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1.
BMC Med Genet ; 21(1): 19, 2020 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-32005173

RESUMO

BACKGROUND: Dilated cardiomyopathy (DCM) is a condition characterized by dilatation and systolic dysfunction of the left ventricle in the absence of severe coronary artery disease or abnormal loading conditions. Mutations in the titin (TTN) and lamin A/C (LMNA) genes are the two most significant contributors in familial DCM. Previously mutations in the desmoplakin (DSP) gene have been associated with arrhythmogenic right ventricular cardiomyopathy (ARVC) and more recently with DCM. METHODS: We describe the cardiac phenotype related to a DSP mutation which was identified in ten unrelated Finnish index patients using next-generation sequencing. Sanger sequencing was used to verify the presence of this DSP variant in the probands' relatives. Medical records were obtained, and clinical evaluation was performed. RESULTS: We identified DSP c.6310delA, p.(Thr2104Glnfs*12) variant in 17 individuals of which 11 (65%) fulfilled the DCM diagnostic criteria. This pathogenic variant presented with left ventricular dilatation, dysfunction and major ventricular arrhythmias. Two patients showed late gadolinium enhancement (LGE) and myocardial edema on cardiac magnetic resonance imaging (MRI) that may suggest inflammatory process at myocardium. CONCLUSIONS: The patients diagnosed with DCM showed an arrhythmogenic phenotype as well as SCD at young age supporting the recently proposed concept of arrhythmogenic cardiomyopathy. This study also demonstrates relatively low penetrance of truncating DSP variant in the probands' family members by the age of 40. Further studies are needed to elucidate the possible relations between myocardial inflammation and pathogenic DSP variants.


Assuntos
Displasia Arritmogênica Ventricular Direita/genética , Cardiomiopatia Dilatada/genética , Desmoplaquinas/genética , Predisposição Genética para Doença , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Displasia Arritmogênica Ventricular Direita/diagnóstico por imagem , Displasia Arritmogênica Ventricular Direita/fisiopatologia , Cardiomiopatia Dilatada/diagnóstico por imagem , Cardiomiopatia Dilatada/fisiopatologia , Meios de Contraste/administração & dosagem , Feminino , Gadolínio/administração & dosagem , Ventrículos do Coração/fisiopatologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Mutação , Linhagem , Penetrância , Disfunção Ventricular Esquerda/diagnóstico por imagem , Disfunção Ventricular Esquerda/genética , Disfunção Ventricular Esquerda/fisiopatologia
2.
Hum Mutat ; 39(11): 1641-1649, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30311378

RESUMO

ClinVar provides open access to variant classifications shared from many clinical laboratories. Although most classifications are consistent across laboratories, classification differences exist. To facilitate resolution of classification differences on a large scale, clinical laboratories were encouraged to reassess outlier classifications of variants with medically significant differences (MSDs). Outliers were identified by first comparing ClinVar submissions from 41 clinical laboratories to detect variants with MSDs between the laboratories (650 variants). Next, MSDs were filtered for variants with ≥3 classifications (244 variants), of which 87.6% (213 variants) had a majority consensus in ClinVar, thus allowing for identification of outlier classifications in need of reassessment. Laboratories with outlier classifications were sent a custom report and encouraged to reassess variants. Results were returned for 204 (96%) variants, of which 62.3% (127) were resolved. Of those 127, 64.6% (82) were resolved due to reassessment prompted by this study and 35.4% (45) resolved by a previously completed reassessment. This study demonstrates a scalable approach to classification resolution and capitalizes on the value of data sharing within ClinVar. These activities will help the community move toward more consistent variant classifications, which will improve the care of patients with, or at risk for, genetic disorders.


Assuntos
Bases de Dados Genéticas , Testes Genéticos/métodos , Variação Genética/genética , Genoma Humano/genética , Humanos
3.
J Cell Sci ; 129(4): 693-705, 2016 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-26743080

RESUMO

Tie2-promoter-mediated loss of peroxisome proliferator-activated receptor gamma (PPARγ, also known as PPARG) in mice leads to osteopetrosis and pulmonary arterial hypertension. Vascular disease is associated with loss of PPARγ in pulmonary microvascular endothelial cells (PMVEC); we evaluated the role of PPARγ in PMVEC functions, such as angiogenesis and migration. The role of PPARγ in angiogenesis was evaluated in Tie2CrePPARγ(flox/flox) and wild-type mice, and in mouse and human PMVECs. RNA sequencing and bioinformatic approaches were utilized to reveal angiogenesis-associated targets for PPARγ. Tie2CrePPARγ(flox/flox) mice showed an impaired angiogenic capacity. Analysis of endothelial progenitor-like cells using bone marrow transplantation combined with evaluation of isolated PMVECs revealed that loss of PPARγ attenuates the migration and angiogenic capacity of mature PMVECs. PPARγ-deficient human PMVECs showed a similar migration defect in culture. Bioinformatic and experimental analyses newly revealed E2F1 as a target of PPARγ in the regulation of PMVEC migration. Disruption of the PPARγ-E2F1 axis was associated with a dysregulated Wnt pathway related to the GSK3B interacting protein (GSKIP). In conclusion, PPARγ plays an important role in sustaining angiogenic potential in mature PMVECs through E2F1-mediated gene regulation.


