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Hypertension ; 74(2): 295-304, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31291149


Subendocardial damage is among the first cardiac manifestations of hypertension and is already present in asymptomatic disease states. Accordingly, markers of subendocardial impairment may facilitate early detection of cardiac damages and risk stratification under these conditions. This study aimed to investigate the impact of subendocardial damage on myocardial microstructure and function to elucidate early pathophysiologic processes and to identify corresponding diagnostic measures. Mice (n=38) were injected with isoproterenol to induce isolated subendocardial scarring or saline as corresponding control. Cardiac function and myocardial deformation were determined by high-frequency echocardiography. The cardiac stress response was assessed in a graded exercise test and during dobutamine stress echocardiography. Myocardial microstructure was studied ex vivo by 7 T diffusion tensor magnetic resonance imaging at a spatial resolution of 100×100×100 µm 3 . Results were correlated with histology and biomarker expression. Subendocardial fibrosis was accompanied by diastolic dysfunction, impaired longitudinal deformation (global peak longitudinal strain [LS]: -12.5±0.5% versus -15.6±0.5%; P<0.001) and elevated biomarker expression (ANP [atrial natriuretic peptide], Galectin-3, and ST2). Systolic function and cardiac stress response remained preserved. Diffusion tensor magnetic resonance imaging revealed a left-shift in helix angle towards lower values in isoproterenol-treated animals, which was mainly determined by subepicardial myofibers (mean helix angle: 2.2±0.8° versus 5.9±1.0°; P<0.01). Longitudinal strain and subepicardial helix angle were highly predictive for subendocardial fibrosis (sensitivity, 82%-92% and specificity, 89%-90%). The results indicate that circumscribed subendocardial damage alone can cause several hallmarks observed in cardiovascular high-risk patients. Microstructural remodeling under these conditions involves also remote regions, and corresponding changes in longitudinal strain and helix angle might serve as diagnostic markers.

Cardiovasc Ultrasound ; 17(1): 7, 2019 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-31010431


Echocardiography is the most commonly applied technique for non-invasive assessment of cardiac function in small animals. Manual tracing of endocardial borders is time consuming and varies with operator experience. Therefore, we aimed to evaluate a novel automated two-dimensional software algorithm (Auto2DE) for small animals and compare it to the standard use of manual 2D-echocardiographic assessment (2DE). We hypothesized that novel Auto2DE will provide rapid and robust data sets, which are in agreement with manually assessed data of animals.2DE and Auto2DE were carried out using a high-resolution imaging-system for small animals. First, validation cohorts of mouse and rat cine loops were used to compare Auto2DE against 2DE. These data were stratified for image quality by a blinded expert in small animal imaging. Second, we evaluated 2DE and Auto2DE in four mouse models and four rat models with different cardiac pathologies.Automated assessment of LV function by 2DE was faster than conventional 2DE analysis and independent of operator experience levels. The accuracy of Auto2DE-assessed data in healthy mice was dependent on cine loop quality, with excellent agreement between Auto2DE and 2DE in cine loops with adequate quality. Auto2DE allowed for valid detection of impaired cardiac function in animal models with pronounced cardiac phenotypes, but yielded poor performance in diabetic animal models independent of image quality.Auto2DE represents a novel automated analysis tool for rapid assessment of LV function, which is suitable for data acquisition in studies with good and very good echocardiographic image quality, but presents systematic problems in specific pathologies.

Hypertension ; 71(4): 599-608, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29437893


Mineralocorticoid receptor antagonists (MRAs) reduce morbidity and mortality in chronic heart failure. Novel nonsteroidal MRAs are currently developed and need to be pharmacologically characterized in comparison to classical steroidal MRAs. A mouse model of cardiac fibrosis induced by short-term isoproterenol injection was used to compare the nonsteroidal MRA finerenone and the steroidal MRA eplerenone in equi-efficient systemic MR blocking dosages. Molecular mechanisms were studied in MR-expressing H9C2/MR+ cardiomyocytes and in MR transcriptional cofactor binding assays. Both MRAs significantly inhibited an isoproterenol-mediated increase of left ventricular mass. Isoproterenol-induced cardiac fibrosis and macrophage invasion were potently blocked by finerenone, whereas eplerenone had no significant effect. Speckle tracking echocardiography revealed a significant improvement of global longitudinal peak strain by finerenone, an effect less prominent with eplerenone. Antifibrotic actions of finerenone were accompanied by a significant inhibition of profibrotic cardiac TNX (tenascin-X) expression, a regulation absent with eplerenone. Finally, we show a higher potency/efficacy and inverse agonism of finerenone versus eplerenone in MR transcriptional cofactor binding assays indicating differential MR cofactor modulation by steroidal and nonsteroidal MRAs. This study demonstrates that the nonsteroidal MRA finerenone potently prevents cardiac fibrosis and improves strain parameters in mice. Cardiac antifibrotic actions of finerenone may result from the inhibition of profibrotic TNX gene expression mediated by differential MR cofactor binding. Selective MR cofactor modulation provides a molecular basis for distinct (pre)-clinical actions of nonsteroidal and steroidal MRAs.

