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2.
Clin Biochem ; 2019 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-31786204

RESUMO

OBJECTIVE: To determine gender-specific reference limits of high-sensitivity (hs) cardiac troponins (cTn) and validity of hs assay designation for both genders. METHODS: After screening with a questionnaire, 827 presumably healthy individuals were further selected based on clinical criteria (n = 740), clinical criteria plus cardiac imaging including stress magnetic resonance imaging or stress echocardiography (n = 726), and extended cardio-pulmonary parameters (n = 626). Blood samples were measured with hs-cTnT (Roche Diagnostics) on a cobas e602 analyzer as well as hs-cTnI (Abbott Diagnostics) on an ARCHITECTi2000SR. The impact of health definition, statistical methods, instrument selection and limit of detection (LoD) on overall and gender-specific 99th percentiles was assessed. RESULTS: Median age was 56 years (50.9% female) for the total study cohort. 99th percentiles for females and males ranged between 13.1 and 13.3 ng/L and 16.8-19.9 ng/L for hs-cTnT as well as 10.3-12.5 ng/L and 27.4-29.7 ng/L for hs-cTnI depending on health definition. Utilization of stricter health definition criteria reduced the difference of the gender-specific 99th percentiles between males and females for hs-cTnT to 3.7 ng/L (males 16.8 ng/L, females 13.1 ng/L), whereas the difference rather increased for hs-cTnI to 19.4 ng/L (males 29.7 ng/L, females 10.3 ng/L). Values > LoD could be measured in the majority of males and females using hs-TnT (81.4-83.3% and 96.5-96.9%, respectively). In contrast, values > LoD could not be observed in the majority of females using hs-cTnI (38.4-41.1%). CONCLUSIONS: In a well-phenotyped healthy cohort, reference values for hs-cTnT were slightly higher, whereas hs-cTnI cut-offs were considerably lower than previously observed. Gender differences were more pronounced in hs-cTnI than in hs-cTnT and were further reduced for hs-cTnT by application of stricter health definition criteria. Contrary to hs-cTnI, hs-cTnT fulfilled criteria for hs designation for both genders.

3.
Clin Res Cardiol ; 108(4): 411-429, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30203190

RESUMO

BACKGROUND: Cardiovascular magnetic resonance (CMR) is the gold standard for the quantitative assessment of cardiac volumes, mass and function. There are, however, various strategies for establishing endocardial borders, the cardiac phase used for measurements and the body dimensions used for indexing these results. The aim of the study was to assess the impact of different strategies on reference values. METHODS AND RESULTS: 362 healthy volunteers (190 men, mean age 51 ± 13 years) underwent a standard CMR protocol. Left ventricular end-diastolic (LV-EDV) and end-systolic (LV-ESV) volumes and LV mass (LV-M) were measured at end systole and end diastole in SSFP sequences using two methods, one of which included papillary muscles and trabecular tissue in the LV-M ("include" approach), while the other excluded this tissue ("exclude" approach). There was a strong correlation between the results for LV volumes and LV ejection fraction (LV-EF) between the "include" and the "exclude" approach, while the mean values were different: LV-EDV: 149.7 ± 32.5 ml vs 160.5 ± 35.0 ml, p < 0.0001; LV-ESV: 48.7 ± 14.5 ml vs 56.4 ± 16.7 ml, p < 0.0001; LV-EF: 67.7 ± 5.4% vs 65.1 ± 5.6%, p < 0.0001. When comparing end-systolic with end-diastolic data, values for LV-M were significantly higher in end systole irrespective of whether papillary muscles and trabecular tissues were included or not. Furthermore, LV-M missed overweight-induced LV hypertrophy when indexed to body surface area (BSA) instead of height. CONCLUSION: Quantitative assessment of LV volumes and mass with inclusion of papillary muscles and trabeculae to myocardial mass resulted in significantly different values, while indexing to BSA and not height may miss LV hypertrophy in terms of overweight.


