The impact of an early intervention home-based program on body composition in preterm-born preschoolers with very low birth weight.

Background and aims: Early child interventions focused on the family prevented neurodevelopmental and behavioral delays and can provide more knowledge regarding responsive feeding, thus creating learning opportunities to promote better quality nutrition and preventing failure to thrive. The aim is to verify the impact of a continuous program of early home-based intervention on the body composition of preschool infants who were born preterm with very low birth weight (VLBW). Methods: This is a longitudinal analysis from a randomized controlled trial, including VLBW preterm children, born in a tertiary hospital in Southern Brazil and followed up at the high-risk institutional ambulatory clinic. Participants were divided into the intervention group (IG): skin-to-skin care with the mother (kangaroo care), breastfeeding policy, and tactile-kinesthetic stimulation by mothers until hospital discharge. Subsequently, they received a program of early intervention with orientation and a total of 10 home visits, independently from the standard evaluation and care that was performed following the 18 months after birth; conventional group (CG): standard care according to the routine of the newborn intensive care unit (NICU), which includes kangaroo care, and attending to their needs in the follow-up program. Body composition estimation was performed using bioelectrical impedance analyses (BIA), and physical activity and feeding practices questionnaires were evaluated at preschool age, as well as anthropometric measurements and biochemical analysis. Results: Data of 41 children at 4.6 ± 0.5 years old were evaluated (CG n = 21 and IG n = 20). Body weight, height, body mass index, waist and arm circumferences, and triceps and subscapular skinfold did not differ between groups. The IG presented higher segmented fat-free mass (FFM) when compared to the CG (right arm FFM: 0.74 vs. 0.65 kg, p = 0.040; trunk FFM: 6.86 vs. 6.09 kg, p = 0.04; right leg FFM: 1.91 vs. 1.73 kg, p = 0.063). Interaction analyses showed that segmented FFM and FFM Index were associated with higher iron content in the IG. In the CG, interaction analyses showed that increased visceral fat area was associated with higher insulin resistance index. Conclusion: An early intervention protocol from NICU to a home-based program performed by the mothers of VLBW preterm children of low-income families presents a small effect on FFM.

Sulforaphane Effects on Cardiac Function and Calcium-Handling-Related Proteins in 2 Experimental Models of Heart Disease: Ischemia-Reperfusion and Infarction.

ABSTRACT: Sulforaphane (SFN) is a natural exogenous antioxidant from cruciferous vegetables already shown to improve cardiac function in cardiovascular diseases. The aim of this study was to analyze the effect of SFN treatment on the cardiac function in 2 experimental models of heart disease, ischemia/reperfusion (I/R) and myocardial infarction (MI), and whether an improvement of the cardiac function could be associated with a modulation of calcium-handling proteins. The study was divided into 2 main experiments: experiment 1, ex vivo with the I/R model and experiment 2, in vivo with the MI model. In the I/R model, rats were divided into control and SFN (0.5 mg/kg/d intraperitoneally for 3 days) groups, and the hearts were submitted to global ischemia (20 minutes) followed by reperfusion (20 minutes) in a Langendorff apparatus. SFN did not change left ventricle systolic and diastolic pressures but increased the contractility and relaxation indexes after 20 minutes of reperfusion. These functional changes were accompanied by a decreased protein expression of ryanodine receptor (RyR) and increased expression of p-phospholamban/phospholamban ratio, without alteration in the sarco/endoplasmic calcium ATPase expression. In the MI model, rats were randomly divided into Sham, MI (MI induced by left coronary artery ligation), Sham + SFN (5 mg/kg/d intraperitoneally for 25 days), and MI + SFN groups. Although SFN did not affect cardiac function, it led to a decreased RyR protein expression and reactive oxygen species levels in the left ventricular of the MI + SFN group. These data indicate that SFN modulates calcium-handling proteins and, thus, cardiac inotropism/lusitropism especially when administered previously to an ischemic event.

Cardioprotective doses of thyroid hormones improve NO bioavailability in erythrocytes and increase HIF-1α expression in the heart of infarcted rats.