Assuntos
Células Endoteliais/fisiologia , PPAR gama/genética , Animais , Transplante de Medula Óssea , Movimento Celular , Células Cultivadas , Fator de Transcrição E2F1/genética , Fator de Transcrição E2F1/metabolismo , Endotélio Vascular/citologia , Endotélio Vascular/fisiologia , Expressão Gênica , Humanos , Pulmão/irrigação sanguínea , Camundongos , Camundongos Transgênicos , Neovascularização Fisiológica , PPAR gama/metabolismo , Ativação Transcricional , Via de Sinalização Wnt , beta Catenina/metabolismo
4.
BMC Med Genet ; 18(1): 86, 2017 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-28818065

RESUMO

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiac disease, involving changes in ventricular myocardial tissue and leading to fatal arrhythmias. Mutations in desmosomal genes are thought to be the main cause of ARVC. However, the exact molecular genetic etiology of the disease still remains largely inconclusive, and this along with large variabilities in clinical manifestations complicate clinical diagnostics. CASE PRESENTATION: We report two families (n = 20) in which a desmoglein-2 (DSG2) missense variant c.1003A > G, p.(Thr335Ala) was discovered in the index patients using next-generation sequencing panels. The presence of this variant in probands' siblings and children was studied by Sanger sequencing. Five homozygotes and nine heterozygotes were found with the mutation. Participants were evaluated clinically where possible, and available medical records were obtained. All patients homozygous for the variant fulfilled the current diagnostic criteria for ARVC, whereas none of the heterozygous subjects had symptoms suggestive of ARVC or other cardiomyopathies. CONCLUSIONS: The homozygous DSG2 variant c.1003A > G co-segregated with ARVC, indicating autosomal recessive inheritance and complete penetrance. More research is needed to establish a detailed understanding of the relevance of rare variants in ARVC associated genes, which is essential for informative genetic counseling and rational family member testing.


Assuntos
Displasia Arritmogênica Ventricular Direita/genética , Desmogleína 2/genética , Idoso , Idoso de 80 Anos ou mais , Displasia Arritmogênica Ventricular Direita/diagnóstico , Feminino , Coração/diagnóstico por imagem , Heterozigoto , Sequenciamento de Nucleotídeos em Larga Escala , Homozigoto , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Linhagem , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNA , Adulto Jovem
5.
Echocardiography ; 33(2): 193-206, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26234651

RESUMO

BACKGROUND: Population and sex-specific reference limits produced with modern ultrasound equipment are needed for accurate clinical echocardiography diagnostics. We report a comprehensive set of reference limits of cardiac function and dimensions in a group of young and middle-aged Finnish men and women produced by the recommendations of European Society of Echocardiography and American Society of Cardiology. METHODS AND RESULTS: Cardiac structure and function was studied in a standardized comprehensive echocardiographic examination in 1,079 healthy volunteers without cardiovascular diseases or major known risk factors participating in the population-based Young Finns study (444 men and 635 women, age range 34 and 49 years). We present sex-specific reference values for echocardiographic parameters reflecting cardiac structure (ventricular and atrial dimensions and volumes, left ventricular wall thickness and mass, aortic root) and function. From the 86 measured parameters, only 7 were not statistically significantly different between sexes. CONCLUSION: The Young Finns study provides echocardiographic reference ranges for cardiac structure and function quantification that can be utilized to enhance the accuracy or echocardiography diagnostics. The results emphasize the need for sex-specific assessment for most echocardiographic parameters.


Assuntos
Doenças Cardiovasculares/diagnóstico por imagem , Adulto , Fatores Etários , Doenças Cardiovasculares/fisiopatologia , Feminino , Finlândia , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Valores de Referência , Reprodutibilidade dos Testes , Fatores de Risco , Fatores Sexuais , Volume Sistólico
6.
Eur Heart J ; 36(34): 2327-37, 2015 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-26084686

