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Diabetic Conditions (diabetic + condition)
Selected AbstractsExpressional changes of ganglioside GM3 during ovarian maturation and early embryonic development in db/db miceDEVELOPMENT GROWTH & DIFFERENTIATION, Issue 1 2003Dong Hoon Kwak Diabetes and obesity cause abnormal development of reproductive processes in a variety of species, but the mechanisms that underlie this effect have not been fully elucidated. This study examined the expressional changes of ganglioside GM3 during ovarian maturation, in vitro fertilization (IVF) and early embryonic development in diabetic/obese db/db mice. In high-performance thin-layer chromatography studies, GM3 expression was conspicuously low in the ovaries of db/db mice compared to non-diabetic db/+ mice. Signal detected by anti-GM3 monoclonal antibody was greatly reduced in the primary, secondary and graffian follicles of db/db mice compared to control mice. Results from IVF with ova and sperm from db/db mice showed that GM3 expression during early embryonic development was obviously decreased compared to db/+ mice. This study also elucidated the effects of high glucose (20 and 30 mm) on early embryonic development in ICR strain mice. High glucose caused a decrease in GM3 expression during early embryonic development. Taken together, the results of this study indicate decreased GM3 expression during ovarian maturation and embryonic development of db/db mice, suggesting that alteration of ganglioside expression induced by the diabetic condition may be implicated in the abnormal follicular embryonic development. [source] Diminished Bone Formation During Diabetic Fracture Healing is Related to the Premature Resorption of Cartilage Associated With Increased Osteoclast Activity,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 4 2007Rayyan A Kayal Abstract Histological and molecular analysis of fracture healing in normal and diabetic animals showed significantly enhanced removal of cartilage in diabetic animals. Increased cartilage turnover was associated with elevated osteoclast numbers, a higher expression of genes that promote osteoclastogenesis, and diminished primary bone formation. Introduction: Diminished bone formation, an increased incidence of nonunions, and delayed fracture healing have been observed in animal models and in patients with diabetes. Fracture healing is characterized by the formation of a stabilizing callus in which cartilage is formed and then resorbed and replaced by bone. To gain insight into how diabetes affects fracture healing, studies were carried out focusing on the impact of diabetes on the transition from cartilage to bone. Materials and Methods: A low-dose treatment protocol of streptozotocin in CD-1 mice was used to induce a type 1 diabetic condition. After mice were hyperglycemic for 3 weeks, controlled closed simple transverse fractures of the tibia were induced and fixed by intramedullary pins. Histomorphometric analysis of the tibias obtained 12, 16, and 22 days after fracture was performed across the fracture callus at 0.5 mm proximal and distal increments using computer-assisted image analysis. Another group of 16-day samples were examined by ,CT. RNA was isolated from a separate set of animals, and the expression of genes that reflect the formation and removal of cartilage and bone was measured by real-time PCR. Results: Molecular analysis of collagen types II and × mRNA expression showed that cartilage formation was the same during the initial period of callus formation. Histomorphometric analysis of day 12 fracture calluses showed that callus size and cartilage area were also similar in normoglycemic and diabetic mice. In contrast, on day 16, callus size, cartilage tissue, and new bone area were 2.0-, 4.4-, and 1.5-fold larger, respectively, in the normoglycemic compared with the diabetic group (p < 0.05). Analysis of ,CT images indicated that the bone volume in the normoglycemic animals was 38% larger than in diabetic animals. There were 78% more osteoclasts in the diabetic group compared with the normoglycemic group (p < 0.05) on day 16, consistent with the reduction in cartilage. Real-time PCR showed significantly elevated levels of mRNA expression for TNF-,, macrophage-colony stimulating factor, RANKL, and vascular endothelial growth factor-A in the diabetic group. Similarly, the mRNA encoding ADAMTS 4 and 5, major aggrecanases that degrade cartilage, was also elevated in diabetic animals. Conclusions: These results suggest that impaired fracture healing in diabetes is characterized by increased rates of cartilage resorption. This premature