Nicotinamide restores tissue NAD+ and improves survival in rodent models of cardiac arrest.

Metabolic suppression in the ischemic heart is characterized by reduced levels of NAD+ and ATP. Since NAD+ is required for most metabolic processes that generate ATP, we hypothesized that nicotinamide restores ischemic tissue NAD+ and improves cardiac function in cardiomyocytes and isolated hearts, and enhances survival in a mouse model of cardiac arrest. Mouse cardiomyocytes were exposed to 30 min simulated ischemia and 90 min reperfusion. NAD+ content dropped 40% by the end of ischemia compared to pre-ischemia. Treatment with 100 µM nicotinamide (NAM) at the start of reperfusion completely restored the cellular level of NAD+ at 15 min of reperfusion. This rescue of NAD+ depletion was associated with improved contractile recovery as early as 10 min post-reperfusion. In a mouse model of cardiac arrest, 100 mg/kg NAM administered IV immediately after cardiopulmonary resuscitation resulted in 100% survival at 4 h as compared to 50% in the saline group. In an isolated rat heart model, the effect of NAM on cardiac function was measured for 20 min following 18 min global ischemia. Rate pressure product was reduced by 26% in the control group following arrest. Cardiac contractile function was completely recovered with NAM treatment given at the start of reperfusion. NAM restored tissue NAD+ and enhanced production of lactate and ATP, while reducing glucose diversion to sorbitol in the heart. We conclude that NAM can rapidly restore cardiac NAD+ following ischemia and enhance glycolysis and contractile recovery, with improved survival in a mouse model of cardiac arrest.

A cell-penetrating PHLPP peptide improves cardiac arrest survival in murine and swine models.

Out-of-hospital cardiac arrest is a leading cause of death in the US, with a mortality rate over 90%. Preclinical studies demonstrate that cooling during cardiopulmonary resuscitation (CPR) is highly beneficial, but can be challenging to implement clinically. No medications exist for improving long-term cardiac arrest survival. We have developed a 20-amino acid peptide, TAT-PHLPP9c, that mimics cooling protection by enhancing AKT activation via PH domain leucine-rich repeat phosphatase 1 (PHLPP1) inhibition. Complementary studies were conducted in mouse and swine. C57BL/6 mice were randomized into blinded saline control and peptide-treatment groups. Following a 12-minute asystolic arrest, TAT-PHLPP9c was administered intravenously during CPR and significantly improved the return of spontaneous circulation, mean arterial blood pressure and cerebral blood flow, cardiac and neurological function, and survival (4 hour and 5 day). It inhibited PHLPP-NHERF1 binding, enhanced AKT but not PKC phosphorylation, decreased pyruvate dehydrogenase phosphorylation and sorbitol production, and increased ATP generation in heart and brain. TAT-PHLPP9c treatment also reduced plasma taurine and glutamate concentrations after resuscitation. The protective benefit of TAT-PHLPP9c was validated in a swine cardiac arrest model of ventricular fibrillation. In conclusion, TAT-PHLPP9c may improve neurologically intact cardiac arrest survival without the need for physical cooling.

Intra-ischemic hypothermia cardioprotection involves modulation of PTEN/Akt/ERK signaling and fatty acid oxidation.

Therapeutic hypothermia (TH) provides cardioprotection from ischemia/reperfusion (I/R) injury. However, it remains unknown how TH regulates metabolic recovery. We tested the hypothesis that TH modulates PTEN, Akt, and ERK1/2, and improves metabolic recovery through mitigation of fatty acid oxidation and taurine release. Left ventricular function was monitored continuously in isolated rat hearts subjected to 20 min of global, no-flow ischemia. Moderate cooling (30°C) was applied at the start of ischemia and hearts were rewarmed after 10 min of reperfusion. The effect of TH on protein phosphorylation and expression at 0 and 30 min of reperfusion was investigated by western blot analysis. Post-ischemic cardiac metabolism was investigated by 13 C-NMR. TH enhanced recovery of cardiac function, reduced taurine release, and enhanced PTEN phosphorylation and expression. Phosphorylation of Akt and ERK1/2 was increased at the end of ischemia but decreased at the end of reperfusion. On NMR analysis, TH-treated hearts displayed decreased fatty acid oxidation. Direct cardioprotection by moderate intra-ischemic TH is associated with decreased fatty acid oxidation, reduced taurine release, enhanced PTEN phosphorylation and expression, and enhanced activation of both Akt and ERK1/2 prior to reperfusion.

Extracorporeal cardiopulmonary resuscitation (eCPR) and cerebral perfusion: A narrative review.

Extracorporeal cardiopulmonary resuscitation (eCPR) is emerging as an effective, lifesaving resuscitation strategy for select patients with prolonged or refractory cardiac arrest. Currently, a paucity of evidence-based recommendations is available to guide clinical management of eCPR patients. Despite promising results from initial clinical trials, neurological injury remains a significant cause of morbidity and mortality. Neuropathology associated with utilization of an extracorporeal circuit may interact significantly with the consequences of a prolonged low-flow state that typically precedes eCPR. In this narrative review, we explore current gaps in knowledge about cerebral perfusion over the course of cardiac arrest and resuscitation with a focus on patients treated with eCPR. We found no studies which investigated regional cerebral blood flow or cerebral autoregulation in human cohorts specific to eCPR. Studies which assessed cerebral perfusion in clinical eCPR were small and limited to near-infrared spectroscopy. Furthermore, no studies prospectively or retrospectively evaluated the relationship between epinephrine and neurological outcomes in eCPR patients. In summary, the field currently lacks a comprehensive understanding of how regional cerebral perfusion and cerebral autoregulation are temporally modified by factors such as pre-eCPR low-flow duration, vasopressors, and circuit flow rate. Elucidating these critical relationships may inform future strategies aimed at improving neurological outcomes in patients treated with lifesaving eCPR.

