Beneficial effects of magnesium treatment on heart rate variability and cardiac ventricular function in diabetic rats

Background: Diabetes mellitus induces life-threatening cardiovascular complications such as cardiac autonomic neuropathy and ventricular dysfunction and is associated with hypomagnesemia. In this study, we investigated the short-term effects of magnesium (Mg2+) treatment on streptozotocin (STZ)-induced diabetic cardiac complications. Methods: Adult Wistar rats were treated once with STZ (50 mg/kg, intraperitoneally [ip]) or vehicle (citrate) and then daily for 7 days with MgSO4 (270 mg/kg, ip) or saline. On the eighth day, in vivo tail-pulse plethysmography was recorded for heart rate variability (HRV) analysis, and ex vivo Langendorff-based left ventricular (LV) pressure–volume parameters were measured using an intraventricular balloon. Measurements of plasma lipid and Mg2+ levels as well as blood glucose and cardiac tissue Mg2+ levels were also performed. Results: Treatment with Mg2+ prevented diabetes-induced alterations in the standard deviation of the averages of normal-to-normal (NN) intervals (SDANN), root mean square differences of successive NN intervals (RMSSD), heart rate, and low-frequency (LF) power–high-frequency (HF) power ratio. In addition, Mg2+ restored orthostatic stress-induced changes in SDANN, RMSSD, and LF–HF ratio in diabetic rats. In isolated hearts, Mg2+ reversed the diabetes-induced decrease in LV end-diastolic elastance and the right shift of end-diastolic equilibrium volume intercept, without altering LV-developed pressure or end-systolic elastance. However, Mg2+ did not prevent the elevation in blood glucose, total cholesterol, and triglycerides or the decrease in high-density lipoprotein cholesterol in diabetes. Plasma- or cardiac tissue Mg2+ was not different among the treatment groups. Conclusion: These results suggest that Mg2+ treatment may attenuate diabetes-induced reduction in HRV and improve LV diastolic distensibility, without preventing hyperglycemia and dyslipidemia. Thus, Mg2+ may have a modulatory role in the early stages of diabetic cardiovascular complications

Cardioprotective effect of fingolimod against calcium paradox-induced myocardial injury in the isolated rat heart

Fingolimod (FTY720) inhibits Ca2+-permeable, Mg2+-sensitive channels called transient receptor potential melastatin 7 (TRPM7), but its effects on Ca2+ paradox (CP)-induced myocardial damage have not been evaluated. We studied the effect of FTY720 on CP-induced myocardial damage, and used other TRPM7 channel inhibitors nordihydroguaiaretic acid (NDGA) and Mg2+ to test if any effect of FTY720 was via TRPM7 inhibition. Langendorff-perfused Wistar rat hearts were treated with FTY720 or NDGA and subjected to a CP protocol consisting of Ca2+ depletion followed by Ca2+ repletion. Hearts of rats pre-treated with MgSO4 were also subjected to CP. Hemodynamic parameters were measured using an intraventricular balloon, and myocardial infarct size was quantified using triphenyltetrazolium chloride stain. TRPM7 proteins in ventricular tissue were detected using immunoblot analysis. FTY720, but not NDGA, decreased CP-induced infarct size. Both FTY720 and NDGA minimized the CP-induced elevation of left ventricular end-diastolic pressure, but only FTY720 ultimately improved ventricular developed pressure. Mg2+ pre-treatment had effect neither on CP-induced infarct size, hemodynamic parameters during CP, nor the level TRPM7 protein expression in ventricular tissue. Overall, FTY720 attenuated CP-induced myocardial damage, with potential therapeutic implications on Ca2+-mediated cardiotoxicity. However, the cardioprotective mechanism of FTY720 seems to be unrelated to TRPM7 channel modulation

Cardioprotective and anti-arrhythmic effects of magnesium pretreatment against ischaemia/reperfusion injury in isoprenaline-induced hypertrophic rat heart

