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1.
Nat Genet ; 36(11): 1162-4, 2004 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-15489853

RESUMO

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is associated with fibrofatty replacement of cardiac myocytes, ventricular tachyarrhythmias and sudden cardiac death. In 32 of 120 unrelated individuals with ARVC, we identified heterozygous mutations in PKP2, which encodes plakophilin-2, an essential armadillo-repeat protein of the cardiac desmosome. In two kindreds with ARVC, disease was incompletely penetrant in most carriers of PKP2 mutations.


Assuntos
Displasia Arritmogênica Ventricular Direita/genética , Mutação , Proteínas/genética , Adolescente , Desmossomos , Feminino , Humanos , Masculino , Dados de Sequência Molecular , Placofilinas
2.
Europace ; 14(2): 224-9, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21946820

RESUMO

AIMS: Mortality in chronic heart failure (CHF) patients with left bundle branch block (LBBB) is high. Cardiac resynchronization therapy (CRT) reduces symptoms and mortality in CHF patients with LBBB. Whether CRT promotes or prevents ventricular tachycardia (VT)/ventricular fibrillation (VF) remains controversial, however. Therefore, we aimed to analyse arrhythmia-related CRT effects and characterized the VT/VF incidence in CRT-defibrillator patients and matched controls with conventional implantable cardioverter-defibrillators (ICDs) for primary prevention of sudden cardiac death. METHODS AND RESULTS: We enrolled 134 patients [110 men, left ventricular ejection fraction (LVEF) 24 ± 8%, 71 coronary artery disease, CRT-ICD 67, conventional ICD matched controls 67, follow-up 31 ± 17 months] and monitored overall survival and the time to a first VT/VF episode. Controls did not have LBBB. They were otherwise matched for age, LVEF, and follow-up duration. Gender and underlying disease did not differ between the groups. Kaplan-Meier analysis revealed more favourable arrhythmia-free survival in CRT-ICD vs. conventional ICD patients [hazard ratio (HR) 2.26, confidence interval (CI) 1.09-4.67, log rank P = 0.023]. The difference persisted in the multivariate Cox regression analysis (HR 3.25, CI 1.18-8.93, P= 0.022). Overall survival was similar in both groups (HR 1.45, CI 0.55-3.82, P = 0.45). CONCLUSIONS: Chronic heart failure patients with LBBB treated with CRT-ICD, experience less and delayed VT/VF episodes compared with matched controls without LBBB receiving conventional ICD. In the long-term, CRT appears to exert antiarrhythmic effects and to attenuate the particularly high arrhythmia-related risk of CHF patients with LBBB. The incremental benefit of adding the ICD option to CRT pacing in LBBB patients appears questionable.


Assuntos
Bloqueio de Ramo/prevenção & controle , Terapia de Ressincronização Cardíaca/estatística & dados numéricos , Desfibriladores Implantáveis/estatística & dados numéricos , Taquicardia Ventricular/prevenção & controle , Fibrilação Ventricular/prevenção & controle , Bloqueio de Ramo/mortalidade , Estudos de Casos e Controles , Terapia Combinada/estatística & dados numéricos , Comorbidade , Intervalo Livre de Doença , Feminino , Alemanha/epidemiologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Prevalência , Medição de Risco , Fatores de Risco , Análise de Sobrevida , Taxa de Sobrevida , Taquicardia Ventricular/mortalidade , Fibrilação Ventricular/mortalidade
3.
Pacing Clin Electrophysiol ; 35(1): 38-43, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22054234

RESUMO

BACKGROUND: The combination of intravenous propofol and midazolam is frequently used to provide unconscious sedation during catheter ablation of atrial fibrillation (AF), but only a very few reports are available on the influence of prolonged propofol infusion on arterial blood gas, blood pressure, and anesthesia-associated complications during ablation of AF. The purpose of this study was to assess tolerance and safety of unconscious sedation with intravenous propofol and midazolam during catheter ablation of AF. METHODS: A total of 316 consecutive patients (age 59 ± 10 years, 68% men) presenting to our center for catheter ablation of symptomatic AF were enrolled prospectively. A total number of 424 procedures were performed under unconscious sedation with propofol and midazolam. SaO(2), electrocardiogram, arterial blood pressure, and arterial blood gases were monitored throughout the procedure. RESULTS: Mean procedure duration was 235 ± 48 minutes. Patients received 1.125 ± 684 mg propofol, 9.5 ± 3 midazolam, and 1.963 ± 813 mL NaCl infusion. Complications during the procedure were identified in eight patients (2.5%, one × coronary air embolization, one × myocardial infarction, four × pericardial effusion, two × pericardial tamponade). All eight patients were symptomatic (distress, report of pain); none of the complications was attributable to unconscious sedation itself. CONCLUSION: Unconscious sedation with propofol and midazolam in AF ablation procedures lasting 3-5 hours did not result in severe changes of vital parameters or serum electrolytes. Anesthesia-associated problems were not observed. Propofol and midazolam can be safely used during catheter ablation of AF.