RESUMO

AIMS: Despite our increased understanding of the genetic basis of dilated cardiomyopathy (DCM), the clinical utility and yield of clinically meaningful findings of comprehensive next-generation sequencing (NGS)-based genetic diagnostics in DCM has been poorly described. We utilized a high-quality oligonucleotide-selective sequencing (OS-Seq)-based targeted sequencing panel to investigate the genetic landscape of DCM in Finnish population and to evaluate the utility of OS-Seq technology as a novel comprehensive diagnostic tool. METHODS AND RESULTS: Using OS-Seq, we targeted and sequenced the coding regions and splice junctions of 101 genes associated with cardiomyopathies in 145 unrelated Finnish patients with DCM. We developed effective bioinformatic variant filtering strategy and implemented strict variant classification scheme to reveal diagnostic yield and genotype-phenotype correlations. Implemented OS-Seq technology provided high coverage of the target region (median coverage 410× and 99.42% of the nucleotides were sequenced at least 15× read depth). Diagnostic yield was 35.2% (familial 47.6% and sporadic 25.6%, P = 0.004) when both pathogenic and likely pathogenic variants are considered as disease causing. Of these, 20 (53%) were titin (TTN) truncations (non-sense and frameshift) affecting all TTN transcripts. TTN truncations accounted for 20.6% and 14.6% of the familial and sporadic DCM cases, respectively. CONCLUSION: Panel-based, high-quality NGS enables high diagnostic yield especially in the familial form of DCM, and bioinformatic variant filtering is a reliable step in the process of interpretation of genomic data in a clinical setting.


Assuntos
Cardiomiopatia Dilatada/genética , Cardiomiopatia Dilatada/epidemiologia , Feminino , Finlândia/epidemiologia , Seguimentos , Mutação da Fase de Leitura/genética , Genótipo , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto/genética , Análise de Sequência com Séries de Oligonucleotídeos , Linhagem , Fenótipo , Recidiva
7.
Am J Physiol Lung Cell Mol Physiol ; 308(10): L1046-57, 2015 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-25820525

RESUMO

Endothelial cell (EC) dysfunction plays a role in the pathobiology of occlusive vasculopathy in pulmonary arterial hypertension (PAH). Purinergic signaling pathways, which consist of extracellular nucleotide and nucleoside-mediated cell signaling through specific receptors, are known to be important regulators of vascular tone and remodeling. Therefore, we hypothesized that abnormalities in the vascular purinergic microenvironment are associated with PAH. Enzymatic clearance is crucial to terminate unnecessary cell activation; one of the most abundantly expressed enzymes on the EC surface is E-NTPDase1/CD39, which hydrolyzes ATP and ADP to AMP. we used histological samples from patients and healthy donors, radioisotope-labeled substrates to measure ectoenzyme activity, and a variety of in vitro approaches to study the role of CD39 in PAH. Immunohistochemistry on human idiopathic PAH (IPAH) patients' lungs demonstrated that CD39 was significantly downregulated in the endothelium of diseased small arteries. Similarly, CD39 expression and activity were decreased in cultured pulmonary ECs from IPAH patients. Suppression of CD39 in vitro resulted in EC phenotypic switch that gave rise to apoptosis-resistant pulmonary arterial endothelial cells and promoted a microenvironment that induced vascular smooth muscle cell migration. we also identified that the ATP receptor P2Y11 is essential for ATP-mediated EC survival. Furthermore, we report that apelin, a known regulator of pulmonary vascular homeostasis, can potentiate the activity of CD39 both in vitro and in vivo. we conclude that sustained attenuation of CD39 activity through ATP accumulation is tightly linked to vascular dysfunction and remodeling in PAH and could represent a novel target for therapy.


Assuntos
Antígenos CD/biossíntese , Apirase/biossíntese , Hipertensão Pulmonar/enzimologia , Artéria Pulmonar/enzimologia , Remodelação Vascular , Trifosfato de Adenosina/metabolismo , Adulto , Apelina , Linhagem Celular , Regulação Enzimológica da Expressão Gênica , Humanos , Hipertensão Pulmonar/patologia , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Masculino , Pessoa de Meia-Idade , Artéria Pulmonar/patologia , Receptores Purinérgicos P2/metabolismo
8.
Am J Med Genet A ; 167A(3): 629-34, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25691416

RESUMO

Timothy syndrome is a rare multiorgan disorder with prolonged QTc interval, congenital heart defects, syndactyly, typical facial features and neurodevelopmental problems. Ventricular tachyarrhythmia is the leading cause of death at early age. Classical Timothy syndrome type 1 (TS1) results from a recurrent de novo CACNA1C mutation, G406R in exon 8 A. An atypical form of Timothy syndrome type 2 (TS2) is caused by mutations in G406R and G402S in the alternatively spliced exon 8. Only one individual for each exon 8 mutations has been described. In contrast to multiorgan disease caused by the mutation in G406R either in exon 8 A or 8, the G402S carrier manifested only an isolated cardiac phenotype with LQTS and cardiac arrest. We describe a teenage patient resuscitated from ventricular fibrillation and treated with an implantable cardioverter defibrillator. She has no other organ manifestations, no syndactyly, normal neurodevelopment and her QTc has ranged between 440-480 ms. There is no family history of arrhythmias or sudden death. Targeted oligonucleotide-selective sequencing (OS-Seq) of channelopathy genes revealed a de novo substitution, G402S in exon 8 of CACNA1C. Direct sequencing of blood and saliva derived DNA showed an identical mutation peak suggesting ubiquitous expression in different tissues. The phenotype of our patient and the previously described patient show an isolated arrhythmia disease with no other organ manifestations of classical Timothy syndrome.