CONTEXT: Infarction leads to a decrease in NO bioavailability in the erythrocytes. Thyroid hormones (TH) present positive effects after infarction. However, there are no studies evaluating the effects of cardioprotective doses of TH in the erythrocytes after infarction. OBJECTIVE: This study aimed to evaluate the effects of TH in NO bioavailability and oxidative stress parameters in the erythrocytes of infarcted rats. MATERIAL AND METHODS: Wistar rats were allocated into the three groups: Sham-operated (SHAM), infarcted (AMI) and infarcted + TH (AMIT). AMIT rats received T4 and T3 for 12 days by gavage. Subsequently, the animals were evaluated by echocardiography and the LV and erythrocytes were collected. RESULTS: TH improved NO bioavailability and increased catalase activity in the erythrocytes. Besides that, TH increased HIF-1α in the heart. CONCLUSION: TH seems to be positive for erythrocytes preventing a decrease in NO bioavailability and increasing antioxidant enzymatic defense after infarction.

Repeatability of the 6-min walk test in non-cystic fibrosis bronchiectasis.

Non-cystic fibrosis bronchiectasis (NCFB) is a chronic lung disease characterized by progressive and irreversible changes of the bronchial tree. The evaluation of exercise capacity is essential to manage this disease. This study aims to determine the within-subject repeatability of two Six Minute Walk Test (6MWT) in adults with NCFB. NCFB. This cross-sectional observational study included 66 NCFB subjects above 18 years-old (mean of 55 ± 17 years old, 68% women). 73% of the participants presented moderate to severe clinical condition classified by Bronchiectasis Severity Index. It showed that these participants walked 16.6 m less (95%CI 3.8 to 29.4; p < 0.01) in the second 6MWT when compared to the first test, with a within-subject coefficient variation of 9.4% (95%CI 7.2-11.2%) and an intra-test reliability with a high intraclass correlation coefficient of 0.88 (95%CI 0.80-0.93). Bland-Altman plot showed an agreement regarding test repeatability, besides presented a large limit of agreement (- 85 to 116 m). Respiratory rate and systolic blood pressure were significantly higher before starting the second test. In conclusion, 6MWT seems to be reproducible in NCFB subjects and vital sign verification should be attentively checked to assess if the patient is fully recovered to perform a second test, as well as the disease severity score. Other studies on this matter should be conducted with a larger number of participants to confirm the findings of the present study.

Duration of neonatal oxygen supplementation, erythropoiesis and blood pressure in young adults born preterm.

BACKGROUND: Although erythropoiesis is impaired and anaemia frequent in neonates born preterm, haematopoiesis in adults born preterm has not been previously studied. OBJECTIVE: We, thus, aimed to evaluate haemoglobin and erythropoietin levels in young adults born preterm, to identify neonatal events associated with erythropoiesis in adulthood and to examine the relationships of haemoglobin levels with respiratory function and blood pressure. METHODS: We assessed a cohort of 101 young adults (ages 18-29) born preterm (≤29 weeks of gestation), in comparison to 105 full-term controls. We measured haemoglobin, erythropoietin levels and blood pressure. We also assessed respiratory function using spirometry. RESULTS: Compared with controls, tobacco use and sex-adjusted haemoglobin levels were 5.3 (95% CI 2.9 to 7.7) g/L higher in preterm-born individuals, but erythropoietin levels were similar. Duration of oxygen supplementation in the neonatal period was independently associated with higher haemoglobin levels in the preterm group. In young adults born preterm with bronchopulmonary dysplasia, airflow limitation was associated with higher haemoglobin levels. Both systolic (SBP) and diastolic (DBP) blood pressure were increased in individuals born preterm (p=0.042 and p=0.0008, respectively). Higher haemoglobin levels were associated with higher SBP and DBP, independently of term or preterm status. Mediation analysis suggests that haemoglobin increase contributes to 37% and 32% of the effect of preterm birth on SBP and DBP, respectively. CONCLUSIONS: Haemoglobin levels are higher in young adults born preterm, while erythropoietin levels are similar, especially in case of bronchopulmonary dysplasia and airflow limitation, and haemoglobin increase is associated with elevated blood pressure in this population.

Increased Incidence but Lack of Association Between Cardiovascular Risk Factors in Adults Born Preterm.

