Super-refractory status epilepticus, rhabdomyolysis, central hyperthermia and cardiomyopathy attributable to spinal anesthesia: a case report and review of literature.

BACKGROUND: There are only six past reports of super-refractory status epilepticus induced by spinal anesthesia. None of those patients have died. Only < 15 mg of bupivacaine was administered to all six of them and to our case. Pathophysiology ensuing such cases remains unclear. CASE PRESENTATION: A 27 year old gravida 2, para 1, mother at 37 weeks of gestation came to the operating theater for an elective cesarean section. She had no significant medical history other than controlled hypothyroidism and one episode of food allergy. Her current pregnancy was uneventful. Her American Society of Anesthesiologists (ASA) grade was 2. She underwent spinal anesthesia and adequate anesthesia was achieved. After 5-7 min she developed a progressive myoclonus. After delivery of a healthy baby, she developed generalized tonic clonic seizures that continued despite the induction of general anesthesia. She had rhabdomyolysis, one brief cardiac arrest and resuscitation, followed by stress cardiomyopathy and central hyperthermia. She died on day four. There were no significant macroscopic or histopathological changes in her brain that explain her super refractory status epilepticus. Heavy bupivacaine samples of the same batch used for this patient were analyzed by two specialized laboratories. National Medicines Quality Assurance Laboratory of Sri Lanka reported that samples failed to confirm United States Pharmacopeia (USP) dextrose specifications and passed other tests. Subsequently, Therapeutic Goods Administration of Australia reported that the drug passed all standard USP quality tests applied to it. Nonetheless, they have detected an unidentified impurity in the medicine. CONCLUSIONS: After reviewing relevant literature, we believe that direct neurotoxicity by bupivacaine is the most probable cause of super-refractory status epilepticus. Super-refractory status epilepticus would have led to her other complications and death. We discuss probable patient factors that would have made her susceptible to neurotoxicity. The impurity in the drug detected by one laboratory also would have contributed to her status epilepticus. We propose several possible mechanisms that would have led to status epilepticus and her death. We discuss the factors that shall guide investigators on future such cases. We suggest ways to minimize similar future incidents. This is an idiosyncratic reaction as well.

Selenium Deficiency as a Risk Factor for Peripartum Cardiomyopathy.

BACKGROUND: Peripartum cardiomyopathy (PPCM) is a multifactorial disease. Although the specific aetiology and pathogenesis of PPCM are unknown, several hypotheses have been proposed, including selenium deficiency. However, the risk of PPCM from selenium deficiency was not previously quantified. This posthoc analysis of peripartum cardiomyopathy in Nigeria (PEACE) registry data aimed to determine if selenium deficiency is an independent risk factor for PPCM. METHODS: Apparently healthy women who delivered within the previous 8 weeks and PPCM patients in Kano, Nigeria, were compared for selenium deficiency (<70µg/L) and other relevant socio-demographic and clinical characteristics. Selenium level was measured at recruitment for each subject. Independent predictors of PPCM were determined using logistic regression models. RESULTS: 159 PPCM patients and 90 age-matched controls were consecutively recruited. 84.9% of the patients and 3.3% of controls had selenium deficiency. Selenium deficiency independently increased the odds for PPCM by 167-fold while both unemployment and lack of formal education independently increased the odds by 3.4-fold. CONCLUSION: Selenium deficiency was highly prevalent among PPCM patients in Kano, Nigeria, and significantly increased the odds for PPCM. These results could justify screening of women in their reproductive years for selenium deficiency, particularly those living in regions with high incidence of PPCM. The results also call for the setting up of a definitive clinical trial of selenium supplementation in PPCM patients with selenium deficiency, to further define its benefits in the treatment of PPCM.

CONTEXTE: La cardiomyopathie péripartum (CMPP) est une maladie multifactorielle. Bien que l'étiologie spécifique et la pathogenèse de la CMPP soient inconnues, plusieurs hypothèses ont été proposées, notamment la carence en sélénium. Cependant, le risque de CMPP lié à la carence en sélénium n'a pas été précédemment quantifié. Cette analyse post-hoc des données du registre de la cardiomyopathie péripartum au Nigéria (PEACE) visait à déterminer si la carence en sélénium est un facteur de risque indépendant de la CMPP. MÉTHODES: Des femmes apparemment en bonne santé ayant accouché dans les 8 semaines précédentes et des patientes atteintes de CMPP à Kano, au Nigéria, ont été comparées pour la carence en sélénium (<70µg/L) et d'autres caractéristiques socio-démographiques et cliniques pertinentes. Le taux de sélénium a été mesuré au recrutement pour chaque sujet. Les prédicteurs indépendants de la CMPP ont été déterminés à l'aide de modèles de régression logistique. RÉSULTATS: 159 patientes atteintes de CMPP et 90 témoins appariés selon l'âge ont été recrutés consécutivement. 84,9% des patientes et 3,3% des témoins présentaient une carence en sélénium. La carence en sélénium augmentait indépendamment les chances de CMPP de 167 fois, tandis que le chômage et le manque d'éducation formelle augmentaient indépendamment les chances de 3,4 fois. CONCLUSION: La carence en sélénium était très répandue parmi les patientes atteintes de CMPP à Kano, au Nigéria, et augmentait significativement les chances de CMPP. Ces résultats pourraient justifier le dépistage de la carence en sélénium chez les femmes en âge de procréer, en particulier celles vivant dans des régions à forte incidence de CMPP. Les résultats appellent également à la mise en place d'un essai clinique définitif sur la supplémentation en sélénium chez les patientes atteintes de CMPP présentant une carence en sélénium, afin de définir davantage ses avantages dans le traitement de la CMPP. MOTS-CLÉS: Cardiomyopathie Péripartum; Carence en Sélénium; Facteur de Risque.

