Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 28
Filter
1.
bioRxiv ; 2024 Jun 09.
Article in English | MEDLINE | ID: mdl-38895483

ABSTRACT

Heart failure with preserved ejection fraction (HFpEF) is increasingly common but its pathogenesis is poorly understood. The ability to assess genetic and pharmacologic interventions is hampered by the lack of robust preclinical mouse models of HFpEF. We have developed a novel "2-hit" model, which combines obesity and insulin resistance with chronic pressure overload to recapitulate clinical features of HFpEF. C57BL6/NJ mice fed a high fat diet for >10 weeks were administered an AAV8-driven vector resulting in constitutive overexpression of mouse Renin1d . Control mice, HFD only, Renin only and HFD-Renin (aka "HFpEF") littermates underwent a battery of cardiac and extracardiac phenotyping. HFD-Renin mice demonstrated obesity and insulin resistance, a 2-3-fold increase in circulating renin levels that resulted in 30-40% increase in left ventricular hypertrophy, preserved systolic function, and diastolic dysfunction indicated by altered E/e', IVRT, and strain measurements; increased left atrial mass; elevated natriuretic peptides; and exercise intolerance. Transcriptomic and metabolomic profiling of HFD-Renin myocardium demonstrated upregulation of pro-fibrotic pathways and downregulation of metabolic pathways, in particular branched chain amino acid catabolism, similar to findings in human HFpEF. Treatment of these mice with the sodium-glucose cotransporter 2 inhibitor empagliflozin, an effective but incompletely understood HFpEF therapy, improved exercise tolerance, left heart enlargement, and insulin homeostasis. The HFD-Renin mouse model recapitulates key features of human HFpEF and will enable studies dissecting the contribution of individual pathogenic drivers to this complex syndrome. Addition of HFD-Renin mice to the preclinical HFpEF model platform allows for orthogonal studies to increase validity in assessment of interventions. NEW & NOTEWORTHY: Heart failure with preserved ejection fraction (HFpEF) is a complex disease to study due to limited preclinical models. We rigorously characterize a new two-hit HFpEF mouse model, which allows for dissecting individual contributions and synergy of major pathogenic drivers, hypertension and diet-induced obesity. The results are consistent and reproducible in two independent laboratories. This high-fidelity pre-clinical model increases the available, orthogonal models needed to improve our understanding of the causes and assessment treatments for HFpEF.

2.
bioRxiv ; 2024 May 02.
Article in English | MEDLINE | ID: mdl-38746425

ABSTRACT

Sodium-glucose co-transporter 2 inhibitors (SGLT2i) are novel, potent heart failure medications with an unknown mechanism of action. We sought to determine if the beneficial actions of SGLT2i in heart failure were on- or off-target, and related to metabolic reprogramming, including increased lipolysis and ketogenesis. The phenotype of mice treated with empagliflozin and genetically engineered mice constitutively lacking SGLT2 mirrored metabolic changes seen in human clinical trials (including reduced blood glucose, increased ketogenesis, and profound glucosuria). In a mouse heart failure model, SGLT2i treatment, but not generalized SGLT2 knockout, resulted in improved systolic function and reduced pathologic cardiac remodeling. SGLT2i treatment of the SGLT2 knockout mice sustained the cardiac benefits, demonstrating an off-target role for these drugs. This benefit is independent of metabolic changes, including ketosis. The mechanism of action and target of SGLT2i in HF remain elusive.

3.
JACC Basic Transl Sci ; 9(1): 1-15, 2024 Jan.
Article in English | MEDLINE | ID: mdl-38362346

ABSTRACT

Recent studies suggest that metabolic dysregulation in patients with heart failure might contribute to myocardial contractile dysfunction. To understand the correlation between function and energy metabolism, we studied the impact of different fuel substrates on human nonfailing or failing cardiomyocytes. Consistent with the concept of metabolic flexibility, nonfailing myocytes exhibited excellent contractility in all fuels provided. However, impaired contractility was observed in failing myocytes when carbohydrates alone were used but was improved when additional substrates were added. This study demonstrates the functional significance of fuel utilization shifts in failing human cardiomyocytes.

