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1.
Cell Physiol Biochem ; 53(6): 961-981, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31820856

RESUMO

BACKGROUND/AIMS: We assessed the effects of ticagrelor, aspirin and prasugrel, started 7days after myocardial ischemia-reperfusion injury on remodeling, inflammation and fibrosis in the rat. We examined whether ticagrelor can affect the number of progenitor cells in the border zone. Ticagrelor, started 24h after myocardial ischemia-reperfusion injury, attenuates the decrease in heart function and adverse remodeling, an effect which is blocked by aspirin. METHODS: Rats underwent 40min ischemia followed by reperfusion. Oral dosing with vehicle, ticagrelor (300mg/kg/d), aspirin (20mg/kg/d), their combination or prasugrel (15mg/kg/d) started 7days after infarction. Echocardiography was used to assess systolic function. Heart tissue were analyzed by rt-PCR, immunoblotting, ELISA and immunohistochemistry 2weeks after infarction. RESULTS: Both ticagrelor and aspirin attenuated the decrease in systolic function and remodeling, an effect that was blocked by their combination. Ticagrelor and aspirin attenuated the increase in ANP, BNP, collagen-I and collagen-III. Again, the effect was blocked by their combination. Ticagrelor increased c-Kit, Sca-1, Ki-67, CD34, attenuated the decrease in CD105 mRNA levels, and attenuated the increase in CD31, whereas aspirin increased Ki-67, suppressed the increase in CD31 and attenuated the decrease in CD105 mRNA levels. Prasugrel did not display any effects. CONCLUSION: Ticagrelor attenuated adverse remodeling and deterioration of left ventricular systolic function despite starting treatment after the myocardial ischemia-reperfusion injury is completed. Aspirin had similar effects; however, when combined with ticagrelor, the protective effects were significantly attenuated. Ticagrelor increased the levels of several markers of stem cells and regeneration, suggesting cardiac healing by recruiting regenerative cells into the infarct.


Assuntos
Apoptose/efeitos dos fármacos , Infarto do Miocárdio/patologia , Inibidores da Agregação de Plaquetas/farmacologia , Ticagrelor/farmacologia , Remodelação Ventricular/efeitos dos fármacos , Animais , Aspirina/farmacologia , Aspirina/uso terapêutico , Fator Natriurético Atrial/genética , Fator Natriurético Atrial/metabolismo , Modelos Animais de Doenças , Quimioterapia Combinada , Endoglina/genética , Endoglina/metabolismo , Fibrose , Regulação da Expressão Gênica/efeitos dos fármacos , Infarto do Miocárdio/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Inibidores da Agregação de Plaquetas/uso terapêutico , Cloridrato de Prasugrel/farmacologia , Cloridrato de Prasugrel/uso terapêutico , Proteínas Proto-Oncogênicas c-kit/genética , Proteínas Proto-Oncogênicas c-kit/metabolismo , Ratos , Ratos Sprague-Dawley , Células-Tronco/citologia , Células-Tronco/efeitos dos fármacos , Células-Tronco/metabolismo , Ticagrelor/uso terapêutico , Função Ventricular Esquerda/efeitos dos fármacos
2.
Kardiologiia ; 59(10S): 4-12, 2019 Sep 17.
Artigo em Russo | MEDLINE | ID: mdl-31876457

RESUMO

AIM: Assess the diagnostic significance of markers of heart failure, to identify the features of clinical symptoms and structural and functional remodeling of the left and right heart in patients with chronic heart failure (CHF) in combination with atrial fibrillation (AF) and chronic obstructive pulmonary disease (COPD). MATERIALS AND METHODS: groups of patients were formed: group 1 - patients with COPD without cardiovascular diseases (n=28), group 2 - patients with CHF and COPD without AF (n=30), group 3 - patients with CHF and AF without COPD (n=33), group 4 (main) - patients with CHF, AF and COPD (n=29). Patients were evaluated for clinical symptoms, 6-minute walk test, echocardiographic study, determined the concentration of natriuretic peptides (NUP): N-terminal fragment of the precursor of cerebral NUP (NT-proBNP) and mid-regional pro-atrial NUP (MR-proANP). RESULTS: In patients with CHF on the background of AF and COPD, a higher score of the severity of clinical symptoms was established in comparison with the 3rd group (p<0,001). The features of heart remodeling in patients of the main group were revealed in comparison with patients with CHF and AF without COPD: lower volume indices of the left (p=0,001) and right (p=0,004) atria and values of the indexed index of the end-diastolic area of the right ventricle (RV) (p=0,007), lower contractility of the RV, the presence of RV hypertrophy. The effect of AF on the structural and functional parameters of the heart in patients with CHF, COPD and AF can be judged by comparison with patients with CHF and COPD without AF: higher values of the size of the RV (p=0,012), indexed index of the end-systolic area of the RV (p<0,001), lower systolic function of the RV on the background of higher pressure in the RV cavity (p=0,001). Defined the highest level of NT-proBNP in patients with CHF, AF and COPD in comparison with its level in patients of the 2nd group (p<0,001) and in patients 3rd groups (p=0,010). Higher levels of MR-proANP were found in patients with CHF and AF without COPD (p<0,001). CONCLUSION: In patients with CHF, AF and COPD, more pronounced clinical symptoms are caused by chronic bronchial obstruction. Pathogenetic features of left and right heart remodeling in patients with CHF on the background of AF and COPD were revealed. For the early detection of HF in patients with AF the greatest diagnostic importance is the determination of the level of MR-proANP, however, in patients with combined AF and COPD the most informative is the determination of the concentration of NT-proBNP.