Recent Advances on Selenium Nutrition and Keshan Disease.

Keshan disease (KD) is a type of endemic cardiomyopathy with an unknown cause. It is primarily found in areas in China with low selenium levels, from northeast to southwest. The nutritional biogeochemical etiology hypothesis suggests that selenium deficiency is a major factor in KD development. Selenium is important in removing free radicals and protecting cells and tissues from peroxide-induced damage. Thus, low environmental selenium may affect the selenium level within the human body, and selenium level differences are commonly observed between healthy people in KD and nonKD areas. From the 1970s to the 1990s, China successfully reduced KD incidence in endemic KD areas through a selenium supplementation program. After years of implementing prevention and control measures, the selenium level of the population in the KD areas has gradually increased, and the prevalence of KD in China has remained low and stable in recent years. Currently, the pathogenesis of KD remains vague, and the effect of selenium supplementation on the prognosis of KD still needs further study. This paper comprehensively reviews selenium deficiency and its connection to KD. Thus, this study aims to offer novel ideas and directions to effectively prevent and treat KD in light of the current situation.

[Interaction between NOD-like receptor protein 3 inflammatory corpuscles and mitochondrial dysfunction in the pathogenesis of septic cardiomyopathy].

Septic cardiomyopathy (SCM) has a high incidence and complex pathogenesis, which can significantly increase the mortality of sepsis patients. NOD-like receptor protein 3 (NLRP3) inflammatory corpuscles play an important role in the pathogenesis of SCM. Mitochondrial dysfunction in cardiomyocytes is also one of the important pathogenesis of SCM. Activation of NLRP3 inflammatory corpuscles is closely related to mitochondrial dysfunction. The study of interaction mechanism between the two is helpful to find a new therapeutic scheme for SCM. This article reviews the interaction between NLRP3 inflammatory corpuscles and mitochondrial dysfunction in the pathogenesis of SCM, as well as the related mechanisms of traditional Chinese medicine (TCM) prevention and treatment of SCM, providing theoretical reference for further exploring therapeutic targets for SCM.

Low Selenium and Low Protein Exacerbate Myocardial Damage in Keshan Disease by Affecting the PINK1/Parkin-mediated Mitochondrial Autophagy Pathway.

OBJECTIVE: Keshan disease (KD) is a myocardial mitochondrial disease closely related to insufficient selenium (Se) and protein intake. PTEN induced putative kinase 1 (PINK1)/Parkin mediated mitochondrial autophagy regulates various physiological and pathological processes in the body. This study aimed to elucidate the relationship between PINK1/Parkin-regulated mitochondrial autophagy and KD-related myocardial injury. METHODS: A low Se and low protein animal model was established. One hundred Wistar rats were randomly divided into 5 groups (control group, low Se group, low protein group, low Se + low protein group, and corn from KD area group). The JC-1 method was used to detect the mitochondrial membrane potential (MMP). ELISA was used to detect serum creatine kinase MB (CK-MB), cardiac troponin I (cTnI), and mitochondrial-glutamicoxalacetic transaminase (M-GOT) levels. RT-PCR and Western blot analysis were used to detect the expression of PINK1, Parkin, sequestome 1 (P62), and microtubule-associated proteins1A/1B light chain 3B (MAP1LC3B). RESULTS: The MMP was significantly decreased and the activity of CK-MB, cTnI, and M-GOT significantly increased in each experimental group (low Se group, low protein group, low Se + low protein group and corn from KD area group) compared with the control group (P<0.05 for all). The mRNA and protein expression levels of PINK1, Parkin and MAP1LC3B were profoundly increased, and those of P62 markedly decreased in the experimental groups compared with the control group (P<0.05 for all). CONCLUSION: Low Se and low protein levels exacerbate myocardial damage in KD by affecting the PINK1/Parkin-mediated mitochondrial autophagy pathway.

Glycolysis-Mediated Activation of v-ATPase by Nicotinamide Mononucleotide Ameliorates Lipid-Induced Cardiomyopathy by Repressing the CD36-TLR4 Axis.