Assuntos
Volume Cardíaco/fisiologia , Ventrículos do Coração/diagnóstico por imagem , Imagem Cinética por Ressonância Magnética/métodos , Função Ventricular Esquerda/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Curva ROC , Reprodutibilidade dos Testes , Adulto Jovem
4.
Clin Res Cardiol ; 108(2): 194-202, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30083858

RESUMO

PURPOSE: Calcification of aortic valve and mitral annulus is associated with cardiovascular risk factors, morbidity and mortality. Assessment of cardiac calcification with echocardiography is feasible, however, only few structured scoring systems have been established so far with limited prognostic data. This study aimed to evaluate an echocardiographic calcification score (echo-CCS) in patients with low/intermediate cardiovascular risk. METHODS: Digitally stored echocardiography studies of 151 patients (median age 64, 49.7% male) from February 2008 to December 2009 were retrospectively reviewed for calcifications of the aortic valve, aortic root, mitral annulus, papillary muscles and ventricular septum. A calcification score ranging from 0 to 5 was assigned to every patient and its relation to computed tomography calcium score, coronary stenosis and ESC SCORE was assessed. Follow-up data were collected from 149 patients (98.7%) with a median of 6.2 years. Logistic regression and Kaplan-Meier analysis were performed to assess the association of the echo-CCS with significant coronary artery disease (≥ 50% stenosis) and risk for cardiac events and all-cause mortality. RESULTS: An association of the echo-CCS with the ESC SCORE (ρ = 0.5; p < 0.001) and a good correlation of the echo-CCS with the Agatston score (ρ = 0.73; p < 0.001) can be observed. Univariate regressions revealed that echo-CCS is a significant predictor for cardiac events [OR = 5.1 (CI: 1.7-15.0); p = 0.003], coronary intervention [OR = 2.8 (CI: 1.3-5.7); p = 0.006], hospitalisation for cardiac symptoms [OR = 2.0 (CI: 1.2-3.4); p = 0.007], all-cause mortality [OR = 2.6 (CI: 1.3-5.5); p = 0.01] and significant CAD [OR = 3.2 (CI: 1.9-5.4); p < 0.001]. CONCLUSIONS: We demonstrated the prevalence of an easily obtainable, radiation-free calcification score in patients with low/intermediate cardiovascular risk. The strong association with CT-calcium scoring may evoke its potential as an alternative method in CV risk assessment.


Assuntos
Calcinose/diagnóstico , Doenças Cardiovasculares/diagnóstico , Vasos Coronários/diagnóstico por imagem , Ecocardiografia/métodos , Valvas Cardíacas/diagnóstico por imagem , Medição de Risco , Calcinose/epidemiologia , Doenças Cardiovasculares/epidemiologia , Causas de Morte/tendências , Estudos de Viabilidade , Feminino , Alemanha/epidemiologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de Doença
5.
Open Heart ; 5(1): e000717, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29531760

RESUMO

Background: Myocardial T1 and extracellular volume (ECV) derived from cardiovascular MRIs are more and more widely accepted as important markers for diagnosis, risk prediction and monitoring of cardiac disease. Yet data regarding long-term stability of myocardial T1 mapping are lacking. The aim of this study was to investigate the long-term stability of native and postcontrast T1 mapping values in healthy volunteers. Methods: 18 strictly selected healthy volunteers (52±10 years, 12 men) were studied on a Philips Achieva 1.5 Tesla scanner. T1 relaxation times were measured before and 15 min after a bolus contrast injection of gadolinium diethylenetriamine penta-acetic acid (DTPA) (0.2 mmol/kg) using a single-breath-hold modified Look-Locker inversion recovery 3(3)3(3)5 sequence. ECV was calculated using native and postcontrast T1 times of myocardium and blood correcting for blood haematocrit. Exams were repeated 3.6±0.5 years later under the same conditions and using the same scan protocols. Results: Cardiac biomarkers (high-sensitivity troponin T and N terminal pro-brain natriuretic peptide) remained unchanged, as well as left ventricular mass, and global and longitudinal function. No significant change occurred regarding native T1 times (1017±24 ms vs 1015±21 ms; P=0.6), postcontrast T1 times (426±38 ms vs 413±20 ms; P=0.13) or ECV (22%±2% vs 23%±2%; P=0.3). Native T1 time and ECV appeared to be better reproducible than postcontrast T1, resulting in lower coefficients of variation (ECV: 3.5%, native T1: 1.3%, postcontrast T1: 6.4%) and smaller limits of agreement (ECV: 2%/-2%, native T1: 39 ms/-35 ms, postcontrast T1: 85 ms/-59 ms). Conclusions: During long-term follow-up, native T1 and ECV values are very robust markers, whereas postcontrast T1 results appear less stable.

