Publications by authors named "Luisa Mestroni"

128 Publications

Genetics of dilated cardiomyopathy.

Curr Opin Cardiol 2021 May;36(3):288-294

Division of Cardiology, University of Colorado Anschutz Medical Campus, Aurora.

Purpose Of Review: Dilated cardiomyopathy (DCM), which include genetic and nongenetic forms, is the most common form of cardiomyopathy. DCM is characterized by left ventricular or biventricular dilation with impaired contraction. In the United States, DCM is a burden to healthcare that accounts for approximately 10,000 deaths and 46,000 hospitalizations annually. In this review, we will focus on the genetic forms of DCM and on recent advances in the understanding of cytoskeletal, sarcomeric, desmosomal, nuclear membrane, and RNA binding genes that contribute to the complexity and genetic heterogeneity of DCM.

Recent Findings: Although mutations in TTN remain the most common identifiable cause of genetic DCM, there is a growing appreciation for arrhythmogenic-prone DCM due to mutations in LMNA, desmosomal genes, and the recently described FLNC gene encoding the structural filamin C protein. Mutations in RBM20 highlight the relevance of RNA splicing regulation in the pathogenesis of DCM. Although expanded genetic testing has improved access to genetic diagnostic studies for many patients, the molecular mechanisms in the pathogenesis of the disease remained largely unknown.

Summary: : The identification of the molecular causes and subsequent insight into the molecular mechanisms of DCM is expanding our understanding of DCM pathogenesis and highlights the complexity of DCM and the need to develop multifaceted strategies to treat the various causes of DCM.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/HCO.0000000000000845DOI Listing
May 2021

HDAC Inhibition Reverses Preexisting Diastolic Dysfunction and Blocks Covert Extracellular Matrix Remodeling.

Circulation 2021 Mar 8. Epub 2021 Mar 8.

Department of Medicine, Division of Cardiology, University of Colorado Anschutz Medical Campus, Aurora, CO; Consortium for Fibrosis Research & Translation, University of Colorado Anschutz Medical Campus, Aurora, CO.

Diastolic dysfunction (DD) is associated with the development of heart failure (HF) and contributes to the pathogenesis of other cardiac maladies, including atrial fibrillation (AF). Inhibition of histone deacetylases (HDACs) has been shown to prevent DD by enhancing myofibril relaxation. Here, we addressed the therapeutic potential of HDAC inhibition in a model of established DD with preserved ejection fraction (EF). Four weeks following uninephrectomy (UNX) and implantation with deoxycorticosterone acetate (DOCA) pellets, when DD was clearly evident, one cohort of mice was administered the clinical-stage HDAC inhibitor ITF2357/Givinostat. Echocardiography, blood pressure measurements, and endpoint invasive hemodynamic analyses were performed. Myofibril mechanics and intact cardiomyocyte relaxation were assessed . Cardiac fibrosis was evaluated by picrosirius red (PSR) staining and second harmonic generation (SHG) microscopy of left ventricular (LV) sections, RNA-sequencing of LV mRNA, mass spectrometry-based evaluation of decellularized LV biopsies, and atomic force microscopy (AFM) determination of LV stiffness. Mechanistic studies were performed with primary rat and human cardiac fibroblasts. HDAC inhibition normalized DD without lowering blood pressure in this model of systemic hypertension. Surprisingly, in contrast to prior models, myofibril relaxation was unimpaired in UNX/DOCA mice. Furthermore, cardiac fibrosis was not evident in any mouse cohorts based on PSR staining or SHG microscopy. However, mass spectrometry revealed induction in the expression of more than one hundred extracellular matrix (ECM) proteins in LVs of UNX/DOCA mice, which correlated with profound tissue stiffening based on AFM. Remarkably, ITF2357/Givinostat treatment blocked ECM expansion and LV stiffening. The HDAC inhibitor was subsequently shown to suppress cardiac fibroblast activation, at least in part, by blunting recruitment of the pro-fibrotic chromatin reader protein, BRD4, to key gene regulatory elements. These findings demonstrate the potential of HDAC inhibition as a therapeutic intervention to reverse existing DD, and establish blockade of ECM remodeling as a second mechanism by which HDAC inhibitors improve ventricular filling. Additionally, our data reveal the existence of pathophysiologically relevant 'covert' or 'hidden' cardiac fibrosis that is below the limit of detection of histochemical stains such as PSR, highlighting the need to evaluate fibrosis of the heart using diverse methodologies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCULATIONAHA.120.046462DOI Listing
March 2021

Cardiac MR Imaging of Muscular Dystrophies.

Curr Probl Diagn Radiol 2021 Jan 9. Epub 2021 Jan 9.

Department of Radiology, University of Colorado - Anschutz Medical Campus, Aurora, CO.

