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1.
J Am Heart Assoc ; 11(9): e025381, 2022 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-35470693

RESUMO

Background Left ventricular hypertrophy (LVH) has often been supposed to be associated with abnormal myocardial blood flow and resistance. The aim of this study was to evaluate and quantify the physiological and pathological changes in myocardial blood flow and microcirculatory resistance in patients with and without LVH attributable to severe aortic stenosis. Methods and Results Absolute coronary blood flow and microvascular resistance were measured using a novel technique with continuous thermodilution and infusion of saline. In addition, myocardial mass was assessed with cardiac magnetic resonance imaging. Fifty-three patients with aortic valve stenosis were enrolled in the study. In 32 patients with LVH, hyperemic blood flow per gram of tissue was significantly decreased compared with 21 patients without LVH (1.26±0.48 versus 1.66±0.65 mL·min-1·g-1; P=0.018), whereas minimal resistance indexed for left ventricular mass was significantly increased in patients with LVH (63 [47-82] versus 43 [35-63] Wood Units·kg; P=0.014). Conclusions Patients with LVH attributable to severe aortic stenosis had lower hyperemic blood flow per gram of myocardium and higher minimal myocardial resistance compared with patients without LVH.


Assuntos
Estenose da Valva Aórtica , Estenose da Valva Aórtica/complicações , Estenose da Valva Aórtica/diagnóstico por imagem , Estenose da Valva Aórtica/patologia , Hemodinâmica , Humanos , Hipertrofia Ventricular Esquerda/patologia , Microcirculação , Miocárdio/patologia
2.
J Am Heart Assoc ; 11(6): e024226, 2022 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-35253475

RESUMO

Background This study examined the associations between quantitative optical coherence tomography angiography (OCTA) parameters and myocardial abnormalities as documented on cardiovascular magnetic resonance imaging in patients with systemic hypertension. Methods and Results We conducted a cross-sectional study of 118 adults with hypertension (197 eyes). Patients underwent cardiovascular magnetic resonance imaging and OCTA (PLEX Elite 9000, Carl Zeiss Meditec). Associations between OCTA parameters (superficial and deep retinal capillary density) and adverse cardiac remodeling (left ventricular mass, remodeling index, interstitial fibrosis, global longitudinal strain, and presence of left ventricular hypertrophy) were studied using multivariable linear regression analysis with generalized estimating equations. Of the 118 patients with hypertension enrolled (65% men; median [interquartile range] age, 59 [13] years), 29% had left ventricular hypertrophy. After adjusting for age, sex, systolic blood pressure, diabetes, and signal strength of OCTA scans, patients with lower superficial capillary density had significantly higher left ventricular mass (ß=-0.150; 95% CI, -0.290 to -0.010), higher interstitial volume (ß=-0.270; 95% CI, -0.535 to -0.0015), and worse global longitudinal strain (ß=-0.109; 95% CI, -0.187 to -0.032). Lower superficial capillary density was found in patients with hypertension with replacement fibrosis versus no replacement fibrosis (16.53±0.64 mm-1 versus 16.96±0.64 mm-1; P=0.003). Conclusions We showed significant correlations between retinal capillary density and adverse cardiac remodeling markers in patients with hypertension, supporting the notion that the OCTA could provide a non-invasive index of microcirculation alteration for vascular risk stratification in people with hypertension.


Assuntos
Hipertensão , Hipertrofia Ventricular Esquerda , Adulto , Estudos Transversais , Feminino , Fibrose , Angiofluoresceinografia/métodos , Humanos , Hipertensão/complicações , Hipertensão/patologia , Hipertrofia Ventricular Esquerda/diagnóstico por imagem , Hipertrofia Ventricular Esquerda/etiologia , Hipertrofia Ventricular Esquerda/patologia , Masculino , Pessoa de Meia-Idade , Vasos Retinianos/diagnóstico por imagem , Vasos Retinianos/patologia , Tomografia de Coerência Óptica/métodos , Remodelação Ventricular
3.
Aging (Albany NY) ; 14(3): 1508-1528, 2022 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-35157609

RESUMO

Left ventricular hypertrophy (LVH) is a pivotal manifestation of hypertensive organ damage associated with an increased cardiovascular risk. However, early diagnostic biomarkers for assessing LVH in patients with hypertension (HT) remain indefinite. Here, multiple bioinformatics tools combined with an experimental verification strategy were used to identify blood biomarkers for hypertensive LVH. GSE74144 mRNA expression profiles were downloaded from the Gene Expression Omnibus (GEO) database to screen candidate biomarkers, which were used to perform weighted gene co-expression network analysis (WGCNA) and establish the least absolute shrinkage and selection operator (LASSO) regression model, combined with support vector machine-recursive feature elimination (SVM-RFE) algorithms. Finally, the potential blood biomarkers were verified in an animal model. A total of 142 hub genes in peripheral blood leukocytes were identified between HT with LVH and HT without LVH, which were mainly involved in the ATP metabolic process, oxidative phosphorylation, and mitochondrial structure and function. Notably, lysosomal associated transmembrane protein 5 (LAPTM5) was identified as the potential diagnostic marker of hypertensive LVH, which showed strong correlations with diverse marker sets of reactive oxygen species (ROS) and autophagy. RT-PCR validation of blood samples and cardiac magnetic resonance imaging (CMRI) showed that the expression of LAPTM5 was significantly higher in the HT with LVH model than in normal controls, LAPTM5 demonstrated a positive association with the left ventricle wall thickness as well as electrocardiogram (ECG) parameters widths of the QRS complex and QTc interval. In conclusion, LAPTM5 may be a potential biomarker for the diagnosis of LVH in patients with HT, and it can provide new insights for future studies on the occurrence and the molecular mechanisms of hypertensive LVH.