6.
J Cardiovasc Magn Reson ; 19(1): 87, 2017 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-29121956

RESUMO

BACKGROUND: To compare the prognostic value of cardiac valve plane displacement (CVPD) on various locations in cardiac light chain (AL) amyloidosis. METHODS: Consecutive patients with biopsy-proven cardiac involvement in AL amyloidosis who had undergone cardiovascular magnetic resonance (CMR) between 2005 and 2014 in our institution, were retrospectively identified and data analyzed. The primary combined endpoint was all-cause mortality or heart transplantation. Systolic CVPD were obtained from standard cine bSSFP in 2-, 3- and 4-chamber views at anterior aortic plane systolic excursion (AAPSE); anterior, anterolateral, inferolateral, inferior, inferoseptal mitral (MAPSE); and lateral tricuspid (TAPSE) annular segments. RESULTS: We identified 68 patients (58 ± 10 years; 59% male). Median follow-up period was 1.2 years (IQR, 0.3-4.1). Significant differences in CVPD between patients who reached a primary endpoint (n = 44) and transplant-free survivors were found only for AAPSE (6.1 mm (IQR, 4.6-9.4) vs. 8.8 mm (IQR, 6.9-10.4); p = 0.02) and MAPSEanterolateral (7.3 mm (IQR, 5.4-11.7) vs. 10.5 mm (IQR, 8.1-13.4); p = 0.03). AAPSE (χ2 = 15.6; p = 0.0002) provided the best predictive value for transplant-free survival compared to all other valvular plane locations. A high-risk cutoff (AAPSE ≤ 7.6 mm) was calculated by ROC analysis to predict all-cause death or heart transplantation within 6 months from index examination (AUC = 0.80; CI: 0.68 to 0.89; p < 0.0001). AAPSE added incremental prognostic power to an imaging prediction model of late gadolinium enhancement and global longitudinal strain (GLS) (∆χ2 = 5.8, p = 0.02) as well as to a clinical model including Karnofsky index and NT-proBNP (∆χ2 = 6.2, p = 0.01). CONCLUSION: In patients with cardiac involvement in AL amyloidosis, systolic CVPD obtained from standard long axis cine views appear to indicate outcome better, when obtained in the anterior aortic plane (AAPSE) and provide incremental prognostic value to LGE and strain measurements.


Assuntos
Cardiomiopatias/diagnóstico por imagem , Amiloidose de Cadeia Leve de Imunoglobulina/diagnóstico por imagem , Imagem por Ressonância Magnética , Contração Miocárdica , Função Ventricular Esquerda , Idoso , Área Sob a Curva , Biópsia , Cardiomiopatias/mortalidade , Cardiomiopatias/fisiopatologia , Cardiomiopatias/cirurgia , Distribuição de Qui-Quadrado , Feminino , Alemanha , Transplante de Coração , Humanos , Amiloidose de Cadeia Leve de Imunoglobulina/mortalidade , Amiloidose de Cadeia Leve de Imunoglobulina/fisiopatologia , Amiloidose de Cadeia Leve de Imunoglobulina/cirurgia , Estimativa de Kaplan-Meier , Avaliação de Estado de Karnofsky , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Valor Preditivo dos Testes , Prognóstico , Modelos de Riscos Proporcionais , Curva ROC , Reprodutibilidade dos Testes , Estudos Retrospectivos , Fatores de Tempo
7.
Eur Heart J Cardiovasc Imaging ; 18(12): 1414-1422, 2017 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-28165128