Preterm birth incurs an increased risk of early cardiovascular events and death. In the general population, cardiovascular risk factors cluster in the context of inflammation and oxidative stress. Whether this also occurs in young adults born preterm is unknown. We analyzed 101 healthy young adults (ages 18-29) born preterm (≤29 weeks of gestation) and 105 full-term controls, predominantly (90%) white. They underwent a comprehensive clinical and biological evaluation, including measurement of blood pressure, lung function (spirometry), glucose metabolism (fasting glucose, glycated hemoglobin, and oral glucose tolerance test), as well as biomarkers of inflammation and oxidative stress. Individuals born preterm were at higher risk than those born full-term of stage ≥1 hypertension (adjusted odds ratio, 2.91 [95% CI, 1.51-5.75]), glucose intolerance (adjusted odds ratio, 2.22 [95% CI, 1.13-4.48]), and airflow limitation (adjusted odds ratio, 3.47 [95% CI, 1.76-7.12]). Hypertension was strongly associated with adiposity and with glucose intolerance in participants born full-term but not in those born preterm. We did not find any group difference in levels of biomarkers of inflammation and oxidative stress. In individuals born preterm, inflammation, and oxidative stress were not related to hypertension or glucose intolerance but were associated with adiposity. In those born preterm, cardiovascular risk factors were not related to each other suggesting different pathophysiological pathways leading to the development of cardiovascular risk following preterm birth. Clinicians should consider screening for these abnormalities irrespectively of other risk factors in this at-risk population. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT03261609.

Short period of high-intensity inspiratory muscle training improves inspiratory muscle strength in patients with chronic kidney disease on hemodialysis: a randomized controlled trial.

BACKGROUND: Chronic kidney disease is a complex disease that impacts multiple organs and systems (including musculoskeletal and cardiorespiratory) leading to reduction of functional capacity. OBJECTIVE: The aim of this study was to investigate the effect of a short period of high intensity inspiratory muscle training on maximum inspiratory pressure, functional capacity and endothelial function of chronic kidney disease patients on hemodialysis. METHODS: This randomized controlled trial enrolled 25 patients who were allocated into two groups: intervention (IMTG=14) and control (CG=11) groups. Intervention patients received the exercise protocol over a period of 5 weeks, 6 times per week, with each session consisting of 5 sets of 10 repetitions with an initial load of 50% progressing to 70% of maximum inspiratory pressure , measured weekly. The primary outcome was inspiratory muscle strength and the secondary outcomes were functional capacity and endothelial function evaluated before and after the training protocol. RESULTS: The inspiratory muscle training induced a marked improvement in maximum inspiratory pressure which was evident after the training period (mean difference 19.0cmH2O - 95%CI 0.4-37.5; IMTG: 102±25.7cmH2O vs CG: 83±19.2; p=0.046). The magnitude of maximum inspiratory pressure improvement was 33.5% at the end of the protocol for the IMTG. Functional capacity and endothelial function did not vary between or within groups. CONCLUSION: A short period of high-intensity inspiratory muscle training for five weeks was able to improve inspiratory muscle strength of chronic kidney disease patients on hemodialysis (ClinicalTrials.gov registration NCT03082404).

TLR (Toll-Like Receptor) 4 Antagonism Prevents Left Ventricular Hypertrophy and Dysfunction Caused by Neonatal Hyperoxia Exposure in Rats.