Assuntos
Fibrilação Atrial/epidemiologia , Fibrilação Atrial/cirurgia , Ablação por Cateter/estatística & dados numéricos , Sedação Profunda/estatística & dados numéricos , Midazolam , Propofol , Combinação de Medicamentos , Feminino , Alemanha/epidemiologia , Humanos , Hipnóticos e Sedativos , Masculino , Pessoa de Meia-Idade , Medição de Risco , Fatores de Risco , Resultado do Tratamento
4.
J Med Genet ; 47(4): 230-5, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19762328

RESUMO

BACKGROUND: Ostium secundum atrial septal defects (ASDII) account for approximately 10% of all congenital heart defects (CHD), and mutations in cardiac transcription factors, including TBX20, were identified as an underlying cause for ASDII. However, very little is known about disease penetrance in families and functional consequences of inherited TBX20 mutations. METHODS: The coding region of TBX20 was directly sequenced in 170 ASDII patients. Functional consequences of one novel mutation were investigated by surface plasmon resonance, CD spectropolarymetry, fluorescence spectrophotometry, luciferase assay and chromatin immunoprecipitation. RESULTS: We found a novel mutation in a highly conserved residue in the T-box DNA binding domain (I121M) segregating with CHD in a three generation kindred. Four mutation carriers revealed cardiac phenotypes in terms of cribriform ASDII, large patent foramen ovale or cardiac valve defects. Interestingly, tertiary hydrophobic interactions within the mutant TBX20 T-box were significantly altered leading to a more dynamic structure of the protein. Moreover, Tbx20-I121M resulted in a significantly enhanced transcriptional activity, which was further increased in the presence of co-transcription factors GATA4/5 and NKX2-5. Occupancy of DNA binding sites on target genes was also increased. CONCLUSIONS: We suggest that TBX20-I121M adopts a more fluid tertiary structure leading to enhanced interactions with cofactors and more stable transcriptional complexes on target DNA sequences. Our data, combined with that of others, suggest that human ASDII may be related to loss-of-function as well as gain-of-function TBX20 mutations.


Assuntos
Forame Oval Patente/genética , Comunicação Interatrial/genética , Valvas Cardíacas/anormalidades , Mutação , Proteínas com Domínio T/genética , Adolescente , Animais , Sequência de Bases , Células COS , Estudos de Casos e Controles , Chlorocebus aethiops , Imunoprecipitação da Cromatina , Dicroísmo Circular , DNA/genética , DNA/metabolismo , Feminino , Forame Oval Patente/metabolismo , Comunicação Interatrial/metabolismo , Humanos , Masculino , Modelos Moleculares , Dados de Sequência Molecular , Linhagem , Alinhamento de Sequência , Homologia Estrutural de Proteína , Proteínas com Domínio T/metabolismo , Ativação Transcricional
5.
Proc Natl Acad Sci U S A ; 105(50): 19762-7, 2008 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-19073933

RESUMO

We analyzed the effect of conditional, alphaMHC-dependent genetic beta-catenin depletion and stabilization on cardiac remodeling following experimental infarct. beta-Catenin depletion significantly improved 4-week survival and left ventricular (LV) function (fractional shortening: CT(Deltaex3-6): 24 +/- 1.9%; beta-cat(Deltaex3-6): 30.2 +/- 1.6%, P < 0.001). beta-Catenin stabilization had opposite effects. No significant changes in adult cardiomyocyte survival or hypertrophy were observed in either transgenic line. Associated with the functional improvement, LV scar cellularity was altered: beta-catenin-depleted mice showed a marked subendocardial and subepicardial layer of small cTnT(pos) cardiomyocytes associated with increased expression of cardiac lineage markers Tbx5 and GATA4. Using a Cre-dependent lacZ reporter gene, we identified a noncardiomyocyte cell population affected by alphaMHC-driven gene recombination localized to these tissue compartments at baseline. These cells were found to be cardiac progenitor cells since they coexpressed markers of proliferation (Ki67) and the cardiomyocyte lineage (alphaMHC, GATA4, Tbx5) but not cardiac Troponin T (cTnT). The cell population overlaps in part with both the previously described c-kit(pos) and stem cell antigen-1 (Sca-1)(pos) precursor cell population but not with the Islet-1(pos) precursor cell pool. An in vitro coculture assay of highly enriched (>95%) Sca-1(pos) cardiac precursor cells from beta-catenin-depleted mice compared to cells isolated from control littermate demonstrated increased differentiation toward alpha-actin(pos) and cTnT(pos) cardiomyocytes after 10 days (CT(Deltaex3-6): 38.0 +/- 1.0% alpha-actin(pos); beta-cat(Deltaex3-6): 49.9 +/- 2.4% alpha-actin(pos), P < 0.001). We conclude that beta-catenin depletion attenuates postinfarct LV remodeling in part through increased differentiation of GATA4(pos)/Sca-1(pos) resident cardiac progenitor cells.


