Abstract 360: Metformin Confers Cardiac and Renal Protection in Sudden Cardiac Arrest

Introduction: Sudden cardiac arrest (SCA) affects over 600,000 Americans yearly with substantial mortality. After resuscitation, multiple system organ damage is common. Metformin has previously demonstrated ischemic protection in cardiac and renal tissues. We retrospectively evaluated kidney damage and cardiac function in a cohort of diabetic SCA patients. We also developed a mouse model of SCA that replicates human pathology and pretreated with metformin to evaluate the molecular changes driving these outcomes. Methods: We performed a retrospective analysis of patients admitted to a single center from 2010 to 2019 after resuscitation from SCA. We included those with a known diabetes prior to arrest. We extracted home medications from nursing and pharmacy medication reconciliations. Our primary exposure of interest was pre-arrest metformin use (vs no or other medications). We compared first day and maximum serum creatinine (SCr) during hospitalization, as well as cardiac ejection fraction (EF) after arrest. To explore the mechanisms underlying these changes, we developed a mouse model of SCA to compare metformin vs non-treated SCA mice. We evaluated EF and renal endpoints including SCr, BUN, and tubular damage 1-day after SCA. Tissues were collected for molecular and histologic studies. Results: We identified 360 diabetic patients of whom 151 (42%) were prescribed metformin at the time of SCA. There were no differences in age, sex, pre-arrest SCr or pre-arrest A1c between metformin and non-metformin treated patients. After SCA, metformin-treated patients had significantly lower initial SCr when compared to non-metformin patients (1.5±0.1 vs 1.7±0.1), 1-day SCr (1.4±0.1 vs 1.7±0.1), max creatinine (1.9±0.1 vs 2.2±0.1 ), and higher EF (49±2 vs 43±2). In the mouse study, pretreatment with metformin group found significantly lower 1-day SCr than non-treated mice (0.40±0.05 vs 1.52±0.22), BUN (64.8±8.2 vs 156.0±39.8), and histologic injury score (0.17±0.71 vs 3.33±0.29), as well as improved 1-day EF (49.6±3.7 vs 38.8±4.5). Conclusions: Our data support a renal- and cardio-protective role for metformin after SCA. Future studies will explore biochemical changes driving protection in the mouse with the goal of discovering translatable therapies.

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A novel ultrasound-guided mouse model of sudden cardiac arrest

10.1101/2020.07.27.222695 ◽

2020 ◽

Author(s):

Cody A. Rutledge ◽

Takuto Chiba ◽

Kevin Redding ◽

Cameron Dezfulian ◽

Sunder Sims-Lucas ◽

...

Keyword(s):

Cardiac Arrest ◽

Mouse Model ◽

Cardiac Function ◽

Potassium Chloride ◽

Direct Injection ◽

Sudden Cardiac Arrest ◽

Left Ventricular ◽

Left Ventricular Cavity ◽

Ultrasound Guided ◽

Human Pathology

AbstractAimMouse models of sudden cardiac arrest are limited by challenges with surgical technique and reliable venous access. To overcome this limitation, we sought to develop a simplified method in the mouse that uses ultrasound-guided injection of potassium chloride directly into the heart.MethodsPotassium chloride was delivered directly into the left ventricular cavity under ultrasound guidance in intubated mice, resulting in immediate asystole. Mice were resuscitated with injection of epinephrine and manual chest compressions and evaluated for survival, body temperature, cardiac function, kidney damage, and diffuse tissue injury.ResultsThe direct injection sudden cardiac arrest model causes rapid asystole with high surgical survival rates and low surgical duration. Sudden cardiac arrest mice with 8-min of asystole have significant cardiac dysfunction at 24 hours and high lethality within the first seven days, where after cardiac function begins to improve. Sudden cardiac arrest mice have secondary organ damage, including significant kidney injury, but no clear evidence of neurologic dysfunction.ConclusionsUltrasound-guided direct injection of potassium chloride allows for rapid and reliable cardiac arrest in the mouse that mirrors human pathology. This technique lowers the barriers to entry for adoption of the mouse model of sudden cardiac arrest, which will improve investigators’ ability to study the mechanisms underlying post-arrest changes.

