RESUMO
Acute ischemic stroke (AIS) is a challenging disease, which needs urgent comprehensive management. Endovascular thrombectomy (EVT), alone or combined with iv thrombolysis, is currently the most effective therapy for patients with acute ischemic stroke (AIS). However, only a limited number of patients are eligible for this time-sensitive treatment. Even though there is still significant room for improvement in the management of this group of patients, up until now there have been no alternative therapies approved for use in clinical practice. However, there is still hope, as clinical research with novel emerging therapies is now generating promising results. These drugs happen to stop or palliate some of the underlying molecular mechanisms involved in cerebral ischemia and secondary brain damage. The aim of this review is to provide a deep understanding of these mechanisms and the pathogenesis of AIS. Later, we will discuss the potential therapies that have already demonstrated, in preclinical or clinical studies, to improve the outcomes of patients with AIS.
Assuntos
Acidente Vascular Cerebral , Humanos , Acidente Vascular Cerebral/terapia , AVC Isquêmico/terapia , Animais , Trombectomia/métodos , Gerenciamento Clínico , Isquemia Encefálica/terapia , Terapia Trombolítica/métodosRESUMO
BACKGROUND: Adverse environmental conditions during intrauterine life, known as fetal programming, significantly contribute to the development of diseases in adulthood. Fetal programming induced by factors like maternal undernutrition leads to low birth weight and increases the risk of cardiometabolic diseases. METHODS: We studied a rat model of maternal undernutrition during gestation (MUN) to investigate gene expression changes in cardiac tissue using RNA-sequencing of day 0-1 litters. Moreover, we analyzed the impact of lactation at day 21, in MUN model and cross-fostering experiments, on cardiac structure and function assessed by transthoracic echocardiography, and gene expression changes though qPCR. RESULTS: Our analysis identified specific genes with altered expression in MUN rats at birth. Two of them, Agt and Pparg, stand out for being associated with cardiac hypertrophy and fibrosis. At the end of the lactation period, MUN males showed increased expression of Agt and decreased expression of Pparg, correlating with cardiac hypertrophy. Cross-fostering experiments revealed that lactation with control breastmilk mitigated these expression changes reducing cardiac hypertrophy in MUN males. CONCLUSIONS: Our findings highlight the interplay between fetal programming, gene expression, and cardiac hypertrophy suggesting that lactation period is a potential intervention window to mitigate the effects of fetal programming. IMPACT: Heart remodeling involves the alteration of several groups of genes and lactation period plays a key role in establishing gene expression modification caused by fetal programming. We could identify expression changes of relevant genes in cardiac tissue induced by undernutrition during fetal life. We expose the contribution of the lactation period in modulating the expression of Agt and Pparg, relevant genes associated with cardiac hypertrophy. This evidence reveal lactation as a crucial intervention window for preventing or countering fetal programming.
Assuntos
Cardiomegalia , Desenvolvimento Fetal , Lactação , Desnutrição , Animais , Feminino , Gravidez , Ratos , Masculino , Cardiomegalia/genética , Cardiomegalia/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , PPAR gama/metabolismo , PPAR gama/genética , Modelos Animais de DoençasRESUMO
Low birth weight (LBW) and accelerated growth during lactation are associated with cardiometabolic disease development. LBW offspring from rats exposed to undernutrition during gestation (MUN) develops hypertension. In this rat model, we tested if slower postnatal growth improves early cardiometabolic alterations. MUN dams were fed ad libitum during gestation days 1-10, with 50% of the daily intake during days 11-21 and ad libitum during lactation. Control dams were always fed ad libitum. Pups were maintained with their own mother or cross-fostered. Body weight and length were recorded weekly, and breastmilk was obtained. At weaning, the heart was evaluated by echocardiography, and aorta structure and adipocytes in white perivascular fat were studied by confocal microscopy (size, % beige-adipocytes by Mitotracker staining). Breastmilk protein and fat content were not significantly different between groups. Compared to controls, MUN males significantly accelerated body weight gain during the exclusive lactation period (days 1-14) while females accelerated during the last week; length growth was slower in MUN rats from both sexes. By weaning, MUN males, but not females, showed reduced diastolic function and hypertrophy in the heart, aorta, and adipocytes; the percentage of beige-type adipocytes was smaller in MUN males and females. Fostering MUN offspring on control dams significantly reduced weight gain rate, cardiovascular, and fat hypertrophy, increasing beige-adipocyte proportion. Control offspring nursed by MUN mothers reduced body growth gain, without cardiovascular modifications. In conclusion, slower growth during lactation can rescue early cardiovascular alterations induced by fetal undernutrition. Exclusive lactation was a key period, despite no modifications in breastmilk macronutrients, suggesting the role of bioactive components. Our data support that lactation is a key period to counteract cardiometabolic disease programming in LBW and a potential intervention window for the mother.