4.
Circ Res ; 132(7): 882-898, 2023 03 31.
Article in English | MEDLINE | ID: mdl-36996176

ABSTRACT

The ketone bodies beta-hydroxybutyrate and acetoacetate are hepatically produced metabolites catabolized in extrahepatic organs. Ketone bodies are a critical cardiac fuel and have diverse roles in the regulation of cellular processes such as metabolism, inflammation, and cellular crosstalk in multiple organs that mediate disease. This review focuses on the role of cardiac ketone metabolism in health and disease with an emphasis on the therapeutic potential of ketosis as a treatment for heart failure (HF). Cardiac metabolic reprogramming, characterized by diminished mitochondrial oxidative metabolism, contributes to cardiac dysfunction and pathologic remodeling during the development of HF. Growing evidence supports an adaptive role for ketone metabolism in HF to promote normal cardiac function and attenuate disease progression. Enhanced cardiac ketone utilization during HF is mediated by increased availability due to systemic ketosis and a cardiac autonomous upregulation of ketolytic enzymes. Therapeutic strategies designed to restore high-capacity fuel metabolism in the heart show promise to address fuel metabolic deficits that underpin the progression of HF. However, the mechanisms involved in the beneficial effects of ketone bodies in HF have yet to be defined and represent important future lines of inquiry. In addition to use as an energy substrate for cardiac mitochondrial oxidation, ketone bodies modulate myocardial utilization of glucose and fatty acids, two vital energy substrates that regulate cardiac function and hypertrophy. The salutary effects of ketone bodies during HF may also include extra-cardiac roles in modulating immune responses, reducing fibrosis, and promoting angiogenesis and vasodilation. Additional pleotropic signaling properties of beta-hydroxybutyrate and AcAc are discussed including epigenetic regulation and protection against oxidative stress. Evidence for the benefit and feasibility of therapeutic ketosis is examined in preclinical and clinical studies. Finally, ongoing clinical trials are reviewed for perspective on translation of ketone therapeutics for the treatment of HF.


Subject(s)
Heart Failure , Ketosis , Humans , Ketones/therapeutic use , 3-Hydroxybutyric Acid/therapeutic use , Epigenesis, Genetic , Ketone Bodies/therapeutic use , Ketone Bodies/metabolism , Heart Failure/metabolism , Ketosis/drug therapy , Ketosis/metabolism , Ketosis/pathology
5.
JACC Basic Transl Sci ; 6(2): 154-170, 2021 Feb.
Article in English | MEDLINE | ID: mdl-33665515

ABSTRACT

A lack of preclinical large animal models of heart failure with preserved ejection fraction (HFpEF) that recapitulate this comorbid-laden syndrome has led to the inability to tease out mechanistic insights and to test novel therapeutic strategies. This study developed a large animal model that integrated multiple comorbid determinants of HFpEF in a miniswine breed that exhibited sensitivity to obesity, metabolic syndrome, and vascular disease with overt clinical signs of heart failure. The combination of a Western diet and 11-deoxycorticosterone acetate salt-induced hypertension in the Göttingen miniswine led to the development of a novel large animal model of HFpEF that exhibited multiorgan involvement and a full spectrum of comorbidities associated with human HFpEF.