Assuntos
Hipertensão , Hipertrofia Ventricular Esquerda , Proteínas de Membrana , Biomarcadores/metabolismo , Biologia Computacional , Ventrículos do Coração , Humanos , Hipertensão/genética , Hipertensão/metabolismo , Hipertensão/patologia , Hipertrofia Ventricular Esquerda/genética , Hipertrofia Ventricular Esquerda/metabolismo , Hipertrofia Ventricular Esquerda/patologia , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo
4.
Zhongguo Zhong Yao Za Zhi ; 47(2): 461-468, 2022 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-35178990

RESUMO

To investigate the effects of leonurine(Leo) on abdominal aortic constriction(AAC)-induced cardiac hypertrophy in rats and its mechanism. A rat model of pressure overload-induced cardiac hypertrophy was established by AAC method. After 27-d intervention with high-dose(30 mg·kg~(-1)) and low-dose(15 mg·kg~(-1)) Leo or positive control drug losartan(5 mg·kg~(-1)), the cardiac function was evaluated by hemodynamic method, followed by the recording of left ventricular systolic pressure(LVSP), left ventricular end-diastolic pressure(LVESP), as well as the maximum rate of increase and decrease in left ventricular pressure(±dp/dt_(max)). The degree of left ventricular hypertrophy was assessed based on heart weight index(HWI) and left ventricular mass index(LVWI). Myocardial tissue changes and the myocardial cell diameter(MD) were measured after hematoxylin-eosin(HE) staining. The contents of angiotensin Ⅱ(AngⅡ) and angiotensin Ⅱ type 1 receptor(AT1 R) in myocardial tissue were detected by ELISA. The level of Ca~(2+) in myocardial tissue was determined by colorimetry. The protein expression levels of phospholipase C(PLC), inositol triphosphate(IP3), AngⅡ, and AT1 R were assayed by Western blot. Real-time quantitative PCR(qRT-PCR) was employed to determine the mRNA expression levels of ß-myosin heavy chain(ß-MHC), atrial natriuretic factor(ANF), AngⅡ, and AT1 R. Compared with the model group, Leo decreased the LVSP, LVEDP, HWI, LVWI and MD values, but increased ±dp/dt_(max) of the left ventricle. Meanwhile, it improved the pathological morphology of myocardial tissue, reduced cardiac hypertrophy, edema, and inflammatory cell infiltration, decreased the protein expression levels of PLC, IP3, AngⅡ, AT1 R, as well as the mRNA expression levels of ß-MHC, ANF, AngⅡ, AT1 R, c-fos, and c-Myc in myocardial tissue. Leo inhibited AAC-induced cardiac hypertrophy possibly by influencing the RAS system.


Assuntos
Cardiomegalia , Hipertrofia Ventricular Esquerda , Angiotensina II/metabolismo , Animais , Cardiomegalia/etiologia , Cardiomegalia/genética , Ácido Gálico/análogos & derivados , Hipertrofia Ventricular Esquerda/metabolismo , Hipertrofia Ventricular Esquerda/patologia , Miocárdio/patologia , Ratos
5.
Front Endocrinol (Lausanne) ; 12: 762250, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34867803

RESUMO

Background: Previous studies have shown that waist-to-height ratio (WHtR) performed similarly well when compared to body mass index (BMI) and waist circumference (WC) for identifying cardiovascular risk factors. However, to our knowledge, the performance of these three adiposity indices for identifying left ventricular hypertrophy (LVH) and left ventricular geometric (LVG) remodeling in youth has not been assessed. We aimed to determine the utility of BMI, WC and WHtR for identifying LVH and LVG in Chinese children. Methods: This study included 1,492 Chinese children aged 6-11 years. Adiposity indices assessed were BMI, WC and WHtR. LVH and high relative wall thickness (RWT) were defined using sex- and age-specific 90th percentile values of left ventricular mass index and RWT, respectively, based on the current population. LVG remodeling included concentric remodeling (CR), eccentric hypertrophy (EH) and concentric hypertrophy (CH), which was defined based on the combination of LVH and high RWT. Results: The magnitude of association of central obesity defined by WHtR with LVH [odds ratio (OR) =10.09, 95% confidence interval (CI) =6.66-15.29] was similar with general obesity defined by BMI (OR=10.49, 95% CI=6.97-15.80), and both were higher than central obesity defined by WC (OR=6.87, 95% CI=4.57-10.33). Compared with BMI, WHtR had better or similar predictive utility for identifying LVH, EH, and CH [the area under the curve (AUC): 0.84 vs. 0.79; 0.84 vs. 0.77; 0.87 vs. 0.88, respectively]; WC had worse or similar discriminatory utility with AUCs of 0.73, 0.70, 0.83, respectively. Conclusion: WHtR performed similarly or better than BMI or WC for identifying LVH and LVG remodeling among Chinese children. WHtR provides a simple and convenient measure of central obesity that might improve the discrimination of children with cardiac structural damage.


Assuntos
Adiposidade/fisiologia , Hipertrofia Ventricular Esquerda/patologia , Remodelação Ventricular/fisiologia , Área Sob a Curva , Pressão Sanguínea/fisiologia , Índice de Massa Corporal , Criança , Estudos Transversais , Feminino , Humanos , Masculino , Obesidade Abdominal/fisiopatologia , Fatores de Risco , Circunferência da Cintura/fisiologia
6.
Int J Mol Sci ; 22(23)2021 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-34884782

RESUMO

Radiation-induced heart disease (RIHD) is a potential late side-effect of thoracic radiotherapy resulting in left ventricular hypertrophy (LVH) and fibrosis due to a complex pathomechanism leading to heart failure. Angiotensin-II receptor blockers (ARBs), including losartan, are frequently used to control heart failure of various etiologies. Preclinical evidence is lacking on the anti-remodeling effects of ARBs in RIHD, while the results of clinical studies are controversial. We aimed at investigating the effects of losartan in a rat model of RIHD. Male Sprague-Dawley rats were studied in three groups: (1) control, (2) radiotherapy (RT) only, (3) RT treated with losartan (per os 10 mg/kg/day), and were followed for 1, 3, or 15 weeks. At 15 weeks post-irradiation, losartan alleviated the echocardiographic and histological signs of LVH and fibrosis and reduced the overexpression of chymase, connective tissue growth factor, and transforming growth factor-beta in the myocardium measured by qPCR; likewise, the level of the SMAD2/3 protein determined by Western blot decreased. In both RT groups, the pro-survival phospho-AKT/AKT and the phospho-ERK1,2/ERK1,2 ratios were increased at week 15. The antiremodeling effects of losartan seem to be associated with the repression of chymase and several elements of the TGF-ß/SMAD signaling pathway in our RIHD model.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Insuficiência Cardíaca/prevenção & controle , Hipertrofia Ventricular Esquerda/tratamento farmacológico , Losartan/uso terapêutico , /tratamento farmacológico , Animais , Quimases/metabolismo , Modelos Animais de Doenças , Hipertrofia Ventricular Esquerda/patologia , Hipertrofia Ventricular Esquerda/prevenção & controle , Masculino , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , /prevenção & controle , Ratos , Ratos Sprague-Dawley , Proteína Smad2/análise , Proteína Smad3/análise , Fator de Crescimento Transformador beta1/análise
7.
Sci Rep ; 11(1): 22812, 2021 11 24.
Artigo em Inglês | MEDLINE | ID: mdl-34819579