Muscular dystrophies (MDs) are a group of inherited disorders caused by mutations that interfere with muscular structure, contraction, or relaxation. As the cardiac sarcomeric unit shares multiple proteins with the skeletal muscle unit, the heart is affected in several MDs, sometimes without apparent musculoskeletal involvement. Early detection of MD-related cardiomyopathy is crucial as timely initiation of cardioprotective therapy can slow adverse cardiac remodeling. Although transthoracic echocardiography is widely used for the evaluation of cardiac morphology and function, it has limitations in terms of reproducibility and image quality. The need for an optimal acoustic window may be particularly challenging to obtain in patients with MDs given their body habitus and position. Cardiac magnetic resonance (CMR) imaging has emerged as a useful tool in the evaluation of patients with MDs. Its superb tissue characterization capability through late gadolinium enhancement, T1 mapping, extracellular volume fraction quantification, and edema imaging detects early cardiac involvement, even when echocardiography and electrocardiogram are unremarkable. MDs that frequently present with cardiac involvement include Duchenne MD, Becker MD, Emery Dreifuss MD, Limb-Girdle MDs, and myotonic dystrophy. The purpose of this review article is to briefly describe the pathophysiology of these entities, discuss their clinical presentation and expected evolution, explain the role of CMR in the diagnosis and follow-up of these patients, and portray the different CMR findings present in MD patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1067/j.cpradiol.2020.12.010DOI Listing
January 2021

Induction of ADAM10 by RT drives fibrosis, resistance, and EMT in pancreatic cancer.

Cancer Res 2021 Feb 1. Epub 2021 Feb 1.

Radiation Oncology, University of Colorado Denver

Stromal fibrosis activates pro-survival and pro-epithelial-to-mesenchymal transition (EMT) pathways in pancreatic ductal adenocarcinoma (PDAC). In patient tumors treated with neoadjuvant stereotactic body radiation therapy (SBRT), we found upregulation of fibrosis, extracellular matrix (ECM), and EMT gene signatures, which can drive therapeutic resistance and tumor invasion. Molecular, functional, and translational analysis identified two cell surface proteins, A disintegrin and metalloprotease 10 (ADAM10) and ephrinB2, as drivers of fibrosis and tumor progression after RT. RT resulted in increased ADAM10 expression in tumor cells, leading to cleavage of ephrinB2, which was also detected in plasma. Pharmacologic or genetic targeting of ADAM10 decreased RT-induced fibrosis and tissue tension, tumor cell migration, and invasion, sensitizing orthotopic tumors to radiation killing and prolonging mouse survival. Inhibition of ADAM10 and genetic ablation of ephrinB2 in fibroblasts reduced the metastatic potential of tumor cells after RT. Stimulation of tumor cells with EphrinB2 FC-protein reversed the reduction in tumor cell invasion with ADAM10 ablation. These findings represent a model of PDAC adaptation that explains resistance and metastasis after radiation therapy and identifies a targetable pathway to enhance RT efficacy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/0008-5472.CAN-20-3892DOI Listing
February 2021

[Diagnostic work-up and clinical management of cardiomyopathies: the operative protocol from the Cardiothoracovascular Department of Trieste, Italy].

G Ital Cardiol (Rome) 2020 Dec;21(12):935-953

S.C. Cardiologia, Dipartimento Cardiotoracovascolare, Centro per la Diagnosi e Cura delle Cardiomiopatie, Azienda Sanitaria Universitaria Giuliano Isontina e Università degli Studi di Trieste.

Cardiomyopathies are primary myocardial disorders, genetically determined, with clinical onset between the third and the fifth decade of life. They represent the main causes of sudden cardiac death and heart failure in the youth. The more common myocardial diseases in clinical practice are dilated cardiomyopathy, arrhythmogenic cardiomyopathy and hypertrophic cardiomyopathy. Next generation sequencing techniques, recently available for genetics researches, together with the diffusion of advanced imaging techniques, permitted in the last years a deeper knowledge of these pathologies. Nevertheless, diagnosis, etiology and several aspects of patients' clinical management remain complex and controversial. This review paper aims to propose some operative flow-charts, derived from scientific evidences and the internal protocol of the Cardiothoracovascular Department of Trieste Hospital, Italian referral Center for cardiomyopathies and heart failure, with more than 30 years of experience in diagnosis and management of patients who suffer from primary myocardial disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1714/3472.34548DOI Listing
December 2020

Nanomaterials for Cardiac Tissue Engineering.

Molecules 2020 Nov 7;25(21). Epub 2020 Nov 7.

Department of Bioengineering, University of Colorado Denver, Anschutz Medical Campus, 12705 E. Montview Avenue, Suite 100, Aurora, CO 80045, USA.

End stage heart failure is a major cause of death in the US. At present, organ transplant and left-ventricular assist devices remain the only viable treatments for these patients. Cardiac tissue engineering presents the possibility of a new option. Nanomaterials such as gold nanorods (AuNRs) and carbon nanotubes (CNTs) present unique properties that are beneficial for cardiac tissue engineering approaches. In particular, these nanomaterials can modulate electrical conductivity, hardness, and roughness of bulk materials to improve tissue functionality. Moreover, they can deliver bioactive cargo to affect cell phenotypes. This review covers recent advances in the use of nanomaterials for cardiac tissue engineering.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/molecules25215189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7664640PMC
November 2020

Precision medicine in laminopathies: insights from the REDLAMINA registry.