BACKGROUND: Chronic overconsumption of lipids followed by their excessive accumulation in the heart leads to cardiomyopathy. The cause of lipid-induced cardiomyopathy involves a pivotal role for the proton-pump vacuolar-type H+-ATPase (v-ATPase), which acidifies endosomes, and for lipid-transporter CD36, which is stored in acidified endosomes. During lipid overexposure, an increased influx of lipids into cardiomyocytes is sensed by v-ATPase, which then disassembles, causing endosomal de-acidification and expulsion of stored CD36 from the endosomes toward the sarcolemma. Once at the sarcolemma, CD36 not only increases lipid uptake but also interacts with inflammatory receptor TLR4 (Toll-like receptor 4), together resulting in lipid-induced insulin resistance, inflammation, fibrosis, and cardiac dysfunction. Strategies inducing v-ATPase reassembly, that is, to achieve CD36 reinternalization, may correct these maladaptive alterations. For this, we used NAD+ (nicotinamide adenine dinucleotide)-precursor nicotinamide mononucleotide (NMN), inducing v-ATPase reassembly by stimulating glycolytic enzymes to bind to v-ATPase. METHODS: Rats/mice on cardiomyopathy-inducing high-fat diets were supplemented with NMN and for comparison with a cocktail of lysine/leucine/arginine (mTORC1 [mechanistic target of rapamycin complex 1]-mediated v-ATPase reassembly). We used the following methods: RNA sequencing, mRNA/protein expression analysis, immunofluorescence microscopy, (co)immunoprecipitation/proximity ligation assay (v-ATPase assembly), myocellular uptake of [3H]chloroquine (endosomal pH), and [14C]palmitate, targeted lipidomics, and echocardiography. To confirm the involvement of v-ATPase in the beneficial effects of both supplementations, mTORC1/v-ATPase inhibitors (rapamycin/bafilomycin A1) were administered. Additionally, 2 heart-specific v-ATPase-knockout mouse models (subunits V1G1/V0d2) were subjected to these measurements. Mechanisms were confirmed in pharmacologically/genetically manipulated cardiomyocyte models of lipid overload. RESULTS: NMN successfully preserved endosomal acidification during myocardial lipid overload by maintaining v-ATPase activity and subsequently prevented CD36-mediated lipid accumulation, CD36-TLR4 interaction toward inflammation, fibrosis, cardiac dysfunction, and whole-body insulin resistance. Lipidomics revealed C18:1-enriched diacylglycerols as lipid class prominently increased by high-fat diet and subsequently reversed/preserved by lysine/leucine/arginine/NMN treatment. Studies with mTORC1/v-ATPase inhibitors and heart-specific v-ATPase-knockout mice further confirmed the pivotal roles of v-ATPase in these beneficial actions. CONCLUSION: NMN preserves heart function during lipid overload by preventing v-ATPase disassembly.

Gramine improves sepsis-induced myocardial dysfunction by binding to NF-κB p105 and inhibiting its ubiquitination.

BACKGROUND: Sepsis and its associated heart failure are among the leading causes of death. Gramine, a natural indole alkaloid, can be extracted from a wide variety of raw plants, and it exhibits therapeutic potential in pathological cardiac hypertrophy. However, the effect of gramine on inflammatory cardiomyopathy, particularly sepsis-induced myocardial injury, remains an unexplored area. PURPOSE: To determine the role of gramine in sepsis-induced myocardial dysfunction and explore its underlying mechanism. STUDY DESIGN AND METHODS: In mice, sepsis was established by intraperitoneally injecting lipopolysaccharide (LPS, 10 mg/kg). Subsequently, the effects of gramine administration (50 or 100 mg/kg) on LPS-triggered cardiac dysfunction in mice were investigated. For in vitro studies, isolated primary cardiomyocytes were used to assess the effect of gramine (25 or 50 µM) on LPS-induced apoptosis and inflammation. Additionally, molecular docking, co-immunoprecipitation and ubiquitination analyzes were conducted to explore the underlying mechanisms. RESULTS: Gramine visibly ameliorated sepsis-induced cardiac dysfunction, inflammatory response, and mortality in vivo. Moreover, it significantly alleviated LPS-induced apoptotic and inflammatory responses in vitro. Furthermore, target prediction for gramine using the SuperPred website indicated that the nuclear factor NF-κB p105 subunit was one of the molecules ranked in priority order with a high model accuracy and a high probability score. Molecular docking studies demonstrated that gramine effectively docked to the death domain of NF-κB p105. Mechanistic studies revealed that gramine suppressed the processing of NF-κB p105 to p50 by inhibiting NF-κB p105 ubiquitination. Additionally, the protective effect of gramine on cardiac injury was almost abolished by overexpressing NF-κB p105. CONCLUSION: Gramine is a promising bioactive small molecule for treating sepsis-induced myocardial dysfunction, which acts by docking to NF-κB p105 and inhibiting NF-κB p105 ubiquitination, thus preventing its processing to NF-κB p50. Therefore, gramine holds potential as a clinical drug for treating myocardial depression during sepsis.

Ameliorating impact of coenzyme Q10 on the profile of adipokines, cardiomyopathy, and hematological markers correlated with the glucotoxicity sequelae in diabetic rats.