Assuntos
Mioblastos Cardíacos/fisiologia , Infarto do Miocárdio/metabolismo , Regeneração , Remodelação Ventricular , beta Catenina/metabolismo , Animais , Diferenciação Celular/genética , Proliferação de Células , Regulação para Baixo , Genes Reporter , Camundongos , Camundongos Transgênicos , Mioblastos Cardíacos/patologia , Infarto do Miocárdio/genética , Infarto do Miocárdio/patologia , Regeneração/genética , Remodelação Ventricular/genética , beta Catenina/genética , beta-Galactosidase/genética
6.
Hum Mol Genet ; 17(18): 2753-65, 2008 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-18505755

RESUMO

Hypertrophic cardiomyopathy (HCM) is a frequent genetic cardiac disease and the most common cause of sudden cardiac death in young individuals. Most of the currently known HCM disease genes encode sarcomeric proteins. Previous studies have shown an association between CSRP3 missense mutations and either dilated cardiomyopathy (DCM) or HCM, but all these studies were unable to provide comprehensive genetic evidence for a causative role of CSRP3 mutations. We used linkage analysis and identified a CSRP3 missense mutation in a large German family affected by HCM. We confirmed CSRP3 as an HCM disease gene. Furthermore, CSRP3 missense mutations segregating with HCM were identified in four other families. We used a newly designed monoclonal antibody to show that muscle LIM protein (MLP), the protein encoded by CSRP3, is mainly a cytosolic component of cardiomyocytes and not tightly anchored to sarcomeric structures. Our functional data from both in vitro and in vivo analyses suggest that at least one of MLP's mutated forms seems to be destabilized in the heart of HCM patients harbouring a CSRP3 missense mutation. We also present evidence for mild skeletal muscle disease in affected persons. Our results support the view that HCM is not exclusively a sarcomeric disease and also suggest that impaired mechano-sensory stress signalling might be involved in the pathogenesis of HCM.


Assuntos
Cardiomiopatia Hipertrófica/genética , Proteínas Musculares/genética , Mutação de Sentido Incorreto , Sarcômeros/genética , Animais , Células COS , Cardiomiopatia Hipertrófica/metabolismo , Linhagem Celular , Chlorocebus aethiops , Feminino , Ligação Genética , Humanos , Proteínas com Domínio LIM , Masculino , Proteínas Musculares/metabolismo , Linhagem , Sarcômeros/metabolismo , População Branca/genética
7.
BMC Med Imaging ; 10: 16, 2010 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-20673350

RESUMO

BACKGROUND: In magnetic resonance (MR) imaging, T1, T2 and T2* relaxation times represent characteristic tissue properties that can be quantified with the help of specific imaging strategies. While there are basic software tools for specific pulse sequences, until now there is no universal software program available to automate pixel-wise mapping of relaxation times from various types of images or MR systems. Such a software program would allow researchers to test and compare new imaging strategies and thus would significantly facilitate research in the area of quantitative tissue characterization. RESULTS: After defining requirements for a universal MR mapping tool, a software program named MRmap was created using a high-level graphics language. Additional features include a manual registration tool for source images with motion artifacts and a tabular DICOM viewer to examine pulse sequence parameters. MRmap was successfully tested on three different computer platforms with image data from three different MR system manufacturers and five different sorts of pulse sequences: multi-image inversion recovery T1; Look-Locker/TOMROP T1; modified Look-Locker (MOLLI) T1; single-echo T2/T2*; and multi-echo T2/T2*. Computing times varied between 2 and 113 seconds. Estimates of relaxation times compared favorably to those obtained from non-automated curve fitting. Completed maps were exported in DICOM format and could be read in standard software packages used for analysis of clinical and research MR data. CONCLUSIONS: MRmap is a flexible cross-platform research tool that enables accurate mapping of relaxation times from various pulse sequences. The software allows researchers to optimize quantitative MR strategies in a manufacturer-independent fashion. The program and its source code were made available as open-source software on the internet.


Assuntos
Algoritmos , Aumento da Imagem/métodos , Interpretação de Imagem Assistida por Computador/métodos , Imageamento por Ressonância Magnética/métodos , Software , Humanos , Linguagens de Programação , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
8.
Basic Res Cardiol ; 104(1): 90-9, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18795223

RESUMO

The familial form of dilated cardiomyopathy (DCM) occurs in about 20%-50% of DCM cases. It is a heterogeneous genetic disease: mutations in more than 20 different genes have been shown to cause familial DCM. LMNA, encoding the nuclear membrane protein lamin A/C, is one of the most important disease gene for that disease. Therefore, we analyzed the LMNA gene in a large cohort of 73 patients with familial DCM. Clinical examination (ECG, echocardiography, and catheterization) was followed by genetic characterization of LMNA by direct sequencing. We detected five heterozygous missense mutations (prevalence 7%) in five different families characterized by severe DCM and heart failure with conduction system disease necessitating pacemaker implantation and heart transplantation. Four of these variants clustered in the protein domain coil 1B, which is important for lamin B interaction and lamin A/C dimerization. Although we identified two novel mutations (E203V, K219T) besides three known ones (E161K, R190Q, R644C), it was remarkable that four mutations represent LMNA hot spots. DCM patients with LMNA mutations show a notable homogenous severe phenotype as we could confirm in our study. Testing LMNA in such families seems to be recommended because genotype information in an individual could definitely be useful for the clinician.