Preterm birth is associated with proinflammatory conditions and alterations in adult cardiac shape and function. Neonatal exposure to high oxygen, a rat model of prematurity-related conditions, leads to cardiac remodeling, fibrosis, and dysfunction. TLR (Toll-like receptor) 4 signaling is a critical link between oxidative stress, inflammation, and the pathogenesis of cardiovascular diseases. The current study sought to investigate the role of TLR4 signaling in neonatal oxygen-induced cardiomyopathy. Male Sprague-Dawley pups were kept in 80% oxygen or room air from day 3 to 10 of life and treated with TLR4 antagonist lipopolysaccharide from the photosynthetic bacterium Rhodobacter sphaeroides(LPS-RS) or saline. Echocardiography was performed at 4, 7, and 12 weeks. At 12 weeks, intraarterial blood pressure was measured before euthanization for histological and biochemical analyses. At day 10, cardiac TLR4, Il (interleukin) 18, and Il1ß expression were increased in oxygen-exposed compared with room air controls. At 4 weeks, compared with room air-saline, saline-, but not LPS-RS treated-, oxygen-exposed animals, exhibited increased left ventricle mass index, reduced ejection fraction, and cardiac output index. Findings were similar at 7 and 12 weeks. LPS-RS did not influence echocardiography in 12 weeks room air animals. Systolic blood pressure was higher in saline- but not LPS-RS treated-oxygen-exposed animals compared with room air-saline and -LPS-RS controls. LPS-RS prevented cardiac fibrosis and cardiomyocytes hypertrophy, the increased TLR4, Myd88, and Il18 gene expression, TRIF expression, and CD68+ macrophages infiltration associated with neonatal oxygen exposure, without impact in room air rats. This study indicates that neonatal exposure to high oxygen programs TLR4 activation, which contributes to cardiac remodeling and dysfunction.

Impact of early life AT1 blockade on adult cardiac morpho-functional changes and the renin-angiotensin system in a model of neonatal high oxygen-induced cardiomyopathy.

We previously reported that neonatal blockade of angiotensin II AT1 receptor prevents cardiac changes in 4 weeks rats with neonatal hyperoxia-induced cardiomyopathy, a recognized model of prematurity-related deleterious conditions. Considering the importance of AT1 receptor and the renin angiotensin system (RAS) in normal development, the present study aimed to investigate the adult effects of neonatal AT1 blockade on left ventricle (LV) in rats exposed to neonatal hyperoxia. Sprague-Dawley pups were exposed to 80% O2 or room air from days 3-10. AT1 blocker (losartan) or H2O were given by gavage from day 8-10. LV function (echo and intraventricular pressure), histology and expression of RAS components were examined in 15-16 weeks old adult males. Losartan treatment prevented myocardial fibrosis, LV wall thickening and stroke volume reduction in rats exposed to high O2 in the neonatal period. However, Losartan treatment of O2-exposed pups led to reduced ejection fraction (EF) and fractional shortening (FS), and did not prevent changes in diastolic function. Losartan also did not prevent increased LV AT2 and decreased angiotensin-(1-7) Mas receptors expression observed in high O2-exposed rats. Neonatal Losartan attenuated long-term impact of neonatal hyperoxia but also led to decreased EF and FS. Increased AT2 and decreased Mas receptor expression observed in O2-exposed group were unaffected by Losartan treatment. Our results show that early life Losartan treatment aimed at preventing cardiac consequences of neonatal deleterious conditions may also comprise detrimental effects that require further investigation prior to clinical translation in developing children.

Kidney Size, Renal Function, Ang (Angiotensin) Peptides, and Blood Pressure in Young Adults Born Preterm.

Preterm birth incurs a higher risk for adult cardiovascular diseases, including hypertension. Because preterm birth may impact nephrogenesis, study objectives were to assess renal size and function of adults born preterm versus full term and to examine their relationship with blood pressure (BP; 24-hour ambulatory BP monitoring) and circulating renin-Ang (angiotensin) system peptides. The study included 92 young adults born (1987-1997) preterm (≤29 weeks of gestation) and term (n=92) matched for age, sex, and race. Young adults born preterm had smaller kidneys (80±17 versus 90±18 cm3/m2; P<0.001), higher urine albumin-to-creatinine ratio (0.70; interquartile range, 0.47-1.14 versus 0.58, interquartile range 0.42 to 0.78 mg/mmol, P=0.007), higher 24-hour systolic (121±9 versus 116±8 mm Hg; P=0.001) and diastolic (69±5 versus 66±6 mm Hg; P=0.004) BP, but similar estimated glomerular filtration rate. BP was inversely correlated with kidney size in preterm participants. Plasma Ang I was higher in preterm versus term participants (36.3; interquartile range, 13.2-62.3 versus 19.4; interquartile range, 9.9-28.1 pg/mL; P<0.001). There was no group difference in renin, Ang II, Ang (1-7), and alamandine. In the preterm, but not in the term group, higher BP was significantly associated with higher renin and alamandine and lower birth weight and gestational age with smaller adult kidney size. Young adults born preterm have smaller kidneys, higher urine albumin-to-creatinine ratio, higher BP, and higher circulating Ang I levels compared with term controls. Preterm young adults with smaller kidneys have higher BP. Clinical Trial Registration- URL: http://www.clinicaltrials.gov . Unique identifier: NCT03261609.

