Comprehensive Management of Stroke: From Mechanisms to Therapeutic Approaches.

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.

Maintenance over Time of the Effect Produced by Esmolol on the Structure and Function of Coronary Arteries in Hypertensive Heart Diseases.

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.

Inhibition of the NFATc4/ERK/AKT Pathway and Improvement of Thiol-Specific Oxidative Stress by Dronedarone Possibly Secondary to the Reduction of Blood Pressure in an Animal Model of Ventricular Hypertrophy.

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.

OXY-SCORE: a new perspective for left ventricular hypertrophy diagnosis.

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.

Plasma protein thiolation index (PTI) as a potential biomarker for left ventricular hypertrophy in humans.

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.

Dronedarone induces regression of coronary artery remodeling related to better global antioxidant status.

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.

Short-term esmolol attenuates remodeling of the thoracic aorta in hypertensive rats by decreasing concentrations of ADMA down-regulated by oxidative stress.

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.