Assuntos
Cardiomiopatia Dilatada/genética , Lamina Tipo A/genética , Mutação , Estudos de Coortes , DNA/genética , DNA/isolamento & purificação , Primers do DNA , Éxons , Feminino , Humanos , Linfócitos/fisiologia , Masculino , Linhagem , Reação em Cadeia da Polimerase , Polimorfismo de Nucleotídeo Único
9.
Catheter Cardiovasc Interv ; 73(3): 361-6, 2009 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-19133676

RESUMO

OBJECTIVES: The aim of the study was to evaluate safety, efficacy, and long-term clinical outcome of percutaneous closure of patent foramen ovale (PFO closure) in a low volume center using the Amplatzer PFO occluder without echocardiographic guidance. BACKGROUND: Most centers perform PFO closure either by transesophageal echocardiography (TEE) or intracardiac echocardiography (ICE) guidance for optimal device selection. As TEE is poorly tolerated by patients in supine position and ICE is a costly alternative that increases vascular access complications, we wanted to assess the safety and efficacy of PFO closure by fluoroscopic guidance only. METHODS: Before PFO closure, all patients had a diagnostic contrast-TEE and morphological classification of PFO. All PFO closures were performed using the 25-mm Amplatzer PFO occluder with fluoroscopic guidance only. Intraprocedural echocardiography was replaced by right atrial opacification using contrast angiography. Contrast TEE was done after 6 weeks, contrast TTE after 3, 6, and 12 months postprocedural. RESULTS: In all 92 patients (52.4 +/- 1.5 years), a 25-mm Amplatzer PFO occluder was implanted in the correct position. Total fluoroscopic time was 8.4 +/- 0.6 minutes and the application of contrast medium was 122.5 +/- 5.8 mL. By contrast-TEE, 12 patients (13 %) showed a small residual shunt (grade 1). During follow-up (2.09 +/- 0.13 years) two patients (2.1%) suffered from a recurrent event (TIA in both cases). CONCLUSIONS: Percutaneous closure of PFO using the 25-mm Amplatzer PFO occluder guided by fluoroscopy only is a safe and efficacious intervention for nearly all patients.


Assuntos
Cateterismo Cardíaco , Ecocardiografia , Forame Oval Patente/terapia , Ultrassonografia de Intervenção , Feminino , Forame Oval Patente/diagnóstico por imagem , Humanos , Masculino , Pessoa de Meia-Idade , Implantação de Prótese , Resultado do Tratamento
10.
Circ Res ; 100(1): 50-60, 2007 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-17158337

RESUMO

Statins are widely used clinical drugs that exert beneficial growth-suppressive effects in patients with cardiac hypertrophy. We investigated the role of the cell cycle inhibitor p21(CIP1/WAF1) (p21) in statin-dependent inhibition of hypertrophic growth in postmitotic cardiomyocytes. We demonstrate that lovastatin fails to inhibit cardiac hypertrophy to angiotensin II in p21(-/-) mice and that reconstitution of p21 function by TAT.p21 protein transduction can rescue statin action in these otherwise normally developed animals. Lovastatin specifically recruits the forkhead box FoxO3a transcription factor to the p21 promoter, mediating transcriptional transactivation of the p21 gene as analyzed in isolated primary cardiomyocytes. Lovastatin also stimulates protein kinase B/Akt kinase activity, and Akt-dependent phosphorylation forces p21 in the cytoplasm, where it inhibits Rho-kinases contributing to the suppression of cardiomyocyte hypertrophy. Loss of p21 or FoxO3a by RNA interference causes a general inhibition of lovastatin signal transduction. These results suggest that p21 functions as FoxO3a downstream target to mediate an statin-derived anti-hypertrophic response. Taken together, our genetic and biochemical data delineate an essential function of p21 for statin-dependent inhibition of cardiac myocyte hypertrophy.


Assuntos
Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Inibidores de Hidroximetilglutaril-CoA Redutases/metabolismo , Miócitos Cardíacos/metabolismo , Transdução de Sinais , Animais , Células Cultivadas , Inibidor de Quinase Dependente de Ciclina p21/deficiência , Inibidor de Quinase Dependente de Ciclina p21/genética , Citoplasma/metabolismo , Proteína Forkhead Box O3 , Fatores de Transcrição Forkhead/antagonistas & inibidores , Fatores de Transcrição Forkhead/efeitos dos fármacos , Fatores de Transcrição Forkhead/fisiologia , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Hipertrofia/prevenção & controle , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Lovastatina/antagonistas & inibidores , Lovastatina/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Fosforilação/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/fisiologia , Interferência de RNA , Ratos , Transcrição Gênica/fisiologia , Quinases Associadas a rho
11.
Circ Res ; 101(3): 268-76, 2007 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-17585070