BACKGROUND: In diabetes, high blood glucose induces glucotoxicity, resulting in the further damage of pancreatic beta-cells and then precipitating diabetic complications. This study was aimed to investigate the relationship between glucotoxicity with the level of adipokines, diabetic cardiomyopathy, and hematological markers. Moreover, the study examined the potential modulatory effect of coenzyme Q10 (CoQ10) on the aforementioned markers associated with the sequelae of diabetes mellitus. MATERIAL AND METHODS: Twenty-four male rats were randomly assigned to receive an injection of STZ to induce diabetes (n = 16) or to remain uninduced (n = 8). The hyperglycemic status was induced in fasting rats by single intraperitoneal injection of STZ (45 mg /kg b.w.) dissolved in citrate buffer (pH 4.5). Three days after STZ injection, rats were divided into three groups; Normal control group (A), Diabetic control group (B), and CoQ10- treated diabetic group (C). The group (C) was fed with the basal diet supplemented with 5 g of CoQ10 per kilogram of diet for three weeks after the diabetes induction. After 21 days, the blood and serum samples were taken to conduct biochemical analyses. Blood glucose was determined by Blood Glucose Monitoring System. Adipokines or cytokines were evaluated by ELISA from a serum sample. Cardiac myopathy biomarkers were estimated by UP-Converting Phosphor Immunoassay Analyzer, and hematological parameters were measured by automatic hematology analyzer. RESULTS: In hyperglycemic rats, the level of fasting blood glucose, and serum level of resistin, omentin, TNF-α, and cardiomyopathy biomarkers significantly increased (P < 0.05). The treatment with CoQ10 significantly decreased the profile of adipokines and cardiomyopathy markers (cardiac enzymes and LPPLA2) in diabetic rats and also reduced glucose levels (P < 0.05). Lymphocyte percentages significantly decreased while significant increases were observed in granulocytes and MID percentages in hyperglycemic rats. CONCLUSION: Diabetic rats had higher serum levels of adipokines and cardiomyopathy markers. Among the hematological markers, GRA% and MID% increased while LYM% decreased. The profile of adipokines and cardiomyopathy markers improved when CoQ10 was supplemented. The study suggests that CoQ10 may have a beneficial effect on improving diabetic complications.

Indole-3-Propionic Acid Protects Against Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is a common but poorly understood form of heart failure, characterized by impaired diastolic function. It is highly heterogeneous with multiple comorbidities, including obesity and diabetes, making human studies difficult. METHODS: Metabolomic analyses in a mouse model of HFpEF showed that levels of indole-3-propionic acid (IPA), a metabolite produced by gut bacteria from tryptophan, were reduced in the plasma and heart tissue of HFpEF mice as compared with controls. We then examined the role of IPA in mouse models of HFpEF as well as 2 human HFpEF cohorts. RESULTS: The protective role and therapeutic effects of IPA were confirmed in mouse models of HFpEF using IPA dietary supplementation. IPA attenuated diastolic dysfunction, metabolic remodeling, oxidative stress, inflammation, gut microbiota dysbiosis, and intestinal epithelial barrier damage. In the heart, IPA suppressed the expression of NNMT (nicotinamide N-methyl transferase), restored nicotinamide, NAD+/NADH, and SIRT3 (sirtuin 3) levels. IPA mediates the protective effects on diastolic dysfunction, at least in part, by promoting the expression of SIRT3. SIRT3 regulation was mediated by IPA binding to the aryl hydrocarbon receptor, as Sirt3 knockdown diminished the effects of IPA on diastolic dysfunction in vivo. The role of the nicotinamide adenine dinucleotide circuit in HFpEF was further confirmed by nicotinamide supplementation, Nnmt knockdown, and Nnmt overexpression in vivo. IPA levels were significantly reduced in patients with HFpEF in 2 independent human cohorts, consistent with a protective function in humans, as well as mice. CONCLUSIONS: Our findings reveal that IPA protects against diastolic dysfunction in HFpEF by enhancing the nicotinamide adenine dinucleotide salvage pathway, suggesting the possibility of therapeutic management by either altering the gut microbiome composition or supplementing the diet with IPA.

Chicoric acid ameliorates sepsis-induced cardiomyopathy via regulating macrophage metabolism reprogramming.

BACKGROUND: Sepsis-related cardiac dysfunction is believed to be a primary cause of high morbidity and mortality. Metabolic reprogramming is closely linked to NLRP3 inflammasome activation and dysregulated glycolysis in activated macrophages, leading to inflammatory responses in septic cardiomyopathy. Succinate dehydrogenase (SDH) and succinate play critical roles in the progression of metabolic reprogramming in macrophages. Inhibition of SDH may be postulated as an effective strategy to attenuate macrophage activation and sepsis-induced cardiac injury. PURPOSE: This investigation was designed to examine the role of potential compounds that target SDH in septic cardiomyopathy and the underlying mechanisms involved. METHODS/RESULTS: From a small molecule pool containing about 179 phenolic compounds, we found that chicoric acid (CA) had the strongest ability to inhibit SDH activity in macrophages. Lipopolysaccharide (LPS) exposure stimulated SDH activity, succinate accumulation and superoxide anion production, promoted mitochondrial dysfunction, and induced the expression of hypoxia-inducible factor-1α (HIF-1α) in macrophages, while CA ameliorated these changes. CA pretreatment reduced glycolysis by elevating the NAD+/NADH ratio in activated macrophages. In addition, CA promoted the dissociation of K(lysine) acetyltransferase 2A (KAT2A) from α-tubulin, and thus reducing α-tubulin acetylation, a critical event in the assembly and activation of NLRP3 inflammasome. Overexpression of KAT2A neutralized the effects of CA, indicating that CA inactivated NLRP3 inflammasome in a specific manner that depended on KAT2A inhibition. Importantly, CA protected the heart against endotoxin insult and improved sepsis-induced cardiac mitochondrial structure and function disruption. Collectively, CA downregulated HIF-1α expression via SDH inactivation and glycolysis downregulation in macrophages, leading to NLRP3 inflammasome inactivation and the improvement of sepsis-induced myocardial injury. CONCLUSION: These results highlight the therapeutic role of CA in the resolution of sepsis-induced cardiac inflammation.

