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1.
J Cardiovasc Magn Reson ; 21(1): 53, 2019 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-31434577

RESUMO

BACKGROUND: The differentiated assessment of functional parameters besides morphological changes is essential for the evaluation of prognosis in systemic immunoglobulin light chain (AL) amyloidosis. METHODS: Seventy-four subjects with AL amyloidosis and presence of late gadolinium enhancement (LGE) pattern typical for cardiac amyloidosis were analyzed. Long axis strain (LAS) and myocardial contraction fraction (MCF), as well as morphological and functional markers, were measured. The primary endpoint was death, while death and heart transplantation served as a composite secondary endpoint. RESULTS: After a median follow-up of 41 months, 29 out of 74 patients died and 10 received a heart transplant. Left ventricular (LV) functional parameters were reduced in patients, who met the composite endpoint (LV ejection fraction 51% vs. 61%, LAS - 6.9% vs - 10%, GLS - 12% vs - 15% and MCF 42% vs. 69%; p <  0.001 for all). In unadjusted univariate analysis, LAS (HR = 1.05, p <  0.001) and MCF (HR = 0.96, p <  0.001) were associated with reduced transplant-free survival. Kaplan-Meier analyses showed a significantly lower event-free survival in patients with reduced MCF. MCF and LAS performed best to identify high risk patients for secondary endpoint (Log-rank test p <  0.001) in a combined model. Using sequential Cox regression analysis, the addition of LAS and MCF to LV ejection fraction led to a significant increase in the predictive power of the model (χ2 (df = 1) = 28.2, p <  0.001). CONCLUSIONS: LAS and MCF as routinely available and robust CMR-derived parameters predict outcome in LGE positive AL amyloidosis. Patients with impaired LV function in combination with reduced LAS and MCF are at the highest risk for death and heart transplantation.

2.
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
3.
Oncotarget ; 9(3): 3069-3080, 2018 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-29423029

RESUMO

Postinfarct cardiac hypertrophy is an independent risk factor for heart failure and sudden death. Regression of cardiac hypertrophy has emerged as a promising strategy in the treatment of myocardial infarction (MI). Here we hypothesized that frizzled1 (FZD1), a receptor of the canonical Wnt signaling pathway, is a novel mediator of ischemia-associated cardiac hypertrophy. MI was induced in mice by left anterior descending (LAD) coronary occlusion. One week after MI, the expression of FZD1 was found to be notably increased in the left ventricles (LVs) of the MI-mice compared to shams. Mouse recombinant FZD1 protein (RFP) was subcutaneously injected in the mice to provoke autoimmunization response. Anti-FZD1 antibody titer was significantly increased in the plasma of RFP-treated mice. RFP significantly mitigated the MI-induced cardiac hypertrophy and improved cardiac function in the MI mouse hearts. Moreover, increased heart and LV weights, myocardial size and the expression of ß-myosin heavy chain in the MI-mice were also found to be attenuated by RFP. FZD1 was found to be significantly up-regulated in hypoxia-treated neonatal rat cardiomyocytes (NRCMs). Silencing FZD1 by siRNA transfection notably repressed the hypoxia-induced myocardial hypertrophy in NRCMs. Mechanistically, activation of canonical Wnt signaling induced by MI, e.g., ß-catenin and glycogen synthase kinase-3ß, was restrained in the LVs of the MI-mice treated by RFP, these inhibition on canonical Wnt signaling was further confirmed in hypoxic NRCMs transfected with FZD1 siRNA. In conclusion, immunization of RFP attenuated cardiac hypertrophy and improved cardiac function in the MI mice via blocking the canonical Wnt signaling pathway.