Rev Esp Cardiol (Engl Ed) 2021 Mar 6;74(3):208-209. Epub 2020 Nov 6.

Division of Cardiology, Cardiovascular Institute and Adult Medical Genetics Program, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.rec.2020.09.021DOI Listing
March 2021

Modifications of Titin Contribute to the Progression of Cardiomyopathy and Represent a Therapeutic Target for Treatment of Heart Failure.

J Clin Med 2020 Aug 26;9(9). Epub 2020 Aug 26.

Adult Medical Genetics Program, Cardiovascular Institute, University of Colorado Anschutz Medical Campus, CO 80045, USA.

Titin is the largest human protein and an essential component of the cardiac sarcomere. With multiple immunoglobulin(Ig)-like domains that serve as molecular springs, titin contributes significantly to the passive tension, systolic function, and diastolic function of the heart. Mutations leading to early termination of titin are the most common genetic cause of dilated cardiomyopathy. Modifications of titin, which change protein length, and relative stiffness affect resting tension of the ventricle and are associated with acquired forms of heart failure. Transcriptional and post-translational changes that increase titin's length and extensibility, making the sarcomere longer and softer, are associated with systolic dysfunction and left ventricular dilation. Modifications of titin that decrease its length and extensibility, making the sarcomere shorter and stiffer, are associated with diastolic dysfunction in animal models. There has been significant progress in understanding the mechanisms by which titin is modified. As molecular pathways that modify titin's mechanical properties are elucidated, they represent therapeutic targets for treatment of both systolic and diastolic dysfunction. In this article, we review titin's contribution to normal cardiac physiology, the pathophysiology of titin truncation variations leading to dilated cardiomyopathy, and transcriptional and post-translational modifications of titin. Emphasis is on how modification of titin can be utilized as a therapeutic target for treatment of heart failure.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/jcm9092770DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564493PMC
August 2020

Current Understanding of the Role of Cytoskeletal Cross-Linkers in the Onset and Development of Cardiomyopathies.

Int J Mol Sci 2020 Aug 15;21(16). Epub 2020 Aug 15.

Department of Engineering and Architecture, University of Trieste, 34127 Trieste, Italy.

Cardiomyopathies affect individuals worldwide, without regard to age, sex and ethnicity and are associated with significant morbidity and mortality. Inherited cardiomyopathies account for a relevant part of these conditions. Although progresses have been made over the years, early diagnosis and curative therapies are still challenging. Understanding the events occurring in normal and diseased cardiac cells is crucial, as they are important determinants of overall heart function. Besides chemical and molecular events, there are also structural and mechanical phenomena that require to be investigated. Cell structure and mechanics largely depend from the cytoskeleton, which is composed by filamentous proteins that can be cross-linked via accessory proteins. Alpha-actinin 2 (ACTN2), filamin C (FLNC) and dystrophin are three major actin cross-linkers that extensively contribute to the regulation of cell structure and mechanics. Hereby, we review the current understanding of the roles played by ACTN2, FLNC and dystrophin in the onset and progress of inherited cardiomyopathies. With our work, we aim to set the stage for new approaches to study the cardiomyopathies, which might reveal new therapeutic targets and broaden the panel of genes to be screened.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms21165865DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7461563PMC
August 2020

Danon Disease-Associated LAMP-2 Deficiency Drives Metabolic Signature Indicative of Mitochondrial Aging and Fibrosis in Cardiac Tissue and hiPSC-Derived Cardiomyocytes.

J Clin Med 2020 Jul 31;9(8). Epub 2020 Jul 31.

Cardiovascular Institute and Adult Medical Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.

Danon disease is a severe X-linked disorder caused by deficiency of the lysosome-associated membrane protein-2 (LAMP-2). Clinical manifestations are phenotypically diverse and consist of hypertrophic and dilated cardiomyopathies, skeletal myopathy, retinopathy, and intellectual dysfunction. Here, we investigated the metabolic landscape of Danon disease by applying a multi-omics approach and combined structural and functional readouts provided by Raman and atomic force microscopy. Using these tools, Danon patient-derived cardiac tissue, primary fibroblasts, and human induced pluripotent stem cells differentiated into cardiomyocytes (hiPSC-CMs) were analyzed. Metabolic profiling indicated LAMP-2 deficiency promoted a switch toward glycolysis accompanied by rerouting of tryptophan metabolism. Cardiomyocytes' energetic balance and NAD+/NADH ratio appeared to be maintained despite mitochondrial aging. In turn, metabolic adaption was accompanied by a senescence-associated signature. Similarly, Danon fibroblasts appeared more stress prone and less biomechanically compliant. Overall, shaping of both morphology and metabolism contributed to the loss of cardiac biomechanical competence that characterizes the clinical progression of Danon disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/jcm9082457DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7465084PMC
July 2020

Understanding the role of titin in dilated cardiomyopathy.