Assuntos
Transtorno Autístico/diagnóstico , Síndrome do QT Longo/diagnóstico , Fenótipo , Sindactilia/diagnóstico , Adolescente , Transtorno Autístico/genética , Canais de Cálcio Tipo L/genética , Eletrocardiografia , Feminino , Estudos de Associação Genética , Estudo de Associação Genômica Ampla , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Síndrome do QT Longo/genética , Mutação , Placofilinas/genética , Sindactilia/genética , Fibrilação Ventricular/diagnóstico , Fibrilação Ventricular/genética , alfa Catenina/genética
9.
Am J Respir Cell Mol Biol ; 50(6): 1118-28, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24433082

RESUMO

Occlusive vasculopathy with intimal hyperplasia and plexogenic arteriopathy are severe histopathological changes characteristic of pulmonary arterial hypertension (PAH). Although a phenotypic switch in pulmonary endothelial cells (ECs) has been suggested to play a critical role in the formation of occlusive lesions, the pathobiology of this process is poorly understood. The goal of this study was to identify novel molecular mechanisms associated with EC dysfunction and PAH-associated bone morphogenetic protein receptor 2 (BMPR2) deficiency during PAH pathogenesis. A bioinfomatics approach, patient samples, and in vitro experiments were used. By combining a metaanalysis of human idiopathic PAH (iPAH)-associated gene-expression microarrays and a unique gene expression-profiling technique in rat endothelium, our bioinformatics approach revealed a PAH-associated dysregulation of genes involving chromatin organization, DNA metabolism, and repair. Our hypothesis that altered DNA repair and loss of genomic stability play a role in PAH was supported by in vitro assays where pulmonary ECs from patients with iPAH and BMPR2-deficient ECs were highly susceptible to DNA damage. Furthermore, we showed that BMPR2 expression is tightly linked to DNA damage control because excessive DNA damage leads to rapid down-regulation of BMPR2 expression. Moreover, we identified breast cancer 1 (BRCA1) as a novel target for BMPR2 signaling and a novel modulator of pulmonary EC homeostasis. We show here that BMPR2 signaling plays a critical role in the regulation of genomic integrity in pulmonary ECs via genes such as BRCA1. We propose that iPAH-associated EC dysfunction and genomic instability are mediated through BMPR2 deficiency-associated loss of DNA damage control.


Assuntos
Receptores de Proteínas Morfogenéticas Ósseas Tipo II/genética , Reparo do DNA , Hipertensão Pulmonar/genética , Animais , Proteína BRCA1/genética , Proteína BRCA1/metabolismo , Receptores de Proteínas Morfogenéticas Ósseas Tipo II/metabolismo , Células COS , Células Cultivadas , Chlorocebus aethiops , Cromatina/genética , Cromatina/metabolismo , Dano ao DNA , Regulação para Baixo , Células Endoteliais/metabolismo , Endotélio Vascular/metabolismo , Hipertensão Pulmonar Primária Familiar , Expressão Gênica , Predisposição Genética para Doença , Humanos , Hipertensão Pulmonar/metabolismo , Pulmão/metabolismo , Artéria Pulmonar/metabolismo , Ratos , Transdução de Sinais
10.
Duodecim ; 129(2): 141-8, 2013.
Artigo em Fi | MEDLINE | ID: mdl-23577577

RESUMO

Novel high-throughput sequencing strategies in genetic diagnostics Capabilities of novel high-throughput DNA sequencing systems have revolutionized genetic research and made it possible to analyze complex eukaryotic genomes. Despite the radical improvements, sequencing of the entire human genome still remains too complicated and expensive for clinical diagnostic applications. Recently developed targeted sequencing strategies provide an immediate technological solution to analyze all clinically significant genomic regions and radically reduce sequencing costs, increase variant detection quality and limit ethical issues. In the near future, these advanced approaches can be applied for diagnostics of several diseases that have known genetic backgrounds and optimization of treatments based on individual genetic traits.