4.
Radiology ; 283(3): 681-691, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28156200

RESUMO

Purpose To assess the utility of established functional markers versus two additional functional markers derived from standard cardiovascular magnetic resonance (MR) images for their incremental diagnostic and prognostic information in patients with nonischemic dilated cardiomyopathy (NIDCM). Materials and Methods Approval was obtained from the local ethics committee. MR images from 453 patients with NIDCM and 150 healthy control subjects were included between 2005 and 2013 and were analyzed retrospectively. Myocardial contraction fraction (MCF) was calculated by dividing left ventricular (LV) stroke volume by LV myocardial volume, and long-axis strain (LAS) was calculated from the distances between the epicardial border of the LV apex and the midpoint of a line connecting the origins of the mitral valve leaflets at end systole and end diastole. Receiver operating characteristic curve, Kaplan-Meier method, Cox regression, and classification and regression tree (CART) analyses were performed for diagnostic and prognostic performances. Results LAS (area under the receiver operating characteristic curve [AUC] = 0.93, P < .001) and MCF (AUC = 0.92, P < .001) can be used to discriminate patients with NIDCM from age- and sex-matched control subjects. A total of 97 patients reached the combined end point during a median follow-up of 4.8 years. In multivariate Cox regression analysis, only LV ejection fraction (EF) and LAS independently indicated the combined end point (hazard ratio = 2.8 and 1.9, respectively; P < .001 for both). In a risk stratification approach with classification and regression tree analysis, combined LV EF and LAS cutoff values were used to stratify patients into three risk groups (log-rank test, P < .001). Conclusion Cardiovascular MR-derived MCF and LAS serve as reliable diagnostic and prognostic markers in patients with NIDCM. LAS, as a marker for longitudinal contractile function, is an independent parameter for outcome and offers incremental information beyond LV EF and the presence of myocardial fibrosis. © RSNA, 2017 Online supplemental material is available for this article.


Assuntos
Cardiomiopatia Dilatada/diagnóstico por imagem , Cardiomiopatia Dilatada/fisiopatologia , Imagem por Ressonância Magnética , Contração Miocárdica , Técnicas de Imagem Cardíaca , Cardiomiopatia Dilatada/mortalidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida
5.
Eur Radiol ; 27(9): 3913-3923, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28188427

RESUMO

OBJECTIVE: To investigate the association of right ventricular long axis strain (RV-LAS), a parameter of longitudinal function, with outcome in patients with non-ischaemic dilated cardiomyopathy (NIDCM). METHODS: In 441 patients with NIDCM, RV-LAS was analysed retrospectively by measuring the length between the epicardial border of the left ventricular apex and the middle of a line connecting the origins of the tricuspidal valve leaflets in end-diastole and end-systole on non-contrast standard cine sequences. RESULTS: The primary endpoint (cardiac death or heart transplantation) occurred in 41 patients, whereas 95 reached the combined endpoint (including cardiac decompensation and sustained ventricular arrhythmias) during a median follow-up of 4.2 years. Kaplan-Meier survival curves showed a poor outcome in patients with RV-LAS values below -10% (log-rank, p < 0.0001). In a risk stratification model RV-LAS improved prediction of outcome in addition to RV ejection fraction (RVEF) and presence of late gadolinium enhancement. Assessment of RV-LAS offered incremental information compared to clinical symptoms, biomarkers and RVEF. Even in the subgroup with normal RVEF (>45%, n = 213) reduced RV-LAS was still associated with poor outcome. CONCLUSION: Assessment of RV-LAS is an independent indicator of outcome in patients with NIDCM and offers incremental information beyond clinical and cardiac MR parameters. KEY POINTS: • Impaired right ventricular longitudinal function (RV-LAS) is associated with poorer cardiac outcomes. • Poor outcome is associated with decreased RV-LAS even in patients with RVEF >45%. • Addition of RV-LAS to known risk factors enhances the power prognostic information.


Assuntos
Cardiomiopatia Dilatada/diagnóstico , Cardiomiopatia Dilatada/mortalidade , Cardiomiopatia Dilatada/cirurgia , Feminino , Gadolínio , Transplante de Coração/mortalidade , Ventrículos do Coração/fisiopatologia , Humanos , Estimativa de Kaplan-Meier , Angiografia por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Miocárdio/patologia , Prognóstico , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Estresse Fisiológico/fisiologia , Disfunção Ventricular Direita/diagnóstico , Disfunção Ventricular Direita/mortalidade
6.
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
7.
J Cardiovasc Magn Reson ; 18(1): 36, 2016 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-27268238

