Perspectives of bilateral thoracic sympathectomy for treatment of heart failure

Surgical neuromodulation therapies are still considered a last resort when standard therapies have failed for patients with progressive heart failure (HF). Although a number of experimental studies have provided robust evidence of its effectiveness, the lack of strong clinical evidence discourages practitioners. Thoracic unilateral sympathectomy has been extensively studied and has failed to show significant clinical improvement in HF patients. Most recently, bilateral sympathectomy effect was associated with a high degree of success in HF models, opening the perspective to be investigated in randomized controlled clinical trials. In addition, a series of clinical trials showed that bilateral sympathectomy was associated with a decreased risk of sudden death, which is an important outcome in patients with HF. These aspects indicates that bilateral sympathectomy could be an important alternative in the treatment of HF wherein pharmacological treatment barely reaches the target dose

Protective role of 17 beta-estradiol treatment in renal injury on female rats submitted to brain death

Background: Clinical and experimental data highlight the consequences of brain death on the quality of organs and demonstrate the importance of donor state to the results of transplantation. Female rats show higher cardio-pulmonary injury linked to decreased concentrations of female sex hormones after brain-dead (BD). This study evaluated the effect of 17 beta-estradiol on brain death induced renal injury in female rats. Methods: Female Wistar rats were randomically allocated into 4 groups: false-operation (Sham), BD, treatment with 17 beta-estradiol (50 mu g/mL, 2 mL/h) 3 h after brain death (E2-T3), or immediately after brain death confirmation (E2-T0). Creatinine, urea, cytokines, and complement system components were quantified. Renal injury markers, such as KIM-1, Caspase-3, BCL-2 and MMP2/9 were evaluated. Results: Brain death leads to increased kidney KIM-1 expression and longer 17 beta-estradiol treatment resulted in downregulation (

Long-term lung inflammation is reduced by estradiol treatment in brain dead female rats

OBJECTIVES: Lung transplantation is limited by the systemic repercussions of brain death (BD). Studies have shown the potential protective role of 17 beta-estradiol on the lungs. Here, we aimed to investigate the effect of estradiol on the long-lasting lung inflammatory state to understand a possible therapeutic application in lung donors with BD. METHODS: Female Wistar rats were separated into 3 groups: BD, subjected to brain death (6h); E2-T0, treated with 17 beta-estradiol (50 mu g/mL, 2 mL/h) immediately after brain death; and E2-T3, treated with 17 beta-estradiol (50 mu g/ml, 2 ml/h) after 3h of BD. Complement system activity and macrophage presence were analyzed. TNF-alpha, IL-1 beta, IL-10, and IL-6 gene expression (RT-PCR) and levels in 24h lung culture medium were quantified. Finally, analysis of caspase-3 gene and protein expression in the lung was performed. RESULTS: Estradiol reduced complement C3 protein and gene expression. The presence of lung macrophages was not modified by estradiol, but the release of inflammatory mediators was reduced and TNF-alpha and IL-1 beta gene expression were reduced in the E2-T3 group. In addition, caspase-3 protein expression was reduced by estradiol in the same group. CONCLUSIONS: Brain death-induced lung inflammation in females is modulated by estradiol treatment. Study data suggest that estradiol can control the inflammatory response by modulating the release of mediators after brain death in the long term. These results strengthen the idea of estradiol as a therapy for donor lungs and improving transplant outcomes

Treatment with 17 beta-estradiol protects donor heart against brain death effects in female rat

The viability of donor organs is reduced by hemodynamic and immunologic alterations caused by brain death (BD). Female rats show higher heart inflammation associated with the reduction in female sex hormones after BD. This study investigated the effect of 17 beta-estradiol (E2) on BD-induced cardiac damage in female rats. Groups of female Wistar rats were assigned: Sham-operation (Sham), brain death (BD), treatment with E2 (50 mu g/ml, 2 ml/h) 3 h after BD (E2-T3), or immediately after BD confirmation (E2-T0). White blood cell (WBC) count was analyzed; cytokines and troponin-I were quantified. Heart histopathological changes and expression of endothelial nitric oxide synthase, endothelin-1, intercellular adhesion molecule-1, BCL-2, and caspase-3 were evaluated. Cardiac function was continuously assessed for 6 h by left ventricular pressure-volume loop analysis. E2 decreased the BD-induced median serum concentration of troponin-I (BD:864.2 vs. E2-T0:401.4;P = 0.009), increased BCL-2 (BD:0.086 vs. E2-T0:0.158; P = 0.0278) and eNOS median expression in the cardiac tissue (BD:0.001 vs. E2-T0:0.03 and E2-T3:0.0175; P <0.0001), and decreased caspase-3 (BD:0.025 vs. E2-T0:0.006 and E2-T3:0.019; P = 0.006), WBC counts, leukocyte infiltration, and hemorrhage. 17 beta-estradiol treatment was effective in reducing cardiac tissue damage in brain-dead female rats owing to its ability to reduce leukocyte infiltration and prevent cardiomyocyte apoptosis