RESUMO

Shear wave (SW) imaging is a novel ultrasound-based technique for assessing tissue characteristics. SW elasticity may be useful to assess the severity of hypertensive left ventricular (LV) hypertrophy. This study aimed to evaluate the efficacy of SW elasticity for assessing the degree of myocardial hypertrophy using hypertensive rats. Rats were divided into hypertension group and control group. SW elasticity was measured on the excised heart. Myocardial hypertrophy was assessed histologically. LV weight was greater in hypertension group. An increase in interventricular septum and LV free wall thicknesses was observed in hypertension group. SW elasticity was significantly higher in hypertension group than in control group (14.6 ± 4.3 kPa vs. 6.5 ± 1.1 kPa, P < 0.01). The cross-sectional area of cardiomyocytes was larger in hypertension group than in control group (397 ± 50 µm2 vs. 243 ± 14 µm2, P < 0.01), and SW elasticity was positively correlated with the cross-sectional area of cardiomyocytes (R = 0.96, P < 0.01). This study showed that SW elasticity was higher in hypertensive rats and was closely correlated with the degree of myocardial hypertrophy, suggesting the efficacy of SW elasticity for estimating the severity of hypertensive LV hypertrophy.


Assuntos
Técnicas de Imagem por Elasticidade , Ventrículos do Coração/diagnóstico por imagem , Hipertensão/complicações , Hipertrofia Ventricular Esquerda/diagnóstico por imagem , Animais , Modelos Animais de Doenças , Ecocardiografia , Ventrículos do Coração/patologia , Ventrículos do Coração/fisiopatologia , Hipertensão/fisiopatologia , Hipertrofia Ventricular Esquerda/etiologia , Hipertrofia Ventricular Esquerda/patologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Masculino , Miócitos Cardíacos/patologia , Valor Preditivo dos Testes , Ratos Endogâmicos Dahl , Índice de Gravidade de Doença , Cloreto de Sódio na Dieta , Função Ventricular Esquerda , Remodelação Ventricular
8.
J Am Heart Assoc ; 10(22): e022077, 2021 11 16.
Artigo em Inglês | MEDLINE | ID: mdl-34743552

RESUMO

Background Cardiac hypertrophy and fibrosis are common adaptive responses to injury and stress, eventually leading to heart failure. Hypoxia signaling is important to the (patho)physiological process of cardiac remodeling. However, the role of endothelial PHD2 (prolyl-4 hydroxylase 2)/hypoxia inducible factor (HIF) signaling in the pathogenesis of cardiac hypertrophy and heart failure remains elusive. Methods and Results Mice with Egln1Tie2Cre (Tie2-Cre-mediated deletion of Egln1 [encoding PHD2]) exhibited left ventricular hypertrophy evident by increased thickness of anterior and posterior wall and left ventricular mass, as well as cardiac fibrosis. Tamoxifen-induced endothelial Egln1 deletion in adult mice also induced left ventricular hypertrophy and fibrosis. Additionally, we observed a marked decrease of PHD2 expression in heart tissues and cardiovascular endothelial cells from patients with cardiomyopathy. Moreover, genetic ablation of Hif2a but not Hif1a in Egln1Tie2Cre mice normalized cardiac size and function. RNA sequencing analysis also demonstrated HIF-2α as a critical mediator of signaling related to cardiac hypertrophy and fibrosis. Pharmacological inhibition of HIF-2α attenuated cardiac hypertrophy and fibrosis in Egln1Tie2Cre mice. Conclusions The present study defines for the first time an unexpected role of endothelial PHD2 deficiency in inducing cardiac hypertrophy and fibrosis in an HIF-2α-dependent manner. PHD2 was markedly decreased in cardiovascular endothelial cells in patients with cardiomyopathy. Thus, targeting PHD2/HIF-2α signaling may represent a novel therapeutic approach for the treatment of pathological cardiac hypertrophy and failure.


Assuntos
Fibrose , Hipertrofia Ventricular Esquerda , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Cardiomegalia/genética , Cardiomegalia/patologia , Células Endoteliais/patologia , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/patologia , Humanos , Hipertrofia Ventricular Esquerda/patologia , Hipóxia/patologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Prolina Dioxigenases do Fator Induzível por Hipóxia/genética , Camundongos , Prolil Hidroxilases
9.
Mediators Inflamm ; 2021: 1376859, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34776787

RESUMO

Transverse aortic constriction (TAC) is a model that mimics pressure overload-induced left ventricular (LV) hypertrophy in mice. Alterations in immune cell functionality can promote cardiac and vascular remodeling. In the present study, we characterized the time course in innate immune cell dynamics in response to TAC in the different tissues of mice. It was determined whether TAC induces a characteristic leukocyte-driven immune response in the myocardium, aorta ascendens and descendens, spleen, blood, and draining lymph nodes supported by cytokine-driven chemotaxis in mice at 3, 6, and 21 days following surgery. We used complex flow cytometry staining combinations to characterize the various innate immune cell subsets and a multiplex array to determine cytokine concentrations in the serum. The results of the current study indicated that leukocytes accumulate in the myocardium and aorta ascendens in response to TAC. The leukocyte dynamics in the myocardium were dominated by the Ly6Clow macrophages with an early accumulation, whereas the response in the aorta ascendens was characterized by a long-lasting proinflammatory phenotype driven by Ly6Chigh macrophages, neutrophils, and activated DCs. In contrast to the high-pressure environment of the aorta ascendens, the tissue of the aorta descendens did not react to TAC with any leukocyte increase. The levels of proinflammatory cytokines in the blood were elevated in response to TAC, indicating a systemic reaction. Moreover, our findings strongly suggest that cardiac macrophages could origin from splenic pools and reach the site of the inflammation via the blood. Based on the current findings, it can be concluded that the high-pressure conditions in the aorta ascendens cause a characteristic immune response, dominated by the accumulation of leukocytes and the activation of DCs that varies in comparison to the immune cell dynamics in the myocardium and the aorta descendens.