RESUMO

BACKGROUND: Long axis strain (LAS) has been shown to be a fast assessable parameter representing global left ventricular (LV) longitudinal function in cardiovascular magnetic resonance (CMR). However, the prognostic value of LAS in cardiomyopathies with reduced left ventricular ejection fraction (LVEF) has not been evaluated yet. METHODS AND RESULTS: In 146 subjects with non-ischemic dilated cardiomyopathy (NIDCM, LVEF ≤45 %) LAS was assessed retrospectively from standard non-contrast SSFP cine sequences by measuring the distance between the epicardial border of the left ventricular apex and the midpoint of a line connecting the origins of the mitral valve leaflets in end-systole and end-diastole. The final values were calculated according to the strain formula. The primary endpoint of the study was defined as a combination of cardiac death, heart transplantation or aborted sudden cardiac death and occurred in 24 subjects during follow-up. Patients with LAS values > -5 % showed a significant higher rate of cardiac events independent of the presence of late gadolinium enhancement (LGE). The multivariate Cox regression analysis revealed that LVEDV/BSA (HR: 1.01, p < 0.05), presence of LGE (HR: 2.51, p < 0.05) and LAS (HR: 1.28, p < 0.05) were independent predictors for cardiac events. In a sequential cox regression analysis LAS offered significant incremental information (p < 0.05) for the prediction of outcome in addition to LGE and LVEDV/BSA. Using a dichotomous three point scoring model for risk stratification, including LVEF <35 %, LAS > -10 % and the presence of LGE, patients with 3 points had a significantly higher risk for cardiac events than those with 2 or less points. CONCLUSION: Assessment of long axis function with LAS offers significant incremental information for the prediction of cardiac events in NIDCM and improves risk stratification beyond established CMR parameters.


Assuntos
Cardiomiopatia Dilatada/diagnóstico por imagem , Imagem Cinética por Ressonância Magnética , Volume Sistólico , Disfunção Ventricular Esquerda/diagnóstico por imagem , Função Ventricular Esquerda , Adulto , Idoso , Fenômenos Biomecânicos , Cardiomiopatia Dilatada/etiologia , Cardiomiopatia Dilatada/fisiopatologia , Cardiomiopatia Dilatada/cirurgia , Distribuição de Qui-Quadrado , Meios de Contraste/administração & dosagem , Morte Súbita Cardíaca/etiologia , Feminino , Transplante de Coração , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Valva Mitral/diagnóstico por imagem , Valva Mitral/fisiopatologia , Análise Multivariada , Variações Dependentes do Observador , Valor Preditivo dos Testes , Prognóstico , Modelos de Riscos Proporcionais , Reprodutibilidade dos Testes , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Fatores de Tempo , Disfunção Ventricular Esquerda/etiologia , Disfunção Ventricular Esquerda/fisiopatologia , Disfunção Ventricular Esquerda/cirurgia
8.
Eur J Radiol ; 85(7): 1322-8, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27235880

RESUMO

PURPOSE: Right ventricular longitudinal axis strain (RV-LAS) is a simple measure of RV longitudinal function. The purpose of this study was the evaluation of its diagnostic performance in non-ischemic dilated cardiomyopathy (NIDCM) and the determination of reference values in controls. METHODS: 217 NIDCM patients and 200 healthy controls were analysed retrospectively regarding the diagnostic performance of RV-LAS using receiver operating characteristic curves in comparison with RV ejection fraction (RVEF), tricuspid annular plane systolic excursion (TAPSE) and global longitudinal strain (RV-GLS). Hereby, four different approaches were evaluated to assess RV-LAS based on different reference points. RV-LAS LVapex/mid was defined as the change in distance between the LV apex and the middle of a line connecting the origins of the tricuspidal valve leaflets in systole and diastole. The ethical approval was obtained in all participants. RESULTS: NIDCM and controls were 48 years in mean. Controls were equally gender distributed, while the proportion of men with NIDCM was higher with 77%. Among the four approaches RV-LAS LVapex/mid provided the highest diagnostic performance for discrimination between NIDCM and controls (AUC=0.94). Of all RV functional parameters RV-LAS LVapex/mid preformed significantly better than RVEF (delta AUC=0.05; p=0.003), TAPSE (delta AUC=0.23; p<0.0001) and RV-GLS (delta AUC=0.31; p<0.0001). A significant correlation was found between RV-LAS LVapex/mid and RVEF (r=-0.65; p<0.0001). The reference mean values for RV-LAS LVapex/mid were -17.4±3.5 for men and -18.5±3.7 for women. CONCLUSION: RV-LAS showed better diagnostic accuracy for RV dysfunction than RVEF, TAPSE and RV-GLS. Furthermore, it has a rapid accessibility and low intra- and interobserver variability.