RESUMO

Aims: Left ventricular hypertrophy (LVH) has strong prognostic implications and is associated with heart failure. Recently, myocardial contraction fraction (MCF) was identified as a useful marker for specifically identifying cardiac amyloidosis (CA). The purpose of this study was to evaluate the diagnostic accuracy of MCF for the discrimination of different forms of LVH. Methods and results: We analysed cardiovascular magnetic resonance (CMR) scans of patients with CA (n = 132), hypertrophic cardiomyopathy (HCM, n = 60), hypertensive heart disease (HHD, n = 38) and in 100 age- and gender-matched healthy controls. MCF was calculated by dividing left ventricular (LV) stroke volume by LV myocardial volume. The diagnostic accuracy of MCF was compared to that of LV ejection fraction (EF) and the mass index (MI). Compared with controls (136.3 ± 24.4%, P < 0.05), mean values for MCF were significantly reduced in LVH (HHD:92.6 ± 20%, HCM:80 ± 20.3%, transthyretin CA:74.9 ± 32.2% and light-chain (AL) CA:50.5 ± 21.4%). MCF performed better than LVEF (AUC = 0.96 vs. AUC = 0.6, P < 0.001) and was comparable to LVMI (AUC = 0.95, P = 0.4) in discriminating LVH from controls. There was a significant yet weak correlation between MCF and LVEF (r = 0.43, P < 0.0001). MCF outperformed LVEF and LVMI in discriminating between different etiologies of LVH and between AL and other forms of LVH (AUC = 0.84, P < 0.0001). Moreover, cut-off values for MCF <50% and LVEF <60% allowed to identify patients with high probability for CA. Conclusion: In patients with heart failure MCF discriminates CA from other forms of LVH. As it can easily be derived from standard, non-contrast cine images, it may be a very useful marker in the diagnostic workup of patients with LVH.


Assuntos
Insuficiência Cardíaca/diagnóstico por imagem , Hipertensão/diagnóstico por imagem , Hipertrofia Ventricular Esquerda/diagnóstico por imagem , Imagem Cinética por Ressonância Magnética/métodos , Contração Miocárdica/fisiologia , Fatores Etários , Amiloidose/diagnóstico por imagem , Amiloidose/epidemiologia , Amiloidose/fisiopatologia , Área Sob a Curva , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Diagnóstico Diferencial , Feminino , Insuficiência Cardíaca/epidemiologia , Insuficiência Cardíaca/fisiopatologia , Hospitais Universitários , Humanos , Hipertensão/epidemiologia , Hipertensão/fisiopatologia , Hipertrofia Ventricular Esquerda/epidemiologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Masculino , Prognóstico , Curva ROC , Valores de Referência , Estudos Retrospectivos , Medição de Risco , Sensibilidade e Especificidade , Índice de Gravidade de Doença , Fatores Sexuais , Volume Sistólico/fisiologia
8.
Clin Res Cardiol ; 106(7): 485-492, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28168514

RESUMO

BACKGROUND: The usage of coronary CT angiography (CTA) is appropriate in patients with acute or chronic chest pain; however the diagnostic accuracy may be challenged with increased Agatston score (AS), increased heart rate, arrhythmia and severe obesity. Thus, we aim to determine the potential of the recently introduced third-generation dual-source CT (DSCT) for CTA in a 'real-life' clinical setting. METHODS: Two hundred and sixty-eight consecutive patients (age: 67 ± 10 years; BMI: 27 ± 5 kg/m²; 61% male) undergoing clinically indicated CTA with DSCT were included in the retrospective single-center analysis. A contrast-enhanced volume dataset was acquired in sequential (SSM) (n = 151) or helical scan mode (HSM) (n = 117). Coronary segments were classified in diagnostic or non-diagnostic image quality. A subset underwent invasive angiography to determine the diagnostic accuracy of CTA. RESULTS: SSM (96.8 ± 6%) and HSM (97.5 ± 8%) provided no significant differences in the overall diagnostic image quality. However, AS had significant influence on diagnostic image quality exclusively in SSM (B = 0.003; p = 0.0001), but not in HSM. Diagnostic image quality significantly decreased in SSM in patients with AS ≥2,000 (p = 0.03). SSM (sensitivity: 93.9%; specificity: 96.7%; PPV: 88.6%; NPV: 98.3%) and HSM (sensitivity: 97.4%; specificity: 94.3%; PPV: 86.0%; NPV: 99.0%) provided comparable diagnostic accuracy (p = n.s.). SSM yielded significantly lower radiation doses as compared to HSM (2.1 ± 2.0 vs. 5.1 ± 3.3 mSv; p = 0.0001) in age and BMI-matched cohorts. CONCLUSION: SSM in third-generation DSCT enables significant dose savings and provides robust diagnostic image quality in patients with AS ≤2000 independent of heart rate, heart rhythm or obesity.


