Search

Funding Acknowledgements Type of funding sources: None. Light pollution disrupts circadian rhythms and increases the development of obesity, but their connection to cardiovascular disease, in particular to malignant arrhythmias, is not well known. Herein, we investigated if female rats exposed to continuous light and high-sucrose diet had altered myocardial gene transcripts and/or protein expression which affects arrhythmogenesis. We then assessed if Omacor® supplementation benefitted affected rats. In a first experiment, adult female spontaneously hypertensive (SHR) and normotensive Wistar rats (WR) were housed under standard 12 h/12 h light/dark cycles or exposed to 6-weeks continuous 300 lux light for 24 h. In a second experiment, adult female WR rats received sucrose diet (30% sucrose solution) continuously (24 h) performed for 8 weeks. Half the rats from both experiments were throughout the experiment treated with 200 mg/100g b.w. Omacor®. Continuous light resulted in higher rat vulnerability to malignant ventricular fibrillation (VF). This was linked with myocardial connexin-43 (Cx43) down-regulation and deteriorated intercellular electrical coupling, due in part to increased pro-inflammatory NF-κB and iNOS transcripts and decreased sarcoplasmic reticulum Ca 2+ ATPase transcripts. Omacor® treatment increased the electrical threshold to induce the VF linked with amelioration of myocardial Cx43 mRNA and Cx43 protein levels and the suppression of NF-κB and iNOS. 8 weeks lasting intake of 30% sucrose solution downregulated Cx43 and PKCε signaling along with an upregulation of myocardial PKCδ and miR-30a rendering the heart prone to ventricular arrhythmias. There was a clear benefit of Omacor® supplementation due to their antiarrhythmic effects associated with the attenuation of myocardial Cx43, PKC, and miR-30a abnormalities. This indicates that rat exposure to continuous light and high-sucrose result in deleterious cardiac alterations jeopardizing intercellular Cx43 channel-mediated electrical communication, thereby increasing the risk of malignant arrhythmias. The adverse effects were attenuated by treatment with Omacor®, thus supporting its potential benefit and the relevance of monitoring omega-3 index in human populations at risk. [ABSTRACT FROM AUTHOR]

This report presents a fatal case of a young female Type I diabetic patient who developed convulsions and loss of consciousness after taking methamphetamine and spending some time in a dance club. During the convulsions, she was given sugar and when no response occurred, her boyfriend who was not experienced in the use of insulin administered a dose of insulin to her. The woman lost consciousness and died despite the efforts of the emergency service. A biochemical analysis revealed a high level of insulin (196.67 mU/L) and low levels of glucose (2.96 mmol/L) and C-peptide (26 pmol/L). Toxicological analysis revealed a methamphetamine concentration of 389 ng/mL and an amphetamine concentration of 19 ng/mL. The forensic perspective of the difficult determination of the contribution of each of the factors to the death, i.e., the pre-existing medical condition (Type I diabetes), the use of methamphetamine, the physical exertion at the dance club, and, finally, the non-indicated administration of insulin, is discussed. The ruling of the court is also reported., (© 2024. The Author(s).)

While essential hypertension (HTN) is very prevalent, pulmonary arterial hypertension (PAH) is very rare in the general population. However, due to progressive heart failure, prognoses and survival rates are much worse in PAH. Patients with PAH are at a higher risk of developing supraventricular arrhythmias and malignant ventricular arrhythmias. The latter underlie sudden cardiac death regardless of the mechanical cardiac dysfunction. Systemic chronic inflammation and oxidative stress are causal factors that increase the risk of the occurrence of cardiac arrhythmias in hypertension. These stressful factors contribute to endothelial dysfunction and arterial pressure overload, resulting in the development of cardiac pro-arrhythmic conditions, including myocardial structural, ion channel and connexin43 (Cx43) channel remodeling and their dysfunction. Myocardial fibrosis appears to be a crucial proarrhythmic substrate linked with myocardial electrical instability due to the downregulation and abnormal topology of electrical coupling protein Cx43. Furthermore, these conditions promote ventricular mechanical dysfunction and heart failure. The treatment algorithm in HTN is superior to PAH, likely due to the paucity of comprehensive pathomechanisms and causal factors for a multitargeted approach in PAH. The intention of this review is to provide information regarding the role of Cx43 in the development of cardiac arrhythmias in hypertensive heart disease. Furthermore, information on the progress of therapy in terms of its cardioprotective and potentially antiarrhythmic effects is included. Specifically, the benefits of sodium glucose co-transporter inhibitors (SGLT2i), as well as sotatercept, pirfenidone, ranolazine, nintedanib, mirabegron and melatonin are discussed. Discovering novel therapeutic and antiarrhythmic strategies may be challenging for further research. Undoubtedly, such research should include protection of the heart from inflammation and oxidative stress, as these are primary pro-arrhythmic factors that jeopardize cardiac Cx43 homeostasis, the integrity of intercalated disk and extracellular matrix, and, thereby, heart function.