The effects of magnesium (Mg2+) on ischaemic complications of pathological cardiac hypertrophy are unclear. In this study, we investigated effects of Mg2+ pretreatment on ischaemia/reperfusion (I/R) injury in isoprenaline (ISO)-induced hypertrophic hearts. Wistar rats were treated for 7 days with different combinations of ISO (1.25 mg/kg) subcutaneously, MgSO4 (270 mg/kg) intraperitoneally, or vehicle (saline). On the eighth day, hearts were either subjected to regional I/R during Langendorff perfusion or histologically stained with haematoxylin and eosin and Masson’s trichrome. Haemodynamic and electrocardiographic parameters were recorded using the PowerLab data-acquisition system. Infarcts were identified by triphenyltetrazolium chloride staining. Plasma Mg2+ was measured using photometric assays. Mg2+ pretreatment significantly decreased I/R-induced infarct size (p = 0.001) and the overall arrhythmia score (p < 0.001) of I/R-induced ventricular ectopics, ventricular tachycardia, and ventricular fibrillation in hypertrophic hearts, but not non-hypertrophied hearts. Mg2+ also improved post-I/R left ventricular developed pressure in hypertrophic hearts. However, Mg2+ did not reverse the ISO-induced myocyte thickening and interstitial fibrosis or increases in heart weight. Plasma Mg2+ was not different among treatment groups. These results suggest that Mg2+ pretreatment may protect against I/R-induced injury and malignant arrhythmias in hypertrophic hearts, possibly via mechanisms unrelated to long-lasting changes in plasma Mg2+ or prevention of structural changes such as fibrosis

Altered adrenergic response in myocytes bordering a chronic myocardial infarction underlies <i>in vivo</i> triggered activity and repolarization instability

Ventricular arrhythmias are a major complication early after myocardial infarction (MI). The heterogeneous peri‐infarct zone forms a substrate for re‐entry while arrhythmia initiation is often associated with sympathetic activation. We studied the mechanisms triggering these post‐MI arrhythmias in vivo and their relation to regional myocyte remodelling. In pigs with chronic MI (6 weeks), in vivo monophasic action potentials were simultaneously recorded in the peri‐infarct and remote regions during adrenergic stimulation with isoproterenol (ISO). Sham animals served as controls. During infusion of ISO in vivo, the incidence of delayed afterdepolarizations (DADs) and beat‐to‐beat variability of repolarization (BVR) was higher in the peri‐infarct than in the remote region. Myocytes isolated from the peri‐infarct region, in comparison to myocytes from the remote region, had more DADs, associated with spontaneous Ca2+ release, and a higher incidence of spontaneous action potentials when exposed to ISO (9.99 ± 4.2 vs. 0.16 ± 0.05 APs/min, p = 0.004); these were suppressed by CaMKII inhibition. Peri‐infarct myocytes also had reduced repolarization reserve and increased BVR (26 ± 10 ms vs. 9 ± 7 ms, p 2+ handling at baseline and myocyte hypertrophy were present throughout the LV. Expression of some of the related genes was however different between the regions. In conclusion, altered myocyte adrenergic responses in the peri‐infarct, but not in the remote region, provide a source of triggered activity in vivo and of repolarization instability amplifying the substrate for re‐entry. These findings stimulate further exploration of region‐specific therapies targeting myocytes and autonomic modulation