Assuntos
Genômica/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Genoma Humano , Genômica/economia , Sequenciamento de Nucleotídeos em Larga Escala/ética , Humanos
11.
Front Cardiovasc Med ; 10: 1130903, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37008330

RESUMO

Background: Pathogenic variants in DSP associate with cardiac and cutaneous manifestations including arrhythmogenic right ventricular cardiomyopathy, dilated cardiomyopathy, curly or wavy hair, and palmoplantar keratoderma (PPK). Episodes of myocardial inflammation associated with DSP cardiomyopathy might be confused in clinical work with myocarditis of other etiologies such as viral. Cardiac magnetic resonance imaging (CMR) may help in differential diagnosis. Methods and results: This study comprised 49 Finnish patients: 34 participants from families with suspected DSP cardiomyopathy (9 index patients and 25 family members) and 15 patients with myocarditis. All 34 participants underwent genetic testing and cardiac evaluation, and 29 of them also underwent CMR. Participants with the DSP variant, numbering 22, were dermatologically examined. The 15 patients with myocarditis underwent CMR and were evaluated during their hospitalization.A heterozygous truncating DSP c.6310delA p.(Thr2104Glnfs*12) variant was confirmed in 29 participants. Only participants with the DSP variant had pacemakers and life-threatening ventricular arrhythmias. Of the participants with the DSP variant, 24% fulfilled cardiomyopathy criteria, and the median age at diagnosis was 53. Upon CMR, myocardial edema was found to be more common in patients with myocarditis. Both groups had a substantial percentage of late gadolinium enhancement (LGE). A ring-like LGE and increased trabeculation were observed only in participants with the DSP variant. All the studied participants with the DSP variant had PPK and curly or wavy hair. Hyperkeratosis developed before the age of 20 in most patients. Conclusions: The DSP c.6310delA p.(Thr2104Glnfs*12) variant associates with curly hair, PPK, and arrhythmogenic cardiomyopathy with increased trabeculation. Cutaneous symptoms developing in childhood and adolescence might help recognize these patients at an earlier stage. CMR, together with dermatologic characteristics, may help in diagnosis.

12.
J Cardiovasc Transl Res ; 16(6): 1276-1286, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37418234

RESUMO

The presence of multiple pathogenic variants in desmosomal genes (DSC2, DSG2, DSP, JUP, and PKP2) in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) has been linked to a severe phenotype. However, the pathogenicity of variants is reclassified frequently, which may result in a changed clinical risk prediction. Here, we present the collection, reclassification, and clinical outcome correlation for the largest series of ARVC patients carrying multiple desmosomal pathogenic variants to date (n = 331). After reclassification, only 29% of patients remained carriers of two (likely) pathogenic variants. They reached the composite endpoint (ventricular arrhythmias, heart failure, and death) significantly earlier than patients with one or no remaining reclassified variant (hazard ratios of 1.9 and 1.8, respectively). Periodic reclassification of variants contributes to more accurate risk stratification and subsequent clinical management strategy. Graphical Abstract.


Assuntos
Displasia Arritmogênica Ventricular Direita , Humanos , Displasia Arritmogênica Ventricular Direita/diagnóstico , Displasia Arritmogênica Ventricular Direita/genética , Placofilinas/genética , Fenótipo , Arritmias Cardíacas , Mutação
13.
ERJ Open Res ; 8(1)2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-35083318

RESUMO

AIM: The prevalence of monogenic disease-causing gene variants in lung transplant recipients with idiopathic pulmonary fibrosis is not fully known. Their impact on clinical outcomes before and after transplantation requires more evidence. PATIENTS AND METHODS: We retrospectively performed sequence analysis of genes associated with pulmonary fibrosis in a cohort of 23 patients with histologically confirmed usual interstitial pneumonia that had previously undergone double lung transplantation. We evaluated the impact of confirmed molecular diagnoses on disease progression, clinical outcomes and incidence of acute rejection or chronic lung allograft dysfunction after transplantation. RESULTS: 15 patients out of 23 (65%) had a variant in a gene associated with interstitial lung disease. 11 patients (48%) received a molecular diagnosis, of which nine involved genes for telomerase function. Five diagnostic variants were found in the gene for Telomerase reverse transcriptase. Two of these variants, p.(Asp684Gly) and p.(Arg774*), seemed to be enriched in Finnish lung transplant recipients. Disease progression and the incidence of acute rejection and chronic lung allograft dysfunction was similar between patients with telomere-related disease and the rest of the study population. The incidence of renal or bone marrow insufficiency or skin malignancies did not differ between the groups. CONCLUSION: Genetic variants are common in lung transplant recipients with pulmonary fibrosis and are most often related to telomerase function. A molecular diagnosis for telomeropathy does not seem to impact disease progression or the risk of complications or allograft dysfunction after transplantation.