Assuntos
Cardiomiopatia Dilatada/diagnóstico por imagem , Imagem por Ressonância Magnética/métodos , Disfunção Ventricular Direita/diagnóstico por imagem , Disfunção Ventricular Direita/patologia , Adulto , Idoso , Feminino , Ventrículos do Coração/diagnóstico por imagem , Ventrículos do Coração/patologia , Humanos , Interpretação de Imagem Assistida por Computador/métodos , Masculino , Pessoa de Meia-Idade , Curva ROC , Reprodutibilidade dos Testes , Estudos Retrospectivos , Adulto Jovem
9.
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
10.
J Cardiovasc Magn Reson ; 17: 69, 2015 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-26253220

RESUMO

BACKGROUND: Assessment of longitudinal function with cardiovascular magnetic resonance (CMR) is limited to measurement of systolic excursion of the mitral annulus (MAPSE) or elaborate strain imaging modalities. The aim of this study was to develop a fast assessable parameter for the measurement of long axis strain (LAS) with CMR. METHODS: 40 healthy volunteers and 125 patients with different forms of cardiomyopathy were retrospectively analyzed. Four different approaches for the assessment of LAS with CMR measuring the distance between the LV apex and a line connecting the origins of the mitral valve leaflets in enddiastole and endsystole were evaluated. Values for LAS were calculated according to the strain formula. RESULTS: LAS derived from the distance of the epicardial apical border to the midpoint of the line connecting the mitral valve insertion points (LAS-epi/mid) proved to be the most reliable parameter for the assessment of LAS among the different approaches. LAS-epi/mid displayed the highest sensitivity (81.6 %) and specificity (97.5 %), furthermore showing the best correlation with feature tracking (FTI) derived transmural longitudinal strain (r = 0.85). Moreover, LAS-epi/mid was non-inferior to FTI in discriminating controls from patients (Area under the curve (AUC) = 0.95 vs. 0.94, p = NS). The time required for analysis of LAS-epi/mid was significantly shorter than for FTI (67 ± 8 s vs. 180 ± 14 s, p < 0.0001). Additionally, LAS-epi/mid performed significantly better than MAPSE (Delta AUC = 0.09; p < 0.005) and the ejection fraction (Delta AUC = 0.11; p = 0.0002). Reference values were derived from 234 selected healthy volunteers. Mean value for LAS-epi/mid was -17.1 ± 2.3 %. Mean values for men were significantly lower compared to women (-16.5 ± 2.2 vs. -17.9 ± 2.1 %; p < 0.0001), while LAS decreased with age. CONCLUSIONS: LAS-epi/mid is a novel and fast assessable parameter for the analysis of global longitudinal function with non-inferiority compared to transmural longitudinal strain.


Assuntos
Cardiomiopatias/diagnóstico , Interpretação de Imagem Assistida por Computador/normas , Imagem Cinética por Ressonância Magnética/normas , Contração Miocárdica , Função Ventricular Esquerda , Adulto , Fatores Etários , Área Sob a Curva , Fenômenos Biomecânicos , Cardiomiopatias/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valva Mitral/fisiopatologia , Valor Preditivo dos Testes , Curva ROC , Valores de Referência , Reprodutibilidade dos Testes , Estudos Retrospectivos , Fatores Sexuais , Estresse Mecânico , Fatores de Tempo
11.
Clin Res Cardiol ; 104(7): 591-602, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25643953