Prolonged population aging and unhealthy lifestyles contribute to the progressive prevalence of arterial hypertension. This is accompanied by low-grade inflammation and over time results in heart dysfunction and failure. Hypertension-induced myocardial structural and ion channel remodeling facilitates the development of both atrial and ventricular fibrillation, and these increase the risk of stroke and sudden death. Herein, we elucidate hypertension-induced impairment of "connexome" cardiomyocyte junctions. This complex ensures cell-to-cell adhesion and coupling for electrical and molecular signal propagation. Connexome dysfunction can be a key factor in promoting the occurrence of both cardiac arrhythmias and heart failure. However, the available literature indicates that arterial hypertension treatment can hamper myocardial structural remodeling, hypertrophy and/or fibrosis, and preserve connexome function. This suggests the pleiotropic effects of antihypertensive agents, including anti-inflammatory. Therefore, further research is required to identify specific molecular targets and pathways that will protect connexomes, and it is also necessary to develop new approaches to maintain heart function in patients suffering from primary or pulmonary arterial hypertension.

This review focuses on cardiac atrophy resulting from mechanical or metabolic unloading due to various conditions, describing some mechanisms and discussing possible strategies or interventions to prevent, attenuate or reverse myocardial atrophy. An improved awareness of these conditions and an increased focus on the identification of mechanisms and therapeutic targets may facilitate the development of the effective treatment or reversion for cardiac atrophy. It appears that a decrement in the left ventricular mass itself may be the central component in cardiac deconditioning, which avoids the occurrence of life-threatening arrhythmias. The depressed myocardial contractility of atrophied myocardium along with the upregulation of electrical coupling protein, connexin43, the maintenance of its topology, and enhanced PKCƐ signalling may be involved in the anti-arrhythmic phenotype. Meanwhile, persistent myocardial atrophy accompanied by oxidative stress and inflammation, as well as extracellular matrix fibrosis, may lead to severe cardiac dysfunction, and heart failure. Data in the literature suggest that the prevention of heart failure via the attenuation or reversion of myocardial atrophy is possible, although this requires further research.

The hearts of spontaneously hypertensive rats (SHR) are prone to malignant arrhythmias, mainly due to disorders of electrical coupling protein Cx43 and the extracellular matrix. Cold acclimation may induce cardio-protection, but the underlying mechanisms remain to be elucidated. We aimed to explore whether the adaptation of 9-month-old hairless SHR M to cold impacts the fundamental cardiac pro-arrhythmia factors, as well as the response to the thyroid status. There were no significant differences in the registered biometric, redox and blood lipids parameters between hairless (SHR M ) and wild type SHR. Prominent findings revealed that myocardial Cx43 and its variant phosphorylated at serine 368 were increased, while an abnormal cardiomyocyte Cx43 distribution was attenuated in hairless SHR M vs. wild type SHR males and females. Moreover, the level of β-catenin, ensuring mechanoelectrical coupling, was increased as well, while extracellular matrix collagen-1 and hydroxyproline were lower and the TGF-β1 and SMAD2/3 pathway was suppressed in hairless SHR M males compared to the wild type strain. Of interest, the extracellular matrix remodeling was less pronounced in females of both hypertensive strains. There were no apparent differences in response to the hypothyroid or hyperthyroid status between SHR strains concerning the examined markers. Our findings imply that hairless SHR M benefit from cold acclimation due to the attenuation of the hypertension-induced adverse downregulation of Cx43 and upregulation of extracellular matrix proteins.