Int J Cardiol 2020 10 4;316:186-187. Epub 2020 Jul 4.

Division of Cardiology, Cardiovascular Institute, Adult Medical Genetics Program, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijcard.2020.06.064DOI Listing
October 2020

Contemporary survival trends and aetiological characterization in non-ischaemic dilated cardiomyopathy.

Eur J Heart Fail 2020 07 26;22(7):1111-1121. Epub 2020 Jun 26.

Cardiovascular Department, Centre for Diagnosis and Management of Cardiomyopathies, Azienda Sanitaria Universitaria Integrata di Trieste (ASUITS), University of Trieste, Trieste, Italy.

Aim: Contemporary survival trends in dilated cardiomyopathy (DCM) are largely unknown. The aim of this study is to investigate clinical descriptors, survival trends and the prognostic impact of aetiological characterization in DCM patients.

Methods And Results: Dilated cardiomyopathy patients were consecutively enrolled and divided into four groups according to the period of enrolment (1978-1984; 1985-1994; 1995-2004; and 2005-2015). A subset of patients with DCM of specific aetiology, enrolled from 2005 to 2015, was also analysed. Over a mean follow-up of 12 ± 8 years, 1284 DCM patients (52 in the 1978-1984 group, 326 in the 1985-1994 group, 379 in the 1995-2004 group, and 527 in the 2005-2015 group) were evaluated. Despite older age (mean age 51 ± 15, 43 ± 15, 45 ± 14, and 52 ± 15 years for the 1978-1984, 1985-1994, 1995-2004, and 2005-2015 groups, respectively; P < 0.001), most of the baseline clinical characteristics improved in the 2005-2015 group, suggesting a less advanced disease stage at diagnosis. Similarly, at competing risk analysis, the annual incidence of all outcome parameters progressively decreased over time (global P < 0.001). At multivariable analysis, the last period of enrolment emerged as independently associated with a reduction in all-cause mortality/heart transplantation (HTx)/ventricular assist device (VAD) implantation (1.46 events/100 patients/year), cardiovascular death/HTx/VAD implantation (0.82 events/100 patients/year) and sudden cardiac death (0.15 events/100 patients/year). Lastly, in 287 patients with DCM of specific aetiology, patients with environmental, toxic, or removable factors appeared to have different phenotypes and prognosis compared to those with genetic, post-myocarditis, or idiopathic DCM (P < 0.001).

Conclusions: Contemporary survival trends in DCM significantly improved, mainly due to a reduction of cardiovascular events. Appropriate aetiological characterization might help in prognostication of DCM patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ejhf.1914DOI Listing
July 2020

The electrocardiogram in the diagnosis and management of patients with dilated cardiomyopathy.

Eur J Heart Fail 2020 07 3;22(7):1097-1107. Epub 2020 Apr 3.

Cardiovascular Department, A.O.U. Ospedali Riuniti, Trieste, Italy.

The term dilated cardiomyopathy (DCM) defines a heterogeneous group of cardiac disorders, which are characterized by left ventricular or biventricular dilatation and systolic dysfunction in the absence of abnormal loading conditions or coronary artery disease sufficient to cause global systolic impairment. In approximately one third of cases, DCM is familial with a genetic pathogenesis and various patterns of inheritance. Although the electrocardiogram (ECG) has been considered traditionally non-specific in DCM, the recently acquired knowledge of the genotype-phenotype correlations provides novel opportunities to identify patterns and abnormalities that may point toward specific DCM subtypes. A learned ECG interpretation in combination with an appropriate use of other ECG-based techniques including ambulatory ECG monitoring, exercise tolerance test and imaging modalities, such as echocardiography and cardiovascular magnetic resonance, may allow the early identification of specific genetic or acquired forms of DCM. Furthermore, ECG abnormalities may reflect the severity of the disease and provide a useful tool in risk stratification and management. In the present review, we discuss the current role of the ECG in the diagnosis and management of DCM. We describe various clinical settings where the appropriate use and interpretation of the ECG can provide invaluable clues, contributing to the important role of this basic tool as cardiovascular medicine evolves.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ejhf.1815DOI Listing
July 2020

Viscoelastic behavior of cardiomyocytes carrying LMNA mutations.

Biorheology 2020 ;57(1):1-14

Department of Engineering and Architecture, University of Trieste, Trieste, Italy.

Background: Laminopathies are genetic diseases caused by mutations in the nuclear lamina.

Objective: Given the clinical impact of laminopathies, understanding mechanical properties of cells bearing lamin mutations will lead to advancement in the treatment of heart failure.