17β-Estradiol Treatment Protects Lungs Against Brain Death Effects in Female Rat Donor

Background: Brain death (BD) affects the viability of lungs for transplantation. A correlation exists between high lung inflammation after BD and the decrease in female sex hormones, especially estradiol. Therefore, we investigated the effects of 17β-estradiol (E2) treatment on the lungs of female brain dead rats. Methods: Female Wistar rats were divided into 4 groups: BD (submitted to BD for 6 h), sham (false-operated), E2-T0 (treated with E2 immediately after BD; 50 μg/ml, 2 ml/h), and E2-T3 (treated with E2 after 3 h of BD; 50 μg/ml, 2 ml/h). Lung edema, hemorrhage, and leukocyte infiltration were analyzed. Adhesion molecules were evaluated and analysis of NO synthase gene and protein expression was performed using RT-PCR and immunohistochemistry, respectively. Release of chemokines and matrix degradation in the lungs were analyzed. Results: BD increased leukocyte infiltration, as shown by intravital microscopy (P=0.017), bronchoalveolar lavage cell count (P=0.016), the release of inflammatory mediators (P=0.02), and expression of adhesion molecules. BD also increased microvascular permeability and the expression and activity of MMP-9 in the lungs. E2 treatment reduced leukocyte infiltration, especially in the E2-T3 group, release of inflammatory mediators, adhesion molecules, and MMP activity in the lungs. Conclusions: E2 treatment was successful in controlling the lung inflammatory response in females submitted to BD. Our results suggest that E2 directly decreases the release of chemokines, restraining cell traffic into the lungs. Thus, E2 has a therapeutic potential, and its role in improving donor lung quality should be explored further

Sex differences in the coagulation process and microvascular perfusion induced by brain death in rats

Brain death (BD) leads to a systemic inflammation associated with the activation of coagulation, which could be related to decreased microcirculatory perfusion. Evidence shows that females exhibit higher platelet aggregability than males. Thus, we investigated sex differences in platelets, coagulation and microcirculatory compromise after BD. BD was induced in male and female (proestrus) Wistar rats. After 3 h, we evaluated: (i) intravital microscopy to evaluate mesenteric perfusion and leucocyte infiltration; (ii) platelet aggregation assay; (iii) rotational thromboelastometry; and (iv) SerumNOx-. Female rats maintained the mesenteric perfusion, whereas male reduced percentage of perfused vessels. Male BD presented higher platelet aggregation than the controls. In contrast, female BD had lower platelet aggregation than the control. Thromboelastometry indicated a reduction in clot firmness with increased clotting time in the female group compared with the male group. SerumNOx-level in female BD was higher than that in the male BD and female control. There is sex dimorphism in platelet function and clotting process, which are altered in different ways by BD. Thus, it is possible to connect the reduction in microcirculatory perfusion in males to intravascular microthrombi formation and the maintenance of perfusion in females to a higher inflammatory response and NO synthesis

Thoracic bilateral sympathectomy attenuates oxidative stress and prevents ventricular remodelling in experimental pulmonary hypertension