Endothelial Colony-Forming Cells in Young Adults Born Preterm: A Novel Link Between Neonatal Complications and Adult Risks for Cardiovascular Disease.

BACKGROUND: Preterm birth is linked to cardiovascular risks and diseases. Endothelial progenitor cells play a critical role in vascular development and repair. Cord blood endothelial progenitor cells of preterm-born infants, especially endothelial colony-forming cells (ECFC), show enhanced susceptibility to prematurity-related pro-oxidant stress. Whether ECFC dysfunction is present in adulthood following preterm birth is unknown. METHODS AND RESULTS: This cross-sectional observational study includes 55 preterm-born (≤29 gestational weeks) young adults (18-29 years old, 38% male) and 55 sex- and age-matched full-term controls. ECFC were isolated from peripheral blood; cell proliferative and vascular cord formation capacities were assessed in vitro. Daytime systolic blood pressure was higher, whereas glucose tolerance and body mass index were lower in preterm-born subjects. ECFC colonies grew in culture for 62% of full-term- and 58% of preterm-born participants. Preterm-born participants have formed ECFC colonies later in culture and have reduced proliferation compared with controls. Only in preterm-born individuals, we observed that the later the ECFC colony grows in culture, the worse was overall ECFC function. In addition, in preterms, elevated systolic blood pressure significantly correlated with reduced ECFC proliferation (rS=-0.463; P=0.030) and numbers of branches formed on matrigel (rS=-0.443; P=0.039). In preterm-born subjects, bronchopulmonary dysplasia was associated with impaired ECFC function, whereas exposure to antenatal steroids related to better ECFC function. CONCLUSIONS: This study is the first to examine ECFC in preterm-born adults and to demonstrate ECFC dysfunction compared with full-term controls. In the preterm-born group, ECFC dysfunction was associated with bronchopulmonary dysplasia, the major prematurity-related neonatal morbidity, and with increased systolic blood pressure into adulthood.

Sulforaphane effects on oxidative stress parameters in culture of adult cardiomyocytes.

The aim of this study was to analyse the effect of sulforaphane (SFN) in cultures of adult cardiomyocytes, evaluating oxidative stress at different times. Cells were isolated, cultured, and divided into 4 groups: Control, SFN (5µM), H2O2 (5µM), and SFN+H2O2 (5µM both), and subdivided into groups undergoing 1 or 24 h of SFN incubation. After 1 h of incubation, reactive oxygen species production was 40% lower in the SFN group than the Control, and lipid peroxidation was 63% higher in the H2O2 group than the Control, and it was reduced in both of the SFN groups. The SOD activity was 59% higher in groups incubated for 24 h than in those incubated for 1 h. Protein expression of SOD-1 and SOD-2 was higher in the 24-h groups compared to the 1-h groups (55% and 24%, respectively). The Nrf2 protein expression in the 1-h groups was 17% higher than in the 24-h groups, and the SFN + H2O2 group had 40% more Nrf2 than the Control in the 1-h groups. Unlike Nrf2, the PGC-1α expression was 69% higher in the 24-h groups in relation to the 1-h groups. Regarding the 24-h groups, the SFN and SFN+H2O2 groups were higher than the Control (32% and 33%, respectively), and the SFN+H2O2 group was increased (21%) compared to H2O2. SFN had a protective action against oxidative damage, but had no effect on the antioxidant enzymes analyzed. The different responses in the expression of Nrf2 and PGC-1α in relation to the incubation times, draws attention to the importance of establishing a timeline of the action of SFN, since there appears to be a temporal difference in its mechanism in adult cardiomyocytes.

Bucindolol attenuates the vascular remodeling of pulmonary arteries by modulating the expression of the endothelin-1 A receptor in rats with pulmonary arterial hypertension.