RESUMO

BACKGROUND: Myocardial deformation measurement is superior to left ventricular ejection fraction in identifying early changes in myocardial contractility and prediction of cardiovascular outcome. The lack of standardization hinders its clinical implementation. The aim of the study is to investigate a novel standardized deformation imaging approach based on the feature tracking algorithm for the assessment of global longitudinal (GLS) and global circumferential strain (GCS) in echocardiography and cardiac magnetic resonance imaging (CMR). METHODS: 70 subjects undergoing CMR were consecutively investigated with echocardiography within a median time of 30 min. GLS and GCS were analyzed with a post-processing software incorporating the same standardized algorithm for both modalities. Global strain was defined as the relative shortening of the whole endocardial contour length and calculated according to the strain formula. RESULTS: Mean GLS values were -16.2 ± 5.3 and -17.3 ± 5.3 % for echocardiography and CMR, respectively. GLS did not differ significantly between the two imaging modalities, which showed strong correlation (r = 0.86), a small bias (-1.1 %) and narrow 95 % limits of agreement (LOA ± 5.4 %). Mean GCS values were -17.9 ± 6.3 and -24.4 ± 7.8 % for echocardiography and CMR, respectively. GCS was significantly underestimated by echocardiography (p < 0.001). A weaker correlation (r = 0.73), a higher bias (-6.5 %) and wider LOA (± 10.5 %) were observed for GCS. GLS showed a strong correlation (r = 0.92) when image quality was good, while correlation dropped to r = 0.82 with poor acoustic windows in echocardiography. GCS assessment revealed only a strong correlation (r = 0.87) when echocardiographic image quality was good. No significant differences for GLS between two different echocardiographic vendors could be detected. CONCLUSIONS: Quantitative assessment of GLS using a standardized software algorithm allows the direct comparison of values acquired irrespective of the imaging modality. GLS may, therefore, serve as a reliable parameter for the assessment of global left ventricular function in clinical routine besides standard evaluation of the ejection fraction.


Assuntos
Algoritmos , Interpretação de Imagem Assistida por Computador/métodos , Imagem Cinética por Ressonância Magnética/métodos , Software , Disfunção Ventricular Esquerda/diagnóstico , Disfunção Ventricular Esquerda/fisiopatologia , Força Compressiva , Ecocardiografia/métodos , Módulo de Elasticidade , Técnicas de Imagem por Elasticidade/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Estresse Mecânico , Volume Sistólico , Resistência à Tração
12.
Hypertension ; 65(2): 335-44, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25489064

RESUMO

Activation of Wnt signaling results in maladaptive cardiac remodeling and cardiomyopathy. Recently, calcium/calmodulin-dependent protein kinase II (CaMKII) was reported to be a pivotal participant in myocardial remodeling. Because CaMKII was suggested as a downstream target of noncanonical Wnt signaling, we aimed to elucidate the role of CaMKII in dishevelled-1-induced cardiomyopathy and the mechanisms underlying its function. Dishevelled-1-induced cardiomyopathy was reversed by deletion of neither CaMKIIδ nor CaMKIIγ. Therefore, dishevelled-1-transgenic mice were crossed with CaMKIIδγ double-knockout mice. These mice displayed a normal cardiac phenotype without cardiac hypertrophy, fibrosis, apoptosis, or left ventricular dysfunction. Further mechanistic analyses unveiled that CaMKIIδγ couples noncanonical Wnt signaling to histone deacetylase 4 and myosin enhancer factor 2. Therefore, our findings indicate that the axis, consisting of dishevelled-1, CaMKII, histone deacetylase 4, and myosin enhancer factor 2, is an attractive therapeutic target for prevention of cardiac remodeling and its progression to left ventricular dysfunction.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/fisiologia , Insuficiência Cardíaca/enzimologia , Histona Desacetilases/fisiologia , Hipertrofia Ventricular Esquerda/enzimologia , Fosfoproteínas/fisiologia , Disfunção Ventricular Esquerda/enzimologia , Proteínas Wnt/fisiologia , Via de Sinalização Wnt/fisiologia , Animais , Apoptose , Benzilaminas/farmacologia , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/antagonistas & inibidores , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/deficiência , Proteínas Desgrenhadas , Fibrose , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/prevenção & controle , Hipertrofia Ventricular Esquerda/diagnóstico por imagem , Hipertrofia Ventricular Esquerda/genética , Hipertrofia Ventricular Esquerda/fisiopatologia , Sistema de Sinalização das MAP Quinases , Fatores de Transcrição MEF2/fisiologia , Camundongos , Camundongos Knockout , Miocárdio/patologia , Fenótipo , Proteína Quinase C/fisiologia , Sulfonamidas/farmacologia , Ultrassonografia , Disfunção Ventricular Esquerda/genética , Disfunção Ventricular Esquerda/fisiopatologia , Remodelação Ventricular , beta Catenina/fisiologia
13.
Amyloid ; 22(1): 45-53, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25492308