loss of cartilage leads to a reduction in callus size and contributes to decreased bone formation and mechanical strength frequently reported in diabetic fracture healing. [source] Accelerated DNA fragmentation of the denture-bearing mucosal epithelium in an animal model of diabetesJOURNAL OF ORAL REHABILITATION, Issue 4 2001Y. Maruo This study examined the effect of masticatory pressure transmitted directly to the hard palate mucosa on the final stage of terminal differentiation of keratinizing system of rats with and without streptozotocin-induced diabetes mellitus. In the nondiabetic rats with masticatory pressure, the number of terminal-deoxynucleotidyl-transferase-mediated deoxyuridine-triphospate-biotin nick end labelling (TUNEL) positive cells tended to increase about twice as much as in the nondiabetic rats without pressure with and without denture. A similar tendency of increase was observed in the diabetic rats without pressure. The synergy of the mechanical pressure and diabetic condition for 2 weeks greatly accelerated the DNA fragmentation, showing 8-fold increase in TUNEL positive cells over the normal control, and caused exfoliation of the stratum corneum. A 4-week exposure of diabetics to the masticatory pressure induced laminar splitting in the midst of the spinosum. Some cells in the stratum granulosum exhibited a sign of DNA fragmentation when laminar splitting took place in the vital cell layer. Premature DNA fragmentation may disturb the adhesion between spinosum cells and prevent the maturation of stratum corneum. Increase in Bax protein-like immunoreactivity in these epithelial cells as revealed by immunocytochemistry may underlie the premature DNA fragmentation in the oral masticatory epithelium under pressure in diabetic patients. [source] The comparison of vitamin C and vitamin E on the protein oxidation of diabetic ratsAUTONOMIC & AUTACOID PHARMACOLOGY, Issue 5 2001H. D. Je Summary 1 We measured the plasma glucose and the glycosylated haemoglobin at the time of sacrifice in streptozotocin-induced diabetic mellitus (DM) rats. 2 In diabetic rats, plasma glucose and glycosylated haemoglobin was increased as compared with normal rats, and vitamin E inhibited the increase of glycosylated haemoglobin level but vitamin C had no effect. 3 The peroxidized proteins and lipids from the diabetic organs such as liver or kidney were measured to assess the oxidative damage. The 2,4-dinitrophenyl-hydrazine (DNPH) incorporation method was used to measure the peroxidized protein. In diabetic rats, DNPH incorporation was increased as compared with normal rats and vitamin E also inhibited the increase of DNPH incorporation but vitamin C had no effect. It suggests that the protein oxidation occurred on the liver in diabetic rats and the oxidative stress is general in the diabetic condition. 4 We measured the systolic arterial pressure and mean arterial pressure in normal rats, nephrectomy (NEPH)-rats, diabetic rats (DM), and NEPH-diabetic rats (NEPH-DM). Blood pressure was significantly increased in DM and NEPH-DM as compared with normal rats. 5 In conclusion, plasma glucose, glycosylated haemoglobin, and the oxidation of proteins or lipid were increased in diabetic rats. Vitamin E decreased the plasma glucose, glycosylated haemoglobin and the oxidation of proteins and lipid, but vitamin C had no effects. [source] Influence of Hyperglycaemia on Chemical-Induced Toxicity: Study with Cyclophosphamide in RatBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 4 2009Kalavatala Saandeep Hyperglycaemia perturbs the critical balance between oxidative stress and anti-oxidant defence mechanisms in the body and thereby alters the response of biological system towards various toxic chemicals. Cyclophosphamide (CP) is a widely prescribed anticancer drug, well-known genotoxic agent as well as used in the development of immunocompromised animal models. The present study investigated the modulating effect of diabetes on the cyclophosphamide-induced cytotoxicity and genotoxicity. The study was performed on male Sprague-Dawley rats (200 ± 10 g). Cyclophosphamide (10 mg/kg) was administered five consecutive days in a week for 3 weeks to both control and diabetic rats. Thiobarbituric acid reactive substances (TBARS) levels were measured in the plasma, liver, kidney and lung tissues. DNA damaging potential of cyclophosphamide under diabetic condition was evaluated using comet and halo assay as an endpoint. To further ascertain the mode of cell death, terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling (TUNEL) assay and immunohistochemical evaluation of p53 was performed. Significant