14.
Am J Physiol Lung Cell Mol Physiol ; 301(1): L12-9, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21398496

RESUMO

Despite advances in the treatment of pulmonary arterial hypertension, a truly restorative therapy has not been achieved. Attention has been given to circulating angiogenic cells (CACs, also termed early endothelial progenitor cells) because of their ability to home to sites of vascular injury and regenerate blood vessels. We studied the efficacy of human CAC therapy in the treatment of pulmonary arterial hypertension at two different stages of disease severity. Cells were isolated from peripheral blood and administered to nude rats on day 14 ("early") or day 21 ("late") after monocrotaline injection. The control group received monocrotaline but no cell treatment. Disease progression was assessed using right heart catheterization and echocardiography at multiple time points. Survival differences, right ventricular hypertrophy (RVH), and vascular hypertrophy were analyzed at the study endpoint. Quantitative PCR was performed to evaluate cell engraftment. Treatment with human CACs either at the early or late time points did not result in increased survival, and therapy did not prevent or reduce the severity of disease compared with control. Histological analysis of RVH and vascular muscularization showed no benefit with therapy compared with control. No detectable signal was seen of human transcript in transplanted lungs at 14 or 21 days after cell transplant. In conclusion, CAC therapy was not associated with increased survival and did not result in either clinical or histological benefits. Future studies should be geared toward either earlier therapeutic time points with varying doses of unmodified CACs or genetically modified cells as a means of delivery of factors to the pulmonary arterial circulation.


Assuntos
Movimento Celular , Células Endoteliais/citologia , Transplante de Células-Tronco , Células-Tronco/citologia , Animais , Artérias/patologia , Hipertensão Pulmonar Primária Familiar , Hemodinâmica , Humanos , Hipertensão Pulmonar/fisiopatologia , Hipertensão Pulmonar/terapia , Hipertrofia Ventricular Direita/fisiopatologia , Hipertrofia Ventricular Direita/terapia , Estimativa de Kaplan-Meier , Monocrotalina , Ratos , Ratos Nus , Remodelação Ventricular
15.
PLoS One ; 16(2): e0245681, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33534821

RESUMO

BACKGROUND: Familial dilated cardiomyopathy (DCM) is typically a monogenic disorder with dominant inheritance. Although over 40 genes have been linked to DCM, more than half of the patients undergoing comprehensive genetic testing are left without molecular diagnosis. Recently, biallelic protein-truncating variants (PTVs) in the nebulin-related anchoring protein gene (NRAP) were identified in a few patients with sporadic DCM. METHODS AND RESULTS: We determined the frequency of rare NRAP variants in a cohort of DCM patients and control patients to further evaluate role of this gene in cardiomyopathies. A retrospective analysis of our internal variant database consisting of 31,639 individuals who underwent genetic testing (either panel or direct exome sequencing) was performed. The DCM group included 577 patients with either a confirmed or suspected DCM diagnosis. A control cohort of 31,062 individuals, including 25,912 individuals with non-cardiac (control group) and 5,150 with non-DCM cardiac indications (Non-DCM cardiac group). Biallelic (n = 6) or two (n = 5) NRAP variants (two PTVs or PTV+missense) were identified in 11 unrelated probands with DCM (1.9%) but none of the controls. None of the 11 probands had an alternative molecular diagnosis. Family member testing supports co-segregation. Biallelic or potentially biallelic NRAP variants were enriched in DCM vs. controls (OR 1052, p<0.0001). Based on the frequency of NRAP PTVs in the gnomAD reference population, and predicting full penetrance, biallelic NRAP variants could explain 0.25%-2.46% of all DCM cases. CONCLUSION: Loss-of-function in NRAP is a cause for autosomal recessive dilated cardiomyopathy, supporting its inclusion in comprehensive genetic testing.


Assuntos
Cardiomiopatia Dilatada , Proteínas Musculares/genética , Adulto , Cardiomiopatia Dilatada/diagnóstico , Cardiomiopatia Dilatada/genética , Pré-Escolar , Feminino , Testes Genéticos , Humanos , Mutação com Perda de Função , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto Jovem
16.
Acta Cardiol ; 65(2): 185-92, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20458826

RESUMO

BACKGROUND: Fabry's disease is an X-linked lysosomal storage disease caused by deficiency of alpha-galactosidase A enzyme activity. Decreased enzyme activity leads to accumulation of glycosphingolipid in different tissues, including endothelial and smooth-muscle cells and cardiomyocytes. OBJECTIVES: There is controversial data on cardiopulmonary involvement in Fabry's disease, because many reports are based on small and selected populations with Fabry's disease. Furthermore, the aetiology of cardiopulmonary symptoms in Fabry's disease is poorly understood. METHODS: We studied cardiopulmonary involvement in seventeen patients with Fabry's disease (20-65 years, 6 men) using ECG, bicycle stress, cardiac magnetic resonance imaging, spirometry, diffusing capacity and pulmonary high-resolution computed tomography (HRCT) tests. Cardiopulmonary symptoms were compared to observed parameters in cardiopulmonary tests. RESULTS: Left ventricular hypertrophy (LVH) and reduced exercise capacity are the most apparent cardiac changes in both genders with Fabry's disease. ECG parameters were normal when excluding changes related to LVH. Spirometry showed mild reduction in vital capacity and forced expiratory volume in one second (FEV I), and mean values in diffusing capacity tests were within normal limits. Generally, only slight morphological pulmonary changes were detected using pulmonary HRCT, and they were not associated with changes in pulmonary function. The self-reported amount of pulmonary symptoms associated only with lower ejection fraction (P < 0.001) and longer QRS-duration (P = 0.04) of all measured cardiopulmonary parameters, whereas cardiac symptoms have no statistically significant association with any of these parameters. CONCLUSION: LVH and reduced exercise capacity are the most apparent cardiopulmonary changes in Fabry's disease but they have only a minor association to cardiopulmonary symptoms.Therefore, routine cardiopulmonary evaluation in Fabry's disease using echocardiography is maybe enough when integrated to counselling for aerobic exercise training.