Sedation and Analgesia for Reduction of Pediatric Ileocolic Intussusception

IMPORTANCE: Ileocolic intussusception is an important cause of intestinal obstruction in children. Reduction of ileocolic intussusception using air or fluid enema is the standard of care. This likely distressing procedure is usually performed without sedation or analgesia, but practice variation exists. OBJECTIVE: To characterize the prevalence of opioid analgesia and sedation and assess their association with intestinal perforation and failed reduction. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study reviewed medical records of children aged 4 to 48 months with attempted reduction of ileocolic intussusception at 86 pediatric tertiary care institutions in 14 countries from January 2017 to December 2019. Of 3555 eligible medical records, 352 were excluded, and 3203 medical records were eligible. Data were analyzed in August 2022. EXPOSURES: Reduction of ileocolic intussusception. MAIN OUTCOMES AND MEASURES: The primary outcomes were opioid analgesia within 120 minutes of reduction based on the therapeutic window of IV morphine and sedation immediately before reduction of intussusception. RESULTS: We included 3203 patients (median [IQR] age, 17 [9-27] months; 2054 of 3203 [64.1%] males). Opioid use was documented in 395 of 3134 patients (12.6%), sedation 334 of 3161 patients (10.6%), and opioids plus sedation in 178 of 3134 patients (5.7%). Perforation was uncommon and occurred in 13 of 3203 patients (0.4%). In the unadjusted analysis, opioids plus sedation (odds ratio [OR], 5.92; 95% CI, 1.28-27.42; P = .02) and a greater number of reduction attempts (OR, 1.48; 95% CI, 1.03-2.11; P = .03) were significantly associated with perforation. In the adjusted analysis, neither of these covariates remained significant. Reductions were successful in 2700 of 3184 attempts (84.8%). In the unadjusted analysis, younger age, no pain assessment at triage, opioids, longer duration of symptoms, hydrostatic enema, and gastrointestinal anomaly were significantly associated with failed reduction. In the adjusted analysis, only younger age (OR, 1.05 per month; 95% CI, 1.03-1.06 per month; P \u3c .001), shorter duration of symptoms (OR, 0.96 per hour; 95% CI, 0.94-0.99 per hour; P = .002), and gastrointestinal anomaly (OR, 6.50; 95% CI, 2.04-20.64; P = .002) remained significant. CONCLUSIONS AND RELEVANCE: This cross-sectional study of pediatric ileocolic intussusception found that more than two-thirds of patients received neither analgesia nor sedation. Neither was associated with intestinal perforation or failed reduction, challenging the widespread practice of withholding analgesia and sedation for reduction of ileocolic intussusception in children

The effects of magnesium treatment on short-term changes in heart rate variability, ventricular function and lipid profile in streptozotocin-induced diabetic rats

INTRODUCTION: Diabetes mellitus is a major and rapidly growing worldwide health problem, causing mortality largely in developing countries such as South Africa. Diabetes induces life threatening cardiovascular complications including cardiac autonomic neuropathy, ventricular dysfunction and dyslipidaemia, which are dependent on the duration and severity of the diabetes. Most complications are identified at a late, irreversible stage following long-standing diabetes; therefore, early detection and treatment of cardiovascular complications may reverse impairments and improve outcomes. The early treatment of diabetic complications remains ineffective, as the associated underlying features, such as electrolyte disturbances, are poorly understood. A key electrolyte disturbance in diabetes is hypomagnesaemia, which is also an independent cardiovascular risk factor. However, the effects of magnesium (Mg²⁺) supplementation are unclear. Therefore, this study investigated the effects of Mg²⁺ treatment on the early manifestations of streptozotocin (STZ)-induced diabetic cardiac complications. METHODS: Adult male Wistar rats were treated once with STZ (50 mg/kg, i.p.) or vehicle (citrate), and daily for seven days with MgSO4 (270 mg/kg, i.p.) or saline. Blood glucose and body weight were monitored daily. On the eighth day, in vivo tail-pulse plethysmography was recorded for analysis of heart rate variability (HRV), a marker of cardiac autonomic function. Ex vivo, Langendorff-based left ventricular (LV) pressure-volume parameters were measured using an intraventricular balloon. Other hearts were stained with Masson's trichrome and haematoxylin and eosin for histological analysis. Cardiac tissue Mg²⁺ concentration as well as plasma lipid- and Mg²⁺ levels were measured by colorimetric assays. RESULTS: Diabetes reduced heart rate and increased the low-frequency (LF)/high-frequency (HF) power ratio. Mg²⁺ treatment prevented theses diabetes-induced changes in heart rate and in the low-frequency (LF)/high-frequency (HF) power ratio (p < 0.05, n = 9/group). In addition, Mg²⁺ restored orthostatic stress induced changes in heart rate, and LF/HF ratio in diabetic rats (p < 0.05, n = 9/group). In isolated hearts, Mg²⁺ reversed the diabetes-induced decrease in LV end-diastolic elastance (p < 0.05, n = 6/group) and the right shift of end diastolic equilibrium volume intercept from 49 ± 6 μ L to 25 ± 5 μL (p < 0.05, n = 6/group), without altering LV developed pressure or end systolic elastance. Diabetes significantly increased plasma triglyceride, total cholesterol and blood glucose (p < 0.05, n = 7/group), and significantly decreased body weight (p < 0.05, n ≥ 16/group) compared to control, but these changes were not prevented by Mg²⁺ treatment. Neither diabetes nor Mg²⁺ treatment altered plasma- and tissue Mg²⁺ levels. Histologically, diabetes and Mg²⁺ treatment also did not alter cardiomyocyte size or the amount of interstitial collagen in myocardial tissue. CONCLUSION: These results show that Mg²⁺ treatment attenuates diabetes-induced autonomic dysfunction and improves LV diastolic distensibility in short-term diabetes. However, the diabetic metabolic disturbances of hyperglycaemia and dyslipidaemia, the changes in cardiac microstructure or the plasma- and cardiac tissue Mg²⁺ levels were uninfluenced by Mg²⁺ treatment. This suggests that Mg²⁺ exerted its beneficial effects independent of these factors, highlighting the underling mechanisms remain to be clarified. The Mg²⁺ levels not measured in this study by which changes could have been mediated was intracellularly; an aspect that should be further explored in future studies. Furthermore, whether these effects would be translatable to chronic diabetes is an important next question. Thus, the results of this study suggest that Mg²⁺ may have a modulatory role in treating early diabetic cardiovascular complications, but future studies will need to clarify the underlying mechanisms