Improvement in Cardiac Morphology Demonstrated by Cardiac Magnetic Resonance Imaging and Echocardiography after Haploidentical Hematopoietic Cell Transplantation in Adults with Sickle Cell Disease.

Cardiopulmonary complications account for approximately 40% of deaths in patients with sickle cell disease (SCD). Diffuse myocardial fibrosis, elevated tricuspid regurgitant jet velocity (TRV) and iron overload are all associated with early mortality. Although HLA-matched sibling hematopoietic cell transplantation (HCT) offers a potential cure, less than 20% of patients have a suitable donor. Haploidentical HCT allows for an increased donor pool and has recently demonstrated improved safety and efficacy. Our group has reported improved cardiac morphology via echocardiography at 1 year after HCT. Here we describe the first use of cardiac magnetic resonance imaging (CMR), the gold standard for measuring volume, mass, and ventricular function, to evaluate changes in cardiac morphology post-HCT in adults with SCD. We analyzed baseline and 1-year data from 12 adults with SCD who underwent nonmyeloablative haploidentical peripheral blood HCT at the National Institutes of Health. Patients underwent noncontrast CMR at 3 T, echocardiography, and laboratory studies. At 1 year after HCT, patients showed marked improvement in cardiac chamber morphology by CMR, including left ventricular (LV) mass (70.2 to 60.1 g/m2; P = .02) and volume (114.5 to 90.6 mL/m2; P = .001). Furthermore, mean TRV normalized by 1 year, suggesting that HCT may offer a survival benefit. Fewer patients had pathologically prolonged native myocardial T1 times, an indirect marker of myocardial fibrosis at 1 year; these data showed a trend toward significance. In this small sample, CMR was very sensitive in detecting cardiac mass and volume changes after HCT and provided complementary information to echocardiography. Notably, post-HCT improvement in cardiac parameters can be attributed only in part to the resolution of anemia; further studies are needed to determine the roles of myocardial fibrosis reversal, improved blood flow, and survival impact after HCT for SCD.

Euphorbia grantii Oliv. standardized extract and its fraction ameliorate doxorubicin-induced cardiomyopathy in Ehrlich carcinoma bearing mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Euphorbia plants have long been used as traditional medicine in China, Europe, America, Turkey, India, Africa, Iran, and Pakistan because of its high medicinal value and health advantages especially as a remedy for several types of cancer. AIM OF THE STUDY: Doxorubicin (DOX) is one of the most frequently prescribed drugs in cancer chemotherapy, with dose-limiting cardiotoxicity. The development of medicinal approaches to attenuate drug's toxicity represents an area of great concern in cancer research. Because research on this topic is still disputed and limited, we aim to investigate the potential of supplementation with Euphorbia grantii Oliv. on DOX-induced cardiomyopathy in Ehrlich carcinoma bearing mice. MATERIALS AND METHODS: The high-performance thin layer chromatography (HPTLC) analysis of total methanolic extract (TE), and its bioactive dichloromethane fraction (DCMF) was applied for the determination of friedelin. Male BALB/c mice were used to keep the Ehrlich ascites tumor cells. The experiment was performed for a 2-weeks period. RESULTS: A good linearity relationship was found to be with correlation coefficient (r2) value of 0.9924 for the isolated friedelin. Limit of detection (LOD) and limit of quantitation (LOQ) was found to be 0.00179, and 0.000537 ng/band respectively for friedelin. The amount of friedelin in the TE and DCMF were determined by using calibration curve of standard as 106.32 ± 5.69 µg, and 159.2 ± 4.24 µg friedelin/mg extract, respectively. DOX-induced cardiomyopathy by decreasing the ejection fraction (EF) compared to the Ehrlich and negative control groups. It resulted in a decrease in the EF by 30 and 39% compared to the other groups. High and low doses of the TE and DCMF did not result in significantly different ejection fractions compared to the Ehrlich group. Co-administration of DCMF with DOX ameliorated the alteration in the serum CKMB and LDH levels. As revealed from histopathological study, DOX impairs viability of cardiac myocytes and DCMF could effectively and extensively counteract this action of DOX and potentially protect the heart from severe toxicity of DOX. CONCLUSIONS: Finally, our results indicated that Euphorbia grantii Oliv. would be the best option to reduce DOX adverse effects.

Ameliorative effect of anisodamine (654-1/654-2) against myocardial dysfunction induced by septic shock via the NF-κB/NLRP-3 or the PI3K-AKT/NF-κB pathway.