OBJECTIVES: Pulmonary arterial hypertension (PAH) is a cardiopulmonary disease that affects the pulmonary vasculature, leading to increased afterload and eventually right ventricular (RV) remodelling and failure. Bilateral sympathectomy (BS) has shown promising results in dampening cardiac remodelling and dysfunction in several heart failure models. In the present study, we investigated whether BS reduces pulmonary arterial remodelling and mitigates RV remodelling and failure. METHODS: PAH was induced in male Wistar rats by intraperitoneal injection of monocrotaline. Rats were divided into 3 groups, involving untreated PAH (n = 15), BS-treated PAH (n = 13) and non-manipulated control rats (n = 13). Three weeks after PAH induction, the rats were anaesthetized and RV function was assessed via the pressure-volume loop catheter approach. Upon completion of the experiment, the lungs and heart were harvested for further analyses. RESULTS: BS was found to prevent pulmonary artery remodelling, with a clear reduction in α-smooth muscle actin and endothelin-1 expression. RV end-systolic pressure was reduced in the BS group, and preload recruitable stroke work was preserved. BS, therefore, mitigated RV remodelling and cardiomyocyte hypertrophy and diminished oxidative stress. CONCLUSIONS: We showed that thoracic BS may be an important treatment option for PAH patients. Blockade of the sympathetic pathway can prevent pulmonary remodelling and protect the RV from oxidative stress, myocardial remodelling and function decay

Effects of sympathectomy on cardiac remodeling in a doxorrubicin-induced dilated cardiomyopathy model

Introduction: The main cause of cardiac transplantation is dilated cardiomyopathy (DCM), in which there are ventricular&nbsp;dilation and systolic dysfunction, leading to congestive heart failure. Ventricular remodeling involves activation of the&nbsp;sympathetic nervous and renin-angiotensin- aldosterone systems. As such, classic treatments include angiotensin-converting&nbsp;enzyme inhibitors (ACEI), beta-blockers and mineralocorticoid receptor antagonists. Once such treatments only delay&nbsp;the development of the disease, it is important to look for better therapeutic options. Experimental models demonstrated&nbsp;the benefits of sympathetic blockade on preserving ventricular function and preventing left ventricle remodeling after&nbsp;myocardial infarction.&nbsp;Objective: We evaluated the influence of bilateral thoracic sympathectomy on left ventricle remodeling and function in a&nbsp;rat model of doxorubicin induced DCM.&nbsp;Methodology: Animals were randomly divided into 4 groups of 7 rats each. DCM only, bilateral sympathectomy (BS)&nbsp;with DCM, ACEI with DCM and also a negative control group (SHAM). DCM was inducted in the experimental groups&nbsp;through weekly intraperitoneal injection of doxorubicin. Fifteen days after the beginning of DCM induction, bilateral&nbsp;sympathectomy was performed by chemical sclerosis of stellate ganglion with ethanol in the BS group. From this same&nbsp;time point until the end of experimental protocol, animals of the ACEI group received daily, through water ingestion, a&nbsp;enalapril maleate dilution. Ten weeks later, left ventricular function was evaluated with the use of a microtip pressureconductance&nbsp;catheter. Also, extracellular fibrosis were evaluated and BCL-2 expression on myocardial tissue were quantified.&nbsp;Partial Results: DCM group showed an increased left ventricular (LV) end-diastolic volume in relation to Sham group(p=0.034). Also, a significant decrease was observed in LV ejection fraction in DCM group, while bilateral sympathectomy&nbsp;were able to preserve this parameter (p=0,001). Furthermore, both treated groups showed an increased LV stroke work&nbsp;compared to DCM group (p=0,002). Myocardial extracellular fibrosis were more present in control group, whereas both&nbsp;BS and ACE inhibitor treatments reduced the areas of fibrotic tissue (p&lt;0,0001), which can be associated with increased&nbsp;expression of anti-apoptotic BCL-2 in treated groups (p=0,0004).&nbsp;Discussion and Conclusion: Sympathetic blockade was able to suppress myocardial tissue fibrosis, most likely due to&nbsp;increasing anti-apoptotic BCL-2 expression. Moreover, LV function was maintained as observed through LV ejection fraction,stroke work and cardiac efficiency levels. Although ACE inhibitor was also able to inhibit extracellular fibrosis and increase&nbsp;BCL- 2 expression, cardiac function has not been preserved as in BS group. Therefore, we conclude that BS was able to&nbsp;decrease myocardial tissue deterioration and also to preserve LV in a doxorubicin model of DCM in rats.&nbsp;Keywords: Sympathectomy; Cardiomyopathy; Cardiac transplantation; Doxorubicin