Methods: Atomic force microscopy (AFM) was used to analyze the viscoelastic behavior of neonatal rat ventricular myocyte cells expressing three human lamin A/C gene (LMNA) mutations.

Results: Cell storage modulus was characterized, by two plateaus, one in the low frequency range, a second one at higher frequencies. The loss modulus instead showed a "bell" shape with a relaxation toward fluid properties at lower frequencies. Mutations shifted the relaxation to higher frequencies, rendering the networks more solid-like. This increase of stiffness with mutations (solid like behavior) was at frequencies around 1 Hz, close to the human heart rate.

Conclusions: These features resulted from a combination of the properties of cytoskeleton filaments and their temporary cross-linker. Our results substantiate that cross-linked filaments contribute, for the most part, to the mechanical strength of the cytoskeleton of the cell studied and the relaxation time is determined by the dissociation dynamics of the cross-linking proteins. The severity of biomechanical defects due to these LMNA mutations correlated with the severity of the clinical phenotype.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3233/BIR-190229DOI Listing
April 2021

Altered microtubule structure, hemichannel localization and beating activity in cardiomyocytes expressing pathologic nuclear lamin A/C.

Heliyon 2020 Jan 23;6(1):e03175. Epub 2020 Jan 23.

Department of Engineering and Architecture, University of Trieste, Trieste, Italy.

Given the clinical effect of laminopathies, understanding lamin mechanical properties will benefit the treatment of heart failure. Here we report a mechano-dynamic study of mutations in neonatal rat ventricular myocytes (NRVM) using single cell spectroscopy with Atomic Force Microscopy (AFM) and measured changes in beating force, frequency and contractile amplitude of selected mutant-expressing cells within cell clusters. Furthermore, since beat-to-beat variations can provide clues on the origin of arrhythmias, we analyzed the beating rate variability using a time-domain method which provides a Poincaré plot. Data were further correlated to cell phenotypes. Immunofluorescence and calcium imaging analysis showed that mutant lamin changed NRVMs beating force and frequency. Additionally, we noted an altered microtubule network organization with shorter filament length, and defective hemichannel membrane localization (Connexin 43). These data highlight the interconnection between nucleoskeleton, cytoskeleton and sarcolemmal structures, and the transcellular consequences of mutant lamin protein in the pathogenesis of the cardiac .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.heliyon.2020.e03175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6992992PMC
January 2020

Transcriptome signature of ventricular arrhythmia in dilated cardiomyopathy reveals increased fibrosis and activated TP53.

J Mol Cell Cardiol 2020 02 18;139:124-134. Epub 2020 Jan 18.

Human Medical Genetics and Genomics, University of Colorado, Aurora, CO, USA; Cardiovascular Institute and Adult Medical Genetics Program, University of Colorado, Aurora, CO, USA. Electronic address:

Aims: One-third of DCM patients experience ventricular tachycardia (VT), but a clear biological basis for this has not been established. The purpose of this study was to identify transcriptome signatures and enriched pathways in the hearts of dilated cardiomyopathy (DCM) patients with VT.

Methods And Results: We used RNA-sequencing in explanted heart tissue from 49 samples: 19 DCM patients with VT, 16 DCM patients without VT, and 14 non-failing controls. We compared each DCM cohort to the controls and identified the genes that were differentially expressed in DCM patients with VT but not without VT. Differentially expressed genes were evaluated using pathway analysis, and pathways of interest were investigated by qRT-PCR validation, Western blot, and microscopy. There were 590 genes differentially expressed in DCM patients with VT that are not differentially expressed in patients without VT. These genes were enriched for genes in the TGFß1 and TP53 signaling pathways. Increased fibrosis and activated TP53 signaling was demonstrated in heart tissue of DCM patients with VT.

Conclusions: Our study supports that distinct biological mechanisms distinguish ventricular arrhythmia in DCM patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.yjmcc.2019.12.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7144813PMC
February 2020

truncations cause arrhythmogenic right ventricular cardiomyopathy.

J Med Genet 2020 04 10;57(4):254-257. Epub 2020 Jan 10.

Division of Cardiology, Johns Hopkins, Baltimore, Maryland, USA.

Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a heart muscle disease that affects predominantly the right ventricle and is part of the spectrum of arrythmogenic cardiomyopathies (ACMs). ARVC is a genetic condition; however, a pathogenic gene variant is found in only half of patients.

Objective: Filamin C gene truncations () have recently been identified in dilated cardiomyopathy with ventricular arrhythmia and sudden cardiac death, a phenotype partially overlapping with ARVC and part of the ACM spectrum. We hypothesised that could be a novel gene associated with ARVC.

Methods: One hundred fifty-six patients meeting 2010 ARVC Task Force Criteria and lacking variants in known ARVC genes were evaluated for variants. Available family members were tested for cosegregation.