RESUMO
We previously observed that esmolol treatment for 48 h reduced vascular lesions in spontaneously hypertensive rats (SHRs). Therefore, we investigated whether this beneficial effect is persistent after withdrawal. Fourteen-month-old SHRs (SHR-Es) were treated with esmolol (300 µg/kg/min) or a vehicle for 48 h. Two separate groups were also given identical treatment, but they were then monitored for a further 1 week and 1 month after drug withdrawal. We analyzed the geometry and composition of the coronary artery, vascular reactivity and plasma redox status. Esmolol significantly decreased wall thickness (medial layer thickness and cell count), external diameter and cross-sectional area of the artery, and this effect persisted 1 month after drug withdrawal. Esmolol significantly improved endothelium-dependent relaxation by ACh (10-9-10-4 mol/L); this effect persisted 1 week (10-9-10-4 mol/L) and 1 month (10-6-10-4 mol/L) after withdrawal. Esmolol reduced the contraction induced by 5-HT (3 × 10-8-3 × 10-5 mol/L), and this effect persisted 1 week after withdrawal (10-6-3 × 10-5 mol/L). Esmolol increased nitrates and reduced glutathione, and it decreased malondialdehyde and carbonyls; this enhancement was maintained 1 month after withdrawal. This study shows that the effect of esmolol on coronary remodeling is persistent after treatment withdrawal in SHRs, and the improvement in plasma oxidative status can be implicated in this effect.
RESUMO
Cardiac output (CO) measurement is mandatory in patients with left ventricular assist devices (LVADs). Thermodilution with pulmonary artery catheter (PAC) remains the clinical gold standard to measure CO in these patients, however it is associated with several complications. Therefore, the agreement between PAC and new, minimally invasive monitoring methods in LVAD needs to be further investigated. The aim of this study was to assess the accuracy and reliability of transpulmonary thermodilution with a PiCCO2 monitor compared with pulmonary artery thermodilution with PAC in a LVAD. Continuous-flow LVADs were implanted in six mini-pigs to assist the left ventricle. We studied two methods of measuring CO-intermittent transpulmonary thermodilution (COTPTD) by PiCCO2 and intermittent pulmonary artery thermodilution by CAP, standard technique (COPTD)-obtained in four consecutive moments of the study: before starting the LVAD (basal moment), and with the LVAD started in normovolemia, hypervolemia (fluid overloading) and hypovolemia (shock hemorrhage). A total of 72 paired measurements were analysed. At the basal moment, COTPTD and COPTD were closely correlated (r 2 = 0.89), with a mean bias of -0.085 ± 0.245 L/min and percentage error of 16%. After 15 min of partial support LVAD, COTPTD and COPTD were closely correlated (r 2 = 0.79), with a mean bias of -0.040 ± 0.417 L/min and percentage error of 26%. After inducing hypervolemia, COTPTD and COPTD were closely correlated (r 2 = 0.78), with a mean bias of -0.093 ± 0.339 L/min and percentage error of 13%. After inducing hypovolemia, COTPTD and COPTD were closely correlated (r 2 = 0.76), with a mean bias of -0.045 ± 0.281 L/min and percentage error of 28%. This study demonstrates a good agreement between transpulmonary thermodilution by PiCCO monitor and pulmonary thermodilution by PAC in the intermittent measurement of CO in a porcine model with a continuous-flow LVAD.