The aim of this study was to investigate the role of the ß-adrenergic blocker bucindolol on endothelial dysfunction and pulmonary vascular remodeling in rats with pulmonary arterial hypertension (PAH). Male Wistar rats were divided into four groups: control, monocrotaline (MCT), control?+?bucindolol and monocrotaline?+?bucindolol (MCT?+?BCD). PAH was induced by an injection of monocrotaline (60?mg/kg i.p.). After two weeks, the animals were treated for seven days with bucindolol (2?mg/kg/day i.p.) or vehicle. Echocardiography was performed upon treatment completion to analyze pulmonary vascular resistance (PVR) and right ventricle (RV) myocardial performance index. Lungs were collected for oxidative stress and western blot analysis, and the pulmonary artery was analyzed for histological and immunohistochemical parameters. The MCT?+?BCD group showed a decrease (32%) in the protein expression of endothelin-1 type A receptor (ETAR) and in the ratio of ETA/endothelin-1 type B receptor (ETBR) (62%) as compared to the MCT group. Bucindolol treatment did not alter oxidative stress, as determined by lipid peroxidation analysis and antioxidant enzyme activities and expression, endothelial nitric oxide synthase immunocontent and decreased nitrotyrosine levels. Moreover, bucindolol improved vascular remodeling of the pulmonary artery in the MCT?+?BCD group by decreasing (21%) PVR and increasing RV workload in relation to MCT.

Acute Effects of Low-Level Laser Therapy on Patients' Functional Capacity in the Postoperative Period of Coronary Artery Bypass Graft Surgery: A Randomized, Crossover, Placebo-Controlled Trial.

OBJECTIVE: The aim of this study was to evaluate the acute effects of low-level laser therapy (LLLT) on the functional capacity to exercise tested by incremental shuttle walking test (ISWT) after coronary artery bypass graft (CABG) surgery. METHODS: Fifteen male patients (60 ± 9 years) were crossed over during the experiment, to compare the outcomes after active LLLT and placebo LLLT treatments. LLLT (850 nm, 200 mW, 30 J to each point, resulting in a total of 240 J per quadriceps muscle), using a multidiode cluster (five spots; 6 J/spot) in eight points per leg was performed 3 min before the ISWT. We analyzed distance walked, Borg scale of perceived exertion, heart rate, and brachial arterial blood pressure. Markers of tissue damage [lactate dehydrogenase (LDH)] and oxidative stress [lipid peroxidation, total thiol levels, and antioxidant enzyme activity of superoxide dismutase (SOD) and catalase (CAT)] were also measured in peripheral blood. RESULTS: Comparison of the distances walked revealed no significant differences between the LLLT and placebo LLLT groups (p = 0.779). Regarding the Borg scale (p = 0.567), heart rate (p = 0.506) as well as systolic and diastolic blood pressure (p = 0.164 and p = 0.140, respectively), no differences were observed between LLLT and placebo LLLT groups. Application of LLLT was not able to change levels of LDH (p = 0.214), oxidative lipid damage (p = 0.733), total thiol levels (p = 0.925), SOD (p = 0.202), and CAT (p = 0.825) enzyme activities. CONCLUSIONS: Acute LLLT improved neither functional capacity to exercise nor the markers of oxidation after CABG. TRIAL REGISTRATION: Registered as a clinical trial (NCT02688426).

Thyroid hormones decrease the proinflammatory TLR4/NF-κß pathway and improve functional parameters of the left ventricle of infarcted rats.

Myocardial infarction leads to oxidative stress and promotes activation of the TLR4/NF-κß proinflammatory pathway. Thyroid hormones (TH) are known to be cardioprotective after infarction. However, there are no studies evaluating whether TH could modulate this pathway in the heart. This study aimed to verify the effect of thyroid hormones on the TLR4/NF-κß pathway after myocardial infarction. Male Wistar rats were allocated into the following groups: Sham-operated (SHAM), sham-operated + TH (SHAMT), infarcted (AMI) and infarcted + TH (AMIT). The treated rats received T4 and T3 (8 and 2 µg 100 g-1 day-1) for 12 days by gavage. Subsequently, the animals were evaluated by echocardiography and euthanized, and the left ventricle was collected for biochemical and molecular analyses. TH modulates TLR4/NF-κß expression in the infarcted hearts of rats and decreases xanthine oxidase expression. These effects were related to cardiac functional improvement after infarction. The cardioprotective effects of T3 and T4 seem to involve an anti-inflammatory action.