Assuntos
Fibrilação Atrial , Insuficiência Cardíaca , Doença Pulmonar Obstrutiva Crônica , Fator Natriurético Atrial , Átrios do Coração , Insuficiência Cardíaca/etiologia , Humanos , Peptídeo Natriurético Encefálico , Fragmentos de Peptídeos , Doença Pulmonar Obstrutiva Crônica/complicações
3.
Cell Physiol Biochem ; 53(4): 587-605, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31535830

RESUMO

BACKGROUND/AIMS: To investigate the role of the sympathetic nervous system (SNS) and renin-angiotensin system (RAS) in renal ischemia/reperfusion-induced (I/R) cardiac inflammatoryprofile. METHODS: Left kidney ischemia was induced in male C57BL/6 mice for 60 min, followed by reperfusion for 12 days, and treatment with or without atenolol, losartan, or enalapril. The expression of vimentin in kidney and atrial natriuretic factor (ANF) in the heart has been investigated by RT-PCR. In cardiac tissue, levels of ß1-adrenoreceptors, adenylyl cyclase, cyclic AMP-dependent protein kinase (PKA), noradrenaline, adrenaline (components of SNS), type 1 angiotensin II receptors (AT1R), angiotensinogen/Ang II and renin (components of RAS) have been measured by Western blotting and HPLC analysis. A panel of cytokines - tumour necrosis factor (TNF-α), interleukin IL-6, and interferon gamma (IFN-γ) - was selected as cardiac inflammatory markers. RESULTS: Renal vimentin mRNA levels increased by >10 times in I/R mice, indicative of kidney injury. ANF, a marker of cardiac lesion, increased after renal I/R, the values being restored to the level of Sham group after atenolol or enalapril treatment. The cardiac inflammatory profile was confirmed by the marked increase in the levels of mRNAs of TNF-α, IL-6, and IFN-γ. Atenolol and losartan reversed the upregulation of TNF-α expression, whereas enalapril restored IL-6 levels to Sham levels; both atenolol and enalapril normalized IFN-γ levels. I/R mice showed upregulation of ß1-adrenoreceptors, adenylyl cyclase, PKA and noradrenaline. Renal I/R increased cardiac levels of AT1R, which decreased after losartan or enalapril treatment. Renin expression also increased, with the upregulation returning to Sham levels after treatment with SNS and RAS blockers. Angiotensinogen/Ang II levels in heart were unaffected by renal I/R, but they were significantly decreased after treatment with losartan and enalapril, whereas increase in renin levels decreased. CONCLUSION: Renal I/R-induced cardiac inflammatory events provoked by the simultaneous upregulation of SNS and RAS in the heart, possibly underpin the mechanism involved in the development of cardiorenal syndrome.


Assuntos
Rim/metabolismo , Miocárdio/metabolismo , Sistema Renina-Angiotensina , Sistema Nervoso Simpático/metabolismo , Animais , Atenolol/farmacologia , Atenolol/uso terapêutico , Fator Natriurético Atrial/genética , Fator Natriurético Atrial/metabolismo , Catecolaminas/metabolismo , Enalapril/farmacologia , Enalapril/uso terapêutico , Interleucina-6/metabolismo , Losartan/farmacologia , Losartan/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptor Tipo 1 de Angiotensina/genética , Receptor Tipo 1 de Angiotensina/metabolismo , Receptores Adrenérgicos beta 1/genética , Receptores Adrenérgicos beta 1/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Sistema Nervoso Simpático/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo , Regulação para Cima/efeitos dos fármacos , Vimentina/genética , Vimentina/metabolismo
4.
PLoS Comput Biol ; 15(9): e1007346, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31513566

RESUMO

We performed a mathematical analysis of the dynamic control loops regulating the vasomotor tone of vascular smooth muscle, blood volume, and mean arterial pressure, which involve the arginine vasopressin (AVP) system, the atrial natriuretic peptide system (ANP), and the renin-angiotensin-aldosterone system (RAAS). Our loop analysis of the AVP-ANP-RAAS system revealed the concurrent presence of two different regulatory mechanisms, which perform the same qualitative function: one affects blood pressure by regulating vasoconstriction, the other by regulating blood volume. Both the systems are candidate oscillators consisting of the negative-feedback loop of a monotone system: they admit a single equilibrium that can either be stable or give rise to oscillatory instability. Also a subsystem, which includes ANP and AVP stimulation of vascular smooth muscle cells, turns out to be a candidate oscillator composed of a monotone system with multiple negative feedback loops, and we show that its oscillatory potential is higher when the delays along all feedback loops are comparable. Our results give insight into the physiological mechanisms ruling long-term homeostasis of blood hydraulic parameters, which operate based on dynamical loops of interactions.


Assuntos
Pressão Sanguínea/fisiologia , Volume Sanguíneo/fisiologia , Homeostase/fisiologia , Modelos Biológicos , Arginina Vasopressina/metabolismo , Fator Natriurético Atrial/metabolismo , Cálcio/metabolismo , Biologia Computacional , Retroalimentação Fisiológica/fisiologia , Humanos , Músculo Liso Vascular/citologia , Sistema Renina-Angiotensina/fisiologia
5.
Environ Pollut ; 255(Pt 1): 113155, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31539850