Assuntos
Miocárdio , Remodelação Ventricular , Animais , Aorta , Cardiomegalia , Constrição , Modelos Animais de Doenças , Fibrose , Hipertrofia Ventricular Esquerda/patologia , Leucócitos , Camundongos , Camundongos Endogâmicos C57BL , Miocárdio/patologia
10.
Sci Rep ; 11(1): 21046, 2021 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-34702868

RESUMO

We investigated the prospective associations of body composition with cardiac structure and function and explored effect modification by sex and whether inflammation was a mediator in these associations. Total body (BF), trunk (TF) and leg fat (LF), and total lean mass (LM) were measured at baseline by a whole body DXA scan. Inflammatory biomarkers and echocardiographic measures were determined both at baseline and follow-up in the Hoorn Study (n = 321). We performed linear regression analyses with body composition measures as determinant and left ventricular ejection fraction (LVEF), left ventricular mass index (LVMI) or left atrial volume index (LAVI) at follow-up as outcome. Additionally, we performed mediation analysis using inflammation at follow-up as mediator. The study population was 67.7 ± 5.2 years and 50% were female. After adjustment, BF, TF and LF, and LM were associated with LVMI with regression coefficients of 2.9 (0.8; 5.1)g/m2.7, 2.3 (0.6; 4.0)g/m2.7, 2.0 (0.04; 4.0)g/m2.7 and - 2.9 (- 5.1; - 0.7)g/m2.7. Body composition measures were not associated with LVEF or LAVI. These associations were not modified by sex or mediated by inflammation. Body composition could play a role in the pathophysiology of LV hypertrophy. Future research should focus on sex differences in regional adiposity in relation with diastolic dysfunction.


Assuntos
Adiposidade , Hipertrofia Ventricular Esquerda , Obesidade , Caracteres Sexuais , Volume Sistólico , Disfunção Ventricular Esquerda , Idoso , Feminino , Seguimentos , Humanos , Hipertrofia Ventricular Esquerda/patologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Masculino , Pessoa de Meia-Idade , Obesidade/patologia , Obesidade/fisiopatologia , Estudos Prospectivos , Disfunção Ventricular Esquerda/patologia , Disfunção Ventricular Esquerda/fisiopatologia
11.
J Alzheimers Dis ; 84(3): 1303-1322, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34657883

RESUMO

BACKGROUND: Markers of altered cardiac function might predict cognitive decline and dementia. OBJECTIVE: This systematic review aims to review the literature that examines the associations of various electrocardiogram (ECG) markers with cognitive decline and dementia in middle-aged and elderly populations. METHODS: We searched PubMed, Embase, and Web of Science through 1 July 2020 for literature and conducted a systematic literature review. We included studies examining the associations of ECG markers (e.g., left ventricular hypertrophy [LVH], spatial QRS-T angle, and QT prolongation) with cognitive function and dementia in adult populations regardless of study setting and design, but excluded studies examining atrial fibrillation and heart rate variability. RESULTS: Fourteen community-based cross-sectional and longitudinal studies were identified. ECG markers were investigated in association with dementia in four prospective studies, and with cognitive decline in ten prospective studies. ECG-assessed LVH was associated with dementia in one study while five heterogeneous prospective studies yielded inconsistent associations with cognitive decline. Regarding ventricular repolarization markers, spatial QRS-T angle was associated with cognitive decline in one study while another study found no association between QT prolongation and cognitive decline. High resting heart rate was associated with both dementia and cognitive decline in one study but not associated with dementia in another study. P-wave abnormality was significantly associated with incident dementia and cognitive decline in one prospective study. CONCLUSION: Some ECG markers were associated with incident dementia and cognitive decline. However, limited number of heterogeneous studies did not allow us to make firm conclusions. Further studies are needed.


Assuntos
Disfunção Cognitiva/diagnóstico , Demência/diagnóstico , Eletrocardiografia , Hipertrofia Ventricular Esquerda/patologia , Síndrome do QT Longo/patologia , Frequência Cardíaca/fisiologia , Humanos
12.
Am J Physiol Heart Circ Physiol ; 321(5): H976-H984, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34559578

RESUMO

Heart failure with a preserved left ventricular (LV) ejection fraction (HFpEF) often arises from a prolonged LV pressure overload (LVPO) and accompanied by abnormal extracellular matrix (ECM) accumulation. The E3 ubiquitin ligase WWP1 is a fundamental determinant ECM turnover. We tested the hypothesis that genetic ablation of Wwp1 would alter the progression of LVPO-induced HFpEF. LV echocardiography in mice with global Wwp1 deletion (n = 23; Wwp1-/-) was performed at 12 wk of age (baseline) and then at 2 and 4 wk following LVPO (transverse aortic banding) or surgery without LVPO induction. Age-matched wild-type mice (Wwp1+/+; n = 23) underwent identical protocols. LV EF remained constant and unchanged with LVPO and LV mass increased in both groups but was lower in the Wwp1-/- mice. With LVPO, the E/A ratio, an index of LV filling, was 3.97 ± 0.46 in Wwp1+/+ but was 1.73 ± 0.19 in the Wwp1-/- group (P < 0.05). At the transcriptional level, mRNA for fibrillar collagens (types I and III) decreased by approximately 50% in Wwp1-/- compared with the Wwp1+/+ group at 4 wk post-LVPO (P < 0.05) and was paralleled by a similar difference in LV fibrillar collagen content as measured by histochemistry. Moreover, mRNA levels for determinants favoring ECM accumulation, such as transforming growth factor (TGF), increased with LVPO, but were lower in the Wwp1-/- group. The absence of Wwp1 reduced the development of left ventricular hypertrophy and subsequent progression to HFpEF. Modulating the WWP1 pathway could be a therapeutic target to alter the natural history of HFpEF.NEW & NOTEWORTHY Heart failure with a preserved left ventricular (LV) ejection fraction (HFpEF) often arises from a prolonged LV pressure overload (LVPO) and is accompanied by abnormal extracellular matrix (ECM) accumulation. It is now recognized that the ECM is a dynamic entity that is regulated at multiple post-transcriptional levels, including the E3 ubiquitin ligases, such as WWP1. In the present study, WWP1 deletion in the context of an LVPO stimulus reduced functional indices of HFpEF progression and determinants of ECM remodeling.