Assuntos
Doença de Fabry/complicações , Doença de Fabry/diagnóstico , Hipertrofia Ventricular Esquerda/diagnóstico , Hipertrofia Ventricular Esquerda/etiologia , Pulmão/fisiopatologia , Adulto , Idoso , Biomarcadores/sangue , Biomarcadores/metabolismo , Diagnóstico Diferencial , Ecocardiografia , Eletrocardiografia , Teste de Esforço , Tolerância ao Exercício , Doença de Fabry/sangue , Doença de Fabry/enzimologia , Doença de Fabry/fisiopatologia , Feminino , Volume Expiratório Forçado , Humanos , Hipertrofia Ventricular Esquerda/sangue , Hipertrofia Ventricular Esquerda/enzimologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Consumo de Oxigênio , Índice de Gravidade de Doença , Espirometria , Tomografia Computadorizada por Raios X , Capacidade Vital , alfa-Galactosidase/sangue , alfa-Galactosidase/metabolismo
17.
ESC Heart Fail ; 7(5): 3013-3021, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32767651

RESUMO

AIMS: Cardiomyopathies comprise a heterogeneous group of diseases, often of genetic origin. We assessed the current practice of genetic counselling and testing in the prospective European Society of Cardiology EURObservational Research Programme Cardiomyopathy Registry. METHODS AND RESULTS: A total of 3208 adult patients from 69 centres in 18 countries were enrolled. Genetic counselling was performed in 60.8% of all patients [75.4% in hypertrophic cardiomyopathy (HCM), 39.2% in dilated cardiomyopathy (DCM), 70.8% in arrhythmogenic right ventricular cardiomyopathy (ARVC), and 49.2% in restrictive cardiomyopathy (RCM), P < 0.001]. Comparing European geographical areas, genetic counselling was performed from 42.4% to 83.3% (P < 0.001). It was provided by a cardiologist (85.3%), geneticist (15.1%), genetic counsellor (11.3%), or a nurse (7.5%) (P < 0.001). Genetic testing was performed in 37.3% of all patients (48.8% in HCM, 18.6% in DCM, 55.6% in ARVC, and 43.6% in RCM, P < 0.001). Index patients with genetic testing were younger at diagnosis and had more familial disease, family history of sudden cardiac death, or implanted cardioverter defibrillators but less co-morbidities than those not tested (P < 0.001 for each comparison). At least one disease-causing variant was found in 41.7% of index patients with genetic testing (43.3% in HCM, 33.3% in DCM, 51.4% in ARVC, and 42.9% in RCM, P = 0.13). CONCLUSIONS: This is the first detailed report on the real-life practice of genetic counselling and testing in cardiomyopathies in Europe. Genetic counselling and testing were performed in a substantial proportion of patients but less often than recommended by European guidelines and much less in DCM than in HCM and ARVC, despite evidence for genetic background.


Assuntos
Cardiomiopatias , Aconselhamento Genético , Adulto , Cardiomiopatias/diagnóstico , Cardiomiopatias/epidemiologia , Cardiomiopatias/genética , Europa (Continente)/epidemiologia , Humanos , Estudos Prospectivos , Sistema de Registros
18.
Eur J Cardiovasc Prev Rehabil ; 16(2): 161-3, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19276983

RESUMO

BACKGROUND AND DESIGN: The purpose of this randomized controlled cross-over study was to determine the acute effects of high doses of alcoholic beverages on circulating markers related to atherosclerosis and fibrinolysis. METHODS: Twenty-two healthy men consumed a high dose (8.1+/-0.9 dl) of alcohol-containing red wine and dealcoholized red wine, and an equal ethanol dose of cognac (2.4+/-0.3 dl). Blood samples were taken before and shortly after interventions. RESULTS: Red wine, unlike dealcoholized red wine and cognac, increased tissue plasminogen activator inhibitor-1 levels significantly, indicating an acute inhibition of fibrinolysis after a high dose. CONCLUSION: Findings may explain the increased risk of cardiovascular mortality among binge drinkers.