RESUMO
Cardiac output (CO) measurement by continuous pulmonary artery thermodilution (CO CTD ) has been studied in patients with pulsatile-flow LVADs (left ventricular assist devices), confirming the clinical utility. However, it has not been validated in patients with continuous-flow LVADs. Therefore, the aim of this study was to assess the validity of CO CTD in continuous-flow LVADs. Continuous-flow LVADs were implanted in six miniature pigs for partial assistance of the left ventricle. Both methods of measuring CO-measurement by CO CTD and intermittent pulmonary artery thermodilution, standard technique (CO ITD )-were used in four consecutive moments of the study: before starting the LVAD (basal moment), and with the LVAD started in normovolemia, hypervolemia (fluid overloading), and hypovolemia (shock hemorrhage). At the basal moment, CO CTD and CO ITD were closely correlated (r 2 = 0.97), with a mean bias of -0.13 ± 0.16 L/min and percentage error of 11%. After 15 min of partial support LVAD, CO CTD and CO ITD were closely correlated (r 2 = 0.91), with a mean bias of 0.31 ± 0.35 L/min and percentage error of 20%. After inducing hypervolemia, CO CTD and CO ITD were closely correlated (r 2 = 0.99), with a mean bias of 0.04 ± 0.07 L/min and percentage error of 5%. After inducing hypovolemia, CO CTD and CO ITD were closely correlated (r 2 = 0.74), with a mean bias of 0.08 ± 0.22 L/min and percentage error of 19%. This study shows that continuous pulmonary thermodilution could be an alternative method of monitoring CO in a porcine model with a continuous-flow LVAD.
RESUMO
Fetal undernutrition is a risk factor for cardiovascular diseases. Male offspring from rats exposed to undernutrition during gestation (MUN) exhibit oxidative stress during perinatal life and develop cardiac dysfunction in ageing. Angiotensin-II is implicated in oxidative stress-mediated cardiovascular fibrosis and remodeling, and lactation is a key developmental window. We aimed to assess if alterations in RAS during lactation participate in cardiac dysfunction associated with fetal undernutrition. Control dams received food ad libitum, and MUN had 50% nutrient restriction during the second half of gestation. Both dams were fed ad libitum during lactation, and male offspring were studied at weaning. We assessed: ventricular structure and function (echocardiography); blood pressure (intra-arterially, anesthetized rats); collagen content and intramyocardial artery structure (Sirius red, Masson Trichromic); myocardial and intramyocardial artery RAS receptors (immunohistochemistry); plasma angiotensin-II (ELISA) and TGF-ß1 protein expression (Western Blot). Compared to Control, MUN offspring exhibited significantly higher plasma Angiotensin-II and a larger left ventricular mass, as well as larger intramyocardial artery media/lumen, interstitial collagen and perivascular collagen. In MUN hearts, TGF-ß1 tended to be higher, and the end-diastolic diameter and E/A ratio were significantly lower with no differences in ejection fraction or blood pressure. In the myocardium, no differences between groups were detected in AT1, AT2 or Mas receptors, with MrgD being significantly lower in the MUN group. In intramyocardial arteries from MUN rats, AT1 and Mas receptors were significantly elevated, while AT2 and MrgD were lower compared to Control. Conclusions. In rats exposed to fetal undernutrition, RAS disbalance and associated cardiac remodeling during lactation may set the basis for later heart dysfunction.
RESUMO
Untreated chronic hypertension causes left ventricular hypertrophy, which is related to the occurrence of atrial fibrillation. Dronedarone is an antiarrhythmic agent recently approved for atrial fibrillation. Our group previously demonstrated that dronedarone produced an early regression of left ventricular hypertrophy after 14 days of treatment in an experimental study. In this study, we analyze the possible mechanisms responsible for this effect. Ten-month-old male spontaneously hypertensive rats (SHRs, n = 16) were randomly divided into therapy groups: SHR-D, which received dronedarone, and hypertensive controls, SHR, which received saline. Ten-month-old male Wistar Kyoto rats (WKY, n = 8), which also received a saline solution, were selected as normotensive controls. After 14 days of treatment, echocardiographic measurements of the left ventricle were performed, blood samples were collected for thiol-specific oxidative stress analysis, and the left ventricles were processed for western blot analysis. Dronedarone significantly lowered the left ventricular mass index and relative wall thickness compared with the SHR control group, and no differences were observed between the SHR-D group and the WKY rats. Interestingly, the SHR-D group showed significantly decreased levels of nuclear factor of activated T cells 4 (p-NFATc4), extracellular-signal-regulated kinase 1/2 (p-ERK1/2), and protein kinase B (p-AKT) compared with the hypertensive controls without statistical differences when compared with the WKY rats. Moreover, the SHR control group showed elevated thiolated protein levels and protein thiolation index (PTI) compared with the WKY rats. After treatment with dronedarone, both parameters decreased with respect to the SHR control group until reaching similar levels to the WKY rats. Our study suggests that dronedarone produces inhibition of the NFATc4/ERK/AKT pathway and improvement of thiol-specific oxidative stress possibly secondary to the reduction of blood pressure in an animal model of ventricular hypertrophy.