6.
Circ Heart Fail ; 14(1): e007684, 2021 01.
Article in English | MEDLINE | ID: mdl-33356362

ABSTRACT

BACKGROUND: Accumulating evidence suggests that the failing heart reprograms fuel metabolism toward increased utilization of ketone bodies and that increasing cardiac ketone delivery ameliorates cardiac dysfunction. As an initial step toward development of ketone therapies, we investigated the effect of chronic oral ketone ester (KE) supplementation as a prevention or treatment strategy in rodent heart failure models. METHODS: Two independent rodent heart failure models were used for the studies: transverse aortic constriction/myocardial infarction (MI) in mice and post-MI remodeling in rats. Seventy-five mice underwent a prevention treatment strategy with a KE comprised of hexanoyl-hexyl-3-hydroxybutyrate KE (KE-1) diet, and 77 rats were treated in either a prevention or treatment regimen using a commercially available ß-hydroxybutyrate-(R)-1,3-butanediol monoester (DeltaG; KE-2) diet. RESULTS: The KE-1 diet in mice elevated ß-hydroxybutyrate levels during nocturnal feeding, whereas the KE-2 diet in rats induced ketonemia throughout a 24-hour period. The KE-1 diet preventive strategy attenuated development of left ventricular dysfunction and remodeling post-transverse aortic constriction/MI (left ventricular ejection fraction±SD, 36±8 in vehicle versus 45±11 in KE-1; P=0.016). The KE-2 diet therapeutic approach also attenuated left ventricular dysfunction and remodeling post-MI (left ventricular ejection fraction, 41±11 in MI-vehicle versus 61±7 in MI-KE-2; P<0.001). In addition, ventricular weight, cardiomyocyte cross-sectional area, and the expression of ANP (atrial natriuretic peptide) were significantly attenuated in the KE-2-treated MI group. However, treatment with KE-2 did not influence cardiac fibrosis post-MI. The myocardial expression of the ketone transporter and 2 ketolytic enzymes was significantly increased in rats fed KE-2 diet along with normalization of myocardial ATP levels to sham values. CONCLUSIONS: Chronic oral supplementation with KE was effective in both prevention and treatment of heart failure in 2 preclinical animal models. In addition, our results indicate that treatment with KE reprogrammed the expression of genes involved in ketone body utilization and normalized myocardial ATP production following MI, consistent with provision of an auxiliary fuel. These findings provide rationale for the assessment of KEs as a treatment for patients with heart failure.


Subject(s)
Dietary Supplements , Heart Failure/physiopathology , Hydroxybutyrates , Myocardial Infarction/physiopathology , Myocardium/metabolism , Stroke Volume/physiology , Ventricular Dysfunction, Left/physiopathology , Adenosine Triphosphate/metabolism , Animals , Aorta/surgery , Atrial Natriuretic Factor/metabolism , Constriction, Pathologic , Fibrosis , Heart Failure/metabolism , Heart Failure/pathology , Heart Ventricles/metabolism , Heart Ventricles/pathology , Mice , Myocardial Infarction/metabolism , Myocardial Infarction/pathology , Myocardium/pathology , Myocytes, Cardiac/pathology , Organ Size , Rats , Ventricular Dysfunction, Left/metabolism , Ventricular Dysfunction, Left/pathology , Ventricular Function, Left
7.
Circ Res ; 126(12): 1685-1702, 2020 06 05.
Article in English | MEDLINE | ID: mdl-32212902

ABSTRACT

RATIONALE: The heart undergoes dramatic developmental changes during the prenatal to postnatal transition, including maturation of cardiac myocyte energy metabolic and contractile machinery. Delineation of the mechanisms involved in cardiac postnatal development could provide new insight into the fetal shifts that occur in the diseased heart and unveil strategies for driving maturation of stem cell-derived cardiac myocytes. OBJECTIVE: To delineate transcriptional drivers of cardiac maturation. METHODS AND RESULTS: We hypothesized that ERR (estrogen-related receptor) α and γ, known transcriptional regulators of postnatal mitochondrial biogenesis and function, serve a role in the broader cardiac maturation program. We devised a strategy to knockdown the expression of ERRα and γ in heart after birth (pn-csERRα/γ [postnatal cardiac-specific ERRα/γ]) in mice. With high levels of knockdown, pn-csERRα/γ knockdown mice exhibited cardiomyopathy with an arrest in mitochondrial maturation. RNA sequence analysis of pn-csERRα/γ knockdown hearts at 5 weeks of age combined with chromatin immunoprecipitation with deep sequencing and functional characterization conducted in human induced pluripotent stem cell-derived cardiac myocytes (hiPSC-CM) demonstrated that ERRγ activates transcription of genes involved in virtually all aspects of postnatal developmental maturation, including mitochondrial energy transduction, contractile function, and ion transport. In addition, ERRγ was found to suppress genes involved in fibroblast activation in hearts of pn-csERRα/γ knockdown mice. Disruption of Esrra and Esrrg in mice during fetal development resulted in perinatal lethality associated with structural and genomic evidence of an arrest in cardiac maturation, including persistent expression of early developmental and noncardiac lineage gene markers including cardiac fibroblast signatures. Lastly, targeted deletion of ESRRA and ESRRG in hiPSC-CM derepressed expression of early (transcription factor 21 or TCF21) and mature (periostin, collagen type III) fibroblast gene signatures. CONCLUSIONS: ERRα and γ are critical regulators of cardiac myocyte maturation, serving as transcriptional activators of adult cardiac metabolic and structural genes, an.d suppressors of noncardiac lineages including fibroblast determination.