BACKGROUND: Septic shock, an extremely dangerous condition that causes impairment of organ function, always largely contributes to mortality in intensive care units. The impact of septic shock-induced organ damage on morbidity and mortality is substantially influenced by myocardial dysfunction. However, it remains unclear whether and in what manner anisodamine (654-1/654-2) ameliorates myocardial dysfunction caused by septic shock. PURPOSE: This study is the pioneering investigation and validation about the protective efficacy of anisodamine (654-1/654-2) against LPS-induced myocardial dysfunction in septic shock rats. It also aims to explore the differences in the underlying molecular mechanisms of both drugs. METHODS: A septic shock model was established in SD rats by after tail vein administration of LPS. 64 rats were distributed into eight groups, such as LPS group, control group, LPS+654-1 group (1.25, 2.5, and 5 mg/kg), and LPS+654-2 group (1.25, 2.5, and 5 mg/kg). The hemodynamics, echocardiography, immunohistochemical analysis, TEM, TUNEL assay, and H&E staining were utilized to assess the septic shock model and myocardial function. Lactic acid, inflammatory markers (IL-1ß, IL-6, and TNF-α), endothelial injure markers (SDC-1, HS and TM) and myocardial injury markers (CK, c-TNT and NT-pro BNP) were assessed using ELISA or biochemical kits. Additionally, the mechanisms of 654-1/654-2 were analyzed using RNA-seq and bioinformatics, and validated using western blotting and RT-PCR. RESULTS: Administration of 654-1/654-2 significantly restored hemodynamics and improved myocardial and endothelial glycocalyx injury in septic shock rats. Furthermore, 654-1/654-2 dose-dependently reduced plasma levels of lactic acid, inflammatory cytokines, and markers of endothelial and myocardial injury. Analyses using RNA-seq, WB and RT-PCR techniques indicated that 654-1/654-2 could mitigate myocardial and endothelial injury by inhibiting the NF-κB and NLRP-3 pathways, and activating the PI3K-AKT pathway. CONCLUSIONS: These findings demonstrated that 654-1/654-2 could alleviate myocardial damage in septic shock rats. Specifically, 654-1 inhibited the NF-κB/NLRP-3 pathway, whereas 654-2 promoted the PI3K-AKT pathway and inhibited the NF-κB pathway, effectively mitigating the inflammatory response and cell apoptosis.

Astilbin protects from sepsis-induced cardiac injury through the NRF2/HO-1 and TLR4/NF-κB pathway.

Cardiac dysfunction and arrhythmia are severe complications of sepsis-induced cardiomyopathy and are associated with an increased risk of morbidity and mortality. Currently, the precise mechanism for sepsis-induced myocardial damage remains unclear. Astilbin, a flavonoid, is reported to have anti-inflammatory, antioxidative, and antiapoptotic properties. However, the effects of astilbin on sepsis-induced cardiomyopathy have not been studied so far. This study aims to investigate the effect of astilbin in sepsis-induced myocardial injury and elucidate the underlying mechanism. In vivo and in vitro sepsis models were created using lipopolysaccharide (LPS) as an inducer in H9C2 cardiomyocytes and C57BL/6 mice, respectively. Our results demonstrated that astilbin reduced myocardial injury and improved cardiac function. Moreover, astilbin prolonged the QT and corrected QT intervals, attenuated myocardial electrical remodeling, and promoted gap junction protein (Cx43) and ion channels expression, thereby reducing the susceptibility of ventricular fibrillation. In addition, astilbin alleviated LPS-induced inflammation, oxidative stress, and apoptosis. Astilbin suppressed the toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) pathway in vivo and in vitro models. Astilbin remarkedly upregulated the nuclear factor erythroid 2-related factor 2 (NRF2) and heme oxygenase 1 (HO-1) expression. The in vitro treatment with an NRF2 inhibitor reversed the inhibition of the TLR4/NF-κB pathway and antioxidant properties of astilbin. Astilbin attenuated LPS-induced myocardial injury, cardiac dysfunction, susceptibility to VF, inflammation, oxidative stress, and apoptosis by activating the NRF2/HO-1 pathway and inhibiting TLR4/ NF-κB pathway. These results suggest that astilbin could be an effective and promising therapeutics target for the treatment of sepsis-induced cardiomyopathy.

Protective Effect of Uridine on Structural and Functional Rearrangements in Heart Mitochondria after a High-Dose Isoprenaline Exposure Modelling Stress-Induced Cardiomyopathy in Rats.

The pyrimidine nucleoside uridine and its phosphorylated derivates have been shown to be involved in the systemic regulation of energy and redox balance and promote the regeneration of many tissues, including the myocardium, although the underlying mechanisms are not fully understood. Moreover, rearrangements in mitochondrial structure and function within cardiomyocytes are the predominant signs of myocardial injury. Accordingly, this study aimed to investigate whether uridine could alleviate acute myocardial injury induced by isoprenaline (ISO) exposure, a rat model of stress-induced cardiomyopathy, and to elucidate the mechanisms of its action related to mitochondrial dysfunction. For this purpose, a biochemical analysis of the relevant serum biomarkers and ECG monitoring were performed in combination with transmission electron microscopy and a comprehensive study of cardiac mitochondrial functions. The administration of ISO (150 mg/kg, twice with an interval of 24 h, s.c.) to rats caused myocardial degenerative changes, a sharp increase in the serum cardiospecific markers troponin I and the AST/ALT ratio, and a decline in the ATP level in the left ventricular myocardium. In parallel, alterations in the organization of sarcomeres with focal disorganization of myofibrils, and ultrastructural and morphological defects in mitochondria, including disturbances in the orientation and packing density of crista membranes, were detected. These malfunctions were improved by pretreatment with uridine (30 mg/kg, twice with an interval of 24 h, i.p.). Uridine also led to the normalization of the QT interval. Moreover, uridine effectively inhibited ISO-induced ROS overproduction and lipid peroxidation in rat heart mitochondria. The administration of uridine partially recovered the protein level of the respiratory chain complex V, along with the rates of ATP synthesis and mitochondrial potassium transport, suggesting the activation of the potassium cycle through the mitoKATP channel. Taken together, these results indicate that uridine ameliorates acute ISO-induced myocardial injury and mitochondrial malfunction, which may be due to the activation of mitochondrial potassium recycling and a mild uncoupling leading to decreased ROS generation and oxidative damage.