RESUMO

Di-(2-ethylhexyl) phthalate (DEHP) is a prevalent environmental contaminant that severely impacts the health of human and animals. Taxifolin (TAX), a plant flavonoid isolated from yew, exerts protective effects on cardiac diseases. Nevertheless, whether DEHP could induce cardiomyocyte hypertrophy and its mechanism remains unclear. This study aimed to highlight the specific molecular mechanisms of DEHP-induced cardiomyocyte hypertrophy and the protective potential of TAX against it. Chicken primary cardiomyocytes were treated with DEHP (500 µM) and/or TAX (0.5 µM) for 24 h. The levels of glucose and adenosine triphosphate (ATP) were detected, and cardiac hypertrophy-related genes were validated by real-time quantitative PCR (qRT-PCR) and Western blot (WB) in vitro. The results showed that DEHP-induced cardiac hypertrophy was ameliorated by TAX, as indicated by the increased cardiomyocyte area and expression of atrial natriuretic peptide (ANP), natriuretic peptides A-like (BNP) and ß-myosin heavy cardiac muscle (ß-MHC). Furthermore, DEHP induced cardiac hypertrophy via the interleukin 6 (IL-6)/Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) pathway in vitro. In addition, DEHP disrupted mitochondrial function and glycometabolism by activating the insulin-like growth factor 1 (IGF1)/phosphatidylinositol 3-kinase (PI3K) pathway and the peroxisome proliferator activated receptors (PPARs)/PPARG coactivator 1 alpha (PGC-1α) pathway to induce cardiac hypertrophy in vitro. Intriguingly, those DEHP-induced changes were obviously alleviated by TAX treatment. Taken together, cardiac hypertrophy was induced by DEHP via activating the IL-6/JAK/STAT3 signaling pathway, triggering glycometabolism disorder and mitochondrial dysfunction in vitro, can be ameliorated by TAX. Our findings may provide a feasible molecular mechanism for the treatment of cardiomyocyte hypertrophy induced by DEHP.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Cardiomegalia/prevenção & controle , Dietilexilftalato/toxicidade , Mitocôndrias/patologia , Miócitos Cardíacos/patologia , Quercetina/análogos & derivados , Animais , Fator Natriurético Atrial/metabolismo , Cardiomegalia/induzido quimicamente , Células Cultivadas , Galinhas/metabolismo , Mitocôndrias/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Quercetina/farmacologia , Miosinas Ventriculares/metabolismo
6.
Crit Care ; 23(1): 259, 2019 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-31337421

RESUMO

BACKGROUND: Intravenous fluids, an essential component of sepsis resuscitation, may paradoxically worsen outcomes by exacerbating endothelial injury. Preclinical models suggest that fluid resuscitation degrades the endothelial glycocalyx, a heparan sulfate-enriched structure necessary for vascular homeostasis. We hypothesized that endothelial glycocalyx degradation is associated with the volume of intravenous fluids administered during early sepsis resuscitation. METHODS: We used mass spectrometry to measure plasma heparan sulfate (a highly sensitive and specific index of systemic endothelial glycocalyx degradation) after 6 h of intravenous fluids in 56 septic shock patients, at presentation and after 24 h of intravenous fluids in 100 sepsis patients, and in two groups of non-infected patients. We compared plasma heparan sulfate concentrations between sepsis and non-sepsis patients, as well as between sepsis survivors and sepsis non-survivors. We used multivariable linear regression to model the association between volume of intravenous fluids and changes in plasma heparan sulfate. RESULTS: Consistent with previous studies, median plasma heparan sulfate was elevated in septic shock patients (118 [IQR, 113-341] ng/ml 6 h after presentation) compared to non-infected controls (61 [45-79] ng/ml), as well as in a second cohort of sepsis patients (283 [155-584] ng/ml) at emergency department presentation) compared to controls (177 [144-262] ng/ml). In the larger sepsis cohort, heparan sulfate predicted in-hospital mortality. In both cohorts, multivariable linear regression adjusting for age and severity of illness demonstrated a significant association between volume of intravenous fluids administered during resuscitation and plasma heparan sulfate. In the second cohort, independent of disease severity and age, each 1 l of intravenous fluids administered was associated with a 200 ng/ml increase in circulating heparan sulfate (p = 0.006) at 24 h after enrollment. CONCLUSIONS: Glycocalyx degradation occurs in sepsis and septic shock and is associated with in-hospital mortality. The volume of intravenous fluids administered during sepsis resuscitation is independently associated with the degree of glycocalyx degradation. These findings suggest a potential mechanism by which intravenous fluid resuscitation strategies may induce iatrogenic endothelial injury.


Assuntos
Endotélio/fisiopatologia , Hidratação/efeitos adversos , Glicocálix/efeitos dos fármacos , Sepse/tratamento farmacológico , Administração Intravenosa , Adulto , Idoso , Angiopoietina-2/análise , Angiopoietina-2/sangue , Fator Natriurético Atrial/análise , Fator Natriurético Atrial/sangue , Biomarcadores/análise , Biomarcadores/sangue , Endotélio/efeitos dos fármacos , Endotélio/metabolismo , Feminino , Hidratação/métodos , Hidratação/estatística & dados numéricos , Glicocálix/metabolismo , Heparitina Sulfato/análise , Heparitina Sulfato/sangue , Humanos , Masculino , Espectrometria de Massas/métodos , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico/análise , Peptídeo Natriurético Encefálico/sangue , Ressuscitação/efeitos adversos , Ressuscitação/métodos , Ressuscitação/estatística & dados numéricos , Sepse/sangue , Sepse/fisiopatologia , Sindecana-1/análise , Sindecana-1/sangue , Trombomodulina/análise , Trombomodulina/sangue , Ativador de Plasminogênio Tecidual/análise , Ativador de Plasminogênio Tecidual/sangue , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/análise , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/sangue
8.
Int J Mol Sci ; 20(13)2019 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-31269783