RESUMO

AIMS: To assess left ventricular long axis shortening (LAS) in patients with AL amyloidosis as a potential predictor for outcome. METHODS AND RESULTS: We performed a de novo echocardiographic analysis of LAS in 120 patients with biopsy-proven AL amyloidosis evaluated at first presentation before specific treatment. Additionally, 47 control subjects were analyzed retrospectivly. LAS was measured using a semiautomatic tissue motion annular displacement software algorithm (TMAD). LAS was significantly better than ejection fraction (EF) (p < 0.0001) and M-mode-derived mitral annular plane systolic excursion (MAPSE) (p < 0.05) discriminating AL patients from control subjects, while being non-inferior compared to tissue Doppler-derived peak systolic mitral annular velocity. One year outcome analysis in patients with AL amyloidosis showed that LAS remained the only significant echocardiographic parameter (HR:0.76; p < 0.005) in a multivariable Cox regression model of echocardiographic values. In a comprehensive clinical model, LAS (HR:0.72, p < 0.0001), cardiac troponin-T (HR:2.86, p < 0.01) and free light chain difference (HR:1.00; p < 0.05) were independently associated with the outcome. Assessment of LAS led to a significant integrated discrimination improvement and offered incremental information compared to EF and biomarkers. The cut-off value for LAS discriminating the endpoint was 5.8%. CONCLUSION: LAS was an independent predictor of survival within the first year and offers incremental information in patients with AL amyloidosis evaluated prior to specific treatment.


Assuntos
Amiloidose/diagnóstico por imagem , Ventrículos do Coração/patologia , Idoso , Amiloidose/mortalidade , Amiloidose/patologia , Feminino , Ventrículos do Coração/diagnóstico por imagem , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Tamanho do Órgão , Prognóstico , Modelos de Riscos Proporcionais , Curva ROC , Estudos Retrospectivos , Ultrassonografia
14.
Am J Physiol Heart Circ Physiol ; 307(8): H1169-77, 2014 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-25128164

RESUMO

Impairment of the cardiac norepinephrine (NE) reuptake by the neuronal NE transporter contributes to enhanced cardiac NE net release in congestive heart failure. Elevated plasma levels of aldosterone (AL) promote sympathetic overstimulation in failing hearts by unclear mechanisms. Our aim was to evaluate if elevated AL and/or alterations in Na(+) intake regulate cardiac NE reuptake. To test the effects of AL and Na(+) on cardiac NE reuptake, Wistar rats were fed a normal-salt (NS) diet (0.2% NaCl), a low-salt (LS) diet (0.015% NaCl), or a high-salt (HS) diet (8% NaCl). Another group of animals received AL infusion alone (0.75 µg/h) or AL infusion plus HS diet. Specific cardiac [(3)H]NE uptake via the NE transporter in a Langendorff preparation and AL plasma levels were measured at different time points between 5 and 42 days of treatment. To compare these findings from healthy animals with a disease model, Dahl salt-sensitive rats were investigated as a model of congestive heart failure with endogenously elevated AL. In summary, neither exogenous nor endogenous elevations of AL alone were sufficient to reduce cardiac NE reuptake. Only the HS diet induced a reduction of NE reuptake by 26%; additional infusion of AL augmented this effect to a further reduction of NE reuptake by 36%. In concordance, Dahl salt-sensitive rats treated with a HS diet displayed elevated AL and a marked reduction of NE reuptake. We conclude that exogenous or endogenous AL elevations alone do not reduce cardiac NE reuptake, but AL serves as an additional factor that negatively regulates cardiac NE reuptake in concert with HS intake.