RESUMO

Nuclear factor kappa B (NF-kappaB) participates in hypertension-induced vascular and target-organ damage. We tested whether or not endothelial cell-specific NF-kappaB suppression would be ameliorative. We generated Cre/lox transgenic mice with endothelial cell-restricted NF-kappaB super-repressor IkappaBalphaDeltaN (Tie-1-DeltaN mice) overexpression. We confirmed cell-specific IkappaBalphaDeltaN expression and reduced NF-kappaB activity after TNF-alpha stimulation in primary endothelial cell culture. To induce hypertension with target-organ damage, we fed mice a high-salt diet and N(omega)-nitro-l-arginine-methyl-ester (L-NAME) and infused angiotensin (Ang) II. This treatment caused a 40-mm Hg blood pressure increase in both Tie-1-DeltaN and control mice. In contrast to control mice, Tie-1-DeltaN mice developed a milder renal injury, reduced inflammation, and less albuminuria. RT-PCR showed significantly reduced expression of the NF-kappaB targets VCAM-1 and ICAM-1, compared with control mice. Thus, the data demonstrate a causal link between endothelial NF-kappaB activation and hypertension-induced renal damage. We conclude that in vivo NF-kappaB suppression in endothelial cells stops a signaling cascade leading to reduced hypertension-induced renal damage despite high blood pressure.


Assuntos
Células Endoteliais/metabolismo , Hipertensão/complicações , Nefropatias/prevenção & controle , NF-kappa B/antagonistas & inibidores , Albuminúria/etiologia , Albuminúria/prevenção & controle , Angiotensina II/toxicidade , Animais , Aterosclerose/fisiopatologia , Células Cultivadas , Regulação da Expressão Gênica , Humanos , Hipertensão/metabolismo , Proteínas I-kappa B/genética , Proteínas I-kappa B/fisiologia , Inflamação/fisiopatologia , Molécula 1 de Adesão Intercelular/biossíntese , Molécula 1 de Adesão Intercelular/genética , Nefropatias/etiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Modelos Cardiovasculares , Inibidor de NF-kappaB alfa , NF-kappa B/fisiologia , NG-Nitroarginina Metil Éster/toxicidade , Nefrite/prevenção & controle , Óxido Nítrico/fisiologia , Óxido Nítrico Sintase Tipo III/antagonistas & inibidores , Especificidade de Órgãos , Receptor de TIE-1/fisiologia , Proteínas Recombinantes de Fusão/fisiologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais , Cloreto de Sódio na Dieta/toxicidade , Fator de Necrose Tumoral alfa/biossíntese , Fator de Necrose Tumoral alfa/genética , Molécula 1 de Adesão de Célula Vascular/biossíntese , Molécula 1 de Adesão de Célula Vascular/genética
12.
Circ Res ; 100(9): 1353-62, 2007 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-17413044

RESUMO

The armadillo-related protein beta-catenin has multiple functions in cardiac tissue homeostasis: stabilization of beta-catenin has been implicated in adult cardiac hypertrophy, and downregulation initiates heart formation in embryogenesis. The protein is also part of the cadherin/catenin complex at the cell membrane, where depletion might result in disturbed cell-cell interaction similar to N-cadherin knockout models. Here, we analyzed the in vivo role of beta-catenin in adult cardiac hypertrophy initiated by angiotensin II (Ang II). The cardiac-specific mifepristone-inducible alphaMHC-CrePR1 transgene was used to induce beta-catenin depletion (loxP-flanked exons 3 to 6, beta-cat(Deltaex3-6) mice) or stabilization (loxP-flanked exon 3, beta-cat(Deltaex3) mice). Levels of beta-catenin were altered both in membrane and nuclear extracts. Analysis of the beta-catenin target genes Axin2 and Tcf-4 confirmed increased beta-catenin-dependent transcription in beta-catenin stabilized mice. In both models, transgenic mice were viable and healthy at age 6 months. beta-Catenin appeared dispensable for cell membrane function. Ang II infusion induced cardiac hypertrophy both in wild-type mice and in mice with beta-catenin depletion. In contrast, mice with stabilized beta-catenin had decreased cross-sectional area at baseline and an abrogated hypertrophic response to Ang II infusion. Stabilizing beta-catenin led to impaired fractional shortening compared with control littermates after Ang II stimulation. This functional deterioration was associated with altered expression of the T-box proteins Tbx5 and Tbx20 at baseline and after Ang II stimulation. In addition, atrophy-related protein IGFBP5 was upregulated in beta-catenin-stabilized mice. These data suggest that beta-catenin downregulation is required for adaptive cardiac hypertrophy.