RESUMO

Atrial natriuretic peptide (ANP) is a cardiac hormone with pleiotropic cardiovascular and metabolic properties including vasodilation, natriuresis and suppression of the renin-angiotensin-aldosterone system. Moreover, ANP induces lipolysis, lipid oxidation, adipocyte browning and ameliorates insulin sensitivity. Studies on ANP genetic variants revealed that subjects with higher ANP plasma levels have lower cardio-metabolic risk. In vivo and in humans, augmenting the ANP pathway has been shown to exert cardiovascular therapeutic actions while ameliorating the metabolic profile. MANP is a novel designer ANP-based peptide with greater and more sustained biological actions than ANP in animal models. Recent studies also demonstrated that MANP lowers blood pressure and inhibits aldosterone in hypertensive subjects whereas cardiometabolic properties of MANP are currently tested in an on-going clinical study in hypertension and metabolic syndrome. Evidence from in vitro, in vivo and in human studies support the concept that ANP and related pathway represent an optimal target for a comprehensive approach to cardiometabolic disease.


Assuntos
Fator Natriurético Atrial/metabolismo , Fator Natriurético Atrial/uso terapêutico , Doenças Cardiovasculares/metabolismo , Doenças Metabólicas/metabolismo , Animais , Fator Natriurético Atrial/genética , Fator Natriurético Atrial/farmacologia , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/genética , Variação Genética , Humanos , Doenças Metabólicas/tratamento farmacológico , Doenças Metabólicas/genética , Terapia de Alvo Molecular
9.
J Toxicol Sci ; 44(7): 505-513, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31270306

RESUMO

Dioxins are a group of structurally related chemicals that persist in the environment. Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the most toxic congener, is a suspected risk factor for cardiac diseases in humans. TCDD induces signs of cardiotoxicity in various animals. Mouse models of TCDD exposure suggest cardiotoxicity phenotypes develop differently depending on the timing and time-course of exposure. In order to clarify and characterize the TCDD-induced cardiotoxicity in the developing period, we utilized mouse pups exposed to TCDD. One day after delivery, groups of nursing C57BL/6J dams were orally administered TCDD at a dose of 0 (Control), 20 (TCDD-20), or 80 µg/kg (TCDD-80) body weight (BW). On postnatal days (PNDs) 7 and 21, pups' hearts were examined by histological and gene expression analyses. The TCDD-80 group was found to have a left ventricular remodeling on PND 7, and to develop heart hypertrophy on PND 21. It was accompanied by fibrosis and increased expression of associated genes, such as those for atrial natriuretic peptide (ANP), ß-myosin heavy chain (ß-MHC), and endothelin-1 (ET-1). These results revealed that TCDD directly induces cardiotoxicity in the postnatal period represented by progressive hypertrophy in which ANP, ß-MHC, and ET-1 have potentials to mediate the cardiac hypertrophy and heart failure.


Assuntos
Cardiomegalia/induzido quimicamente , Cardiomegalia/genética , Cardiotoxicidade , Poluentes Ambientais/metabolismo , Poluentes Ambientais/toxicidade , Insuficiência Cardíaca/induzido quimicamente , Insuficiência Cardíaca/genética , Lactação/metabolismo , Dibenzodioxinas Policloradas/metabolismo , Dibenzodioxinas Policloradas/toxicidade , Administração Oral , Animais , Animais Recém-Nascidos , Fator Natriurético Atrial/genética , Fator Natriurético Atrial/metabolismo , Endotelina-1/genética , Endotelina-1/metabolismo , Poluentes Ambientais/administração & dosagem , Feminino , Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos Endogâmicos C57BL , Modelos Animais , Cadeias Pesadas de Miosina/genética , Cadeias Pesadas de Miosina/metabolismo , Dibenzodioxinas Policloradas/administração & dosagem , Gravidez
10.
Zoolog Sci ; 36(3): 215-222, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-31251490

RESUMO

Anurans occupy a wide variety of habitats of diverse salinities, and their osmoregulatory ability is strongly regulated by hormones. In this study, we compared the adaptability and hormonal responses to osmotic stress between two kajika frogs, Buergeria japonica (B.j.) and B. buergeri, (B.b.), which inhabit coastal brackish waters (BW) in the Ryukyu Islands and freshwater (FW) in the Honshu, respectively. Both hematocrit and plasma Na+ concentration were significantly higher in B.j. than in B.b. when both were kept in FW. After transfer to one-third seawater (simulating the natural BW environment), which is slightly hypertonic to their body fluids, their body mass decreased and plasma Na concentration increased significantly in both species. After transfer, plasma Na+ concentration increased significantly in both species. We examined the gene expression of two major osmoregulatory hormones, arginine vasotocin (AVT) and atrial natriuretic peptide (ANP), after partial cloning of their cDNAs. ANP mRNA levels were more than 10-fold higher in B.j. than in B.b. in FW, but no significant difference was observed for AVT mRNA levels due to high variability, although the mean value of B.j. was twice that of B.b. Both AVT and ANP mRNA levels increased significantly after transfer to BW in B.b. but not in B.j., probably because of the high levels in FW. These results suggest that B.j. maintains high plasma Na+ concentration and anp gene expression to prepare for the future encounter of the high salinity. The unique preparatory mechanism may allow B.j. wide distribution in oceanic islands.