RESUMO
BACKGROUND: A recently developed global indicator of oxidative stress (OXY-SCORE), by combining individual plasma biomarkers of oxidative damage and antioxidant capacity, has been validated in several pathologies, but not in left ventricular hypertrophy (LVH). The aim of this study was to design and calculate a plasma oxidative stress global index for patients with LVH. METHODS: A total of 70 consecutive adult patients were recruited in our institution and assigned to one of the two study groups (control group/LVH group) by an echocardiography study. We evaluated plasmatic biomarkers of oxidative damage (malondialdehyde and thiolated proteins) and antioxidant defense (total thiols, reduced glutathione, total antioxidant capacity, catalase, and superoxide dismutase activities) by spectrophotometry/fluorimetry in order to calculate a plasma oxidative stress global index (OXY-SCORE) in relation to LVH. RESULTS: The OXY-SCORE exhibited a highly significant difference between the groups (p < 0.001). The area under the receiver operating characteristic curve was 0.74 (95% confidence interval (CI), 0.62-0.85; p < 0.001). At a cut-off value of -1, the 68.6% sensitivity and 68.6% specificity values suggest that OXY-SCORE could be used to screen for LVH. A multivariable logistic regression model showed a positive association (p = 0.001) between OXY-SCORE and LVH [odds ratio = 0.55 (95% CI, 0.39-0.79)], independent of gender, age, smoking, glucose, systolic and diastolic arterial pressure, dyslipidemia, estimated glomerular filtration rate, body mass index, and valvular/coronary disease. CONCLUSION: OXY-SCORE could help in the diagnosis of LVH and could be used to monitor treatment response.
RESUMO
BACKGROUND: Our group has previously shown that short-term treatment (48â¯h) with esmolol reduces left ventricular hypertrophy (LVH) in spontaneously hypertensive rats (SHRs). However, we do not know the mechanism that explain this effect. The aim of this study was to assess the role that the subcellular organelle phenotype plays in early cardiac reverse after short-term treatment with esmolol. METHODS: 14-Month-old male SHRs were randomly assigned to receive esmolol (300⯵g/kg/min) (SHR-E) or vehicle (SHR). Age-matched male Wistar-Kyoto rats (WKY) served as controls. After 48â¯h of treatment, an ultrastructural analysis of heart tissue (left ventricle) was performed. We studied cardiomyocyte ultrastructural remodeling of subcellular organelles by electronic microcopy in all groups. RESULTS: SHR group showed significant morphometric and stereological changes in mitochondria and subcellular organelles (cytoplasm and nucleus, myofibril structure, mitochondria structure, Z-Disk, intercalated disk, T-system and cystern), and also changes in the extracellular matrix (collagen) with respect to WKY group. Esmolol significantly improved the morphology and stereology mitochondrial, reduced the organelle phenotype abnormalities but no produced changes in the extracellular matrix with respect to SHR group. Interesantly, parameters of mitochondria (regularity factor, ellipsoidal form factor and density of volume), and all parameters of subcellular organelles returned to the normality in SHR-E. CONCLUSION: Our results show that left ventricular hypertrophy reversal after short-term treatment with esmolol is associated with reversal of subcellular organelle phenotype.
Assuntos
Hipertrofia Ventricular Esquerda/tratamento farmacológico , Miocárdio/patologia , Miocárdio/ultraestrutura , Organelas/patologia , Organelas/ultraestrutura , Propanolaminas/farmacologia , Animais , Coração/fisiopatologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Ratos Endogâmicos SHR , Ratos Endogâmicos WKYRESUMO
Dronedarone is recommended for the treatment of atrial fibrillation. However, we do not know its effect on vascular remodeling. This study was designed to assess whether dronedarone has the potential to improve the intramyocardial artery remodeling induced by chronic hypertension. Ten-month-old male spontaneously hypertensive rats (SHR) were randomly assigned to receive dronedarone (100 mg/kg) or vehicle. Age-matched male Wistar-Kyoto rats served as controls. After 14 days of treatment, we studied the structure (geometry and fibrosis) of the intramyocardial artery using histological analysis. Nitric oxide (NO) in plasma was analyzed. In the untreated SHR, we observed a significant increase in external diameter, lumen diameter, wall width, cross-sectional area, and collagen volume density, as was expected in the experimental model. Dronedarone induced a significant decrease in wall width, cross-sectional area, and collagen volume density in SHR-D in comparison with untreated SHR. The values obtained in SHR-D were similar in the WKY control group. We found significantly higher NO levels in plasma in SHR-D than in untreated SHR. Dronedarone improves the intramyocardial artery remodeling induced by chronic hypertension in SHR through increased nitric oxide bioavailability.
