Redox imbalance in patients with heart failure and ICD/CRT-D intervention. Can it be an underappreciated and overlooked arrhythmogenic factor? A first preliminary clinical study.

Introduction: Redox imbalance and oxidative stress are involved in the pathogenesis of arrhythmias. They also play a significant role in pathogenesis of heart failure (HF). In patients with HFand implanted cardioverter-defibrillator (ICD) or cardiac resynchronization therapy defibrillator (CRT-D), the direct current shocks may be responsible for additional redox disturbances and additionally increase arrhythmia risk. However, the precise role of oxidative stress in potentially fatal arrhythmias and shock induction remains unclear. Methods: 36 patients with diagnosed HF and implanted ICD/CRT-D were included in this study. Patients were qualified to the study group in case of registered ventricular arrhythmia and adequate ICD/CRT-D intervention. The control group consisted of patients without arrhythmia with elective replacement indicator (ERI) status. Activity of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione (GSH) in erythrocyte (RBC), SOD, GPx activity and reactive oxygen/nitrogen species (ROS/RNS) concentration in plasma were determined. The values were correlated with glucose, TSH, uric acid, Mg and ion concentrations. Results: In the perishock period, we found a significant decrease in RBC and extracellular (EC) SOD and RBC CAT activity (p = 0.0110, p = 0.0055 and p = 0.0002, respectively). EC GPx activity was also lower (p = 0.0313). In all patients, a decrease in the concentration of all forms of glutathione was observed compared to the ERI group. Important association between ROS/RNS and GSH, Mg, TSH and uric acid was shown. A relationship between the activity of GSH and antioxidant enzymes was found. Furthermore, an association between oxidative stress and ionic imbalance has also been demonstrated. The patients had an unchanged de Haan antioxidant ratio and glutathione redox potential. Conclusion: Here we show significant redox disturbances in patients with HF and ICD/CRT-D interventions. Oxidative stress may be an additional risk factor for the development of arrhythmia in patients with HF. The detailed role of oxidative stress in ventricular arrhythmias requires further research already undertaken by our team.

Mitoquinone Alleviates Donation after Cardiac Death Kidney Injury during Hypothermic Machine Perfusion in Rat Model.

Transplanted organs are subjected to harmful conditions through stopping blood flow, hypothermic storage of the graft, and subsequent reperfusion. In particular, kidneys donated from patients after cardiac arrest (DCD) are classified as more vulnerable to ischemia-reperfusion injury (IRI). Hypothermic machine perfusion is proposed as a solution for better kidney storage before transplantation, and it is a good platform for additional graft treatment. Antioxidants have gained interest in regenerative medicine due to their ability to scavenge reactive oxygen species (ROS), which play a key role in IRI. We evaluated the effect of Mitoquinone (MitoQ), a strong mitochondria-targeted antioxidant, administered directly to the perfusing buffer. Rat kidneys were isolated, randomly classified into one of the following groups, donation after brainstem death (DBD), DCD, and DCD with MitoQ, and perfused for 22 hours with a hypothermic machine perfusion system. Subsequently, we detected levels of kidney injury (KIM-1) and oxidative stress (ROS/RNS, cytochrome C oxidase, and mitochondrial integrity) markers. We compared the activation of the apoptosis pathway (caspase 3 and 9), the concentration of phosphorylated Akt (pAkt), and the pAkt/total Akt ratio. MitoQ reduces KIM-1 concentration, total ROS/RNS, and the level of caspases. We observed a decrease in pAkt and the pAkt/total Akt ratio after drug administration. The length of warm ischemia time negatively impacts the graft condition. However, MitoQ added to the perfusing system as an 'on pump' therapy mitigates injury to the kidney before transplantation by inhibiting apoptosis and reducing ROS/RNS levels. We propose MitoQ as a potential drug for DCD graft preconditioning.

Punica granatum L. Polyphenolic Extract as an Antioxidant to Prevent Kidney Injury in Metabolic Syndrome Rats.