Calcium channel blockers for preventing cardiomyopathy due to iron overload in people with transfusion-dependent beta thalassaemia.

BACKGROUND: Beta-thalassaemia is an inherited blood disorder that reduces the production of haemoglobin. The most severe form requires recurrent blood transfusions, which can lead to iron overload. Cardiovascular dysfunction caused by iron overload is the leading cause of morbidity and mortality in people with transfusion-dependent beta-thalassaemia. Iron chelation therapy has reduced the severity of systemic iron overload, but removal of iron from the myocardium requires a very proactive preventive strategy. There is evidence that calcium channel blockers may reduce myocardial iron deposition. This is an update of a Cochrane Review first published in 2018. OBJECTIVES: To assess the effects of calcium channel blockers plus standard iron chelation therapy, compared with standard iron chelation therapy (alone or with a placebo), on cardiomyopathy due to iron overload in people with transfusion-dependent beta thalassaemia. SEARCH METHODS: We searched the Cochrane Haemoglobinopathies Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books, to 13 January 2022. We also searched ongoing trials databases and the reference lists of relevant articles and reviews. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of calcium channel blockers combined with standard chelation therapy versus standard chelation therapy alone or combined with placebo in people with transfusion-dependent beta thalassaemia. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. We used GRADE to assess certainty of evidence. MAIN RESULTS: We included six RCTs (five parallel-group trials and one cross-over trial) with 253 participants; there were 126 participants in the amlodipine arms and 127 in the control arms. The certainty of the evidence was low for most outcomes at 12 months; the evidence for liver iron concentration was of moderate certainty, and the evidence for adverse events was of very low certainty. Amlodipine plus standard iron chelation compared with standard iron chelation (alone or with placebo) may have little or no effect on cardiac T2* values at 12 months (mean difference (MD) 1.30 ms, 95% confidence interval (CI) -0.53 to 3.14; 4 trials, 191 participants; low-certainty evidence) and left ventricular ejection fraction (LVEF) at 12 months (MD 0.81%, 95% CI -0.92% to 2.54%; 3 trials, 136 participants; low-certainty evidence). Amlodipine plus standard iron chelation compared with standard iron chelation (alone or with placebo) may reduce myocardial iron concentration (MIC) after 12 months (MD -0.27 mg/g, 95% CI -0.46 to -0.08; 3 trials, 138 participants; low-certainty evidence). The results of our analysis suggest that amlodipine has little or no effect on heart T2*, MIC, or LVEF after six months, but the evidence is very uncertain. Amlodipine plus standard iron chelation compared with standard iron chelation (alone or with placebo) may increase liver T2* values after 12 months (MD 1.48 ms, 95% CI 0.27 to 2.69; 3 trials, 127 participants; low-certainty evidence), but may have little or no effect on serum ferritin at 12 months (MD 0.07 µg/mL, 95% CI -0.20 to 0.35; 4 trials, 187 participants; low-certainty evidence), and probably has little or no effect on liver iron concentration (LIC) after 12 months (MD -0.86 mg/g, 95% CI -4.39 to 2.66; 2 trials, 123 participants; moderate-certainty evidence). The results of our analysis suggest that amlodipine has little or no effect on serum ferritin, liver T2* values, or LIC after six months, but the evidence is very uncertain. The included trials did not report any serious adverse events at six or 12 months of intervention. The studies did report mild adverse effects such as oedema, dizziness, mild cutaneous allergy, joint swelling, and mild gastrointestinal symptoms. Amlodipine may be associated with a higher risk of oedema (risk ratio (RR) 5.54, 95% CI 1.24 to 24.76; 4 trials, 167 participants; very low-certainty evidence). We found no difference between the groups in the occurrence of other adverse events, but the evidence was very uncertain. No trials reported mortality, cardiac function assessments other than echocardiographic estimation of LVEF, electrocardiographic abnormalities, quality of life, compliance with treatment, or cost of interventions. AUTHORS' CONCLUSIONS: The available evidence suggests that calcium channel blockers may reduce MIC and may increase liver T2* values in people with transfusion-dependent beta thalassaemia. Longer-term multicentre RCTs are needed to assess the efficacy and safety of calcium channel blockers for myocardial iron overload, especially in younger children. Future trials should also investigate the role of baseline MIC in the response to calcium channel blockers, and include a cost-effectiveness analysis.

Epilepsy and Coenzyme Q10 deficiency with COQ4 variants.