Assuntos
Angiografia por Tomografia Computadorizada/métodos , Angiografia Coronária/métodos , Estenose Coronária/diagnóstico , Vasos Coronários/diagnóstico por imagem , Tomografia Computadorizada Multidetectores/métodos , Idoso , Feminino , Seguimentos , Humanos , Masculino , Doses de Radiação , Reprodutibilidade dos Testes , Estudos Retrospectivos
9.
Int J Cardiovasc Imaging ; 33(5): 721-729, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28110433

RESUMO

Cardiac valve plane displacement (CVPD) reflects longitudinal LV function. The purpose of the present study was to determine regional heterogeneity of CVPD in healthy adults to provide normal values by cardiac magnetic resonance (CMR). We measured the anterior aortic plane systolic excursion (AAPSE); the anterior, anterolateral, inferolateral, inferior, and inferoseptal mitral annular plane systolic excursion (MAPSE); and the lateral tricuspid annulus plane systolic excursion (TAPSE). Systolic excursion was measured as the distance from peak end-diastolic to peak end-sysstolic annular position (peak-to-peak) in cine images acquired in 2-, 3- and 4-chamber views. Echocardiographic measurements of CVPD were performed in M-Mode as previously described. We retrospectively analyzed 209 healthy Caucasians (57% men), who participated in the Heidelberg normal cohort between March 2009 and September 2014. The analysis was possible in all participants. Mean values were: AAPSE = 14 ± 3 mm (8-20); MAPSEanterior = 14 ± 3 mm (8-20); MAPSEanterolateral = 16 ± 3 mm (10-22); MAPSEinferolateral = 16 ± 3 mm (10-22); MAPSEinferior = 17 ± 3 mm (11-23); MAPSEinferoseptal = 13 ± 3 mm (7-19) and TAPSE = 26 ± 4 mm (18-34) respectively. MAPSE was significantly elevated in lateral compared to septal regions (p = 0.0001). Sex-differences for CVPD were not found. Age-dependency of CVPD revealed distinct regional differences. AAPSE decreased the most with age (B=-0.48; p = 0.0001), whereas MAPSEinferior was the least age-dependent site (B=-0.17; p = 0.01). AAPSE revealed favorable intra-/interobserver reproducibility and interstudy agreement. Intermethod-comparison of CMR and M-Mode echocardiography showed good agreement between both measurements of CVPD. Age-stratified normal values of regional CVPD are provided. AAPSE revealed the most pronounced age-related decrease and provided favorable reproducibility compared to other regions of cardiac valve plane.


Assuntos
Valva Aórtica/diagnóstico por imagem , Imagem Cinética por Ressonância Magnética , Valva Mitral/diagnóstico por imagem , Valva Tricúspide/diagnóstico por imagem , Função Ventricular Esquerda , Adulto , Distribuição por Idade , Valva Aórtica/fisiologia , Ecocardiografia , Grupo com Ancestrais do Continente Europeu , Feminino , Alemanha , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Valva Mitral/fisiologia , Variações Dependentes do Observador , Valor Preditivo dos Testes , Valores de Referência , Reprodutibilidade dos Testes , Estudos Retrospectivos , Valva Tricúspide/fisiologia
10.
PLoS One ; 11(1): e0146988, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26811901