Results: We identified two unique variants in two families (c.6565 G>T, p.Glu2189Ter and c.8107delG, p.Asp2703ThrfsTer69), with phenotypes of dominant RV disease fulfilling 'definite' diagnosis of ARVC according to the 2010 Task Force Criteria. Variants in other cardiomyopathy genes were excluded in both kindreds, and segregation analysis revealed that p.Asp2703ThrfsTer69 was a de novo variant. In both families, the disease phenotype was characterised by prominent ventricular arrhythmias and sudden cardiac arrest.

Conclusion: The identification of as a novel cause of ARVC in two unrelated families expands the spectrum of ARVC disease genes for this disorder. Our findings should prompt inclusion of genetic testing in ARVC to improve diagnostic yield and testing of at-risk relatives in ARVC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jmedgenet-2019-106394DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7539291PMC
April 2020

The Giant Protein Titin's Role in Cardiomyopathy: Genetic, Transcriptional, and Post-translational Modifications of TTN and Their Contribution to Cardiac Disease.

Front Physiol 2019 28;10:1436. Epub 2019 Nov 28.

Adult Medical Genetics Program and Cardiovascular Institute, University of Colorado Anschutz Medical Campus, Aurora, CO, United States.

Dilated cardiomyopathy (DCM) is a leading cause of heart failure, sudden cardiac death and heart transplant. DCM is inherited in approximately 50% of cases, in which the most frequent genetic defects are truncation variants of the titin gene (tv). encodes titin, which is the largest protein in the body and is an essential component of the sarcomere. Titin serves as a biological spring, spanning half of the sarcomere and connecting the Z-disk to the M-line, with scaffold and signaling functions. Truncations of titin are believed to lead to either haploinsufficiency and loss-of-function, or to a "poison peptide" effect. However, other titin mechanisms are postulated to influence cardiac function including post-translational modifications, in particular changes in titin phosphorylation that alters the stiffness of the protein, and diversity of alternative splicing that generates different titin isoforms. In this article, we review the role of mutations in development of DCM, how differential expression of titin isoforms relate to DCM pathophysiology, and discuss how post-translational modifications of titin can affect cardiomyocyte function. Current research efforts aim to elucidate the contribution of titin to myofibril assembly, stability, and signal transduction, and how mutant titin leads to cardiac dysfunction and human disease. Future research will need to translate this knowledge toward novel therapeutic approaches that can modulate titin transcriptional and post-translational defects to treat DCM and heart failure.

Highlights: - Titin (TTN) truncation variants are the most frequent cause of dilated cardiomyopathy, one of the main causes of heart failure and heart transplant. Titin is a giant protein, and the mechanisms causing the disease are both complex and still incompletely understood.- This review discusses the role of titin in myocardial function and in disease. In particular, we discuss TTN gene structure, the complexity of genotype-phenotype correlation in human disease, the physiology of TTN and the role of post-translation modification.- Additional studies will be required to clarify whether missense variants are associated with cardiac disease. While initial studies suggested a role of non-synonymous variants in arrhythmogenic cardiomyopathy, confirmatory investigations have been hampered by the complexity of the protein structure and function.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphys.2019.01436DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6892752PMC
November 2019

Knock Down of Plakophillin 2 Dysregulates Adhesion Pathway through Upregulation of miR200b and Alters the Mechanical Properties in Cardiac Cells.

Cells 2019 12 14;8(12). Epub 2019 Dec 14.

Engineering and Architecture Department, University of Trieste, 34127 Trieste, Italy.

Mutations in genes encoding intercalated disk/desmosome proteins, such as plakophilin 2 (PKP2), cause arrhythmogenic cardiomyopathy (ACM). Desmosomes are responsible for myocyte-myocyte attachment and maintaining mechanical integrity of the myocardium. We knocked down in HL-1 mouse atrial cardiomyocytes (HL-1) and characterized their biomechanical properties. Gene expression was analyzed by RNA-Sequencing, microarray, and qPCR. Immunofluorescence was used to detect changes in cytoskeleton and focal adhesion. Antagomirs were used to knock down expression of selected microRNA (miR) in the rescue experiments. Knockdown of was associated with decreased cardiomyocyte stiffness and work of detachment, and increased plasticity index. Altered mechanical properties were associated with impaired actin cytoskeleton in HL-1 cells. Analysis of differentially expressed genes identified focal adhesion and actin cytoskeleton amongst the most dysregulated pathways, and miR200 family (a, b, and 429) as the most upregulated miRs in HL-1 cells. Knockdown of miR-200b but not miR-200a, miR-429, by sequence-specific shRNAs partially rescued integrin-α1 () levels, actin organization, cell adhesion (on collagen), and stiffness. PKP2 deficiency alters cardiomyocytes adhesion through a mechanism that involves upregulation of miR-200b and suppression of expression. These findings provide new insights into the molecular basis of altered mechanosensing in ACM.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cells8121639DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6952926PMC
December 2019

Baseline Characteristics of the VANISH Cohort.

Circ Heart Fail 2019 12 9;12(12):e006231. Epub 2019 Dec 9.