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A novel ultrasound-guided mouse model of sudden cardiac arrest

PLoS ONE ◽

10.1371/journal.pone.0237292 ◽

2020 ◽

Vol 15 (12) ◽

pp. e0237292

Author(s):

Cody A. Rutledge ◽

Takuto Chiba ◽

Kevin Redding ◽

Cameron Dezfulian ◽

Sunder Sims-Lucas ◽

...

Keyword(s):

Cardiac Arrest ◽

Mouse Model ◽

Cardiac Function ◽

Potassium Chloride ◽

Direct Injection ◽

Sudden Cardiac Arrest ◽

Left Ventricular ◽

Left Ventricular Cavity ◽

Ultrasound Guided ◽

Human Pathology

Aim Mouse models of sudden cardiac arrest are limited by challenges with surgical technique and obtaining reliable venous access. To overcome this limitation, we sought to develop a simplified method in the mouse that uses ultrasound-guided injection of potassium chloride directly into the heart. Methods Potassium chloride was delivered directly into the left ventricular cavity under ultrasound guidance in intubated mice, resulting in immediate asystole. Mice were resuscitated with injection of epinephrine and manual chest compressions and evaluated for survival, body temperature, cardiac function, kidney damage, and diffuse tissue injury. Results The direct injection sudden cardiac arrest model causes rapid asystole with high surgical survival rates and short surgical duration. Sudden cardiac arrest mice with 8-min of asystole have significant cardiac dysfunction at 24 hours and high lethality within the first seven days, where after cardiac function begins to improve. Sudden cardiac arrest mice have secondary organ damage, including significant kidney injury but no significant change to neurologic function. Conclusions Ultrasound-guided direct injection of potassium chloride allows for rapid and reliable cardiac arrest in the mouse that mirrors human pathology without the need for intravenous access. This technique will improve investigators’ ability to study the mechanisms underlying post-arrest changes in a mouse model.

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Increasing triacylglycerol formation and lipid storage by unsaturated lipids protects renal proximal tubules in diabetes

10.1101/2021.09.07.459360 ◽

2021 ◽

Author(s):

Albert Pérez-Martí ◽

Suresh Ramakrishnan ◽

Jiayi Li ◽

Aurelien Dugourd ◽

Martijn R. Molenaar ◽

...

Keyword(s):

Er Stress ◽

Organ Damage ◽

Phospholipid Metabolism ◽

Lipid Storage ◽

Diabetic Patients ◽

Tubular Damage ◽

Membrane Order ◽

Unsaturated Lipids ◽

Renal Proximal Tubular Cells ◽

Renal Proximal Tubular

AbstractIn diabetic patients, dyslipidemia frequently contributes to organ damage such as diabetic kidney disease (DKD). DKD is associated with excessive renal deposition of triacylglycerol (TAG) in lipid droplets (LD). Yet, it is unclear whether LDs play a protective or damaging role and how this might be influenced by dietary patterns. By using a diabetes mouse model, we find here that high fat diet enriched in the unsaturated oleic acid (OA) caused more lipid storage in LDs in renal proximal tubular cells (PTC) but less tubular damage than a corresponding butter diet with the saturated palmitic acid (PA). Mechanistically, we identify endoplasmic reticulum (ER) stress as the main cause of PA-induced PTC injury. ER stress is caused by elevated cellular levels of saturated TAG precursors and to higher membrane order in the ER. The resulting cell death is preceded by a transcriptional rewiring of phospholipid metabolism. Simultaneous addition of OA rescues the cytotoxic effects by normalizing membrane order and by increasing the total TAG amount. The latter also stimulates the formation of LDs that in turn can release unsaturated lipids upon demand by lipolysis. Our study thus clarifies mechanisms underlying PA-induced cell stress in PTCs and emphasizes the importance of olive oil for the prevention of DKD.