RESUMO

AIMS: Inhibition of ß-adrenergic signalling plays a key role in treatment of heart failure. Gsα is essential for ß-adrenergic signal transduction. In order to reduce side-effects of beta-adrenergic inhibition diminishing ß-adrenergic signalling in the heart at the level of Gsα is a promising option. METHODS AND RESULTS: We analyzed the influence of Gsα on regulation of myocardial function and development of cardiac hypertrophy, using a transgenic mouse model (C57BL6/J mice) overexpressing a dominant negative Gsα-mutant under control of the α-MHC-promotor. Cardiac phenotype was characterized in vivo and in vitro and under acute and chronic ß-adrenergic stimulation. At rest, Gsα-DN-mice showed bradycardia (602 ± 13 vs. 660 ± 17 bpm, p<0.05) and decreased dp/dtmax (5037 ± 546- vs. 6835 ± 505 mmHg/s, p = 0.02). No significant differences were found regarding ejection fraction, heart weight and cardiomyocyte size. ß-blockade by propranolol revealed no baseline differences of hemodynamic parameters between wildtype and Gsα-DN-mice. Acute adrenergic stimulation resulted in decreased ß-adrenergic responsiveness in Gsα-DN-mice. Under chronic adrenergic stimulation, wildtype mice developed myocardial hypertrophy associated with increase of LV/BW-ratio by 23% (4.4 ± 0.2 vs. 3.5 ± 0.1 mg/g, p<0.01) and cardiac myocyte size by 24% (14927 ± 442 px vs. 12013 ± 583 px, p<0.001). In contrast, both parameters were unchanged in Gsα-DN-mice after chronic isoproterenol stimulation. CONCLUSION: Overexpression of a dominant negative mutant of Gsα leads to decreased ß-adrenergic responsiveness and is protective against isoproterenol-induced hypertrophy. Thus, Gsα-DN-mice provide novel insights into ß-adrenergic signal transduction and its modulation in myocardial overload and failure.


Assuntos
Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Miocárdio/metabolismo , Agonistas Adrenérgicos beta , Animais , Cardiomegalia/induzido quimicamente , Cardiomegalia/metabolismo , Tamanho Celular , AMP Cíclico/metabolismo , Subunidades alfa Gs de Proteínas de Ligação ao GTP/metabolismo , Expressão Gênica , Frequência Cardíaca , Isoproterenol/farmacologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Miócitos Cardíacos/fisiologia , Transdução de Sinais , Volume Sistólico , Função Ventricular Esquerda , Pressão Ventricular
11.
J Am Soc Echocardiogr ; 29(12): 1188-1196, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-28042785

RESUMO

BACKGROUND: Anterior aortic plane systolic excursion (AAPSE) was evaluated in the present pilot study as a novel echocardiographic indicator of transplant-free survival in patients with systemic light-chain amyloidosis. METHODS: Eighty-nine patients with light-chain amyloidosis were included in the post-hoc analysis. A subgroup of 54 patients with biopsy-proven cardiac amyloid infiltration were compared with 41 healthy individuals to evaluate the discriminative ability of echocardiographic findings. AAPSE is defined as the systolic excursion of the anterior aortic margin. To quantify AAPSE, the M-mode cursor was placed on the aortic valve plane in parasternal long-axis view at end-diastole. Index echocardiography had been performed before chemotherapy. Median follow-up duration was 2.4 years. The primary combined end point was heart transplantation or overall death. RESULTS: Mean AAPSE was 14 ± 2 mm in healthy individuals (mean age=57 ± 10 years; 56% men; BMI=25 ± 4 kg/m2). AAPSE < 11 mm separated patients from age-, gender-, and BMI-matched control subjects with 93% sensitivity and 97% specificity. Median transplant-free survival of patients with AAPSE < 5 mm was 0.7 versus 4.8 years (P = .0001). AAPSE was an independent indicator of transplant-free survival in multivariate Cox regression (echocardiographic model: hazard ratio=0.72 [P = .03]; biomarker model: hazard ratio=0.62 [P = .0001]). Sequential regression analysis suggested incremental power of AAPSE as a marker of transplant-free survival. An ejection fraction-based model with an overall χ2 value of 22.8 was improved by the addition of log NT-proBNP (χ2 = 32.6, P < .005), troponin-T (χ2 = 39.6, P < .01), and AAPSE (χ2 = 54.0, P < .0001). CONCLUSIONS: AAPSE is suggested as an indicator of transplant-free survival in patients with systemic light-chain amyloidosis. AAPSE provided significant incremental value to established staging models.