Assuntos
Anuros/fisiologia , Ecossistema , Águas Salinas/química , Tolerância ao Sal/fisiologia , Animais , Fator Natriurético Atrial/metabolismo , Clonagem Molecular , Regulação da Expressão Gênica/efeitos dos fármacos , Japão , Masculino , Osmorregulação/fisiologia , RNA/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Cloreto de Sódio/farmacologia , Vasotocina/metabolismo
11.
Biomarkers ; 24(6): 615-621, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31215249

RESUMO

Purpose: The aim of this study is to evaluate plasma biomarkers as predictors for peripheral arterial disease (PAD). Materials and methods: Prospective longitudinal cohort study of middle-aged individuals from the cardiovascular cohort of the Malmö Diet and Cancer study (MDCS) (n = 5550; 1991-94). Cystatin C, copeptin, N-terminal pro-B-type natriuretic peptide (N-BNP), midregional proatrial natriuretic peptide (MR-proANP), mid-regional proadrenomedullin (MR-proADM), and conventional risk factors were measured at baseline. The diagnosis of symptomatic PAD was validated in 97% of the cases. Results: Cumulative incidence of PAD during median follow up of 23.4 years was 4.4% (men 5.9%, women 3.3%). Adjusted for age, sex, smoking, body mass index, hypertension, diabetes mellitus and total cholesterol, copeptin (hazard ratio [HR] 1.46; 95% confidence interval [CI] 1.19-1.80), N-BNP (HR 1.28; 95% CI 1.11-1.48), and cystatin C (HR 1.19; 95% CI 1.10-1.29) were independently associated with incident PAD. Subjects with the three biomarkers copeptin, N-BNP, and cystatin C in the highest quartiles, ran a high risk of incident PAD (HR 3.29; 95% CI 1.76-6.17) compared to those with no biomarker in the highest quartile. Conclusion: Copeptin, N-BNP, and cystatin C were associated with incident symptomatic PAD, implying that these biomarkers are sensitive indicators of early subclinical PAD. Clinical significance First prospective longitudinal cohort study evaluating Cystatin C, copeptin, N-terminal pro-B-type natriuretic peptide (N-BNP), midregional proatrial natriuretic peptide (MR-proANP), and mid-regional proadrenomedullin (MR-proADM) as predictors for peripheral arterial disease (PAD). Copeptin, N-BNP, and Cystatin C where independently associated with incident symptomatic PAD after adjustment for conventional risk factors. Copeptin, N-BNP, and Cystatin C seem to be sensitive indicators of early subclinical PAD.


Assuntos
Cistatina C/sangue , Glicopeptídeos/sangue , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Doença Arterial Periférica/diagnóstico , Adrenomedulina/sangue , Idoso , Fator Natriurético Atrial/sangue , Biomarcadores/sangue , Colesterol/sangue , Diabetes Mellitus/fisiopatologia , Feminino , Humanos , Hipertensão/fisiopatologia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Doença Arterial Periférica/sangue , Doença Arterial Periférica/epidemiologia , Doença Arterial Periférica/fisiopatologia , Estudos Prospectivos , Precursores de Proteínas/sangue , Fatores de Risco , Fatores Sexuais , Fumar/fisiopatologia , Suécia/epidemiologia
12.
J Korean Med Sci ; 34(17): e133, 2019 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-31050223

RESUMO

BACKGROUND: There have been few studies to evaluate the prognostic implications of guideline-directed therapy according to the temporal course of heart failure. This study assessed the relationship between adherence to guideline-directed therapy at discharge and 60-day clinical outcomes in de novo acute heart failure (AHF) and acute decompensated chronic heart failure (ADCHF) separately. METHODS: Among 5,625 AHF patients who were recruited from a multicenter cohort registry of Korean Acute Heart Failure, 2,769 patients with reduced ejection fraction were analyzed. Guideline-directed therapies were defined as the use of angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor II blocker (ARB), ß-blocker, and mineralocorticoid receptor antagonist. RESULTS: In de novo AHF, ACEI or ARB reduced re-hospitalization (hazard ratio [HR], 0.57; 95% confidence interval [CI], 0.34-0.95), mortality (HR, 0.41; 95% CI, 0.24-0.69) and composite endpoint (HR, 0.52; 95% CI, 0.36-0.77) rates. Beta-blockers reduced re-hospitalization (HR, 0.62; 95% CI, 0.41-0.95) and composite endpoint (HR, 0.65; 95% CI, 0.47-0.90) rates. In ADCHF, adherence to ACEI or ARB was associated with only mortality and ß-blockers with composite endpoint. CONCLUSION: The prognostic implications of adherence to guideline-directed therapy at discharge were more pronounced in de novo heart failure. We recommend that guideline-directed therapy be started as early as possible in the course of heart failure with reduced ejection fraction.


Assuntos
Fidelidade a Diretrizes , Insuficiência Cardíaca/diagnóstico , Doença Aguda , Antagonistas Adrenérgicos beta/uso terapêutico , Idoso , Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Fator Natriurético Atrial/análise , Estudos de Coortes , Feminino , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/mortalidade , Hospitalização/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Alta do Paciente , Prognóstico , Modelos de Riscos Proporcionais , Estudos Prospectivos , Precursores de Proteínas/análise , Sistema de Registros , Taxa de Sobrevida
13.
Arch Endocrinol Metab ; 63(2): 121-127, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31038593