Assuntos
Vasos Coronários , Dronedarona/farmacologia , Hipertensão , Óxido Nítrico/sangue , Remodelação Vascular/efeitos dos fármacos , Animais , Doença Crônica , Vasos Coronários/metabolismo , Vasos Coronários/patologia , Vasos Coronários/fisiopatologia , Hipertensão/sangue , Hipertensão/tratamento farmacológico , Hipertensão/patologia , Hipertensão/fisiopatologia , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKYRESUMO
BACKGROUND: Left ventricular hypertrophy (LVH) has been associated with oxidative stress, although not with the protein thiolation index (PTI). This study explored the potential use of PTI as a biomarker of oxidative stress in patients with LVH. METHODS: We recruited 70 consecutive patients (n = 35 LVH and n = 35 non-LVH) based on an echocardiography study in our institution (left ventricular mass indexed to body surface area). Plasma levels of both S-thiolated protein and total thiols were measured as biomarkers of oxidative stress by spectrophotometry, and PTI was calculated as the molar ratio between S-thiolated proteins and the total thiol concentration. RESULTS: Values for plasma S-thiolated proteins were higher in patients with LVH than in the control group (P = 0.01). There were no differences in total thiols between the LVH group and the control group. Finally, PTI was higher in patients with LVH than in the control group (P = 0.001). The area under the ROC curve was 0.75 (95% CI, 0.63-0.86; P<0.001), sensitivity was 70.6%, and specificity was 68.6%, thus suggesting that PTI could be used to screen for LVH. A multivariable logistic regression model showed a positive association (P = 0.02) between PTI and LVH (OR = 1.24 [95% CI, 1.03-1.49]) independently of gender (OR = 3.39 [95% CI, 0.60-18.91]), age (OR = 1.03 [95% CI, 0.96-1.10]), smoking (OR = 5.15 [95% CI, 0.51-51.44]), glucose (OR = 0.99 [95% CI, 0.97-1.01]), systolic arterial pressure (OR = 1.10 [CI 1.03-1.17]), diastolic arterial pressure (OR = 0.94 [CI 0.87-1.02]), dyslipidemia (OR = 1.46 [95% CI, 0.25-8.55]), estimated glomerular filtration rate (OR = 0.98 [95% CI, 0.96-1.01]), body mass index (OR = 1.03 [95% CI, 0.90-1.10]), and valvular and/or coronary disease (OR = 5.27 [95% CI, 1.02-27.21]). CONCLUSIONS: The present study suggests that PTI could be a new biomarker of oxidative stress in patients with LVH.
Assuntos
Proteínas Sanguíneas/metabolismo , Hipertrofia Ventricular Esquerda/diagnóstico , Compostos de Sulfidrila/sangue , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Estudos de Casos e Controles , Feminino , Humanos , Hipertrofia Ventricular Esquerda/metabolismo , Masculino , Pessoa de Meia-Idade , Estresse OxidativoRESUMO
BACKGROUND AND AIMS: Dronedarone is a new multichannel-blocking antiarrhythmic for the treatment of patients with atrial fibrillation. Our group has demonstrated that dronedarone produces regression of cardiac remodeling; however, its effect on the remodeling of the elastic arteries has not yet been reported. We aim to assess the effects of dronedarone on the regression of thoracic aortic remodeling in spontaneously hypertensive rats (SHRs). METHOD: Ten-month-old male SHRs were randomly assigned to an intervention group (SHR-D), where the animals received dronedarone treatment (100 mg/kg), to a control group (SHR) where rats were given vehicle, or to a group (SHR-A) where they were given amiodarone. A fourth group of normotensive control rats (Wistar-Kyoto rats, WKY) was also added. After two weeks of treatment, we studied the structure, the elastic fiber content of the thoracic aorta using histological techniques and confocal microscopy, and the vascular mechanical properties using an organ bath and isometric tension analysis. A mass spectrometric determination of symmetric dimethylarginine (SDMA) concentrations was performed. RESULTS: SHR group developed the classic remodeling expected from the experimental model: outward hypertrophic remodeling, increased elastic fiber content and wall stiffness. However, the SHR-D group showed statistically significantly lower values for aortic tunica media thickness, wall to lumen ratio, external diameter, cross-sectional area, volume density of the elastic fibers, wall stiffness, and aortic SDMA concentration when compared to the SHR group. These parameters were similar in the SHR and SHR-A groups. Interestingly, the values for tunica media thickness, volume density of the elastic fibers, wall stiffness, and SDMA concentration obtained from the SHR-D group were similar to those measured in the WKY group. CONCLUSION: These results suggest that dronedarone improves the structure and passive mechanical properties of the thoracic aorta in hypertensive rats, and that this protective effect could be associated with a reduction in the concentration of aortic SDMA.