Subject(s)
Heart/embryology , Myocytes, Cardiac/metabolism , Receptors, Estrogen/metabolism , Animals , Basic Helix-Loop-Helix Transcription Factors/metabolism , Cells, Cultured , Gene Expression Regulation, Developmental , Heart/growth & development , Humans , Induced Pluripotent Stem Cells/cytology , Mice , Mitochondria, Heart/metabolism , Myocytes, Cardiac/cytology , Receptors, Estrogen/genetics , Signal Transduction , ERRalpha Estrogen-Related Receptor
8.
Circ Res ; 126(2): 197-199, 2020 01 17.
Article in English | MEDLINE | ID: mdl-31944916
9.
JCI Insight ; 4(4)2019 02 21.
Article in English | MEDLINE | ID: mdl-30668551

ABSTRACT

Evidence has emerged that the failing heart increases utilization of ketone bodies. We sought to determine whether this fuel shift is adaptive. Mice rendered incapable of oxidizing the ketone body 3-hydroxybutyrate (3OHB) in the heart exhibited worsened heart failure in response to fasting or a pressure overload/ischemic insult compared with WT controls. Increased delivery of 3OHB ameliorated pathologic cardiac remodeling and dysfunction in mice and in a canine pacing model of progressive heart failure. 3OHB was shown to enhance bioenergetic thermodynamics of isolated mitochondria in the context of limiting levels of fatty acids. These results indicate that the heart utilizes 3OHB as a metabolic stress defense and suggest that strategies aimed at increasing ketone delivery to the heart could prove useful in the treatment of heart failure.


Subject(s)
3-Hydroxybutyric Acid/metabolism , Energy Metabolism , Heart Failure/metabolism , Heart Ventricles/metabolism , Myocardium/metabolism , Animals , Disease Models, Animal , Disease Progression , Dogs , Female , Heart Failure/etiology , Heart Failure/pathology , Heart Ventricles/cytology , Heart Ventricles/pathology , Humans , Hydroxybutyrate Dehydrogenase/genetics , Hydroxybutyrate Dehydrogenase/metabolism , Isolated Heart Preparation , Male , Mice , Mice, Knockout , Mitochondria/metabolism , Mitochondria/pathology , Myocardium/cytology , Myocardium/pathology , Oxidation-Reduction , Stress, Physiological , Thermodynamics , Ventricular Remodeling
10.
JACC Basic Transl Sci ; 2(3): 244-253, 2017 Jun.
Article in English | MEDLINE | ID: mdl-29152600

ABSTRACT

xtracorporeal membrane oxygenation (ECMO) is used in cardiopulmonary resuscitation (CPR) of refractory cardiac arrest. We used a 2×2 study design to compare ECMO versus CPR and epinephrine versus placebo in a porcine model of ischemic refractory ventricular fibrillation (VF). Pigs underwent 5 minutes of untreated VF, 10 minutes of CPR, and were randomized to receive epinephrine versus placebo for another 35 minutes. Animals were further randomized to LAD reperfusion at minute 45 with ongoing CPR versus veno-arterial ECMO cannulation at minute 45 of CPR and subsequent LAD reperfusion. Four-hour survival was improved with ECMO while epinephrine showed no effect.