RESUMO

OBJECTIVE: We investigated the utility of maternal fetuin-A, N-terminal proatrial natriuretic peptide (pro-ANP), high-sensitivity C-reactive protein (hs-CRP), and fasting glucose levels at 11-14 gestation weeks for predicting pregnancies complicated by gestational diabetes mellitus (GDM). SUBJECTS AND METHODS: This prospective cohort study included 327 low-risk pregnant women who completed antenatal follow-up at a tertiary research hospital between January and April 2014. Maternal blood samples were collected between 11-14 gestational weeks in the first trimester of pregnancy and then stored at -80 °C until further analyses. During follow-up, 29 (8.8%) women developed GDM. The study population was compared 1:2 with age- and body mass index-matched pregnant women who did not develop GDM (n = 59). Fasting plasma glucose (FPG) levels and serum fetuin-A, pro-ANP, and hs-CRP levels were measured using automated immunoassay systems. RESULTS: There was a significant negative correlation between fetuin-A and hs-CRP (CC = -0.21, p = 0.047) and a positive correlation between FPG and hs-CRP (CC = 0.251, p = 0.018). The areas under the receiver operating characteristic curve for diagnosing GDM were 0.337 (p = 0.013), 0.702 (p = 0.002), and 0.738 (p < 0.001) for fetuin-A, hs-CRP, and FPG, respectively. The optimal cut-off values were > 4.65, < 166, and > 88.5 mg/dL for maternal hs-CRP, fetuin-A, and FPG, respectively. CONCLUSION: Reduced fetuin-A, elevated hs-CRP, and FPG levels in women in the first trimester can be used for the early detection of GDM. Further research is needed before accepting these biomarkers as valid screening tests for GDM.


Assuntos
Fator Natriurético Atrial/sangue , Glicemia/análise , Proteína C-Reativa/análise , Diabetes Gestacional/sangue , Precursores de Proteínas/sangue , alfa-2-Glicoproteína-HS/análise , Adulto , Fator Natriurético Atrial/metabolismo , Biomarcadores/sangue , Biomarcadores/metabolismo , Glicemia/metabolismo , Índice de Massa Corporal , Proteína C-Reativa/metabolismo , Diabetes Gestacional/metabolismo , Feminino , Idade Gestacional , Humanos , Valor Preditivo dos Testes , Gravidez , Primeiro Trimestre da Gravidez/sangue , Estudos Prospectivos , Precursores de Proteínas/metabolismo , Sensibilidade e Especificidade , alfa-2-Glicoproteína-HS/metabolismo
14.
Int J Mol Sci ; 20(9)2019 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-31071921

RESUMO

Activation of multiple pathways is associated with cardiac hypertrophy and heart failure. We previously published that CXCR4 negatively regulates ß-adrenergic receptor (ß-AR) signaling and ultimately limits ß-adrenergic diastolic (Ca2+) accumulation in cardiac myocytes. In isolated adult rat cardiac myocytes; CXCL12 treatment prevented isoproterenol-induced hypertrophy and interrupted the calcineurin/NFAT pathway. Moreover; cardiac specific CXCR4 knockout mice show significant hypertrophy and develop cardiac dysfunction in response to chronic catecholamine exposure in an isoproterenol-induced (ISO) heart failure model. We set this study to determine the structural and functional consequences of CXCR4 myocardial knockout in the absence of exogenous stress. Cardiac phenotype and function were examined using (1) gated cardiac magnetic resonance imaging (MRI); (2) terminal cardiac catheterization with in vivo hemodynamics; (3) histological analysis of left ventricular (LV) cardiomyocyte dimension; fibrosis; and; (4) transition electron microscopy at 2-; 6- and 12-months of age to determine the regulatory role of CXCR4 in cardiomyopathy. Cardiomyocyte specific-CXCR4 knockout (CXCR4 cKO) mice demonstrate a progressive cardiac dysfunction leading to cardiac failure by 12-months of age. Histological assessments of CXCR4 cKO at 6-months of age revealed significant tissue fibrosis in knockout mice versus wild-type. The expression of atrial naturietic factor (ANF); a marker of cardiac hypertrophy; was also increased with a subsequent increase in gross heart weights. Furthermore, there were derangements in both the number and the size of the mitochondria within CXCR4 cKO hearts. Moreover, CXCR4 cKO mice were more sensitive to catocholamines, their response to ß-AR agonist challenge via acute isoproterenol (ISO) infusion demonstrated a greater increase in ejection fraction, dp/dtmax, and contractility index. Interestingly, prior to ISO infusion, there were significant differences in baseline hemodynamics between the CXCR4 cKO compared to littermate controls. However, upon administering ISO, the CXCR4 cKO responded in a robust manner overcoming the baseline hemodynamic deficits reaching WT values supporting our previous data that CXCR4 negatively regulates ß-AR signaling. This further supports that, in the absence of the physiologic negative modulation, there is an overactivation of down-stream pathways, which contribute to the development and progression of contractile dysfunction. Our results demonstrated that CXCR4 plays a non-developmental role in regulating cardiac function and that CXCR4 cKO mice develop a progressive cardiomyopathy leading to clinical heart failure.


Assuntos
Cardiomiopatias/genética , Insuficiência Cardíaca/genética , Receptores CXCR4/genética , Animais , Fator Natriurético Atrial/genética , Cardiomiopatias/fisiopatologia , Quimiocina CXCL12/genética , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Coração/efeitos dos fármacos , Coração/fisiopatologia , Insuficiência Cardíaca/fisiopatologia , Humanos , Isoproterenol/administração & dosagem , Camundongos , Camundongos Knockout , Mitocôndrias Cardíacas/genética , Mitocôndrias Cardíacas/patologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Receptores Adrenérgicos beta/genética , Transdução de Sinais/genética
15.
Int J Mol Sci ; 20(9)2019 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-31072047

RESUMO

C-type natriuretic peptide (CNP) is an autocrine and paracrine mediator released by endothelial cells, cardiomyocytes and fibroblasts that regulates vital physiological functions in the cardiovascular system. These roles are conveyed via two cognate receptors, natriuretic peptide receptor B (NPR-B) and natriuretic peptide receptor C (NPR-C), which activate different signalling pathways that mediate complementary yet distinct cellular responses. Traditionally, CNP has been deemed the endothelial component of the natriuretic peptide system, while its sibling peptides, atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), are considered the endocrine guardians of cardiac function and blood volume. However, accumulating evidence indicates that CNP not only modulates vascular tone and blood pressure, but also governs a wide range of cardiovascular effects including the control of inflammation, angiogenesis, smooth muscle and endothelial cell proliferation, atherosclerosis, cardiomyocyte contractility, hypertrophy, fibrosis, and cardiac electrophysiology. This review will focus on the novel physiological functions ascribed to CNP, the receptors/signalling mechanisms involved in mediating its cardioprotective effects, and the development of therapeutics targeting CNP signalling pathways in different disease pathologies.