Assuntos
Aorta/diagnóstico por imagem , Cardiomiopatia Restritiva/diagnóstico por imagem , Cardiomiopatia Restritiva/mortalidade , Ecocardiografia/métodos , Amiloidose de Cadeia Leve de Imunoglobulina/diagnóstico por imagem , Amiloidose de Cadeia Leve de Imunoglobulina/mortalidade , Cardiomiopatia Restritiva/cirurgia , Intervalo Livre de Doença , Ecocardiografia/estatística & dados numéricos , Feminino , Alemanha/epidemiologia , Transplante de Coração/mortalidade , Transplante de Coração/estatística & dados numéricos , Humanos , Amiloidose de Cadeia Leve de Imunoglobulina/cirurgia , Masculino , Pessoa de Meia-Idade , Prevalência , Prognóstico , Reprodutibilidade dos Testes , Fatores de Risco , Sensibilidade e Especificidade , Taxa de Sobrevida , Resultado do Tratamento
12.
PLoS One ; 8(9): e70848, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24023715

RESUMO

BACKGROUND: A prerequisite of hypertrophic response of the myocardium is an increase in protein synthesis. A central regulator of translation initiation is Eukaryotic initiation factor 2B (eIF2B). Here we assessed the hypothesis that regulation of protein synthesis via eIF2Bε is essential to cardiac hypertrophic response in vivo. METHODS: Two transgenic mouse lines were generated with cardiac restricted overexpression of eIF2Bε or its mutant eIF2Bε-eIFS(535)A, which cannot be inactivated by phosphorylation through GSK-3ß. RESULTS: (1) Under baseline conditions eIF2Bε transgenic mice showed no difference in cardiac phenotype compared to wild type, whereas in the mutant eIF2Bε-S(535)A an increase in LV/tibia length (7.5 ± 0.4 mg/mm vs. 6.2 ± 0.2 mg/mm, p<0.001) and cardiomyocyte cross sectional area (13004 ± 570 vs. 10843 ± 347 RU, p<0.01) was observed. (2) Cardiac overexpression of eIF2Bε did not change the response of the heart to pathologic stress induced by chronic isoproterenol treatment. (3) Cardiac overexpression of the eIF2Bε transgene was followed by overexpression of DYRK2 which is known to prime the inhibitory action of GSK-3ß on eIF2Bε, while DYRK1A and GSK-3ß itself were not increased. (4) In C57BL/6 mice after 48 h of isoproterenol-stimulation or aortic banding, eIF2Bε was increased and DYRK2 was concomitantly decreased. (5) In line with these in vivo findings, siRNA knockdown of DYRK2 in cultured cardiomyocytes resulted in decreased levels of p(S535)- eIF2Bε, (6) whereas adenoviral induced overexpression of DYRK2 was accompanied by clearly increased phosphorylation of eIF2Bε, indicating a coordinated response pattern (7) Adenoviral induced overexpression of DYRK2 leads to significantly reduced cardiomyocyte size and diminishes hypertrophic response to adrenergic stimulation. CONCLUSIONS: The interaction of GSK-3ß and its priming kinase DYRK2 regulate the activity of eIF2Bε in cardiac myocytes. DYRK2 is a novel negative regulator of cardiomyocyte growth. DYRK2 could serve as a therapeutic option to regulate myocardial growth.


Assuntos
Fator de Iniciação 2B em Eucariotos/metabolismo , Quinase 3 da Glicogênio Sintase/metabolismo , Miócitos Cardíacos/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/metabolismo , Animais , Células Cultivadas , Ecocardiografia , Fator de Iniciação 2B em Eucariotos/genética , Quinase 3 da Glicogênio Sintase/genética , Glicogênio Sintase Quinase 3 beta , Hipertrofia Ventricular Esquerda/genética , Hipertrofia Ventricular Esquerda/metabolismo , Imunoprecipitação , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas Serina-Treonina Quinases/genética , Proteínas Tirosina Quinases/genética , RNA Interferente Pequeno/genética , Reação em Cadeia da Polimerase em Tempo Real
13.
Hypertension ; 61(6): 1177-83, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23509077