Assuntos
Aorta Torácica/metabolismo , Arginina/análogos & derivados , Dronedarona/farmacologia , Hipertensão/tratamento farmacológico , Remodelação Vascular/efeitos dos fármacos , Animais , Aorta Torácica/patologia , Arginina/metabolismo , Hipertensão/metabolismo , Hipertensão/patologia , Masculino , Microscopia Confocal , Distribuição Aleatória , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKYRESUMO
Our group previously demonstrated that dronedarone induces regression of left ventricular hypertrophy in spontaneously hypertensive rats (SHRs). We assessed changes in vascular remodeling and oxidative stress following short-term use of this agent. The coronary artery was isolated from 10-month-old male SHRs treated with 100 mg kg-1 dronedarone once daily for 14 days (SHR-D group), and age-matched untreated SHRs were used as hypertensive controls. We analyzed the geometry and composition of the artery and constructed dose-response curves for acetylcholine and serotonin (5-HT). We calculated a global score (OXY-SCORE) from plasma biomarkers of oxidative status: carbonyl levels, thiol levels, reduced glutathione levels, total antioxidant capacity, and superoxide anion scavenging activity. Finally, we analyzed asymmetric dimethylarginine (ADMA) concentrations in plasma. Dronedarone significantly decreased wall thickness (medial and adventitial layer thickness and cell count) and the cross-sectional area of the artery. Dronedarone significantly improved endothelium-dependent relaxation and reduced the contraction induced by 5-HT. The OXY-SCORE was negative in the SHR model group (suggesting an enhanced oxidative status) and was positive in the SHR-D group (suggesting enhanced antioxidant defense). Dronedarone significantly decreased the concentrations of ADMA. We conclude that dronedarone improves coronary artery remodeling in SHRs. The better global antioxidant status after treatment with dronedarone and decreased plasma ADMA levels could contribute to the cardiovascular protective effect of dronedarone.
Assuntos
Antioxidantes/metabolismo , Vasos Coronários/efeitos dos fármacos , Dronedarona/farmacologia , Remodelação Vascular/efeitos dos fármacos , Animais , Arginina/análogos & derivados , Arginina/sangue , Vasos Coronários/patologia , Vasos Coronários/fisiologia , Masculino , Óxido Nítrico/fisiologia , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Vasoconstrição/efeitos dos fármacosRESUMO
Our group has previously demonstrated that short-term treatment with esmolol reduces left ventricular hypertrophy (LVH) in spontaneously hypertensive rats (SHRs). The present study aimed to assess the molecular mechanisms related to this effect. Fourteen-month-old male SHRs were treated intravenously with saline as vehicle (SHR) or esmolol (SHR-E) (300 µg/kg/min). Age-matched vehicle-treated male Wistar-Kyoto (WKY) rats served as controls. After 48 hours of treatment, the hearts were harvested and left ventricular tissue was separated and processed for Western blot analysis to determine the levels of Akt, NF-κB, NFATc4, Creb1, Serca2a, Erk1/2, and Sapk/Jnk. Biomarkers of oxidative stress, such as catalase, protein carbonyls, total thiols, and total antioxidant capacity were evaluated. Esmolol reversed the levels of p-NFATc4, p-Akt, and p-NF-κB in SHRs to the phospholevels of these proteins in WKY rats without modifying p-Erk1/2, p-Sapk/Jnk, p-Creb1, or Serca2a in SHR. Compared with SHR, esmolol increased catalase activity and reduced protein carbonyls without modifying total thiols or total antioxidant capacity. Short-term treatment with esmolol reverses LVH in aged SHRs by downregulation of Akt/NF-κB and NFATc4 activity. Esmolol treatment also increases catalase activity and reduces oxidative stress in SHRs with LVH.