increase in DNA damage was revealed by the comet assay parameters, halo assay indicated the level of cytotoxicity and the oxidative stress was measured using the TBARS assay in the diabetic rats receiving cyclophosphamide treatment. The toxic effects were more prominent in diabetic animals as compared to non-diabetic rats. Cyclophosphamide treatment and diabetic condition per se led to increase in the p53 + and TUNEL + cells in the liver and kidney of rats. Under diabetic condition, further increase in the p53 + and TUNEL + cells was observed in response to cyclophosphamide. In the present study, we report that hyperglycaemic condition exaggerates the cyclophosphamide-induced toxicity and the response was found to be tissue specific. [source] Activation of dorsal horn microglia contributes to diabetes-induced tactile allodynia via extracellular signal-regulated protein kinase signalingGLIA, Issue 4 2008Makoto Tsuda Abstract Painful neuropathy is one of the most common complications of diabetes, one hallmark of which is tactile allodynia (pain hypersensitivity to innocuous stimulation). The underlying mechanisms of tactile allodynia are, however, poorly understood. Emerging evidence indicates that, following nerve injury, activated microglia in the spinal cord play a crucial role in tactile allodynia. However, it remains unknown whether spinal microglia are activated under diabetic conditions and whether they contribute to diabetes-induced tactile allodynia. In the present study, using streptozotocin (STZ)-induced diabetic rats that displayed tactile allodynia, we found several morphological changes of activated microglia in the dorsal horn. These included increases in Iba1 and OX-42 labeling (markers of microglia), hypertrophic morphology, the thickness and the retraction of processes, and in the number of activated microglia cells. Furthermore, in the dorsal horn of STZ diabetic rats, extracellular signal-regulated protein kinase (ERK) and an upstream kinase, Src-family kinase (SFK), both of which are implicated in microglial functions, were activated exclusively in microglia. Moreover, inhibition of ERK phosphorylation in the dorsal horn by intrathecal administration of U0126, an inhibitor of ERK activation, produced a striking alleviation of existing, long-term tactile allodynia of diabetic rats. We also found that a single administration of U0126 reduced the expression of allodynia. Together, these results suggest that activated dorsal horn microglia may be a crucial component of diabetes-induced tactile allodynia, mediated, in part, by the ERK signaling pathway. Thus, inhibiting microglia activation in the dorsal horn may represent a therapeutic strategy for treating diabetic tactile allodynia. © 2008 Wiley-Liss, Inc. [source] Changes in oxidative balance in rat pericytes exposed to diabetic conditionsJOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 1 2004A. Manea Abstract Recent data indicate that the oxidative stress plays an important role in the pathogenesis of diabetes and its complications such as retinopathy, nephropathy and accelerated atherosclerosis. In diabetic retinopathy, it was demonstrated a selective loss of pericytes accompanied by capillary basement membrane thickening, increased permeability and neovascularization. This study was designed to investigate the role of diabetic conditions such as high glucose, AGE-Lysine, and angiotensin II in the modulation of antioxidant enzymes activities, glutathione level and reactive oxygen species (ROS) production in pericytes. The activity of antioxidant enzymes: superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and total glutathione (GSH) was measured spectrophotometrically. The production of ROS was detected by spectrofluorimetry and fluorescence microscopy after loading the cells with 2,-7, dichlorofluoresceine diacetate; as positive control H2O2 was used. Intracellular calcium was determined using Fura 2 AM assay. The results showed that the cells cultured in high glucose alone, do not exhibit major changes in the antioxidant enzyme activities. The presence of AGE-Lys or Ang II induced the increase of SOD activity. Their combination decreased significantly GPx activity and GSH level. Athree times increase in ROS production and a significant impairment of intracellular calcium homeostasis was detected in cells cultured in the presence of the three pro-diabetic agents used. In conclusion, our data indicate that diabetic conditions induce in pericytes: (i) an increase of ROS and SOD activity, (ii) a decrease in GPx activity and GSH level, (iii) a major perturbation of the intracellular calcium