The prevention of cardiac life-threatening ventricular fibrillation and stroke-provoking atrial fibrillation remains a serious global clinical issue, with ongoing need for novel approaches. Numerous experimental and clinical studies suggest that oxidative stress and inflammation are deleterious to cardiovascular health, and can increase heart susceptibility to arrhythmias. It is quite interesting, however, that various cardio-protective compounds with antiarrhythmic properties are potent anti-oxidative and anti-inflammatory agents. These most likely target the pro-arrhythmia primary mechanisms. This review and literature-based analysis presents a realistic view of antiarrhythmic efficacy and the molecular mechanisms of current pharmaceuticals in clinical use. These include the sodium-glucose cotransporter-2 inhibitors used in diabetes treatment, statins in dyslipidemia and naturally protective omega-3 fatty acids. This approach supports the hypothesis that prevention or attenuation of oxidative and inflammatory stress can abolish pro-arrhythmic factors and the development of an arrhythmia substrate. This could prove a powerful tool of reducing cardiac arrhythmia burden.

Light pollution disturbs circadian rhythm, and this can also be deleterious to the heart by increased susceptibility to arrhythmias. Herein, we investigated if rats exposed to continuous light had altered myocardial gene transcripts and/or protein expression which affects arrhythmogenesis. We then assessed if Omacor ® supplementation benefitted affected rats. Male and female spontaneously hypertensive (SHR) and normotensive Wistar rats (WR) were housed under standard 12 h/12 h light/dark cycles or exposed to 6-weeks continuous 300 lux light for 24 h. Half the rats were then treated with 200 mg/100 g b.w. Omacor ® . Continuous light resulted in higher male rat vulnerability to malignant ventricular fibrillation (VF). This was linked with myocardial connexin-43 (Cx43) down-regulation and deteriorated intercellular electrical coupling, due in part to increased pro-inflammatory NF-κB and iNOS transcripts and decreased sarcoplasmic reticulum Ca 2+ ATPase transcripts. Omacor ® treatment increased the electrical threshold to induce the VF linked with amelioration of myocardial Cx43 mRNA and Cx43 protein levels and the suppression of NF-κB and iNOS. This indicates that rat exposure to continuous light results in deleterious cardiac alterations jeopardizing intercellular Cx43 channel-mediated electrical communication, thereby increasing the risk of malignant arrhythmias. The adverse effects were attenuated by treatment with Omacor ® , thus supporting its potential benefit and the relevance of monitoring omega-3 index in human populations at risk.

Radiation damage of healthy tissues represents one of the complications of radiotherapy effectiveness. This study is focused on the screening of potentially effective drugs routinely used in medical practice and involved in the mechanism of radiation injury, namely for radiation-induced production of free radicals in the body. Experiments in rats revealed significant reduction of oxidative stress (malondialdehyde) and inflammatory marker (tumor necrosis factor α) in 10 Gy irradiated groups after administration of atorvastatin and a slight decrease after tadalafil administration, which indicates that one of the possible mechanisms for mitigation of radiation-induced cardiac damage could be the modulation of nitric oxide (NO) in endothelium and phosphodiesterase 5. In addition, miRNAs were analyzed as potential markers and therapeutically effective molecules. Expression of miRNA-21 and miRNA-15b showed the most significant changes after irradiation. Atorvastatin and tadalafil normalized changes of miRNA (miRNA-1, miRNA-15b, miRNA-21) expression levels in irradiated hearts. This screening study concludes that administration of specific drugs could mitigate the negative impact of radiation on the heart, but more detailed experiments oriented to other aspects of drug effectiveness and their exact mechanisms are still needed.

Cardiac connexin-43 (Cx43) creates gap junction channels (GJCs) at intercellular contacts and hemi-channels (HCs) at the peri-junctional plasma membrane and sarcolemmal caveolae/rafts compartments. GJCs are fundamental for the direct cardiac cell-to-cell transmission of electrical and molecular signals which ensures synchronous myocardial contraction. The HCs and structurally similar pannexin1 (Panx1) channels are active in stressful conditions. These channels are essential for paracrine and autocrine communication through the release of ions and signaling molecules to the extracellular environment, or for uptake from it. The HCs and Panx1 channel-opening profoundly affects intracellular ionic homeostasis and redox status and facilitates via purinergic signaling pro-inflammatory and pro-fibrotic processes. These conditions promote cardiac arrhythmogenesis due to the impairment of the GJCs and selective ion channel function. Crosstalk between GJCs and HCs/Panx1 channels could be crucial in the development of arrhythmogenic substrates, including fibrosis. Despite the knowledge gap in the regulation of these channels, current evidence indicates that HCs and Panx1 channel activation can enhance the risk of cardiac arrhythmias. It is extremely challenging to target HCs and Panx1 channels by inhibitory agents to hamper development of cardiac rhythm disorders. Progress in this field may contribute to novel therapeutic approaches for patients prone to develop atrial or ventricular fibrillation.