Applying the Lean Startup Method to Structure Project-Based, Student-Driven Curricular Enhancements.

PROBLEM: Formal medical student engagement in curricular evaluation provides significant value through identification of opportunities for curricular change. Students provide diverse perspectives and have a unique vantage point, which allows them to see aspects of the curriculum that educators and administrators might not recognize. Current descriptions of student engagement are focused largely on collection, analysis, and presentation of summative feedback in the pre-clerkship curriculum. However, medical students could potentially contribute to curricular improvement in ways extending beyond post hoc curricular evaluation. Student teams focused on identification of specific needs and project-based implementation of solutions represent one means of doing so but require a structured, organizing method in order to succeed. INTERVENTION: We describe a novel, project-based, student-driven medical education initiative, the Special Projects Team, which is focused on identifying opportunities for forward-looking curricular enhancements beyond single courses or rotations. We adapted and implemented the lean startup method, a model for project management, in order to address the need for organization and accountability in the Special Projects Team. Members of the Special Projects Team were recruited from the first- and second-year medical school classes in the 2018-2020 academic years and provided with training on the lean startup method. Team members selected and pursued projects according to the principles of lean startup method, reporting their progress to the chair of the Special Projects Team and other team members at monthly meetings with pre-defined structure. CONTEXT: The Special Projects Team is part of the local Student Curricular Board at the Chicago campus of the University of Illinois College of Medicine. The Student Curricular Board is responsible for conducting curricular evaluation and improvement, operating under the local medical student council with financial support from the Office of Curricular Affairs. Direct supervision of the Special Projects Team is provided by a student chair, the executive board of the Student Curricular Board, and the curricular dean. IMPACT: The projects initiated as part of the Special Projects Team covered a broad range of themes, including curricular evaluation, technology, and student experiences. Lean startup method contributed to sustained project success and frequent reassessment across the two years of our experience, with aggregate project success or continuation rate of 68.4% (13/19 projects). We further demonstrate how lean startup method increased productivity while providing structure and accountability for a student-led medical education team. LESSONS LEARNED: Lean startup method can be used to structure student-driven, project-based curricular enhancements. This approach is broadly applicable to other medical schools with implementation requiring only a motivated student team, faculty advisor, and basic knowledge of the lean startup method.

TAT delivery of a PTEN peptide inhibitor has direct cardioprotective effects and improves outcomes in rodent models of cardiac arrest.

We have recently shown that pharmacologic inhibition of PTEN significantly increases cardiac arrest survival in a mouse model, however, this protection required pretreatment 30 min before the arrest. To improve the onset of PTEN inhibition during cardiac arrest treatment, we have designed a TAT fused cell-permeable peptide (TAT-PTEN9c) based on the C-terminal PDZ binding motif of PTEN for rapid tissue delivery and protection. Western blot analysis demonstrated that TAT-PTEN9c peptide significantly enhanced Akt activation in mouse cardiomyocytes in a concentration- and time-dependent manner. Mice were subjected to 8 min asystolic arrest followed by CPR, and 30 mice with successful CPR were then randomly assigned to receive either saline or TAT-PTEN9c treatment. Survival was significantly increased in TAT-PTEN9c-treated mice compared with that of saline control at 4 h after CPR. The treated mice had increased Akt phosphorylation at 30 min resuscitation with significantly decreased sorbitol content in heart or brain tissues and reduced release of taurine and glutamate in blood, suggesting improved glucose metabolism. In an isolated rat heart Langendorff model, direct effects of TAT-PTEN9c on cardiac function were measured for 20 min following 20 min global ischemia. Rate pressure product was reduced by >20% for both TAT vehicle and nontreatment groups following arrest. Cardiac contractile function was completely recovered with TAT-PTEN9c treatment given at the start of reperfusion. We conclude that TAT-PTEN9c enhances Akt activation and decreases glucose shunting to the polyol pathway in critical organs, thereby preventing osmotic injury and early cardiovascular collapse and death.NEW & NOTEWORTHY We have designed a cell-permeable peptide, TAT-PTEN9c, to improve cardiac arrest survival. It blocked endogenous PTEN binding to its adaptor and enhanced Akt signaling in mouse cardiomyocytes. It improved mouse survival after cardiac arrest, which is related to improved glucose metabolism and reduced glucose shunting to sorbitol in critical organs.

The Impact of Pazopanib on the Cardiovascular System.

Pazopanib is an approved treatment for renal cell carcinoma and a second-line treatment for nonadipocytic soft-tissue sarcoma. However, its clinical efficacy is limited by its cardiovascular side effects. Pazopanib and other vascular endothelial growth factor receptor tyrosine kinase inhibitors have been associated with the development of hypertension, QT interval prolongation, and other cardiovascular events; however, these mechanisms are largely unknown. Gaining a deeper understanding of these mechanisms is essential for the development of appropriate surveillance strategies and possible diagnostic biomarkers to allow us to monitor patients and modulate therapy prior to significant cardiac insult. This approach will be vital in keeping patients on these life-saving therapies and may be applicable to other tyrosine kinase inhibitors as well. In this review, we provide a comprehensive overview of the preclinical and clinical side effects of pazopanib with a focus on the mechanisms responsible for its toxicity to the cardiovascular system.