Assuntos
Etanolaminas/metabolismo , Miocárdio/metabolismo , Peptídeo Natriurético Tipo C/genética , Comunicação Parácrina/genética , Fenetilaminas/metabolismo , Fator Natriurético Atrial/genética , Sistema Cardiovascular/metabolismo , Sistema Cardiovascular/patologia , Células Endoteliais/metabolismo , Humanos , Miócitos Cardíacos/metabolismo , Peptídeo Natriurético Encefálico/genética , Peptídeo Natriurético Tipo C/metabolismo , Receptores do Fator Natriurético Atrial/genética
16.
Internist (Berl) ; 60(6): 587-596, 2019 Jun.
Artigo em Alemão | MEDLINE | ID: mdl-31089771

RESUMO

Biomarkers may help to rapidly differentiate heart failure from noncardiac causes of acute dyspnea. Natriuretic peptides are especially useful for this purpose and should be measured in all patients presenting with acute onset dyspnea. Due to their excellent negative predictive value, a normal serum concentration of natriuretic peptides makes acute heart failure unlikely. Assays exist for B­type natriuretic peptide (BNP), N­terminal pro-B-type natriuretic peptide (NT-proBNP) and midregional pro-atrial natriuretic peptide (MR-proANP) with established cut-offs in the acute setting. Importantly, in patients treated with an angiotensin receptor-neprilysin inhibitor (ARNI), NT-proBNP (or MR-proANP) should be used instead of BNP, since the latter is increased by ARNI treatment. Besides their established diagnostic value in heart failure patients, the measurement of natriuretic peptides provides prognostic information and may help in guiding therapy. Additionally, multiple other biomarkers reflect several pathophysiological processes involved in heart failure patients. Their diagnostic and prognostic impact in heart failure needs to be established.


Assuntos
Biomarcadores/sangue , Dispneia/diagnóstico , Insuficiência Cardíaca/diagnóstico , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Doença Aguda , Fator Natriurético Atrial/sangue , Dispneia/sangue , Insuficiência Cardíaca/sangue , Humanos , Prognóstico
17.
Zhongguo Zhong Yao Za Zhi ; 44(8): 1642-1647, 2019 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-31090329

RESUMO

This paper was aimed to investigate the inhibitory effect of aconitine(AC) on angiotensin Ⅱ(Ang Ⅱ)-induced H9 c2 cell hypertrophy and explore its mechanism of action. The model of hypertrophy was induced by Ang Ⅱ(1×10-6 mol·L-1),and cardiomyocytes were incubated with different concentrations of AC. Western blot was used to quantify the protein expression levels of atrial natriuretic peptide(ANP),brain natriuretic peptide(BNP),ß-myosin heavy chain(ß-MHC),and α-smooth muscle actin(α-SMA). Real-time quantitative PCR(qRT-PCR) was used to quantify the mRNA expression levels of cardiac hypertrophic markers ANP,BNP and ß-MHC. In addition,the fluorescence intensity of the F-actin marker,an important component of myofibrils,was detected by using laser confocal microscope. AC could significantly reverse the increase of total protein content in H9 c2 cells induced by Ang Ⅱ; qRT-PCR results showed that AC could significantly inhibit the ANP,BNP and ß-MHC mRNA up-regulation induced by AngⅡ. Western blot results showed that AC could significantly inhibit the ANP,BNP and ß-MHC protein up-regulation induced by AngⅡ. In addition,F-actin expression induced by Ang Ⅱ could be inhibited by AC,and multiple indicators of cardiomyocyte hypertrophy induced by Ang Ⅱ could be down-regulated,indicating that AC may inhibit cardiac hypertrophy by inhibiting the expression of hypertrophic factors,providing new clues for exploring the cardiovascular protection of AC.


Assuntos
Aconitina/farmacologia , Angiotensina II , Miócitos Cardíacos/efeitos dos fármacos , Actinas/metabolismo , Fator Natriurético Atrial/metabolismo , Miosinas Cardíacas/metabolismo , Cardiomegalia , Células Cultivadas , Humanos , Hipertrofia , Cadeias Pesadas de Miosina/metabolismo , Peptídeo Natriurético Encefálico/metabolismo
18.
ACS Appl Mater Interfaces ; 11(17): 15316-15321, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30969098