R-DECO: an open-source Matlab based graphical user interface for the detection and correction of R-peaks

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Temporal beat-to-beat variability of repolarizationTemporal beat-to-beat variability of repolarization (BVR) changes predict imminent non-sustained ventricular tachycardia in ischaemic heart disease patients

The temporal changes in peri-arrhythmic BVR may be a non-invasive method to predicted imminent NSVT events in IHD patients.status: Published onlin

Myofibroblast modulation of cardiac myocyte structure and function

After myocardial infarction, resident fibroblasts (Fb) differentiate towards myofibroblasts (MyoFb), generating the scar tissue and the interstitial fibrosis seen in the adjacent myocardium. Fb and MyoFb have the potential to interact with cardiac myocytes (CMs) but insight into the phenotype-specific role and mode of interaction is still incomplete. Our objectives are to further define the modulation of CMs by MyoFbs compared to Fbs, as well as the role of direct contact through gap junctions vs. soluble mediators, using Fbs and CMs from pig left ventricle. Fbs were treated to maintain an undifferentiated state (SD-208) or to attain full differentiation to MyoFb (TGF-β1). Fbs and MyoFbs were co-cultured with CMs, with the possibility of direct contact or separated by a Thincert membrane. Only in direct co-culture, both Fbs and MyoFbs were able to decrease CM viability after 2 days. Only MyoFbs induced significant distal spreading of CMs in both direct and indirect co-culture. MyoFbs, but not Fbs, readily made connections with CMs in direct co-culture and connexin 43 expression in MyoFb was higher than in Fb. When coupled to CMs, MyoFbs reduced the CM action potential duration and hyperpolarized the CM resting membrane potential. Uncoupling reversed these effects. In conclusion, MyoFbs, but not Fbs, alter the CM structural phenotype. MyoFbs, but not Fbs, are likely to electrically connect to CMs and thereby modulate the CM membrane potential. These data provide further support for an active role of MyoFbs in the arrhythmogenic substrate after cardiac remodelling.status: publishe

Incomplete Assembly of the Dystrophin-Associated Protein Complex in 2D and 3D-Cultured Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes

International audienceHuman induced pluripotent stem cells derived cardiomyocytes (hiPSC-CM) are increasingly used to study genetic diseases on a human background. However, the lack of a fully mature adult cardiomyocyte phenotype of hiPSC-CM may be limiting the scope of these studies. Muscular dystrophies and concomitant cardiomyopathies result from mutations in genes encoding proteins of the dystrophin-associated protein complex (DAPC), which is a multi-protein membrane-spanning complex. We examined the expression of DAPC components in hiPSC-CM, which underwent maturation in 2D and 3D culture protocols. The results were compared with human adult cardiac tissue and isolated cardiomyocytes. We found that similarly to adult cardiomyocytes, hiPSC-CM express dystrophin, in line with previous studies on Duchenne’s disease. β-dystroglycan was also expressed, but, contrary to findings in adult cardiomyocytes, none of the sarcoglycans nor α-dystroglycan were, despite the presence of their mRNA. In conclusion, despite the robust expression of dystrophin, the absence of several other DAPC protein components cautions for reliance on commonly used protocols for hiPSC-CM maturation for functional assessment of the complete DAPC