Introduction: Obesity and metabolic syndrome (MetS) constitute a rapidly increasing health problem and contribute to the development of multiple comorbidities like acute and chronic kidney disease. Insulin resistance, inappropriate lipolysis, and excess of free fatty acids (FFAs) are associated with glomerulus hyperfiltration and atherosclerosis. The important component of MetS, oxidative stress, is also involved in the destabilization of kidney function and the progression of kidney injury. Natural polyphenols have the ability to reduce the harmful effect of reactive oxygen and nitrogen species (ROS/RNS). Extract derived from Punica granatum L. is rich in punicalagin that demonstrates positive effects in MetS and its associated diseases. The aim of the study was to investigate the effect of bioactive substances of pomegranate peel to kidney damage associated with the MetS. Methods: In this study, we compared biomarkers of oxidative stress in kidney tissue of adult male Zucker Diabetic Fatty (ZDF) rats with MetS and healthy controls that were treated with Punica granatum L. extract at a dose of 100 or 200 mg/kg. Additionally, we evaluated the effect of polyphenolic extract on kidney injury markers and remodeling. The concentration of ROS/RNS, oxLDL, glutathione (GSH), kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), metalloproteinase 2 and 9 (MMP-2, MMP-9), and the activity of superoxide dismutase (SOD) and catalase (CAT) were measured. Results: The data showed significant differences in oxidative stress markers between treated and untreated MetS rats. ROS/RNS levels, oxLDL concentration, and SOD activity were lower, whereas CAT activity was higher in rats with MetS receiving polyphenolic extract. After administration of the extract, markers for kidney injury (NGAL, KIM-1) decreased. Conclusion: Our study confirmed the usefulness of pomegranate polyphenols in the treatment of MetS and the prevention of kidney damage. However, further, more detailed research is required to establish the mechanism of polyphenol protection.

Antioxidants in Arrhythmia Treatment-Still a Controversy? A Review of Selected Clinical and Laboratory Research.

Antioxidants are substances that can prevent damage to cells caused by free radicals. Production of reactive oxygen species and the presence of oxidative stress play an important role in cardiac arrhythmias. Currently used antiarrhythmic drugs have many side effects. The research on animals and humans using antioxidants (such as vitamins C and E, resveratrol and synthetic substances) yields many interesting but inconclusive results. Natural antioxidants, such as vitamins C and E, can reduce the recurrence of atrial fibrillation (AF) after successful electrical cardioversion and protect against AF after cardiac surgery, but do not affect the incidence of atrial arrhythmias in critically ill patients with trauma. Vitamins C and E may also effectively treat ventricular tachycardia, ventricular fibrillation and long QT-related arrhythmias. Another natural antioxidant-resveratrol-may effectively treat AF and ventricular arrhythmias caused by ischaemia-reperfusion injury. It reduces the mortality associated with life-threatening ventricular arrhythmias and can be used to prevent myocardial remodelling. Statins also show antioxidant activity. Their action is related to the reduction of oxidative stress and anti-inflammatory effect. Therefore, statins can reduce the post-operative risk of AF and may be useful in lowering its recurrence rate after successful cardioversion. Promising results also apply to polyphenols, nitric oxide synthase inhibitors and MitoTEMPO. Although few clinical trials have been conducted, the use of antioxidants in treating arrhythmias is an interesting prospect.

Oxidative Stress, HSP70/HSP90 and eNOS/iNOS Serum Levels in Professional Divers during Hyperbaric Exposition.

Heat shock proteins (HSPs) have protective effects against oxidative stress and decompression sickness. Nitric oxide may reduce bubble formation during decompression and its activity is regulated by HSPs. A simulated dive can cause the HSP response. The aim of this study was to describe the effect of simulated dives on the antioxidant system, HSPs, and nitric oxide synthase response and demonste the relationship between the concentration of HSPs and the intensification of oxidative stress. A total of 20 healthy professional divers took part in training, consisting of simulated dry dives in a hyperbaric chamber and split into experiment I (30 m exposure, 400 kPa) and experiment II (60 m exposure, 700 kPa) over 24 h. The activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) and the concentrations of malondialdehyde (MDA), heat shock protein 70 (HSP70), heat shock protein 90 (HSP90), endothelial (eNOS) and inducible (iNOS) nitric oxide synthase were measured. Increases in the activity of SOD and MDA concentration were demonstrated. The activity of GPx depended on the dive profile. The HSP70 serum level in both experiments was significantly lower after the dives. The mean HSP90 level was significantly higher after the simulated dive at 60 m. A significant relationship between HSP concentration and SOD/GPx activity was demonstrated. eNOS concentration increased after 60 m exposure. No change in iNOS concentration was observed. In conclusions, the simulated dive significantly affected the antioxidant system, heat shock protein expression and nitric oxide synthase; however, the changes depend on the diving conditions. There is a relationship between the expression of HSPs and the intensity of oxidative stress.