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P5644Hypoglycemic episodes increase the risk of ventricular arrhythmias and sudden cardiac arrest in patients with type 2 diabetes - a nationwide cohort study

European Heart Journal ◽

10.1093/eurheartj/ehz746.0587 ◽

2019 ◽

Vol 40 (Supplement_1) ◽

Author(s):

Y C Hsieh ◽

Y C Liao ◽

C H Li ◽

J C Lin ◽

C J Weng ◽

...

Keyword(s):

Cardiac Arrest ◽

Sudden Cardiac Arrest ◽

Control Group ◽

Diabetic Patients ◽

Hypoglycemic Episode ◽

Kaplan Meier ◽

Patients With Diabetes ◽

Diagnosed Diabetes ◽

The Impact

Abstract Background Hypoglycemic episode (HE) increases the risk of cardiovascular mortality. The impact of HE on the risk of sudden death remains unclear. We hypothesized that HE increases the risks of ventricular arrhythmia (VA) and sudden cardiac arrest (SCA), and that anti-diabetic agents (ADAs) causing hypoglycemia also increase the risks of VA and SCA. Methods Patients aged ≥20 years with newly diagnosed diabetes were identified from the Taiwan National Insurance Database. HE was defined as the presentation of hypoglycemic coma or specified/unspecified hypoglycemia. For control group, we included diabetic patients without HE, and they were frequency-matched to the HE group at a 4:1 ratio. The primary outcome was the occurrence of any event of VA (including ventricular tachycardia and fibrillation) and SCA during the defined follow-up periods. Multivariate Cox hazards regression model was used to evaluate the hazard ratio (HR) for VA or SCA. Results A total of 54,303 diabetic patients were screened with 1,037 of them in the HE group, and 4,148 in the control group. During a mean follow-up period of 3.3±2.5 years, 29 VA/SCA events had occurred. Compared to the control group, the HE group had a higher incidence of VA/SCA (adjusted HR: 2.42, p=0.04). Diabetic patients medicated with insulin for glycemic control increased the risk of VA/SCA compared to those without insulin (adjusted HR: 3.05, p=0.01). Kaplan-Meier survival curves Conclusions HEs in patients with diabetes increased the risks of VA and SCA compared to those without. Their use of insulin also independently increased the risk of VA/SCA.

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Metformin Confers Cardiac and Renal Protection in Sudden Cardiac Arrest via AMPK Activation

10.1101/2021.08.24.457506 ◽

2021 ◽

Author(s):

Cody A. Rutledge ◽

Claudia Lagranha ◽

Takuto Chiba ◽

Kevin Redding ◽

Donna B. Stolz ◽

...

Keyword(s):

Cardiac Arrest ◽

Reperfusion Injury ◽

Ischemia Reperfusion Injury ◽

Mitochondrial Dynamics ◽

Ischemia Reperfusion ◽

Sudden Cardiac Arrest ◽

The United States ◽

Kidney Damage ◽

Diabetic Patients ◽

Ampk Activation

AbstractSudden cardiac arrest (SCA) affects over 600,000 individuals annually in the United States and is associated with substantial mortality. After resuscitation, multi-system organ damage is common and largely attributable to ischemia-reperfusion injury. The anti-diabetic drug metformin improves cardiac outcomes in models of myocardial ischemia and ischemia-reperfusion. In this study, we evaluated the role of metformin pretreatment in a mouse model of SCA. We found that two weeks of metformin pretreatment protects cardiac ejection fraction and reduces acute kidney injury post-SCA in non-diabetic mice. Further, metformin pretreatment prior to SCA activates AMPK signaling and is associated with altered mitochondrial dynamics and markers of autophagy following arrest. Direct AMPK activation and inhibition studies demonstrate that activation is necessary and sufficient for metformin-mediated protection of cardiac and renal tissues in this model. We were unable to demonstrate cardiac improvement with a single-dose metformin rescue therapy. Importantly, the protective findings translate into patients. We retrospectively evaluated the extent of cardiac and kidney damage in diabetic patients resuscitated from SCA. Metformin-treated patients have less evidence of heart and kidney damage after arrest than diabetics who have not received metformin. Together, these data support AMPK activation as a preventive mechanism in ischemia-reperfusion injury.Graphical Abstract

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