Coenzyme Q10 (CoQ10) is one of the essential substances for mitochondrial energy synthesis and extra-mitochondrial vital function. Primary CoQ10 deficiency is a rare disease resulting from interruption of CoQ10 biosynthetic pathway and biallelic COQ4 variants are one of the genetic etiologies recognized in this hereditary disorder. The clinical heterogenicity is broad with wide onset age from prenatal period to adulthood. The typical manifestations include early pharmacoresistant seizure, severe cognition and/or developmental delay, dystonia, ataxia, and spasticity. Patients may also have multisystemic involvements such as cardiomyopathy, lactic acidosis or gastro-esophageal regurgitation disease. Oral CoQ10 supplement is the major therapeutic medication currently. Among those patients, c.370G > A variant is the most common pathogenic variant detected, especially in Asian population. This phenomenon also suggests that this specific allele may be the founder variants in Asia. In this article, we report two siblings with infantile onset seizures, developmental delay, cardiomyopathy, and diffuse brain atrophy. Genetic analysis of both two cases revealed homozygous COQ4 c.370G > A (p.Gly124Ser) variants. We also review the clinical manifestations of primary CoQ10 deficiency patients and possible treatment categories, which are still under survey. As oral CoQ10 supplement may improve or stabilize disease severity, early precise diagnosis of primary CoQ10 deficiency and early treatment are the most important issues. This review article helps to further understand clinical spectrum and treatment categories of primary CoQ10 deficiency with COQ4 variant.

Systemic primary carnitine deficiency induces severe arrhythmia due to shortening of QT interval.

BACKGROUND: Systemic primary carnitine deficiency (PCD) is characterized by cardiomyopathy and arrhythmia. Without carnitine supplementation, progression is usually towards fatal cardiac decompensation. While the cardiomyopathy is most likely secondary to energy deficiency, the mechanism of arrhythmia is unclear, and may be related to a short QT interval. OBJECTIVE: We aim to describe rhythmic manifestations at diagnosis and with carnitine supplementation. METHODS: French patients diagnosed for PCD were retrospectively included. Clinical and para clinical data at diagnosis and during follow-up were collected. Electrocardiograms with QT interval measurements were blinded reviewed by two paediatric cardiologists. RESULTS: Nineteen patients (median age at diagnosis 2.3 years (extremes 0.3-28.9)) followed in 8 French centres were included. At diagnosis, 21% of patients (4/19) had arrhythmia (2 ventricular fibrillations, 1 ventricular tachycardia and 1 sudden death), and 84% (16/19) had cardiomyopathy. Six electrocardiograms before treatment out of 11 available displayed a short QT (QTc < 340 ms). Median corrected QTc after carnitine supplementation was 404 ms (extremes 341-447) versus 350 ms (extremes 282-421) before treatment (p < 0.001). The whole QTc was prolonged, and no patient reached the criterion of short QT syndrome with carnitine supplementation. Three patients died, probably from rhythmic cause without carnitine supplementation (two extra-hospital sudden deaths and one non-recoverable rhythmic storm before carnitine supplementation), whereas no rhythmic complication occurred in patients with carnitine supplementation. CONCLUSION: PCD is associated with shortening of the QT interval inducing severe arrhythmia. A potential explanation would be a toxic effect of accumulated fatty acid and metabolites on ionic channels embedded in the cell membrane. Carnitine supplementation normalizes the QTc and prevents arrhythmia. Newborn screening of primary carnitine deficiency would prevent avoidable deaths.

Systematic in vivo candidate evaluation uncovers therapeutic targets for LMNA dilated cardiomyopathy and risk of Lamin A toxicity.

BACKGROUND: Dilated cardiomyopathy (DCM) is a severe, non-ischemic heart disease which ultimately results in heart failure (HF). Decades of research on DCM have revealed diverse aetiologies. Among them, familial DCM is the major form of DCM, with pathogenic variants in LMNA being the second most common form of autosomal dominant DCM. LMNA DCM is a multifactorial and complex disease with no specific treatment thus far. Many studies have demonstrated that perturbing candidates related to various dysregulated pathways ameliorate LMNA DCM. However, it is unknown whether these candidates could serve as potential therapeutic targets especially in long term efficacy. METHODS: We evaluated 14 potential candidates including Lmna gene products (Lamin A and Lamin C), key signaling pathways (Tgfß/Smad, mTor and Fgf/Mapk), calcium handling, proliferation regulators and modifiers of LINC complex function in a cardiac specific Lmna DCM model. Positive candidates for improved cardiac function were further assessed by survival analysis. Suppressive roles and mechanisms of these candidates in ameliorating Lmna DCM were dissected by comparing marker gene expression, Tgfß signaling pathway activation, fibrosis, inflammation, proliferation and DNA damage. Furthermore, transcriptome profiling compared the differences between Lamin A and Lamin C treatment. RESULTS: Cardiac function was restored by several positive candidates (Smad3, Yy1, Bmp7, Ctgf, aYAP1, Sun1, Lamin A, and Lamin C), which significantly correlated with suppression of HF/fibrosis marker expression and cardiac fibrosis in Lmna DCM. Lamin C or Sun1 shRNA administration achieved consistent, prolonged survival which highly correlated with reduced heart inflammation and DNA damage. Importantly, Lamin A treatment improved but could not reproduce long term survival, and Lamin A administration to healthy hearts itself induced DCM. Mechanistically, we identified this lapse as caused by a dose-dependent toxicity of Lamin A, which was independent from its maturation. CONCLUSIONS: In vivo candidate evaluation revealed that supplementation of Lamin C or knockdown of Sun1 significantly suppressed Lmna DCM and achieve prolonged survival. Conversely, Lamin A supplementation did not rescue long term survival and may impart detrimental cardiotoxicity risk. This study highlights a potential of advancing Lamin C and Sun1 as therapeutic targets for the treatment of LMNA DCM.