Polish Experiences of Pain Treatment by Paramedics in relation to Good Practices of Pain Treatment: A Register-Based Study.

Background: Pain is frequently encountered in the prehospital setting. The treatment of pain is one of the priority activities for paramedics. Methods: 1048576 patients under the care of EMS over a 7-month period were included in this study. Data included using pain scale and pain score, the initial diagnosis, analgesic treatment and the given drug obtained from the Ambulance Emergency Procedure Cards. Results: The complete absence of pain was detected in 43.9% (95% CI 43.8-44.0) of patients, mild pain in 17.0% (95% CI 16.9-17.1), moderate pain in 11.6% (95% CI 11.5-11.7), and severe pain in 4.9% (95% CI 4.9-4.9) of cases. In 22.5% (95% CI 22.4-22.6), no pain rating scale was used. 98.0% (95% CI 97.9-98.1) of patients with mild, 96.1% (95% CI 96.0-96.2) with moderate, and 94.0% (95% CI 93.9-94.1) with severe pain did not receive any pain medication. The most commonly used drugs in all groups were metamizole and ketoprofen. The greatest analgesic effect was observed in the group of patients with severe pain. Pain decreased by an average of 3.2 NRS points in the drug-free group and 3.1 NRS points in the treated group. The most commonly documented diagnoses in all groups of patients were signs and diseases not classified in other groups (ICD-10 R00-R99), injuries and consequences of external causes (ICD-10 S00-T98), and diseases of the circulatory system (ICD-10 I00-I99). Conclusions: Paramedics may use a variety of medications but use them rarely. Adding metamizole to the list of medications used by paramedics has made it one of the most commonly used drugs. Regardless of whether the drug was used or not, the analgesic effect was similar.

Heat Shock Proteins in Oxidative Stress and Ischemia/Reperfusion Injury and Benefits from Physical Exercises: A Review to the Current Knowledge.

Heat shock proteins (HSPs) are molecular chaperones produced in response to oxidative stress (OS). These proteins are involved in the folding of newly synthesized proteins and refolding of damaged or misfolded proteins. Recent studies have been focused on the regulatory role of HSPs in OS and ischemia/reperfusion injury (I/R) where reactive oxygen species (ROS) play a major role. ROS perform many functions, including cell signaling. Unfortunately, they are also the cause of pathological processes leading to various diseases. Biological pathways such as p38 MAPK, HSP70 and Akt/GSK-3ß/eNOS, HSP70, JAK2/STAT3 or PI3K/Akt/HSP70, and HSF1/Nrf2-Keap1 are considered in the relationship between HSP and OS. New pathophysiological mechanisms involving ROS are being discovered and described the protein network of HSP interactions. Understanding of the mechanisms involved, e.g., in I/R, is important to the development of treatment methods. HSPs are multifunctional proteins because they closely interact with the antioxidant and the nitric oxide generation systems, such as HSP70/HSP90/NOS. A deficiency or excess of antioxidants modulates the activation of HSF and subsequent HSP biosynthesis. It is well known that HSPs are involved in the regulation of several redox processes and play an important role in protein-protein interactions. The latest research focuses on determining the role of HSPs in OS, their antioxidant activity, and the possibility of using HSPs in the treatment of I/R consequences. Physical exercises are important in patients with cardiovascular diseases, as they affect the expression of HSPs and the development of OS.

The influence of oxidative stress induced by iron on telomere length.

Oxidative stress can be induced by increased concentrations of iron in the body and consequently can cause shortening of telomeres. Telomeres, called mitotic clocks, are non-coding fragments at the end of chromosomes. During the replication of genetic material they are shortened, playing the role of ageing biomarkers in eukaryotes. In human endothelial cells, oxidative stress causes a decrease in telomerase activity. Shortening of chromosomes in telomeric parts was found in patients with primary hemochromatosis and in patients taking supplements containing iron. Increased level of transferrin saturation is associated with the presence of shorter telomeres in the chromosomes of leukocytes. The relationship between iron status and telomere length is still not fully understood.