Assuntos
Remodelação Ventricular , beta Catenina/fisiologia , Angiotensina II/farmacologia , Animais , Cardiomegalia/etiologia , Regulação da Expressão Gênica , Proteína 5 de Ligação a Fator de Crescimento Semelhante à Insulina/genética , Camundongos , Camundongos Endogâmicos C57BL , Proteínas com Domínio T/genética , beta Catenina/antagonistas & inibidores , beta Catenina/genética
13.
Europace ; 11(7): 924-30, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19447808

RESUMO

AIMS: Data from previous defibrillator studies raised concern about right ventricular pacing (RVP) promoting heart failure progression and mortality in implantable cardioverter/defibrillator (ICD) patients. The present observational study re-examined the association of RVP, survival, and ventricular tachyarrhythmias/ventricular fibrillation (VT/VF) in routine ICD patients with restrictively programmed pacing. METHODS AND RESULTS: In 213 ICD patients [183 men, left ventricular ejection fraction (LVEF) 37 +/- 15%, follow-up 37 +/- 18 months, no advanced atrioventricular (AV) block], the RVP proportion, survival, and the time to a first appropriate VT/VF episode were assessed. Electrograms were validated and the overall survival was determined. The RVP prevalence was dichotomized at > or = 30% (high RVP) vs. <30% (low RVP). High RVP (RVP 94%, n = 24) and low RVP (RVP 0%, n = 189) patients had similar LVEF, underlying heart disease, ICD indication, and medication. Multivariate Cox regression showed no difference in survival without appropriate VT/VF treatment [odds ratio (OR): 0.92, 95% confidence interval (CI): 0.41-2.04, P = 0.83]. Overall survival was significantly more favourable in low RVP patients (OR: 0.34, CI: 0.13-0.91, P = 0.03). CONCLUSION: Frequent RVP is associated with impaired survival in ICD patients despite conservative pacing settings. Implantable cardioverter/defibrillator patients requiring concomitant bradycardia pacing should be cared for with particular attention to clinical worsening. Right ventricular pacing prevention and alternative modalities of ventricular pacing need prospective evaluation.


Assuntos
Desfibriladores Implantáveis/estatística & dados numéricos , Cardioversão Elétrica/mortalidade , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/prevenção & controle , Disfunção Ventricular Direita/mortalidade , Disfunção Ventricular Direita/prevenção & controle , Feminino , Alemanha/epidemiologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Medição de Risco/métodos , Fatores de Risco , Análise de Sobrevida , Taxa de Sobrevida , Taquicardia Ventricular , Resultado do Tratamento
14.
Pacing Clin Electrophysiol ; 32 Suppl 1: S16-20, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19250084

RESUMO

BACKGROUND: Implantable cardioverter-defibrillators (ICD) implanted after an episode of ventricular tachyarrhythmia (VTA) or in patients at high risk of VTA lower the long-term mortality. Comparisons of the clinical outcomes of the two indications are scarce. METHODS: The study enrolled 360 consecutive ICD recipients. The device was implanted for secondary prevention in 150 patients, whose mean age was 60 +/- 14 years, and mean left ventricular ejection fraction (LVEF) was 40 +/- 16%, and for primary prevention in 210 patients, whose mean age was 61 +/- 11 years, and mean LVEF was 31 +/- 13%. All-cause mortality and time to first appropriate ICD therapy were measured. RESULTS: The two study groups were similar with respect to age and prevalence of coronary artery disease. Mean LVEF was higher in the secondary prevention group (P = 0.001). Cox regression analysis revealed a significantly shorter time to first appropriate ICD therapy in the secondary prevention group (HR = 0.51, 95% CI = 0.30 - 0.87, P = 0.01). Over a mean follow-up of 37 +/- 19 months, the all-cause mortality in the overall population was 12.7%, and was similar in both subgroups (HR = 0.99, 95% CI = 0.55-1.77, P = 0.97). CONCLUSIONS: The long-term mortality in this unselected population of ICD recipients was low. Patients treated for secondary prevention received earlier appropriate ICD therapy than patients treated for primary prevention. Long-term mortality was similar in both groups. The higher VT incidence of VTA was effectively treated by the ICD and was not associated with a higher mortality.


Assuntos
Morte Súbita Cardíaca/epidemiologia , Morte Súbita Cardíaca/prevenção & controle , Desfibriladores Implantáveis/estatística & dados numéricos , Cardioversão Elétrica/mortalidade , Medição de Risco/métodos , Taquicardia Ventricular/mortalidade , Taquicardia Ventricular/prevenção & controle , Comorbidade , Cardioversão Elétrica/instrumentação , Feminino , Alemanha/epidemiologia , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Prevalência , Fatores de Risco , Análise de Sobrevida , Taxa de Sobrevida , Resultado do Tratamento
15.
Pacing Clin Electrophysiol ; 32(5): 604-13, 2009 May.
Artigo em Inglês | MEDLINE | ID: mdl-19422581