Brigham and Women's Hospital, Boston, MA (A.L.C., C.A.M., S.D.S., E.J.O., E.B., C.Y.H.).

Background: The VANISH trial (Valsartan for Attenuating Disease Evolution in Early Sarcomeric Hypertrophic Cardiomyopathy) targeted young sarcomeric gene mutation carriers with early-stage hypertrophic cardiomyopathy (HCM) to test whether valsartan can modify disease progression. We describe the baseline characteristics of the VANISH cohort and compare to previous trials evaluating angiotensin receptor blockers.

Methods: Applying a randomized, double-blinded, placebo-controlled design, 178 participants with nonobstructive HCM (age, 23.3±10.1 years; 61% men) were randomized in the primary cohort and 34 (age, 16.5±4.9 years; 50% men) in the exploratory cohort of sarcomeric mutation carriers without left ventricular hypertrophy.

Results: In the primary cohort, maximal left ventricular wall thickness was 17±4 mm for adults and score 7.0±4.5 for children. Nineteen percent had late gadolinium enhancement on cardiac magnetic resonance. Mean peak oxygen consumption was 33 mL/kg per minute, and 92% of participants were New York Heart Association functional class I. New York Heart Association class II was associated with older age, variants, and more prominent imaging abnormalities. Six previous trials of angiotensin receptor blockers in HCM enrolled a median of 24 patients (range, 19-133) with mean age of 51.2 years; 42% of patients were in New York Heart Association class ≥II, and sarcomeric mutations were not required.

Conclusions: The VANISH cohort is much larger, younger, less heterogeneous, and has less advanced disease than prior angiotensin receptor blocker trials in HCM. Participants had relatively normal functional capacity and mild HCM features. New York Heart Association functional class II symptoms were associated with older age, more prominent imaging abnormalities, and variants, suggesting both phenotype and genotype contribute to disease manifestations.

Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01912534.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCHEARTFAILURE.119.006231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7219518PMC
December 2019

Lamin A/C Cardiomyopathy: Implications for Treatment.

Curr Cardiol Rep 2019 11 26;21(12):160. Epub 2019 Nov 26.

Molecular Genetics, Cardiovascular Institute, University of Colorado Denver Anschutz Medical Campus, 12700 E 19th Ave #F442, Aurora, CO, 80045-2507, USA.

Purpose Of Review: The purpose of this review is to provide an update on lamin A/C (LMNA)-related cardiomyopathy and discuss the current recommendations and progress in the management of this disease. LMNA-related cardiomyopathy, an inherited autosomal dominant disease, is one of the most common causes of dilated cardiomyopathy and is characterized by steady progression toward heart failure and high risks of arrhythmias and sudden cardiac death.

Recent Findings: We discuss recent advances in the understanding of the molecular mechanisms of the disease including altered cell biomechanics, which may represent novel therapeutic targets to advance the current management approach, which relies on standard heart failure recommendations. Future therapeutic approaches include repurposed molecularly directed drugs, siRNA-based gene silencing, and genome editing. LMNA-related cardiomyopathy is the focus of active in vitro and in vivo research, which is expected to generate novel biomarkers and identify new therapeutic targets. LMNA-related cardiomyopathy trials are currently underway.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11886-019-1224-7DOI Listing
November 2019

Fruit and Vegetable Concentrate Supplementation and Cardiovascular Health: A Systematic Review from a Public Health Perspective.

J Clin Med 2019 Nov 8;8(11). Epub 2019 Nov 8.

Unit of Biostatistics, Epidemiology and Public Health, Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova, 35131 Padova, Italy.

Fruits and vegetables (FV) are very important for the prevention of noncommunicable diseases (NCDs), but it has been demonstrated that FV consumption is below that recommended. Several companies have worked to offer FV concentrates, but it remains unclear whether they represent a potentially effective means of reducing the burden of NCDs. The present study provides a systematic review aimed at assessing the effect of FV concentrate supplementation on select parameters that are known to be risk factors for NCDs. The systematic review was done according to the PRISMA guidelines. Relevant studies were identified through the online databases PubMed, Scopus, Web of Science, and Embase. The physiological parameters of interest were total cholesterol, low-density lipoprotein, plasmatic homocysteine, systolic blood pressure, and body mass index. Data extraction was performed in duplicate. The results of the systematic review provided input for a Markov chain simulation model aimed at estimating the public health consequences of various scenarios of FV concentrate utilization on NCDs burden. The present results suggest a positive and significant role of FV concentrate supplementation on select parameters known to affect the risk of NCDs. Such an effect might be hypothesized to turn into mitigation of the burden of those NCDs modulated by the physiological parameters analyzed in the present systematic review.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/jcm8111914DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6912365PMC
November 2019

2019 HRS expert consensus statement on evaluation, risk stratification, and management of arrhythmogenic cardiomyopathy: Executive summary.

Heart Rhythm 2019 11;16(11):e373-e407

University of Rochester Medical Center, Rochester, New York.