Assuntos
Aldosterona/sangue , Miocárdio/metabolismo , Norepinefrina/metabolismo , Cloreto de Sódio na Dieta/metabolismo , Animais , Transporte Biológico , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/metabolismo , Masculino , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/genética , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/metabolismo , Ratos , Ratos Endogâmicos Dahl , Ratos Wistar , Cloreto de Sódio na Dieta/efeitos adversos
15.
FEBS Lett ; 588(14): 2230-7, 2014 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-24879894

RESUMO

The Wnt signaling pathway was identified as crucial mediator of cardiomyocyte hypertrophy. In this study we found that activation of non-canonical Wnt signaling by Wnt5a stimulates protein synthesis and enlargement of cardiomyocyte surface area. These hypertrophic features were inhibited in Dapper-1 (Dpr1) depleted cells. On the molecular level, we observed inhibition of the non-canonical Wnt/planar-cell-polarity (PCP) pathway denoted by reduction of c-jun-n-terminal-kinase (JNK) phosphorylation. Upstream of JNK, increased protein levels of the Wnt/PCP trans-membrane receptor van-Gogh-like-2 (Vangl2) were observed along with an enrichment of Vangl2 in perinuclear located vesicles. The findings suggest that Dpr1 is essential for execution of the Wnt/PCP pathway and regulation of the Vangl2/JNK axis. Depletion of Dpr1 inhibits non-canonical Wnt signaling induced cardiomyocyte hypertrophy by blocking Wnt/PCP signaling.


Assuntos
Miócitos Cardíacos/metabolismo , Proteínas Nucleares/fisiologia , Proteínas Wnt/metabolismo , Via de Sinalização Wnt , Animais , Cardiomegalia/metabolismo , Tamanho Celular , Células Cultivadas , Vesículas Citoplasmáticas/metabolismo , Sistema de Sinalização das MAP Quinases , Infarto do Miocárdio/metabolismo , Miócitos Cardíacos/patologia , Miócitos Cardíacos/fisiologia , Transporte Proteico , Ratos , Ratos Wistar , Proteína Wnt-5a
16.
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
17.
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
18.
Clin Res Cardiol ; 101(4): 273-80, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22139127

RESUMO

BACKGROUND: Evaluation of left ventricular function (LV) is one of the most important tasks of echocardiography. Left ventricular longitudinal function has been recognized to differentiate myocardial disorders better than ejection fraction (EF) alone. But recent parameters are still dependent on image quality and time consuming. METHODS: Transthoracic echocardiography, tissue Doppler imaging, strain imaging and assessment of longitudinal function with a tissue motion annular displacement (TMAD) tracking algorithm were performed in 152 patients with various cardiac pathologies and 47 healthy volunteers in a clinical routine setting. RESULTS: Measures of longitudinal function such as LV peak systolic strain (SR, r² = 0.88, p < 0.001) and peak systolic strain rate (SRR, r² = 0.78, p < 0.001) correlated highly with TMAD. Tissue motion annular displacement was ultrafast and less time-consuming compared to strain imaging (8.2 ± 2.2 s, p < 0.001). Significantly more patients with reduced image quality could be analyzed compared to strain imaging (p < 0.001). The intra- and inter-observer variabilities were very low with 1.3 ± 1% and 1.7 ± 1.2%. Tissue motion annular displacement correlated well with clinical parameters (NYHA, r = -0.71, p < 0.001) as well as NT-proBNP (r = -0.73, p < 0.001) and identified patients with structural heart disease with a significantly higher sensitivity 92.1% and specificity 95.7% than did EF, SR, SRR or NT-proBNP (Cut-off:14.2%, p < 0.01). In a subgroup of patients with systemic light chain amyloidosis and preserved EF (>50%, n = 54), TMAD was significantly reduced, especially in those without any signs of cardiac involvement and was superior to other parameters of longitudinal function (p < 0.05). CONCLUSIONS: Tissue motion annular displacement is a rapid, sensitive and reproducible method for the assessment of LV longitudinal function, which is less dependent on image quality.