RESUMO

Nanoparticles have been assessed in preclinical models of atherosclerosis for detection of plaque complexity and treatment. However, their successful clinical translation has been hampered by less than satisfactory plaque detection and lack of a general strategy for assessing the translational potential of nanoparticles. Herein, nanoparticles based on comb-co-polymer assemblies were synthesized through a modular construction approach with precise control over the conjugation of multiple functional building blocks for in vivo evaluation. This high level of design control also allows physicochemical properties to be varied in a controllable fashion. Through conjugation of c-atrial natriuretic factor (CANF) peptide and radiolabeling with 64Cu, the 64Cu-CANF-comb nanoparticle was assessed for plaque imaging by targeting natriuretic peptide clearance receptor (NPRC) in a double-injury atherosclerosis model in rabbits. The prolonged blood circulation and enhanced binding capacity of 64Cu-CANF-comb nanoparticles provided sensitive and specific imaging of NPRC overexpressed in atherosclerotic lesions by positron emission tomography at intervals during the progression of the disease. Ex vivo tissue validation using autoradiography and immunostaining on human carotid endarterectomy specimens demonstrated specific binding of 64Cu-CANF-comb to human NPRC receptors. Taken together, this study not only shows the potential of NPRC-targeted 64Cu-CANF-comb nanoparticles for increased sensitivity to an epitope that increases during atherosclerosis plaque development but also provides a useful strategy for the general design and assessment of the translational potential of nanoparticles in cardiovascular imaging.


Assuntos
Nanopartículas/química , Tomografia por Emissão de Pósitrons , Animais , Aterosclerose/diagnóstico por imagem , Aterosclerose/patologia , Fator Natriurético Atrial/química , Fator Natriurético Atrial/metabolismo , Radioisótopos de Cobre/química , Modelos Animais de Doenças , Artéria Femoral/diagnóstico por imagem , Humanos , Placa Aterosclerótica/diagnóstico por imagem , Placa Aterosclerótica/patologia , Coelhos , Compostos Radiofarmacêuticos/química , Receptores do Fator Natriurético Atrial/química , Receptores do Fator Natriurético Atrial/metabolismo
19.
J Vet Med Sci ; 81(5): 776-779, 2019 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-30930345

RESUMO

This study investigated the direct effects of non-steroidal anti-inflammatory drugs (NSAIDs) and atrial natriuretic peptide (ANP) on canine-derived vascular endothelial cells (VECs). VECs were isolated and cultured from canine arteries and veins. The mRNA expressions of vascular endothelial growth factor receptor 2, cyclooxygenase-2, and natriuretic peptide receptor 1 were detected in the cultured VECs. The viability of the cultured VECs was reduced in a dose-dependent manner by meloxicam, carprofen, and robenacoxib. By contrast, dose escalations of ANP had only marginal influence on the viability of cultured VECs. NSAIDs may potentially serve as not only analgesic agents against cancerous and perioperative pain but also as adjuvant anti-angiogenic drugs in dogs with malignant tumors.


Assuntos
Inibidores da Angiogênese/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Fator Natriurético Atrial/farmacologia , Endotélio Vascular/efeitos dos fármacos , Animais , Carbazóis/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Difenilamina/análogos & derivados , Difenilamina/farmacologia , Cães , Expressão Gênica , Meloxicam/farmacologia , Fenilacetatos/farmacologia , RNA Mensageiro , Receptores do Fator Natriurético Atrial/genética , Receptores do Fator Natriurético Atrial/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
20.
Cardiovasc Diabetol ; 18(1): 45, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30935417

RESUMO

BACKGROUND: Sodium glucose co-transporter 2 inhibitor (SGLT2i), a new class of anti-diabetic drugs acting on inhibiting glucose resorption by kidneys, is shown beneficial in reduction of heart failure hospitalization and cardiovascular mortality. The mechanisms remain unclear. We hypothesized that SGLT2i, empagliflozin can improve cardiac hemodynamics in non-diabetic hypertensive heart failure. METHODS AND RESULTS: The hypertensive heart failure model had been created by feeding spontaneous hypertensive rats (SHR) with high fat diet for 32 weeks (total n = 13). Half SHRs were randomized to be administered with SGLT2i, empagliflozin at 20 mg/kg/day for 12 weeks. After evaluation of electrocardiography and echocardiography, invasive hemodynamic study was performed and followed by blood sample collection and tissue analyses. Empagliflozin exhibited cardiac (improved atrial and ventricular remodeling) and renal protection, while plasma glucose level was not affected. Empagliflozin normalized both end-systolic and end-diastolic volume in SHR, in parallel with parameters in echocardiographic evaluation. Empagliflozin also normalized systolic dysfunction, in terms of the reduced maximal velocity of pressure incline and the slope of end-systolic pressure volume relationship in SHR. In histological analysis, empagliflozin significantly attenuated cardiac fibrosis in both atrial and ventricular tissues. The upregulation of atrial and ventricular expression of PPARα, ACADM, natriuretic peptides (NPPA and NPPB), and TNF-α in SHR, was all restored by treatment of empagliflozin. CONCLUSIONS: Empagliflozin improves hemodynamics in our hypertensive heart failure rat model, associated with renal protection, attenuated cardiac fibrosis, and normalization of HF genes. Our results contribute some understanding of the pleiotropic effects of empagliflozin on improving heart function.


Assuntos
Compostos Benzidrílicos/farmacologia , Glucosídeos/farmacologia , Insuficiência Cardíaca/tratamento farmacológico , Hemodinâmica/efeitos dos fármacos , Hipertensão/complicações , Miocárdio/patologia , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Função Ventricular Esquerda/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos , Animais , Função do Átrio Esquerdo/efeitos dos fármacos , Fator Natriurético Atrial/genética , Fator Natriurético Atrial/metabolismo , Dieta Hiperlipídica , Modelos Animais de Doenças , Ácidos Graxos/metabolismo , Fibrose , Regulação da Expressão Gênica , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/fisiopatologia , Hipertensão/fisiopatologia , Masculino , Miocárdio/metabolismo , Peptídeo Natriurético Encefálico/genética , Peptídeo Natriurético Encefálico/metabolismo , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Recuperação de Função Fisiológica , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
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