Arrhythmogenic cardiomyopathy (ACM) is an arrhythmogenic disorder of the myocardium not secondary to ischemic, hypertensive, or valvular heart disease. ACM incorporates a broad spectrum of genetic, systemic, infectious, and inflammatory disorders. This designation includes, but is not limited to, arrhythmogenic right/left ventricular cardiomyopathy, cardiac amyloidosis, sarcoidosis, Chagas disease, and left ventricular noncompaction. The ACM phenotype overlaps with other cardiomyopathies, particularly dilated cardiomyopathy with arrhythmia presentation that may be associated with ventricular dilatation and/or impaired systolic function. This expert consensus statement provides the clinician with guidance on evaluation and management of ACM and includes clinically relevant information on genetics and disease mechanisms. PICO questions were utilized to evaluate contemporary evidence and provide clinical guidance related to exercise in arrhythmogenic right ventricular cardiomyopathy. Recommendations were developed and approved by an expert writing group, after a systematic literature search with evidence tables, and discussion of their own clinical experience, to present the current knowledge in the field. Each recommendation is presented using the Class of Recommendation and Level of Evidence system formulated by the American College of Cardiology and the American Heart Association and is accompanied by references and explanatory text to provide essential context. The ongoing recognition of the genetic basis of ACM provides the opportunity to examine the diverse triggers and potential common pathway for the development of disease and arrhythmia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.hrthm.2019.09.019DOI Listing
November 2019

Genetic Risk of Arrhythmic Phenotypes in Patients With Dilated Cardiomyopathy.

J Am Coll Cardiol 2019 09;74(11):1480-1490

Cardiovascular Institute and Adult Medical Genetics Program, University of Colorado Anschutz Medical Campus, Aurora, Colorado. Electronic address:

Background: Genotype-phenotype correlations in dilated cardiomyopathy (DCM) and, in particular, the effects of gene variants on clinical outcomes remain poorly understood.

Objectives: The purpose of this study was to investigate the prognostic role of genetic variant carrier status in a large cohort of DCM patients.

Methods: A total of 487 DCM patients were analyzed by next-generation sequencing and categorized the disease genes into functional gene groups. The following composite outcome measures were assessed: 1) all-cause mortality; 2) heart failure-related death, heart transplantation, or destination left ventricular assist device implantation (DHF/HTx/VAD); and 3) sudden cardiac death/sustained ventricular tachycardia/ventricular fibrillation (SCD/VT/VF).

Results: A total of 183 pathogenic/likely pathogenic variants were found in 178 patients (37%): 54 (11%) Titin; 19 (4%) Lamin A/C (LMNA); 24 (5%) structural cytoskeleton-Z disk genes; 16 (3.5%) desmosomal genes; 46 (9.5%) sarcomeric genes; 8 (1.6%) ion channel genes; and 11 (2.5%) other genes. All-cause mortality was no different between variant carriers and noncarriers (p = 0.99). A trend toward worse SCD/VT/VF (p = 0.062) and DHF/HTx/VAD (p = 0.061) was found in carriers. Carriers of desmosomal and LMNA variants experienced the highest rate of SCD/VT/VF, which was independent of the left ventricular ejection fraction.

Conclusions: Desmosomal and LMNA gene variants identify the subset of DCM patients who are at greatest risk for SCD and life-threatening ventricular arrhythmias, regardless of the left ventricular ejection fraction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jacc.2019.06.072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6750731PMC
September 2019

Ankyrin-B dysfunction predisposes to arrhythmogenic cardiomyopathy and is amenable to therapy.

J Clin Invest 2019 07 2;129(8):3171-3184. Epub 2019 Jul 2.

Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.

Arrhythmogenic cardiomyopathy (ACM) is an inherited arrhythmia syndrome characterized by severe structural and electrical cardiac phenotypes, including myocardial fibrofatty replacement and sudden cardiac death. Clinical management of ACM is largely palliative, owing to an absence of therapies that target its underlying pathophysiology, which stems partially from our limited insight into the condition. Following identification of deceased ACM probands possessing ANK2 rare variants and evidence of ankyrin-B loss of function on cardiac tissue analysis, an ANK2 mouse model was found to develop dramatic structural abnormalities reflective of human ACM, including biventricular dilation, reduced ejection fraction, cardiac fibrosis, and premature death. Desmosomal structure and function appeared preserved in diseased human and murine specimens in the presence of markedly abnormal β-catenin expression and patterning, leading to identification of a previously unknown interaction between ankyrin-B and β-catenin. A pharmacological activator of the WNT/β-catenin pathway, SB-216763, successfully prevented and partially reversed the murine ACM phenotypes. Our findings introduce what we believe to be a new pathway for ACM, a role of ankyrin-B in cardiac structure and signaling, a molecular link between ankyrin-B and β-catenin, and evidence for targeted activation of the WNT/β-catenin pathway as a potential treatment for this disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/JCI125538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6668697PMC
July 2019