RESUMO

Heart failure has an increasing contribution to cardiovascular disease burden and is governed by the myocardial remodeling process. The contribution of Wnt signaling to cardiac remodeling has recently drawn significant attention. Here, we report that upregulation of Dapper-1 in a transgenic mouse model activates the canonical/ß-catenin-dependent Wnt pathway through dishevelled-2. These mice exhibited increased heart weight/tibia length ratio, myocyte cross-sectional area, and upregulation of hypertrophic marker genes compared with wild-type mice. Furthermore, impairment of left ventricular systolic and diastolic function was observed in all indicating features of myocardial remodeling. Depletion of Dapper-1 and dishevelled-2 in cardiomyocytes demonstrated that Dapper-1 functions upstream of dishevelled-2 and that activity of both Dapper-1 and dishevelled-2 is essential for activating canonical Wnt signaling. Moreover, Dapper-1 depletion alleviated Wnt3a- and phenylephrine-induced cardiomyocyte hypertrophy. These observations provide evidence that Dapper-1-mediated activation of canonical Wnt signaling is necessary and sufficient to induce cardiomyocyte hypertrophy. Inhibition of this pathway may thus serve as a novel therapeutic strategy for alleviating cardiac hypertrophy.


Assuntos
Cardiomegalia/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Miócitos Cardíacos/efeitos dos fármacos , RNA Mensageiro/genética , Regulação para Cima , Remodelação Ventricular/genética , Via de Sinalização Wnt/genética , Animais , Cardiomegalia/metabolismo , Cardiomegalia/fisiopatologia , Modelos Animais de Doenças , Peptídeos e Proteínas de Sinalização Intracelular/biossíntese , Camundongos , Camundongos Transgênicos , Miocárdio/metabolismo , Miocárdio/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Proteínas de Ligação a RNA , Ratos
14.
Naunyn Schmiedebergs Arch Pharmacol ; 381(4): 285-95, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20107770

RESUMO

Sustained left ventricular hypertrophy (LVH) accelerates cardiac dysfunction and heart failure. Previous reports have suggested that activation of the peroxisome proliferator-activated receptor gamma (PPARgamma)-dependent pathway is involved in development of cardiac hypertrophy. Thiazolidinediones (TZDs) such as pioglitazone activate PPARgamma and are clinically used as antidiabetics. Given inconsistent reports regarding effects of TZDs on LVH, we examined in the present study the influence of pioglitazone on LVH in a rat model of aortic banding. Aortic banding was induced in rats by clipping the ascending aorta. Animals received pioglitazone (3 mg/kg/day) or placebo. Echocardiographic, hemodynamic, histological, and biochemical measurements were performed after 2 and 4 weeks. Pressure gradient was comparable between pioglitazone- and placebo-treated animals after 2 and 4 weeks. Left ventricular function was not different between the groups. In sham as well as in banded animals, LV/body weight ratio was increased in pioglitazone- as compared to placebo-treated animals after 2 and 4 weeks. Furthermore, an increase in myocyte size and atrial natriuretic factor was observed in pioglitazone- compared to placebo-treated animals 4 weeks after aortic banding as well. The results of this study demonstrate that activation of PPARgamma via pioglitazone does not protect the myocardium from pressure overload-induced LVH in a rat model of aortic banding. The findings rather indicate a pro-hypertrophic effect of pioglitazone treatment after aortic banding.


Assuntos
Hipertrofia Ventricular Esquerda/fisiopatologia , Hipoglicemiantes/farmacologia , PPAR gama/efeitos dos fármacos , Tiazolidinedionas/farmacologia , Animais , Aorta Torácica/cirurgia , Fator Natriurético Atrial/efeitos dos fármacos , Fator Natriurético Atrial/metabolismo , Modelos Animais de Doenças , Ecocardiografia , Hipertrofia Ventricular Esquerda/induzido quimicamente , Hipoglicemiantes/toxicidade , Masculino , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , PPAR gama/metabolismo , Pioglitazona , Ratos , Ratos Wistar , Tiazolidinedionas/toxicidade , Função Ventricular Esquerda/efeitos dos fármacos
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