Assuntos
Consumo de Bebidas Alcoólicas/efeitos adversos , Aterosclerose/etiologia , Doenças Cardiovasculares/etiologia , Etanol/efeitos adversos , Fibrinólise/efeitos dos fármacos , Vinho/efeitos adversos , Adulto , Consumo de Bebidas Alcoólicas/sangue , Aterosclerose/sangue , Biomarcadores/sangue , Doenças Cardiovasculares/sangue , Estudos Cross-Over , Etanol/sangue , Humanos , Mediadores da Inflamação/sangue , Masculino , Inibidor 1 de Ativador de Plasminogênio/sangue , Adulto Jovem
19.
Cardiovasc Ultrasound ; 6: 25, 2008 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-18522727

RESUMO

BACKGROUND: The cardioprotective effects of certain alcoholic beverages are partly related to their polyphenol content, which may improve the vasodilatory reactivity of arteries. Effect of cognac on coronary circulation, however, remains unknown. The purpose of this randomized controlled cross-over study was to determine whether moderate doses of cognac improve coronary reactivity as assessed with cold pressor testing (CPT) and coronary flow reserve (CFR) measurement. METHODS: Study group consisted of 23 subjects. Coronary flow velocity and epicardial diameter was assessed using transthoracic echocardiography at rest, during CPT and adenosine infusion-derived CFR measurements before drinking, after a moderate (1.2 +/- 0.1 dl) and an escalating high dose (total amount 2.4 +/- 0.3 dl) of cognac. To explore the bioavailability of antioxidants, the antioxidant contents of cognac was measured and the absorption from the digestive tract was verified by plasma antioxidant capacity determination. RESULTS: Serum alcohol levels increased to 1.2 +/- 0.2 per thousand and plasma antioxidant capacity from 301 +/- 43.9 micromol/l to 320 +/- 25.0 micromol/l by 7.6 +/- 11.8%, (p = 0.01) after high doses of cognac. There was no significant change in flow velocity during CPT after cognac ingestion compared to control day. CFR was 4.4 +/- 0.8, 4.1 +/- 0.9 (p = NS), and 4.5 +/- 1.2 (p = NS) before drinking and after moderate and high doses on cognac day, and 4.5 +/- 1.4, and 4.0 +/- 1.2 (p = NS) on control day. CONCLUSION: Cognac increased plasma antioxidant capacity, but it had no effect on coronary circulation in healthy young men. TRIAL REGISTRATION: NCT00330213.


Assuntos
Bebidas Alcoólicas , Antioxidantes/metabolismo , Velocidade do Fluxo Sanguíneo , Circulação Coronária/efeitos dos fármacos , Doença das Coronárias/fisiopatologia , Etanol/administração & dosagem , Vasodilatação/efeitos dos fármacos , Adulto , Consumo de Bebidas Alcoólicas , Análise de Variância , Antioxidantes/administração & dosagem , Velocidade do Fluxo Sanguíneo/efeitos dos fármacos , Estudos Cross-Over , Finlândia , Humanos , Masculino , Probabilidade , Valores de Referência , Sensibilidade e Especificidade , Ultrassonografia Doppler de Pulso , Resistência Vascular
20.
PLoS One ; 13(9): e0203422, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30235249

RESUMO

During the last two decades, mutations in sarcomere genes have found to comprise the most common cause for hypertrophic cardiomyopathy (HCM), but still significant number of patients with dominant HCM in the family are left without molecular genetic diagnosis. Next generation sequencing (NGS) does not only enable evaluation of established HCM genes but also candidate genes for cardiomyopathy are frequently tested which may lead to a situation where conclusive interpretation of the variant requires extensive family studies. We aimed to characterize the phenotype related to a variant in the junctophilin-2 (JPH2) gene, which is less known non-sarcomeric candidate gene. In addition, we did extensive review of the literature and databases about JPH2 variation in association with cardiac disease. We characterize nine Finnish index patients with HCM and heterozygous for JPH2 c.482C>A, p.(Thr161Lys) variant were included and segregation studies were performed. We identified 20 individuals affected with HCM with or without systolic heart failure and conduction abnormalities in the nine Finnish families with JPH2 p.(Thr161Lys) variant. We found 26 heterozygotes with the variant and penetrance was 71% by age 60 and 100% by age 80. Co-segregation of the variant with HCM phenotype was observed in six families. Main clinical features were left ventricular hypertrophy, arrhythmia vulnerability and conduction abnormalities including third degree AV-block. In some patients end-stage severe left ventricular heart failure with normal or mildly enlarged diastolic dimensions was detected. In conclusion, we propose that the heterozygous JPH2 p.(Thr161Lys) variant is a new Finnish mutation causing atypical HCM.


Assuntos
Cardiomiopatia Hipertrófica Familiar/genética , Insuficiência Cardíaca/genética , Heterozigoto , Proteínas de Membrana/genética , Proteínas Musculares/genética , Mutação de Sentido Incorreto , Adolescente , Adulto , Substituição de Aminoácidos , Criança , Feminino , Finlândia , Humanos , Masculino , Pessoa de Meia-Idade
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