Secoisolariciresinol diglucoside attenuates cardiac hypertrophy and oxidative stress in monocrotaline-induced right heart dysfunction.

Pulmonary arterial hypertension (PAH) occurs when remodeling of pulmonary vessels leads to increased pulmonary vascular resistance resulting in increased pulmonary arterial pressure. Increased pulmonary arterial pressure results in right ventricle hypertrophy and eventually heart failure. Oxidative stress has been implicated in the pathogenesis of PAH and may play a role in the regulation of cellular signaling involved in cardiac response to pressure overload. Secoisolariciresinol diglucoside (SDG), a component from flaxseed, has been shown to reduce cardiac oxidative stress in various pathophysiological conditions. We investigated the potential protective effects of SDG in a monocrotaline-induced model of PAH. Five- to six-week-old male Wistar rats were given a single intraperitoneal injection of monocrotaline (60 mg/kg) and sacrificed 21 days later where heart, lung, and plasma were collected. SDG (25 mg/kg) was given via gavage as either a 21-day co-treatment or pre-treatment of 14 days before monocrotaline administration and continued for 21 days. Monocrotaline led to right ventricle hypertrophy, increased lipid peroxidation, and elevated plasma levels of alanine transaminase (ALT) and aspartate transaminase (AST). Co-treatment with SDG did not attenuate hypertrophy or ALT and AST levels but decreased reactive oxygen species (ROS) levels and catalase and superoxide dismutase activity compared to the monocrotaline-treated group. Pre-treatment with SDG decreased right ventricle hypertrophy, ROS levels, lipid peroxidation, catalase, superoxide dismutase, and glutathione peroxidase activity and plasma levels of ALT and AST when compared to the monocrotaline group. These findings indicate that pre-treatment with SDG provided better protection than co-treatment in this model of right heart dysfunction, suggesting an important role for SDG in PAH and right ventricular remodeling.

Effect of Free and Nanoencapsulated Copaiba Oil on Monocrotaline-induced Pulmonary Arterial Hypertension.

Copaiba oil comes from an Amazonian tree and has been used as an alternative medicine in Brazil. However, it has not been investigated yet in the treatment of cardiovascular diseases. This study was designed to test whether copaiba oil or nanocapsules containing this oil could modulate monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH). Male Wistar rats (170 ± 20 g) received oil or nanocapsules containing this oil (400 mg/kg) by gavage daily for 1 week. At the end of this period, a single injection of MCT (60 mg/kg i.p.) was administered and measurements were performed after 3 weeks. The animals were divided into 6 groups: control, copaiba oil, nanocapsules with copaiba oil, MCT, oil + MCT, and nanocapsules + MCT. Afterward, echocardiographic assessments were performed, and rats were killed to collect hearts for morphometry and oxidative stress. MCT promoted a significant increase in pulmonary vascular resistance, right ventricle (RV) hypertrophy, and RV oxidative stress. Both oil and copaiba nanocapsules significantly reduced RV hypertrophy and oxidative stress. Pulmonary vascular resistance was reduced by copaiba oil in natura but not by nanocapsules. In conclusion, copaiba oil seems to offer protection against MCT-induced PAH. Our preliminary results suggest that copaiba oil may be an important adjuvant treatment for PAH.

Sulforaphane effects on postinfarction cardiac remodeling in rats: modulation of redox-sensitive prosurvival and proapoptotic proteins.