homeostasis. The data may explain the structural and functional abnormalities of pericytes characteristic for diabetic retinopathy. [source] Thioredoxin interacting protein (TXNIP) induces inflammation through chromatin modification in retinal capillary endothelial cells under diabetic conditionsJOURNAL OF CELLULAR PHYSIOLOGY, Issue 1 2009Lorena Perrone Chronic hyperglycemia and activation of receptor for advanced glycation end products (RAGE) are known risk factors for microvascular disease development in diabetic retinopathy. Thioredoxin-interacting protein (TXNIP), an endogenous inhibitor of antioxidant thioredoxin (TRX), plays a causative role in diabetes and its vascular complications. Herein we investigate whether HG and RAGE induce inflammation in rat retinal endothelial cells (EC) under diabetic conditions in culture through TXNIP activation and whether epigenetic mechanisms play a role in inflammatory gene expression. We show that RAGE activation by its ligand S100B or HG treatment of retinal EC induces the expression of TXNIP and inflammatory genes such as Cox2, VEGF-A, and ICAM1. TXNIP silencing by siRNA impedes RAGE and HG effects while stable over-expression of a cDNA for human TXNIP in EC elevates inflammation. p38 MAPK-NF-,B signaling pathway and histone H3 lysine (K) nine modifications are involved in TXNIP-induced inflammation. Chromatin immunoprecipitation (ChIP) assays reveal that TXNIP over-expression in EC abolishes H3K9 tri-methylation, a marker for gene inactivation, and increases H3K9 acetylation, an indicator of gene induction, at proximal Cox2 promoter bearing the NF-,B-binding site. These findings have important implications toward understanding the molecular mechanisms of ocular inflammation and endothelial dysfunction in diabetic retinopathy. J. Cell. Physiol. 221: 262,272, 2009. © 2009 Wiley-Liss, Inc [source] Vitreous Fluid and/or Urine Glucose Concentrations in 1335 Civil Aviation Accident Pilot Fatalities,JOURNAL OF FORENSIC SCIENCES, Issue 3 2009Arvind K. Chaturvedi Ph.D. Abstract:, During aviation accident investigations, vitreous fluid and urine samples from pilot fatalities are analyzed for glucose and blood for hemoglobin A1c (HbA1c) to monitor diabetic pilots and to discover other pilots with undiagnosed/unreported diabetes. The prevalence of elevated glucose concentrations in fatally injured pilots was evaluated by searching the Civil Aerospace Medical Institute's Toxicology Database for the period 1998,2005. Out of 1335 pilots involving 363 vitreous fluid, 365 urine, and 607 vitreous fluid and urine analyses, 43 pilots had elevated glucose in vitreous fluid (>125 mg/dL) and/or in urine (>100 mg/dL). Of the 20 pilots whose blood samples were analyzed, nine had >6% HbA1c,four were known diabetics, and five were unknown diabetics. Urinary glucose levels were elevated in all 13 known hyperglycemic pilots. A considerable number of pilots (30 of 43) had elevated glucose and HbA1c (5 of 20), suggesting undiagnosed/unreported diabetic conditions. [source] C-peptide prevents nociceptive sensory neuropathy in type 1 diabetesANNALS OF NEUROLOGY, Issue 6 2004Hideki Kamiya MD We examined the effects of C-peptide replacement on unmyelinated fiber function in the hind paw, sural nerve C-fiber morphometry, sciatic nerve neurotrophins, and the expression of neurotrophic receptors and content of neuropeptides in dorsal root ganglia in type 1 diabetic BB/Wor-rats. C-peptide replacement from onset of diabetes had no effect on hyperglycemia, but it significantly prevented progressive thermal hyperalgesia and prevented C-fiber atrophy, degeneration, and loss. These findings were associated with preventive effects on impaired availability of nerve growth factor and neurotrophin 3 in the sciatic nerve and significant prevention of perturbed expression of insulin, insulin growth factor,1, nerve growth factor, and neurotrophin 3 receptors in dorsal root ganglion cells. These beneficial effects translated into prevention of the decreased content of dorsal root ganglia nociceptive peptides such as substance P and calcitonin gene,related peptide. From these findings we conclude that replacement of insulinomimetic C-peptide prevents abnormalities of neurotrophins, their receptors, and nociceptive neuropeptides in type 1 BB/Wor-rats, resulting in the prevention of C-fiber pathology and nociceptive sensory nerve dysfunction. The data indicate that perturbed insulin/C-peptide action plays an important pathogenetic role in nociceptive sensory neuropathy and that C-peptide replacement may be of benefit in treating painful diabetic neuropathy in insulin-deficient