Assuntos
Envelhecimento/metabolismo , Hipertrofia Ventricular Esquerda/tratamento farmacológico , NF-kappa B/metabolismo , Fatores de Transcrição NFATC/metabolismo , Propanolaminas/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Antioxidantes/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Catalase/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Frequência Cardíaca/efeitos dos fármacos , Hipertrofia Ventricular Esquerda/fisiopatologia , Masculino , Miocárdio/patologia , Estresse Oxidativo/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Propanolaminas/administração & dosagem , Propanolaminas/farmacologia , Carbonilação Proteica/efeitos dos fármacos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Sístole/efeitos dos fármacos , Fatores de TempoRESUMO
BACKGROUND AND AIMS: Left ventricular hypertrophy (LVH) in hypertension is associated with a greater risk of sustained supraventricular/atrial arrhythmias. Dronedarone is an antiarrhythmic agent that was recently approved for the treatment of atrial fibrillation. However, its effect on early regression of LVH has not been reported. We tested the hypothesis that short-term administration of dronedarone induces early regression of LVH in spontaneously hypertensive rats (SHRs). METHODS: Ten-month-old male SHRs were randomly assigned to an intervention group (SHR-D), where animals received dronedarone treatment (100 mg/kg) for a period of 14 days, or to a control group (SHR) where rats were given vehicle. A third group with normotensive control rats (WKY) was also added. At the end of the treatment with dronedarone we studied the cardiac anatomy and function in all the rats using transthoracic echocardiogram, cardiac metabolism using the PET/CT study (2-deoxy-2[18F]fluoro-D-glucose) and cardiac structure by histological analysis of myocyte size and collagen content. RESULTS: The hypertensive vehicle treated SHR rats developed the classic cardiac pattern of hypertensive cardiomyopathy as expected for the experimental model, with increases in left ventricular wall thickness, a metabolic shift towards an increase in glucose use and increases in myocyte and collagen content. However, the SHR-D rats showed statistically significant lower values in comparison to SHR group for septal wall thickness, posterior wall thickness, ventricular mass, glucose myocardial uptake, size of left ventricular cardiomyocytes and collagen content. All these values obtained in SHR-D rats were similar to the values measured in the normotensive WKY control group. CONCLUSION: The results suggest by three alternative and complementary ways (analysis of anatomy and cardiac function, metabolism and histological structure) that dronedarone has the potential to reverse the LVH induced by arterial hypertension in the SHR model of compensated ventricular hypertrophy.
Assuntos
Amiodarona/análogos & derivados , Cardiopatias/tratamento farmacológico , Hipertensão/tratamento farmacológico , Hipertrofia Ventricular Esquerda/tratamento farmacológico , Amiodarona/administração & dosagem , Animais , Fibrilação Atrial/diagnóstico por imagem , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/fisiopatologia , Remodelamento Atrial/efeitos dos fármacos , Dronedarona , Cardiopatias/diagnóstico por imagem , Cardiopatias/fisiopatologia , Humanos , Hipertensão/diagnóstico por imagem , Hipertensão/fisiopatologia , Hipertrofia Ventricular Esquerda/diagnóstico por imagem , Hipertrofia Ventricular Esquerda/fisiopatologia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Ratos , Ratos Endogâmicos SHR/fisiologiaRESUMO
BACKGROUND AND AIMS: Fetal undernutrition is a risk factor for heart disease in both genders, despite the protection of women against hypertension development. Using a rat model of maternal undernutrition (MUN) we aimed to assess possible sex differences in the development of cardiac alterations and the implication of hypertension and cardiac oxidative stress. METHODS: Male and female offspring from rats fed ad libitum (control) or with 50% of the normal daily intake during the second half of gestation (MUN) were used. Heart weight/body weight ratio (HW/BW), hemodynamic parameters (anaesthetized rats) and plasma brain natriuretic peptide (BNP, ELISA) were assessed in 21-day, 6-month and 22-month old rats. Plasma testosterone (ELISA) and cardiac protein expression of enzymes related to reactive oxygen species synthesis (p22phox, xanthine-oxidase) and degradation (catalase, Cu/Zn-SOD, Mn-SOD, Ec-SOD) were evaluated in 21-day and 6-month old rats (Western Blot). Heart structure and function was studied at the age of 22 months (echocardiography). RESULTS: At the age of 21 days MUN males exhibited significantly larger HW/BW and cardiac p22phox expression while females had reduced p22phox expression, compared to their respective sex-matched controls. At the age of 6-months, MUN males showed significantly larger blood pressure and cardiac xanthine-oxidase expression; MUN females were normotensive and had a lower cardiac expression of antioxidant enzymes, compared to their respective sex-matched controls. At the age of 22 months, both MUN males and females showed larger HW/BW and left ventricular mass and lower ejection fraction compared to sex-matched controls; only MUN males exhibited hypertension and a larger plasma BNP compared to aged male controls. CONCLUSIONS: 1) During perinatal life females exposed to fetal undernutrition are protected from cardiac alterations, but in ageing they exhibit ventricular hypertrophy and functional loss, like MUN males; 2) cardiac oxidative stress might be implicated in the observed heart alterations in both sexes and 3) the severity of cardiac damage might be greater in males due to hypertension.