RESUMO

BACKGROUND: Most patients with symptomatic sinus node disease (SND) receive DDDR pacemakers (PM) in order to cover SND and atrioventricular (AV) block from the outset. But the concern about adverse effects of right ventricular pacing (RVP) is increasing. So far, data on the incidence of AV block in SND are based on clinical events. The study undertakes to assess and appraise AV block and atrial tachyarrhythmias (AT) from memory and electrograms of a dual-chamber PM set to an AAIR-DDDR switch mode (AAISafeR). METHODS: A dual-chamber PM incorporating the AAISafeR mode was implanted in 58 patients (70 +/- 10 years, 28 males) with SND, but without AV block >I. AV block and AT episodes were retrieved from the PM memory and validated from electrograms. AV block episodes were classified potentially relevant while comprising AV block III or AV block I/II during exercise. RESULTS: The patients experienced a median of 90 (interquartile range 7-1,084) commutations. Possibly relevant AV block occurred in 32 patients (55%). Validation revealed high-quality PM-based categorization. The RVP prevalence was 0% (0-16%). The median AT prevalence was 0.03 (0-26) min/day. RVP was the only multivariate predictor of AT (P = 0.001). CONCLUSIONS: Potentially relevant AV block occurs frequently in patients with SND. Nonetheless, the RVP prevalence is kept low through the AAISafeR mode. The protection of SND patients with demand-actuated ventricular pacing appears reasonable. The AT prevalence is low in SND patients treated by the AAISafeR mode. Even low RVP proportions appear to favor AT. Prospective evaluation is needed.


Assuntos
Bloqueio Atrioventricular/complicações , Bloqueio Atrioventricular/diagnóstico , Diagnóstico por Computador/métodos , Eletrocardiografia/métodos , Marca-Passo Artificial , Síndrome do Nó Sinusal/complicações , Síndrome do Nó Sinusal/diagnóstico , Idoso , Feminino , Alemanha , Humanos , Masculino , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
16.
Am Heart J ; 155(5): 890-5, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-18440338

RESUMO

BACKGROUND: Effectiveness, safety, and other factors associated with success of cardioversion (CV) of atrial fibrillation (AF) have not yet been evaluated in patients with reduced left ventricular ejection fraction. We studied 148 consecutive patients with left ventricular dysfunction (ejection fraction < or = 45%), who underwent electrical CV for AF in our department. The patients had New York Heart Association heart failure ranging from class II to IV. The overall CV success rate was 71%. We relied on univariate and multivariate regression and sought variables influencing success rate. Conversion success did not correlate with New York Heart Association class. Instead, we found that the greatest predictor was the degree of heart failure treatment. Patients receiving beta-blockers, angiotensin-converting enzyme inhibitors or angiotension receptor blockers, plus mineralocorticoid receptor blockers had the greatest chance for conversion success. Success was more likely in patients with coronary artery disease (91%) than in patients with nonischemic cardiomyopathy. CONCLUSIONS: Cardioversion is a safe and effective method for the restoration of sinus rhythm in patients with AF and reduced left ventricular ejection fraction. Our findings underscore the value of aggressive heart failure treatment before CV in patients with AF.


Assuntos
Fibrilação Atrial/etiologia , Fibrilação Atrial/terapia , Cardioversão Elétrica , Insuficiência Cardíaca/tratamento farmacológico , Disfunção Ventricular Esquerda/complicações , Antagonistas Adrenérgicos beta/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Volume Sistólico , Resultado do Tratamento , Disfunção Ventricular Esquerda/tratamento farmacológico
17.
Mol Genet Metab ; 95(1-2): 74-80, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18678517

RESUMO

Familial Dilated Cardiomyopathy (FDCM) is caused by mutations in genes encoding myocardial force transduction proteins. Desmoglein-2 (DSG2) and Desmocollin-2 (DSC2) provide cellular adhesion and force transduction by cell-to-cell anchorage. To test whether perturbations of DSG2 or DSC2 exhibit a pathogenic impact on DCM pathogenesis, we sequenced both genes in 73 patients with FDCM and assessed prevalence of missense variations in matched control cohorts. We detected two missense variations in DSG2 (V55M and V919G) which were absent in 360 control alleles. Surprisingly, both variants were previously reported in patients with arrhythmogenic right ventricular cardiomyopathy. Yet, in the present study only the DSG2-V55M variant showed segregation with DCM in a family pedigree. Subsequent, analysis of 538 patients with idiopathic DCM and 617 consecutive control individuals resulted in identification of thirteen DSG2-V55M carriers with DCM, whereas only three control subjects harbored the variant. DSG2 immunostaining revealed pale structures of the intercalated disc in myocardium of one unique homozygous DSG2-V55M carrier. Furthermore, myocardial desmosomal structures were significantly shortened when compared to DCM myocardium negative for DSG2-V55M. Thus, our study identified the DSG2-V55M polymorphism as a novel risk variant for DCM associated with shortened desmosomes of the cardiac intercalated disc.


Assuntos
Cardiomiopatia Dilatada/genética , Desmogleína 2/genética , Predisposição Genética para Doença , Mutação de Sentido Incorreto , Adolescente , Adulto , Idoso , Sequência de Aminoácidos , Cardiomiopatia Dilatada/metabolismo , Estudos de Casos e Controles , Células Cultivadas , Criança , Pré-Escolar , Estudos de Coortes , Desmogleína 2/química , Desmogleína 2/metabolismo , Desmossomos/química , Desmossomos/metabolismo , Desmossomos/ultraestrutura , Feminino , Alemanha , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Miocárdio/química , Miocárdio/metabolismo , Miocárdio/ultraestrutura , Linhagem , Fenótipo , Alinhamento de Sequência
18.
J Card Fail ; 14(10): 856-60, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19041050