diabetic conditions. Ann Neurol 2004 [source] Disturbed morphogenesis of cardiac outflow tract and increased rate of aortic arch anomalies in the offspring of diabetic ratsBIRTH DEFECTS RESEARCH, Issue 12 2004Daniël G.M. Molin Abstract BACKGROUND Maternal diabetes (MD) is a risk factor for offspring to develop cardiovascular anomalies; this is of growing clinical concern since the number of women in childbearing age with compromised glucose homeostasis is increasing. Hyperglycemia abrogates cardiovascular development in vitro; however, a link to cardiovascular defects in diabetic offspring remains to be investigated. METHODS We have studied cardiovascular development in offspring of MD rats by examining serial histological sections of GD 12.0,18.0 offspring. Development of pharyngeal arch artery malformations was analyzed and related to intracardiac anomalies. RESULTS Pharyngeal arch artery and intracardiac defects were present in 27 of 37 MD GD 13.0,18.0 offspring. Early sixth arch arteries showed abrogated arteriogenesis, whereas fourth arch artery defects developed as a result of abnormal remodeling. Morphometrical analysis showed increased apoptosis in regressing artery segments and reduced apoptosis in persisting artery segments. Double outlet right ventricle with infundibular stenosis (tetralogy of Fallot) was predominantly found in combination with sixth artery defects and pulmonary atresia. As confirmed by morphometric analysis and three-dimensional (3D)-reconstructions, outflow tract defects coincided with endocardial cushion hypoplasia. Cases with teratology of Fallot additionally showed a shorter outflow tract. No relation with apoptosis or disturbed neural crest cell migration was found. CONCLUSIONS Our data uniquely demonstrate mechanistic differences involved in the development of sixth and fourth artery anomalies. Whereas increased apoptosis induces fourth artery anomalies, pulmonary outflow obstruction abrogates sixth artery differentiation independent of apoptosis. The model presented allows analysis of diabetic conditions on cardiovascular development in vivo, essential for elucidating this teratology. Birth Defects Research (Part A), 2004. © 2004 Wiley-Liss, Inc. [source] Induction of squamous cell carcinoma of forestomach in diabetic rats by single alloxan treatmentCANCER SCIENCE, Issue 10 2006Yasushi Kodama Male rats of WBN/Kob strain are one of the diabetic model animals and develop long-lasting diabetic symptoms and some complications from about 40 weeks of age without any treatment. A single intravenous dose of alloxan, a non-genotoxic diabetogenic chemical, frequently induced proliferative lesions of squamous epithelium in tongue, esophagus and forestomach of male and female WBN/Kob rats, and hastened the onset and acceleration of diabetic conditions. Histopathologically, proliferative changes of squamous cell of forestomach varied with the severity of hyperplasia in alloxan-treated rats (100% of 31 males and 94.1% of 17 females) and progressed to SCC in approximately 20% of all rats. Metastasis to regional lymph nodes was also observed in two cases. Proliferative changes were most severe in the forestomach and were constantly accompanied with chronic suppurative inflammation of the mucosal epithelium with infection of filamentous fungi and/or bacterial colonies. In contrast, forestomach of the spontaneously diabetic male rats showed only slight hyperplasia of the mucosal epithelium confined to the limiting ridge in approximately 30% of the cases. All non-diabetic female rats showed neither proliferative changes nor the inflammatory process in the mucosa. Immunohistochemically, COX-2 and iNOS were positive in these chronic suppurative inflammatory lesions accompanied by proliferative squamous epithelium. From these results, it is suggested that chronic inflammatory processes play an important role in the pathogenesis of alloxan-induced SCC. An experimental system of alloxan-induced SCC might serve as a suitable model for the study of the inflammation-related promotion of carcinogenesis. (Cancer Sci 2006; 97: 1023,1030) [source] 2264: Expression and role of aquaporins in diabetic retinopathyACTA OPHTHALMOLOGICA, Issue 2010E MOTULSKY Purpose Aquaporins (AQP) are involved in water movements but also in cell proliferation. The aim of our study is to investigate their potential role in diabetic retinopathy Methods In vitro, human and mouse RPE cell line will be grown under different conditions. Expression of AQPs will be investigated by RT-PCR and Western blot. Immunofluorescence will be used to determine AQP expression on retinal section from normal and NOD