Cardiac β-adrenergic overstimulation results in oxidative stress, hypertrophy, ischemia, lesion, and fibrosis rendering the heart vulnerable to malignant arrhythmias. We aimed to explore the anti-arrhythmic efficacy of the anti-oxidative and anti-inflammatory compounds, melatonin, and omega-3, and their mechanisms of actions in normotensive and hypertensive rats exposed to isoproterenol (ISO) induced β-adrenergic overdrive. Eight-month-old, male SHR, and Wistar rats were injected during 7 days with ISO (cumulative dose, 118 mg/kg). ISO rats were either untreated or concomitantly treated with melatonin (10 mg/kg/day) or omega-3 (Omacor, 1.68 g/kg/day) until 60 days of ISO withdrawal and compared to non-ISO controls. Findings showed that both melatonin and omega-3 increased threshold current to induce ventricular fibrillation (VF) in ISO rats regardless of the strain. Prolonged treatment with these compounds resulted in significant suppression of ISO-induced extracellular matrix alterations, as indicated by reduced areas of diffuse fibrosis and decline of hydroxyproline, collagen-1, SMAD2/3, and TGF-β1 protein levels. Importantly, the highly pro-arrhythmic ISO-induced disordered cardiomyocyte distribution of electrical coupling protein, connexin-43 (Cx43), and its remodeling (lateralization) were significantly attenuated by melatonin and omega-3 in Wistar as well as SHR hearts. In parallel, both compounds prevented the post-ISO-related increase in Cx43 variant phosphorylated at serine 368 along with PKCε, which are known to modulate Cx43 remodeling. Melatonin and omega-3 increased SOD1 or SOD2 protein levels in ISO-exposed rats of both strains. Altogether, the results indicate that anti-arrhythmic effects of melatonin and omega-3 might be attributed to the protection of myocardial Cx43 topology and suppression of fibrosis in the setting of oxidative stress induced by catecholamine overdrive in normotensive and hypertensive rats.

Background: MicroRNAs (miRNAs) are new generation biomarkers used in oncology, cardiology, metabolic syndrome, obesity or in neurology. miRNAs are short non-coding RNA molecules that regulate gene expression in eukaryotes., Aim: To compare a new commercial method for establishing miRNA (imunoassay) with a commercial kit RT qPCR., Methods: RNA was isolated from whole blood samples obtained from four healthy volunteers. The isolates were liquated and miRNA-93-5p and miRNA-23a-3p were measured independently with commercial hsa-miR-93-5p miREIA and hsa-miR-23a-3p miREIA, and commercial RT-qPCR kits., Results: Both miRNAs had good analytical characteristics, very good correlation with RT qPCR. The results between immunoassay and RT qPCR did not statistically differ. A method based on ELISA was faster (2 h with ELISA vs. 3 h with qPCR) and had lower CV then a method based on RT qPCR (see more text)., Conclusion: MicroRNAs from blood or derived fractions are particularly interesting candidates for routine laboratory applications. The immunoassay can be performed on any device that processes the ELISA plates and is therefore available in almost every laboratory.

The gene MTNR1B encodes a receptor for melatonin. Melatonin receptors are expressed in human β-cells, which implies that genetic variants might affect glucose tolerance. Meta-analysis confirmed that the rs10830963 shows the most robust association. The aim of the study was to assess the rs10830963 in Czech GDM patients and controls and to study relations between the SNP and biochemical as well as anthropometric characteristics. Our cohort consisted of 880 women; 458 were diagnosed with GDM, and 422 were normoglycemic controls without history of GDM. Despite similar BMI, the GDM group showed higher WHR, waist circumference, abdominal circumference, and total body fat content. The risk allele G was more frequent in the GDM group (38.3 versus 29.4% in controls, OR 1.49 CI95% [1.22; 1.82]; P OR = 0.0001). In spite of higher frequency, the G allele in the GDM group was not associated with any markers of glucose metabolism. In contrast, controls showed significant association of the allele G with FPG and with postchallenge glycemia during the oGTT. Frequency analysis indicates that rs10830963 is involved in gestational diabetes in Czech women. However, the association of the SNP with glucose metabolism, which is obvious in controls, is covert in women who have experienced GDM.