PLoS Genet ; 14(1): e1007171, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29320510


Adipose tissue lipolysis occurs during the development of heart failure as a consequence of chronic adrenergic stimulation. However, the impact of enhanced adipose triacylglycerol hydrolysis mediated by adipose triglyceride lipase (ATGL) on cardiac function is unclear. To investigate the role of adipose tissue lipolysis during heart failure, we generated mice with tissue-specific deletion of ATGL (atATGL-KO). atATGL-KO mice were subjected to transverse aortic constriction (TAC) to induce pressure-mediated cardiac failure. The cardiac mouse lipidome and the human plasma lipidome from healthy controls (n = 10) and patients with systolic heart failure (HFrEF, n = 13) were analyzed by MS-based shotgun lipidomics. TAC-induced increases in left ventricular mass (LVM) and diastolic LV inner diameter were significantly attenuated in atATGL-KO mice compared to wild type (wt) -mice. More importantly, atATGL-KO mice were protected against TAC-induced systolic LV failure. Perturbation of lipolysis in the adipose tissue of atATGL-KO mice resulted in the prevention of the major cardiac lipidome changes observed after TAC in wt-mice. Profound changes occurred in the lipid class of phosphatidylethanolamines (PE) in which multiple PE-species were markedly induced in failing wt-hearts, which was attenuated in atATGL-KO hearts. Moreover, selected heart failure-induced PE species in mouse hearts were also induced in plasma samples from patients with chronic heart failure. TAC-induced cardiac PE induction resulted in decreased PC/ PE-species ratios associated with increased apoptotic marker expression in failing wt-hearts, a process absent in atATGL-KO hearts. Perturbation of adipose tissue lipolysis by ATGL-deficiency ameliorated pressure-induced heart failure and the potentially deleterious cardiac lipidome changes that accompany this pathological process, namely the induction of specific PE species. Non-cardiac ATGL-mediated modulation of the cardiac lipidome may play an important role in the pathogenesis of chronic heart failure.

Tecido Adiposo/metabolismo , Insuficiência Cardíaca/etiologia , Hipertensão/complicações , Lipase/fisiologia , Metabolismo dos Lipídeos/genética , Miocárdio/metabolismo , Disfunção Ventricular Esquerda/etiologia , Animais , Estudos de Casos e Controles , Células Cultivadas , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/fisiopatologia , Humanos , Hipertensão/genética , Hipertensão/metabolismo , Lipase/genética , Lipase/metabolismo , Masculino , Metaboloma/genética , Camundongos , Camundongos Knockout , Miócitos Cardíacos/metabolismo , Disfunção Ventricular Esquerda/genética , Disfunção Ventricular Esquerda/metabolismo , Remodelação Ventricular
J Am Soc Echocardiogr ; 30(12): 1239-1250.e2, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29066223


BACKGROUND: The subendocardium is highly vulnerable to damage and is thus affected even in subclinical disease stages. Therefore, methods reflecting subendocardial status are of great clinical relevance for the early detection of cardiac damage and the prevention of functional impairment. The aim of this study was to investigate the potential ability of myocardial strain parameters to evaluate changes within the subendocardium. METHODS: Male 129/Sv mice were injected with isoproterenol (ISO; n = 32) to induce isolated subendocardial fibrotic lesions or saline as appropriate control (n = 15). Transthoracic echocardiography was performed using a 30-MHz linear-frequency transducer coupled to a high-resolution imaging system, and acquired images were analyzed for conventional and strain parameters. The degree of collagen content within the different cardiac layers was quantified by histologic analysis and serum levels of tissue inhibitor of metalloproteinase-1, a biomarker for fibrosis, were assessed. RESULTS: ISO treatment induced a marked increase in subendocardial collagen content in response to cell loss (control vs ISO, 0.6 ± 0.3% vs 5.8 ± 0.9%; P < .001) and resulted in a moderate increase in left ventricular wall thickness with preserved systolic function. Global longitudinal peak strain (LS) and longitudinal strain rate were significantly decreased in ISO-treated animals (LS, -15.49% vs -11.49% [P = .001]; longitudinal strain rate, -4.81 vs -3.88 sec-1 [P < .05]), whereas radial and circumferential strain values remained unchanged. Global LS was associated with subendocardial collagen content (r = 0.46, P = .01) and tissue inhibitor of metalloproteinase-1 serum level (r = 0.52, P < .05). Further statistical analyses identified global LS as a superior predictor for the presence of subendocardial fibrosis (sensitivity, 84%; specificity, 80%; cutoff value, -14.4%). CONCLUSION: Assessment of LS may provide a noninvasive method for the detection of subendocardial damage and may consequently improve early diagnosis of cardiac diseases.

Ecocardiografia/métodos , Endocárdio/diagnóstico por imagem , Ventrículos do Coração/diagnóstico por imagem , Disfunção Ventricular Esquerda/diagnóstico , Animais , Modelos Animais de Doenças , Masculino , Camundongos , Reprodutibilidade dos Testes