Assuntos
Insuficiência Cardíaca/enzimologia , Ventrículos do Coração/enzimologia , Hipertrofia Ventricular Esquerda/enzimologia , Ubiquitina-Proteína Ligases/deficiência , Disfunção Ventricular Esquerda/enzimologia , Função Ventricular Esquerda , Remodelação Ventricular , Animais , Aorta/fisiopatologia , Aorta/cirurgia , Diástole , Modelos Animais de Doenças , Progressão da Doença , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Feminino , Colágenos Fibrilares/genética , Colágenos Fibrilares/metabolismo , Deleção de Genes , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/fisiopatologia , Ventrículos do Coração/patologia , Ventrículos do Coração/fisiopatologia , Hipertrofia Ventricular Esquerda/genética , Hipertrofia Ventricular Esquerda/patologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fatores de Tempo , Ubiquitina-Proteína Ligases/genética , Disfunção Ventricular Esquerda/genética , Disfunção Ventricular Esquerda/patologia , Disfunção Ventricular Esquerda/fisiopatologia
13.
Am J Physiol Heart Circ Physiol ; 321(5): H940-H947, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34559582

RESUMO

Right-sided heart failure is a common consequence of pulmonary arterial hypertension. Overloading the right ventricle results in right ventricular hypertrophy, which progresses to failure in a process characterized by impaired Ca2+ dynamics and force production that is linked with transverse (t)-tubule remodeling. This also unloads the left ventricle, which consequently atrophies. Experimental left-ventricular unloading can result in t-tubule remodeling, but it is currently unclear if this occurs in right-sided heart failure. In this work, we used a model of monocrotaline (MCT)-induced right heart failure in male rats, using confocal microscopy to investigate cellular remodeling of t-tubules, junctophilin-2 (JPH2), and ryanodine receptor-2 (RyR2). We examined remodeling across tissue anatomical regions of both ventricles: in trabeculae, papillary muscles, and free walls. Our analyses revealed that MCT hearts demonstrated a significant loss of t-tubule periodicity, disruption of the normal sarcomere striated pattern with JPH2 labeling, and also a disorganized striated pattern of RyR2, a feature not previously reported in right heart failure. Remodeling of JPH2 and RyR2 in the MCT heart was more pronounced in papillary muscles and trabeculae compared with free walls, particularly in the left ventricle. We find that these structures, commonly used as ex vivo muscle preparations, are more sensitive to the disease process.NEW & NOTEWORTHY In this work, we demonstrate that t-tubule remodeling occurs in the atrophied left ventricle as well as the overloaded right ventricle after right-side heart failure. Moreover, we identify that t-tubule remodeling in both ventricles is linked to sarcoplasmic reticulum remodeling as indicated by decreased labeling periodicity of both the Ca2+ release channel, RyR2, and the cardiac junction-forming protein, JPH2, that forms a link between the sarcoplasmic reticulum and sarcolemma. Studies developing treatments for right-sided heart failure should consider effects on both the right and left ventricle.


Assuntos
Insuficiência Cardíaca/fisiopatologia , Ventrículos do Coração/fisiopatologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Sarcômeros/patologia , Função Ventricular Esquerda , Função Ventricular Direita , Remodelação Ventricular , Animais , Sinalização do Cálcio , Modelos Animais de Doenças , Insuficiência Cardíaca/induzido quimicamente , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/patologia , Ventrículos do Coração/metabolismo , Ventrículos do Coração/patologia , Hipertrofia Ventricular Esquerda/induzido quimicamente , Hipertrofia Ventricular Esquerda/metabolismo , Hipertrofia Ventricular Esquerda/patologia , Hipertrofia Ventricular Direita/induzido quimicamente , Hipertrofia Ventricular Direita/metabolismo , Hipertrofia Ventricular Direita/patologia , Hipertrofia Ventricular Direita/fisiopatologia , Masculino , Proteínas de Membrana/metabolismo , Monocrotalina , Ratos Wistar , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Sarcômeros/metabolismo
14.
Am J Physiol Heart Circ Physiol ; 321(5): H850-H864, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34477461

RESUMO

Molecular mechanisms underlying cardiac dysfunction and subsequent heart failure in diabetic cardiomyopathy are incompletely understood. Initially we intended to test the role of G protein-coupled receptor kinase 2 (GRK2), a potential mediator of cardiac dysfunction in diabetic cardiomyopathy, but found that control animals on HFD did not develop cardiomyopathy. Cardiac function was preserved in both wild-type and GRK2 knockout animals fed high-fat diet as indicated by preserved left ventricular ejection fraction (LVEF) although heart mass was increased. The absence of cardiac dysfunction led us to rigorously evaluate the utility of diet-induced obesity to model diabetic cardiomyopathy in mice. Using pure C57BL/6J animals and various diets formulated with different sources of fat-lard (32% saturated fat, 68% unsaturated fat) or hydrogenated coconut oil (95% saturated fat), we consistently observed left ventricular hypertrophy, preserved LVEF, and preserved contractility measured by invasive hemodynamics in animals fed high-fat diet. Gene expression patterns that characterize pathological hypertrophy were not induced, but a modest induction of various collagen isoforms and matrix metalloproteinases was observed in heart with high-fat diet feeding. PPARα-target genes that enhance lipid utilization such as Pdk4, CD36, AcadL, and Cpt1b were induced, but mitochondrial energetics was not impaired. These results suggest that although long-term fat feeding in mice induces cardiac hypertrophy and increases cardiac fatty acid metabolism, it may not be sufficient to activate pathological hypertrophic mechanisms that impair cardiac function or induce cardiac fibrosis. Thus, additional factors that are currently not understood may contribute to the cardiac abnormalities previously reported by many groups.NEW & NOTEWORTHY Dietary fat overload (DFO) is widely used to model diabetic cardiomyopathy but the utility of this model is controversial. We comprehensively characterized cardiac contractile and mitochondrial function in C57BL6/J mice fed with lard-based or saturated fat-enriched diets initiated at two ages. Despite cardiac hypertrophy, contractile and mitochondrial function is preserved, and molecular adaptations likely limit lipotoxicity. The resilience of these hearts to DFO underscores the need to develop robust alternative models of diabetic cardiomyopathy.