diabetic mice, and on on vitreoretinal membranes removed from patients with proliferative retinopathy Results Human ARPE-19 cells expressed AQP4, while mouse B6-RPE07 cells expressed AQP1. Hypertonic conditions strongly decrease AQP4 expression in ARPE-19, but not AQP1 expression in B6-RPE07 cells. In B6-RPE07 cells, significantly decrease in AQP1 expression was obtained following TNF, treatment. In normal mice, AQP1 and AQP4 expression were restricted to the photoreceptor layer and to the Müller cells, respectively. Retinal endothelial cells did not express AQP1. No AQP4 expression was detected in RPE cells. AQP1 was strongly expressed by choroidal endothelial cells, rendering difficult the evaluation of AQP1 expression by RPE cells in vivo Conclusion Our preliminary data confirms that blood retinal barrier cells express AQPs in vitro and in vivo. More studies are needed to precise the nature and regulation of this expression in normal and diabetic conditions. We hope that our combined in vitro and in vivo approaches might help to better understand this complex aspect of retinal biology [source] Antioxidants reduce diabetic damage in bovine lenses in cultureACTA OPHTHALMOLOGICA, Issue 2009A DOVRAT Purpose Background: There are several theories regarding possible mechanisms leading to diabetic cataract. Few of them include oxidation stress. Aims: Investigation of the mechanisms of cataract formation under diabetic conditions, and examination of the effects of N-acetyl-L-cysteine (NAC), (which is a precursor of glutathione and an anti-inflammatory agent) and derivatives of Desferrioxamine (DFO)(which is an iron chelator and reduces oxidative stress) on diabetic cataract. Methods The experiments included 78 bovine lenses. The lenses were divided into eight different treatments including controls and lenses incubated with high glucose levels (450 mg %) with or without each one of the antioxidants. The intact lenses were incubated for a period of two weeks in our special organ culture conditions. Lens optical quality was analyzed every 24 hours. At the end of the culture period, oxidation was followed in the lens epithelial cells with dichlorofluorescein assay and lens proteins were analyzed by SDS and 2D gel electrophoresis. Results High levels of glucose in the culture medium caused optical damage to bovine lenses, increased lens volume due to swelling, increased oxidation of lens epithelial cells, and caused changes in lens beta crystallin. The anti-oxidants reduced this damage. NAC and Zn-DFO protected the lenses better than DFO. Conclusion Antioxidants can protect the lens from high glucose damage. This study was supported in part by a grant from the Esther and Chaim Coppel Trust and by the Guzik Ophthalmology Research Fund [source] A Metabolic Mechanism For Cardiac K+ Channel RemodellingCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 1-2 2002George J Rozanski SUMMARY 1. Electrical remodelling of the ventricle is a common pathogenic feature of cardiovascular disease states that lead to heart failure. Experimental data suggest this change in electrophysiological phenotype is largely due to downregulation of K+ channels involved in repolarization of the action potential. 2. Voltage-clamp studies of the transient outward current (Ito) in diabetic cardiomyopathy support a metabolic mechanism for K+ channel downregulation. In particular, Ito density is significantly increased in diabetic rat isolated ventricular myocytes treated in vitro with insulin or agents that activate pyruvate dehydrogenase. Recent data suggest this mechanism is not limited to diabetic conditions, because metabolic stimuli that upregulate Ito in diabetic rat myocytes act similarly in non- diabetic models of heart failure. 3. Depressed Ito channel activity is also reversed by experimental conditions that increase myocyte levels of reduced glutathione, indicating that oxidative stress is involved in electrical remodelling. Moreover, upregulation of Ito density by activators of glucose utilization is blocked by inhibitors of glutathione metabolism, supporting the premise that there is a functional link between glucose utilization and the glutathione system. 4. Electrophysiological studies of diabetic and non-diabetic disease conditions affecting the heart suggest Ito channels are regulated by a redox-sensitive mechanism, where glucose utilization plays an essential role in maintaining a normally reduced state of the myocyte. This hypothesis has implications for clinical approaches aimed at reversing pathogenic electrical remodelling in a variety of cardiovascular disease states. [source] | |||||||||||||