hill Matthew C, Arduini Alessandro, Fleming Stephen J, Melanson Michelle, Hayat Sikander, Kost-Alimova Maria, Atwa Ondine, Ye Jiangchuan, Bedi Kenneth C, Nahrendorf Matthias, Kaushik Virendar K, Stegmann Christian M, Margulies Kenneth B, Tucker Nathan R, Ellinor Patrick T,
Abstract
Heart failure encompasses a heterogeneous set of clinical features that converge on impaired cardiac contractile function and presents a growing public health concern. Previous work has highlighted changes in both transcription and protein expression in failing hearts, but may overlook molecular changes in less prevalent cell types. Here we identify extensive molecular alterations in failing hearts at single-cell resolution by performing single-nucleus RNA sequencing of nearly 600,000 nuclei in left ventricle samples from 11 hearts with dilated cardiomyopathy and 15 hearts with hypertrophic cardiomyopathy as well as 16 non-failing hearts. The transcriptional profiles of dilated or hypertrophic cardiomyopathy hearts broadly converged at the tissue and cell-type level. Further, a subset of hearts from patients with cardiomyopathy harbour a unique population of activated fibroblasts that is almost entirely absent from non-failing samples. We performed a CRISPR-knockout screen in primary human cardiac fibroblasts to evaluate this fibrotic cell state transition; knockout of genes associated with fibroblast transition resulted in a reduction of myofibroblast cell-state transition upon TGF?1 stimulation for a subset of genes. Our results provide insights into the transcriptional diversity of the human heart in health and disease as well as new potential therapeutic targets and biomarkers for heart failure.
© 2022. The Author(s), under exclusive licence to Springer Nature Limited.
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Hypogammaglobulinaemia and B cell lymphopaenia in Barth syndrome.
BMJ Case Rep2022 Jun;15(6):. doi: e249254.
Kudlaty Elizabeth, Agnihotri Neha, Khojah Amer,
Abstract
Barth syndrome (BTHS) is an X linked recessive disorder caused by a mutation in the tafazzin (TAZ) gene classically associated with the triad of neutropaenia and cardiac and skeletal myopathies. Here we present a case of BTHS in a 2-month-old male patient found to have a novel variant of the TAZ gene (hemizygous c.639G>A) leading to early termination of the tafazzin protein (p.Trp213Ter) with presumed loss of function. Our patient was found to have dilated cardiomyopathy, cyclic neutropaenia and growth delays, which in combination with genetic work-up confirmed the diagnosis of BTHS. He also experienced repeated bacterial and viral infections, prompting an immunological work-up which revealed persistent B cell lymphopaenia and hypogammaglobulinaemia. He ultimately required subcutaneous immunoglobulin replacement and GM-CSF for ongoing hypogammaglobulinaemia and neutropaenia. To our knowledge, this case is the first report of BTHS associated with B cell lymphopaenia and hypogammaglobulinaemia.
© BMJ Publishing Group Limited 2022. No commercial re-use. See rights and permissions. Published by BMJ.
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Knockout of Sorbin And SH3 Domain Containing 2 (Sorbs2) in Cardiomyocytes Leads to Dilated Cardiomyopathy in Mice.
J Am Heart Assoc2022 Jun;():e025687. doi: 10.1161/JAHA.122.025687.
McLendon Jared M, Zhang Xiaoming, Matasic Daniel S, Kumar Mohit, Koval Olha M, Grumbach Isabella M, Sadayappan Sakthivel, London Barry, Boudreau Ryan L,
Abstract
Background Sorbin and SH3 domain containing 2 (Sorbs2) protein is a cytoskeletal adaptor with an emerging role in cardiac biology and disease; yet, its potential relevance to adult-onset cardiomyopathies remains underexplored. Sorbs2 global knockout mice display lethal arrhythmogenic cardiomyopathy; however, the causative mechanisms remain unclear. Herein, we examine Sorbs2 dysregulation in heart failure, characterize novel Sorbs2 cardiomyocyte-specific knockout mice (Sorbs2-cKO), and explore associations between Sorbs2 genetic variations and human cardiovascular disease. Methods and Results Bioinformatic analyses show myocardial Sorbs2 mRNA is consistently upregulated in humans with adult-onset cardiomyopathies and in heart failure models. We generated Sorbs2-cKO mice and report that they develop progressive systolic dysfunction and enlarged cardiac chambers, and they die with congestive heart failure at about 1 year old. After 3 months, Sorbs2-cKO mice begin to show atrial enlargement and P-wave anomalies, without dysregulation of action potential-associated ion channel and gap junction protein expressions. After 6 months, Sorbs2-cKO mice exhibit impaired contractility in dobutamine-treated hearts and skinned myofibers, without dysregulation of contractile protein expressions. From our comprehensive survey of potential mechanisms, we found that within 4 months, Sorbs2-cKO hearts have defective microtubule polymerization and compensatory upregulation of structural cytoskeletal and adapter proteins, suggesting that this early intracellular structural remodeling is responsible for contractile dysfunction. Finally, we identified genetic variants that associate with decreased Sorbs2 expression and human cardiac phenotypes, including conduction abnormalities, atrial enlargement, and dilated cardiomyopathy, consistent with Sorbs2-cKO mice phenotypes. Conclusions Our studies show that Sorbs2 is essential for maintaining structural integrity in cardiomyocytes, likely through strengthening the interactions between microtubules and other cytoskeletal proteins at cross-link sites.
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