Assuntos
Cardiomiopatias Diabéticas/etiologia , Dieta Hiperlipídica , Hipertrofia Ventricular Esquerda/etiologia , Obesidade/complicações , Volume Sistólico , Disfunção Ventricular Esquerda/etiologia , Função Ventricular Esquerda , Fatores Etários , Animais , Cardiomiopatias Diabéticas/enzimologia , Cardiomiopatias Diabéticas/patologia , Cardiomiopatias Diabéticas/fisiopatologia , Modelos Animais de Doenças , Metabolismo Energético , Feminino , Fibrose , Quinase 2 de Receptor Acoplado a Proteína G/genética , Quinase 2 de Receptor Acoplado a Proteína G/metabolismo , Hipertrofia Ventricular Esquerda/enzimologia , Hipertrofia Ventricular Esquerda/patologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias Cardíacas/enzimologia , Mitocôndrias Cardíacas/patologia , Miocárdio/enzimologia , Miocárdio/patologia , Disfunção Ventricular Esquerda/enzimologia , Disfunção Ventricular Esquerda/patologia , Disfunção Ventricular Esquerda/fisiopatologia , Remodelação Ventricular
15.
Pharmacology ; 106(11-12): 667-681, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34518478

RESUMO

INTRODUCTION: Silent information regulator 1 (SIRT1) has been extensively investigated in the cardiovascular system and has been shown to play a pivotal role in mediating cell death/survival, energy production, and oxidative stress. However, the functional role of SIRT1 in pressure overload-induced cardiac hypertrophy and dysfunction remains unclear. Resveratrol (Rsv), a widely used activator of SIRT1, has been reported to protect against cardiovascular disease. We here examine whether activation of SIRT1 by Rsv attenuate pressure overload-induced cardiac hypertrophy and to identify the underlying molecular mechanisms. METHODS: In vivo, rat model of pressure overload-induced myocardial hypertrophy was established by abdominal aorta constriction (AAC) procedure. In vitro, Angiotensin II (Ang II) was applied to induce hypertrophy in cultured neonatal rat cardiomyocytes (NCMs). Hemodynamics and histological analyses of the heart were evaluated. The expression of SIRT1, transforming growth factor-ß1 (TGF-ß1)/phosphorylated (p)-small mother against decapentaplegic (Smad)3 and hypertrophic markers were determined by immunofluorescence, real-time PCR, and Western blotting techniques. RESULTS: In the current study, Rsv treatment improved left ventricular function and reduced left ventricular hypertrophy and cardiac fibrosis significantly in the pressure overload rats. The expression of SIRT1 was significantly reduced, while the expression of TGF-ß1/p-Smad3 was significantly enhanced in AAC afflicted rat heart. Strikingly, treatment with Rsv restored the expressions of SIRT1 and TGF-ß1/p-Smad3 under AAC influence. However, SIRT1 inhibitor Sirtinol (Snl) markedly prevented the effects of Rsv, which suggest that SIRT1 signaling pathway was involved in the cardiac protective effect of Rsv. In vitro studies performed in Ang II-induced hypertrophy in NCMs confirmed the cardiac protective effect of Rsv. Furthermore, the study presented that SIRT1 negatively correlated with the cardiac hypertrophy, cardiac fibrosis, and the TGF-ß1/p-Smad3 expression. CONCLUSIONS: Taken together, these results indicated that activation of SIRT1 by Rsv attenuates cardiac hypertrophy, cardiac fibrosis, and improves cardiac function possibly via regulation of the TGF-ß1/p-Smad3 signaling pathway. Our study may provide a potential therapeutic strategy for cardiac hypertrophy.


Assuntos
Cardiomegalia/patologia , Resveratrol/farmacologia , Sirtuína 1/efeitos dos fármacos , Fator de Crescimento Transformador beta1/antagonistas & inibidores , Animais , Modelos Animais de Doenças , Fibrose/patologia , Hemodinâmica/efeitos dos fármacos , Hipertrofia Ventricular Esquerda/patologia , Masculino , Células Musculares/efeitos dos fármacos , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Proteína Smad3/efeitos dos fármacos , Função Ventricular/efeitos dos fármacos
16.
Am J Physiol Heart Circ Physiol ; 321(5): H825-H838, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34533401

RESUMO

Cardiovascular complications are the leading cause of death, and elevated levels of asymmetric dimethyarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, are implicated in their pathophysiology. We investigated the role of dimethylarginine dimethylaminohydrolase 1 (DDAH1), an enzyme hydrolyzing ADMA, in prevention of cardiovascular remodeling during hypertension. We hypothesized that the animals overexpressing DDAH1 will be protected from angiotensin II (ANG II)-induced end organ damage. Angiotensin II (ANG II) was infused in two doses: 0.75 and 1.5 mg/kg/day in DDAH1 transgenic mice (DDAH1 TG) and wild-type (WT) littermates for 2 or 4 wk. Echocardiography was performed in the first and fourth weeks of the infusion, systolic blood pressure (SBP) was measured weekly, and cardiac hypertrophy and vascular remodeling was assessed by histology. Increase in SBP after 1 wk of ANG II infusion was not different between the groups, whereas TG mice had lower SBP at later time points. TG mice were protected from cardiovascular remodeling after 2 wk of ANG II infusion in the high dose and after 4 wk in the moderate dose. TG mice had higher left ventricular lumen-to-wall ratio, lower cardiomyocyte cross-sectional area, and less interstitial fibrosis compared with WT controls. In aorta, TG mice had less adventitial fibrosis, lower medial thickness with preserved elastin content, lower counts of inflammatory cells, lower levels of active matrix metalloproteinase-2, and showed better endothelium-dependent relaxation. We demonstrated that overexpression of DDAH1 protects from ANG II-induced cardiovascular remodeling and progression of hypertension by preserving endothelial function and limiting inflammation.NEW & NOTEWORTHY We showed that overexpression of dimethylarginine dimethylaminohydrolase 1 (DDAH1) protects from angiotensin II-induced cardiovascular damage, progression of hypertension, and adverse vascular remodeling in vivo. This protective effect is associated with decreased levels of asymmetric dimethylarginine, preservation of endothelial function, inhibition of cardiovascular inflammation, and lower activity of matrix metalloproteinase-2. Our findings are highly clinically relevant, because they suggest that upregulation of DDAH1 might be a promising therapeutic approach against angiotensin II-induced end organ damage.