Assuntos
Transtornos da Nutrição Fetal , Hipertensão/metabolismo , Estresse Oxidativo , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Animais , Peso Corporal , Feminino , Hemodinâmica , Hormônios/sangue , Hipertensão/sangue , Hipertensão/patologia , Hipertensão/fisiopatologia , Masculino , Mães , Miocárdio/metabolismo , Miocárdio/patologia , Peptídeo Natriurético Encefálico/metabolismo , Tamanho do Órgão , Gravidez , Efeitos Tardios da Exposição Pré-Natal/sangue , Efeitos Tardios da Exposição Pré-Natal/patologia , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Fatores de Risco , Caracteres Sexuais , Fatores de TempoRESUMO
BACKGROUND: Spontaneously hypertensive rats (SHR) serve as a model of genetic hypertension. Adverse remodeling of a coronary artery has been reported in SHR. This model is used to study new therapies in regression vascular remodeling. However, no data are available that show remodeling of the intramyocardial branch of the obtuse marginal artery in 10-month-old SHR. This study was designed to assess remodeling (changes in vascular structure and fibrosis) of this coronary artery. METHODS AND RESULTS: The study was performed on 10-month-old male SHR (n=7) and normotensive control Wistar Kyoto rats (WKY) (n=7). Using histology, we show that the external diameter, lumen diameter, wall width, and cross-sectional area of the intramyocardial artery were significantly greater in SHR than in WKY. The wall-to-lumen ratio was similar in SHR and WKY. The collagen volume density of the intramyocardial artery in SHR was significantly greater than in WKY. CONCLUSIONS: Our results show hypertrophic outward remodeling in the intramyocardial branch of the obtuse marginal artery of the left ventricle in SHR. This artery can serve as a new vascular bed from adult SHR to study novel therapies in regression coronary artery remodeling.
Assuntos
Vasos Coronários/patologia , Hipertensão/patologia , Miocárdio/patologia , Remodelação Vascular , Animais , Modelos Animais de Doenças , Hipertensão/complicações , Hipertensão/fisiopatologia , Hipertrofia/etiologia , Masculino , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKYRESUMO
Esmolol produces early regression of left ventricular hypertrophy and improves coronary artery remodeling, although the impact of short-term treatment with this beta-blocker on remodeling in large arteries has not yet been studied. We hypothesized that even a short (48h) course of esmolol might alter remodeling of the aorta in the spontaneously hypertensive rat (SHR). Fourteen-month-old male SHRs were treated intravenously with vehicle (SHR, n=8) or esmolol (SHR-E, n=8) (300µg/kg/min). Age-matched, vehicle-treated male Wistar-Kyoto rats (WKY, n=8) served as controls. After 48h, we studied the structure, volume density of elastic fibers, and passive mechanical properties of the aorta. Determination of asymmetrical dimethylarginine concentrations and total protein carbonyls in the aorta were analyzed. Esmolol significantly attenuated abnormal aortic wall thickness, cross-sectional area, wall-to-lumen ratio, volume density of elastic fibers, and wall stiffness. The protective effect of esmolol could be related to a decrease in asymmetrical dimethylarginine levels after down-regulation by oxidative stress. These findings could play a key role in the selection of antihypertensive therapy in patients with hypertension and aortic remodeling.