This study investigated whether sulforaphane (SFN), a compound found in cruciferous vegetables, could attenuate the progression of post-myocardial infarction (MI) cardiac remodeling. Male Wistar rats (350 g) were allocated to four groups: SHAM (n=8), SHAM+SFN (n=7), MI (n=8) and MI+SFN (n=5). On the third day after surgery, cardiac function was assessed and SFN treatment (5 mg/kg/day) was started. At the end of 25 days of treatment, cardiac function was assessed and heart was collected to measure collagen content, oxidative stress and protein kinase. MI and MI+SFN groups presented cardiac dysfunction, without signs of congestion. Sulforaphane reduced fibrosis (2.1-fold) in infarcted rats, which was associated with a slight attenuation in the cardiac remodeling process. Both infarcted groups presented increases in the oxidative markers xanthine oxidase and 4-hydroxinonenal, as well as a parallel increase in the antioxidant enzymes glutathione peroxidase and superoxide dismutase. Moreover, sulforaphane stimulated the cytoprotective heme oxygenase-1 (HO-1) (38%). Oxidative markers correlated with ERK 1/2 activation. In the MI+SFN group, up-regulation of ERK 1/2 (34%) and Akt (35%), as well as down-regulation of p38 (52%), was observed. This change in the prosurvival kinase balance in the MI+SFN group was related to a down-regulation of apoptosis pathways (Bax/Bcl-2/caspase-3). Sulforaphane was unable to modulate autophagy. Taken together, sulforaphane increased HO-1, which may generate a redox environment in the cardiac tissue favorable to activation of prosurvival and deactivation of prodeath pathways. In conclusion, this natural compound contributes to attenuation of the fibrotic process, which may contribute to mitigation against the progression of cardiac remodeling postinfarction.

Sulforaphane improves oxidative status without attenuating the inflammatory response or cardiac impairment induced by ischemia-reperfusion in rats.

Sulforaphane, a natural isothiocyanate, demonstrates cardioprotection associated with its capacity to stimulate endogenous antioxidants and to inhibit inflammation. The aim of this study was to investigate whether sulforaphane is capable of attenuating oxidative stress and inflammatory responses through the TLR4/MyD88/NFκB pathway, and thereby could modulate post-ischemic ventricular function in isolated rat hearts submitted to ischemia and reperfusion. Male Wistar rats received sulforaphane (10 mg·kg(-1)·day(-1)) or vehicle i.p. for 3 days. Global ischemia was performed using isolated hearts, 24 h after the last injection, by interruption of the perfusion flow. The protocol included a 20 min pre-ischemic period followed by 20 min of ischemia and a 20 min reperfusion. Although no changes in mechanical function were observed, sulforaphane induced a significant increase in superoxide dismutase and heme oxygenase-1 expression (both 66%) and significantly reduced reactive oxygen species levels (7%). No differences were observed for catalase and glutathione peroxidase expression or their activities, nor for thioredoxin reductase, glutaredoxin reductase and glutathione-S-transferase. No differences were found in lipid peroxidation or TLR4, MyD88, and NF-κB expression. In conclusion, although sulforaphane was able to stimulate endogenous antioxidants modestly, this result did not impact inflammatory signaling or cardiac function of hearts submitted to ischemia and reperfusion.

Thyroid hormones improve cardiac function and decrease expression of pro-apoptotic proteins in the heart of rats 14 days after infarction.

Apoptosis is a key process associated with pathological cardiac remodelling in early-phase post-myocardial infarction. In this context, several studies have demonstrated an anti-apoptotic effect of thyroid hormones (TH). The aim of this study was to evaluate the effects of TH on the expression of proteins associated with the apoptotic process 14 days after infarction. Male Wistar rats (300-350 g) (n = 8/group) were divided into four groups: Sham-operated (SHAM), infarcted (AMI), sham-operated + TH (SHAMT) and infarcted + TH (AMIT). For 12 days, the animals received T3 and T4 [2 and 8 µg/(100 g day)] by gavage. After this, the rats were submitted to haemodynamic and echocardiographic analysis, and then were sacrificed and the heart tissue was collected for molecular analysis. Statistical analyses included two-way ANOVA with Student-Newman-Keuls post test. Ethics Committee number: 23262. TH administration prevented the loss of ventricular wall thickness and improved cardiac function in the infarcted rats 14 days after the injury. AMI rats presented an increase in the pro-apoptotic proteins p53 and JNK. The hormonal treatment prevented this increase in AMIT rats. In addition, TH administration decreased the Bax:Bcl-2 ratio in the infarcted rats. TH administration improved cardiac functional parameters, and decreased the expression of pro-apoptotic proteins 14 days after myocardial infarction.