Assuntos
Amidoidrolases/biossíntese , Aorta/enzimologia , Pressão Sanguínea , Ventrículos do Coração/enzimologia , Hipertensão/enzimologia , Hipertrofia Ventricular Esquerda/enzimologia , Remodelação Vascular , Função Ventricular Esquerda , Remodelação Ventricular , Amidoidrolases/genética , Angiotensina II , Animais , Aorta/patologia , Aorta/fisiopatologia , Modelos Animais de Doenças , Indução Enzimática , Fibrose , Ventrículos do Coração/patologia , Ventrículos do Coração/fisiopatologia , Hipertensão/induzido quimicamente , Hipertensão/patologia , Hipertensão/fisiopatologia , Hipertrofia Ventricular Esquerda/induzido quimicamente , Hipertrofia Ventricular Esquerda/patologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Mediadores da Inflamação/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fatores de Tempo , Vasodilatação
17.
BMC Cardiovasc Disord ; 21(1): 403, 2021 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-34418957

RESUMO

BACKGROUND: Cardiomyocyte metabolism changes before cardiac remodeling, but its role in early cardiac hypertrophy detection remains unclear. This study investigated early changes in plasma metabolomics in a pressure-overload cardiac hypertrophy model induced by transverse aortic constriction (TAC). METHODS: The TAC model was constructed by partly ligating the aortic arch. Twelve Sprague-Dawley rats were randomly divided into the TAC group (n = 6) and sham group (n = 6). Three weeks after surgery, cardiac echocardiography was performed to assess cardiac remodeling and function. Hematoxylin/eosin (HE), Masson, and wheat germ agglutinin (WGA) stains were used to observe pathological changes. Plasma metabolites were detected by UPLC-QTOFMS and Q-TOFMS. Specific metabolites were screened by orthogonal partial least squares discriminant analysis (OPLS-DA). Metabolic pathways were characterized by Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, and the predictive value of the screened metabolites was analyzed by receiver operating characteristic (ROC) curve analysis. RESULTS: Three weeks after surgery, the TAC and sham groups had similar left heart function and interventricular septum and diastolic left ventricular posterior wall thicknesses. However, on pathological examination, the cross-sectional area of cardiomyocytes and myocardial fibrosis severity were significantly elevated in TAC rats. OPLS-DA showed different metabolic patterns between the TAC and sham groups. Based on the criteria VIP > 1 and P < 0.05, 13 metabolites were screened out. KEGG analysis identified disrupted lysine degradation through the related metabolites 5-aminopentanoic acid, N6-acetyl-L-lysine, and L-lysine, with areas under the ROC curve (AUCs) of 0.917, 0.889, and 0.806, respectively, for predicting compensated cardiomyocyte hypertrophy. CONCLUSION: Disruption of lysine degradation might be involved in early cardiac hypertrophy development, and related metabolites might be potential predictive and interventional targets for subclinical cardiomyocyte hypertrophy.


Assuntos
Metabolismo Energético , Hipertrofia Ventricular Esquerda/metabolismo , Lisina/metabolismo , Miocárdio/metabolismo , Função Ventricular Esquerda , Remodelação Ventricular , Animais , Aorta Torácica/fisiopatologia , Aorta Torácica/cirurgia , Pressão Arterial , Modelos Animais de Doenças , Fibrose , Hipertrofia Ventricular Esquerda/etiologia , Hipertrofia Ventricular Esquerda/patologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Ligadura , Masculino , Metaboloma , Metabolômica , Miocárdio/patologia , Proteólise , Ratos Sprague-Dawley , Fatores de Tempo
18.
Am J Physiol Heart Circ Physiol ; 321(4): H615-H632, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34415186

RESUMO

Cardiac dysfunction in heart failure (HF) and diabetic cardiomyopathy (DCM) is associated with aberrant intracellular Ca2+ handling and impaired mitochondrial function accompanied with reduced mitochondrial calcium concentration (mito-[Ca2+]). Pharmacological or genetic facilitation of mito-Ca2+ uptake was shown to restore Ca2+ transient amplitude in DCM and HF, improving contractility. However, recent reports suggest that pharmacological enhancement of mito-Ca2+ uptake can exacerbate ryanodine receptor-mediated spontaneous sarcoplasmic reticulum (SR) Ca2+ release in ventricular myocytes (VMs) from diseased animals, increasing propensity to stress-induced ventricular tachyarrhythmia. To test whether chronic recovery of mito-[Ca2+] restores systolic Ca2+ release without adverse effects in diastole, we overexpressed mitochondrial Ca2+ uniporter (MCU) in VMs from male rat hearts with hypertrophy induced by thoracic aortic banding (TAB). Measurement of mito-[Ca2+] using genetic probe mtRCamp1h revealed that mito-[Ca2+] in TAB VMs paced at 2 Hz under ß-adrenergic stimulation is lower compared with shams. Adenoviral 2.5-fold MCU overexpression in TAB VMs fully restored mito-[Ca2+]. However, it failed to improve cytosolic Ca2+ handling and reduce proarrhythmic spontaneous Ca2+ waves. Furthermore, mitochondrial-targeted genetic probes MLS-HyPer7 and OMM-HyPer revealed a significant increase in emission of reactive oxygen species (ROS) in TAB VMs with 2.5-fold MCU overexpression. Conversely, 1.5-fold MCU overexpression in TABs, that led to partial restoration of mito-[Ca2+], reduced mitochondria-derived reactive oxygen species (mito-ROS) and spontaneous Ca2+ waves. Our findings emphasize the key role of elevated mito-ROS in disease-related proarrhythmic Ca2+ mishandling. These data establish nonlinear mito-[Ca2+]/mito-ROS relationship, whereby partial restoration of mito-[Ca2+] in diseased VMs is protective, whereas further enhancement of MCU-mediated Ca2+ uptake exacerbates damaging mito-ROS emission.NEW & NOTEWORTHY Defective intracellular Ca2+ homeostasis and aberrant mitochondrial function are common features in cardiac disease. Here, we directly compared potential benefits of mito-ROS scavenging and restoration of mito-Ca2+ uptake by overexpressing MCU in ventricular myocytes from hypertrophic rat hearts. Experiments using novel mito-ROS and Ca2+ biosensors demonstrated that mito-ROS scavenging rescued both cytosolic and mito-Ca2+ homeostasis, whereas moderate and high MCU overexpression demonstrated disparate effects on mito-ROS emission, with only a moderate increase in MCU being beneficial.