Assuntos
Ecocardiografia Doppler em Cores/métodos , Cardiopatias/fisiopatologia , Valva Mitral/diagnóstico por imagem , Função Ventricular Esquerda , Idoso , Algoritmos , Estudos de Casos e Controles , Humanos , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Sístole
19.
Am J Physiol Heart Circ Physiol ; 302(2): H420-30, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22058151

RESUMO

The attenuation of adverse myocardial remodeling and pathological left ventricular (LV) hypertrophy is one of the hallmarks for improving the prognosis after myocardial infarction (MI). The protein kinase Akt plays a central role in regulating cardiac hypertrophy, but the in vivo effects of chronic pharmacological inhibition of Akt are unknown. We investigated the effect of chronic Akt blockade with deguelin on the development of pathological [MI and aortic banding (AB)] and physiological (controlled treadmill running) hypertrophy. Primary cardiomyocyte cultures were incubated with 10 µmol deguelin for 48 h, and Wistar rats were treated orally with deguelin (4.0 mg·kg(-1)·day(-1)) for 4 wk starting 1 day after the induction of MI or AB. Exercise-trained animals received deguelin for 4 wk during the training period. In vitro, we observed reduced phosphorylation of Akt and glycogen synthase kinase (GSK)-3ß after an incubation with deguelin, whereas MAPK signaling was not significantly affected. In vivo, treatment with deguelin led to attenuated phosphorylation of Akt and GSK-3ß 4 wk after MI. These animals showed significantly increased heart weights and impaired LV function with increased end-diastolic diameters (12.0 ± 0.3 vs. 11.1 ± 0.3 mm, P < 0.05), end-diastolic volumes (439 ± 8 vs. 388 ± 18 µl, P < 0.05), and cardiomyocyte sizes (+20%, P < 0.05) compared with MI animals receiving vehicle treatment. Furthermore, activation of Ca(2+)/calmodulin-dependent kinase II in deguelin-treated MI animals was increased compared with the vehicle-treated group. Four wk after AB, we observed an augmentation of pathological hypertrophy in the deguelin-treated group with a significant increase in heart weights and cardiomyocyte sizes (>20%, P < 0.05). In contrast, the development of physiological hypertrophy was inhibited by deguelin treatment in exercise-trained animals. In conclusion, chronic Akt blockade with deguelin aggravates adverse myocardial remodeling and antagonizes physiological hypertrophy.


Assuntos
Cardiomegalia Induzida por Exercícios/fisiologia , Cardiomegalia/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Cardiomegalia/patologia , Inibidores Enzimáticos/farmacologia , Masculino , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Fosforilação/efeitos dos fármacos , Condicionamento Físico Animal/fisiologia , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Ratos , Ratos Wistar , Rotenona/análogos & derivados , Rotenona/farmacologia
20.
Autophagy ; 6(2): 304-6, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20104016

RESUMO

The extent of adverse myocardial remodeling contributes essentially to the prognosis after myocardial infarction (MI). Currently, therapeutic strategies that inhibit remodeling are limited to inhibition of neurohumoral activation. mTOR-dependent signaling mechanisms are centrally involved in the myocardial remodeling process. There exists a controversy as to whether autophagy is beneficial in the setting of myocardial infarction. We now provide evidence that induction of autophagy by inhibition of mTOR with everolimus (RAD) prevents adverse left ventricular remodeling and limits infarct size following myocardial infarction. mTOR inhibition increases autophagy and concomitantly decreases proteasome activity especially in the border zone of the infarcted myocardium. The induction of autophagy via mTOR inhibition is a novel potential therapeutic approach to limit infarct size and to attenuate adverse left ventricular remodeling following MI.


Assuntos
Autofagia , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Autofagia/efeitos dos fármacos , Everolimo , Imunossupressores/farmacologia , Imunossupressores/uso terapêutico , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Infarto do Miocárdio/tratamento farmacológico , Miocárdio/metabolismo , Miocárdio/patologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais/fisiologia , Sirolimo/análogos & derivados , Sirolimo/farmacologia , Sirolimo/uso terapêutico , Serina-Treonina Quinases TOR , Ubiquitina/metabolismo , Remodelação Ventricular/efeitos dos fármacos
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