RESUMO

BACKGROUND: Cardiac involvement in Churg-Strauss vasculitis worsens the prognosis. Early detection is, therefore, warranted. Cardiac magnetic resonance (CMR) can visualize various forms of inflammatory changes in the myocardium. We tested whether CMR could elucidate cardiac damage in patients with biopsy-proven Churg-Strauss syndrome and clinical evidence of cardiac involvement. METHODS AND RESULTS: Eleven patients underwent a CMR protocol including cine imaging for left ventricular function in long axes, T2-weighted imaging for edema detection, and contrast-enhanced T1-weighting for early and late gadolinium enhancement. CMR detected various form of myocardial injury in all patients. Systolic left ventricular function was impaired in 6 patients. Mean left ventricular ejection fraction was 45 +/- 15%. Left ventricular size was mildly enlarged (left ventricular end-diastolic volume index 94 +/- 23 mL/m(2)). Edema was present in 4 cases; 7 patients had pericardial effusion. Six patients had increased early contrast uptake. CMR detected late enhancement lesions in 9 of 11 patients, even in those with normal left ventricular size and function. CONCLUSIONS: CMR has the potential to detect myocardial injury in Churg-Strauss syndrome even when left ventricular function appears normal.


Assuntos
Síndrome de Churg-Strauss/patologia , Imagem Ecoplanar/métodos , Miocárdio/patologia , Adulto , Idoso , Sistema Cardiovascular/patologia , Síndrome de Churg-Strauss/diagnóstico , Feminino , Seguimentos , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Projetos Piloto
19.
Eur J Heart Fail ; 10(11): 1149-51, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18926768

RESUMO

Peripartum cardiomyopathy (PPCM) is a potentially devastating cause of heart failure that affects women late in pregnancy or in early puerperium. Recent findings showed that a 16 kDa fragment of prolactin may induce myocardial damage, and this offered a new option of treating PPCM by blocking prolactin with bromocriptine. We report on a 35-year-old woman with a twin gravidity who gave birth to two healthy boys at day 36/6 and developed a potentially fatal PPCM. Within 3 days since delivery she suffered from severe symptoms of heart failure (orthopnoea, pleural and pericardial effusion, reduced systolic function LVEF 15%). Bromocriptine 2.5 mg bid was added to standard heart failure therapy at day 6 after delivery, and within a week the patient recovered to NYHA functional class II. 2 months later she presented in a good state, NYHA class I, and MRI confirmed an LVEF of 60%. Balancing the potential side effects of bromocriptine against the very poor prognosis in severe PPCM our case supports the use of bromocriptine as a specific novel therapy.


Assuntos
Bromocriptina/uso terapêutico , Cardiomiopatias/tratamento farmacológico , Antagonistas de Hormônios/uso terapêutico , Período Pós-Parto , Complicações Cardiovasculares na Gravidez/tratamento farmacológico , Recuperação de Função Fisiológica , Adulto , Bromocriptina/administração & dosagem , Cardiomiopatias/complicações , Feminino , Seguimentos , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/etiologia , Antagonistas de Hormônios/administração & dosagem , Humanos , Recém-Nascido , Imageamento por Ressonância Magnética , Masculino , Gravidez , Complicações Cardiovasculares na Gravidez/diagnóstico , Resultado da Gravidez
20.
Eur J Heart Fail ; 10(10): 1026-32, 2008 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-18760666

RESUMO

BACKGROUND AND AIMS: While management programmes (MPs) for chronic heart failure (CHF) are clinically effective, their cost-effectiveness remains uncertain. Thus, this study sought to determine the cost-effectiveness of MPs. METHODS AND RESULTS: We developed a Markov model to estimate life expectancy, quality-adjusted life expectancy, lifetime costs, and the incremental cost-effectiveness of MPs as compared to standard care. Standard care was defined by the EuroHeart Failure Survey for Germany, MP efficacy was derived from our recent meta-analysis and cost estimates were based on the German healthcare system. For a population with a mean age 67 years (35% female) at onset of CHF, our model predicted an average quality-adjusted life expectancy of 2.64 years for standard care and 2.83 years for MP. MP yielded additional lifetime costs of euro1700 resulting in an incremental cost-utility ratio (ICUR) of euro8900 (95% CI: dominant to 177,100) per quality-adjusted life year (QALY) gained. Sensitivity analyses demonstrated that the ICUR was sensitive to age and sex. CONCLUSION: MPs increase life expectancy in patients with CHF by an average of 84 days and increase lifetime cost of care by approximately euro1700. MPs improve outcomes in a cost-effective manner, although they are not cost-saving on a lifetime horizon.


Assuntos
Técnicas de Apoio para a Decisão , Insuficiência Cardíaca/economia , Expectativa de Vida , Avaliação de Programas e Projetos de Saúde , Anos de Vida Ajustados por Qualidade de Vida , Idoso , Doença Crônica , Feminino , Humanos , Masculino , Cadeias de Markov , Modelos Estatísticos , Desenvolvimento de Programas
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