Assuntos
Arritmias Cardíacas/metabolismo , Canais de Cálcio/metabolismo , Sinalização do Cálcio , Cálcio/metabolismo , Hipertrofia Ventricular Esquerda/metabolismo , Mitocôndrias Cardíacas/metabolismo , Miócitos Cardíacos/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Agonistas Adrenérgicos beta/farmacologia , Animais , Arritmias Cardíacas/genética , Arritmias Cardíacas/patologia , Arritmias Cardíacas/fisiopatologia , Técnicas Biossensoriais , Canais de Cálcio/genética , Sinalização do Cálcio/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Frequência Cardíaca , Hipertrofia Ventricular Esquerda/genética , Hipertrofia Ventricular Esquerda/patologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Masculino , Microscopia Confocal , Mitocôndrias Cardíacas/efeitos dos fármacos , Mitocôndrias Cardíacas/genética , Mitocôndrias Cardíacas/patologia , Contração Miocárdica , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Ratos Sprague-Dawley , Regulação para Cima , Função Ventricular Esquerda , Remodelação Ventricular
19.
J Clin Endocrinol Metab ; 106(11): e4327-e4339, 2021 10 21.
Artigo em Inglês | MEDLINE | ID: mdl-34223895

RESUMO

CONTEXT: Lipodystrophy syndromes are rare disorders of deficient adipose tissue, low leptin, and severe metabolic disease, affecting all adipose depots (generalized lipodystrophy, GLD) or only some (partial lipodystrophy, PLD). Left ventricular (LV) hypertrophy is common (especially in GLD); mechanisms may include hyperglycemia, dyslipidemia, or hyperinsulinemia. OBJECTIVE: Determine effects of recombinant leptin (metreleptin) on cardiac structure and function in lipodystrophy. METHODS: Open-label treatment study of 38 subjects (18 GLD, 20 PLD) at the National Institutes of Health before and after 1 (N = 27), and 3 to 5 years (N = 23) of metreleptin. Outcomes were echocardiograms, blood pressure (BP), triglycerides, A1c, and homeostasis model assessment of insulin resistance. RESULTS: In GLD, metreleptin lowered triglycerides (median [interquartile range] 740 [403-1239], 138 [88-196], 211 [136-558] mg/dL at baseline, 1 year, 3-5 years, P < .0001), A1c (9.5 ±â€…3.0, 6.5 ±â€…1.6, 6.5 ±â€…1.9%, P < .001), and HOMA-IR (34.1 [15.2-43.5], 8.7 [2.4-16.0], 8.9 [2.1-16.4], P < .001). Only HOMA-IR improved in PLD (P < .01). Systolic BP decreased in GLD but not PLD. Metreleptin improved cardiac parameters in patients with GLD, including reduced posterior wall thickness (9.8 ±â€…1.7, 9.1 ±â€…1.3, 8.3 ±â€…1.7 mm, P < .01), and LV mass (140.7 ±â€…45.9, 128.7 ±â€…37.9, 110.9 ±â€…29.1 g, P < .01), and increased septal e' velocity (8.6 ±â€…1.7, 10.0 ±â€…2.1, 10.7 ±â€…2.4 cm/s, P < .01). Changes remained significant after adjustment for BP. In GLD, multivariate models suggested that reduced posterior wall thickness and LV mass index correlated with reduced triglycerides and increased septal e' velocity correlated with reduced A1c. No changes in echocardiographic parameters were seen in PLD. CONCLUSION: Metreleptin attenuated cardiac hypertrophy and improved septal e' velocity in GLD, which may be mediated by reduced lipotoxicity and glucose toxicity. The applicability of these findings to leptin-sufficient populations remains to be determined.


Assuntos
Cardiomegalia/prevenção & controle , Hipertrofia Ventricular Esquerda/prevenção & controle , Leptina/análogos & derivados , Lipodistrofia/complicações , Lipodistrofia/tratamento farmacológico , Adolescente , Adulto , Pressão Sanguínea , Cardiomegalia/etiologia , Ecocardiografia , Feminino , Hemoglobina A Glicada/análise , Humanos , Hipertrofia Ventricular Esquerda/patologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Resistência à Insulina , Leptina/uso terapêutico , Lipodistrofia/patologia , Lipodistrofia Generalizada Congênita/complicações , Lipodistrofia Generalizada Congênita/dietoterapia , Masculino , Pessoa de Meia-Idade , National Institutes of Health (U.S.) , Estudos Prospectivos , Triglicerídeos/sangue , Estados Unidos , Septo Interventricular/patologia , Septo Interventricular/fisiopatologia , Adulto Jovem
20.
J Cardiovasc Pharmacol ; 78(1): e55-e64, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34232225

RESUMO

ABSTRACT: Left ventricular hypertrophy (LVH) makes the heart vulnerable to ischemia/reperfusion (IR) injury. Angiotensin (Ang) (1-7) is recognized as a cardioprotective peptide. We investigated the effect of polyphenol resveratrol on myocardial IR injury after hypertrophy and examined cardiac content of Ang (1-7) and transcription of its receptor (MasR). Rats were divided into sham-operated, LVH, IR, LVH + IR, and resveratrol + LVH + IR groups. Myocardial hypertrophy and IR models were created by abdominal aortic banding and left coronary artery occlusion, respectively. To evaluate the electrocardiogram parameters and incidence of arrhythmias, electrocardiogram was recorded by subcutaneous leads (lead II). Blood pressure was measured through the left carotid artery. Infarct size was determined by the triphenyl tetrazolium chloride staining. The Ang (1-7) level was evaluated by immunohistochemistry. The Mas receptor mRNA level was assessed by the real-time real time reverse transcription polymerase chain reaction technique. QT-interval duration, infarct size, and incidence of ischemia-induced arrhythmia were significantly higher in the LVH + IR group. However, in the resveratrol-treated group, these parameters were decreased significantly. The cardiac level of Ang (1-7) was decreased in untreated hypertrophied hearts (LVH and LVH + IR groups). Pretreatment with resveratrol normalized the cardiac level of Ang (1-7). The mRNA level of Mas receptor was increased in all of hypertrophied hearts in the presence or absence of resveratrol. Resveratrol can decrease IR injury in rats with LVH. The anti-ischemic effect of resveratrol may be related to the enhancement of Ang (1-7)/MasR axis.


Assuntos
Angiotensina I/metabolismo , Hipertrofia Ventricular Esquerda/tratamento farmacológico , Infarto do Miocárdio/prevenção & controle , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miocárdio/metabolismo , Fragmentos de Peptídeos/metabolismo , Resveratrol/farmacologia , Animais , Modelos Animais de Doenças , Hipertrofia Ventricular Esquerda/metabolismo , Hipertrofia Ventricular Esquerda/patologia , Masculino , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Miocárdio/patologia , Ratos Wistar , Taquicardia Ventricular/metabolismo , Taquicardia Ventricular/prevenção & controle , Fibrilação Ventricular/metabolismo , Fibrilação Ventricular/prevenção & controle
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