11.
Resuscitation ; 116: 8-15, 2017 07.
Article in English | MEDLINE | ID: mdl-28408349

ABSTRACT

BACKGROUND: Out-of-hospital cardiac arrest (CA) is a prevalent medical crisis resulting in severe injury to the heart and brain and an overall survival of less than 10%. Mitochondrial dysfunction is predicted to be a key determinant of poor outcomes following prolonged CA. However, the onset and severity of mitochondrial dysfunction during CA and cardiopulmonary resuscitation (CPR) is not fully understood. Ischemic postconditioning (IPC), controlled pauses during the initiation of CPR, has been shown to improve cardiac function and neurologically favorable outcomes after 15min of CA. We tested the hypothesis that mitochondrial dysfunction develops during prolonged CA and can be rescued with IPC during CPR (IPC-CPR). METHODS: A total of 63 swine were randomized to no ischemia (Naïve), 19min of ventricular fibrillation (VF) CA without CPR (Untreated VF), or 15min of CA with 4min of reperfusion with either standard CPR (S-CPR) or IPC-CPR. Mitochondria were isolated from the heart and brain to quantify respiration, rate of ATP synthesis, and calcium retention capacity (CRC). Reactive oxygen species (ROS) production was quantified from fresh frozen heart and brain tissue. RESULTS: Compared to Naïve, Untreated VF induced cardiac and brain ROS overproduction concurrent with decreased mitochondrial respiratory coupling and CRC, as well as decreased cardiac ATP synthesis. Compared to Untreated VF, S-CPR attenuated brain ROS overproduction but had no other effect on mitochondrial function in the heart or brain. Compared to Untreated VF, IPC-CPR improved cardiac mitochondrial respiratory coupling and rate of ATP synthesis, and decreased ROS overproduction in the heart and brain. CONCLUSIONS: Fifteen minutes of VF CA results in diminished mitochondrial respiration, ATP synthesis, CRC, and increased ROS production in the heart and brain. IPC-CPR attenuates cardiac mitochondrial dysfunction caused by prolonged VF CA after only 4min of reperfusion, suggesting that IPC-CPR is an effective intervention to reduce cardiac injury. However, reperfusion with both CPR methods had limited effect on mitochondrial function in the brain, emphasizing an important physiological divergence in post-arrest recovery between those two vital organs.


Subject(s)
Brain/blood supply , Cardiopulmonary Resuscitation/methods , Ischemic Postconditioning/methods , Mitochondria/physiology , Out-of-Hospital Cardiac Arrest/therapy , Animals , Brain/physiology , Disease Models, Animal , Heart/physiopathology , Mitochondria, Heart/physiology , Out-of-Hospital Cardiac Arrest/physiopathology , Random Allocation , Swine , Ventricular Fibrillation
12.
Curr Opin Crit Care ; 23(3): 215-222, 2017 Jun.
Article in English | MEDLINE | ID: mdl-28346232

ABSTRACT

PURPOSE OF REVIEW: Survival with favorable neurological function after cardiac arrest remains low. The purpose of this review is to identify recent advances that focus on neuroprotection during cardiopulmonary resuscitation (CPR). RECENT FINDINGS: Multiple strategies have been shown to enhance neuroprotection during CPR. Brain perfusion during CPR is increased with therapies such as active compression decompression CPR and intrathoracic pressure regulation that improve cardiac preload and decrease intracranial pressure. Head Up CPR has been shown to decrease intracranial pressure thereby increasing cerebral perfusion pressure and cerebral blood flow. Sodium nitroprusside enhanced CPR increases cerebral perfusion, facilitates heat exchange, and improves neurologic survival in swine after cardiac arrest. Postconditioning has been administered during CPR in laboratory settings. Poloxamer 188, a membrane stabilizer, and ischemic postconditioning have been shown to improve cardiac and neural function after cardiac arrest in animal models. Postconditioning with inhaled gases protects the myocardium, with more evidence mounting for the potential for neural protection. SUMMARY: Multiple promising neuroprotective therapies are being developed in animal models of cardiac arrest, and are in early stages of human trials. These therapies have the potential to be bundled together to improve rates of favorable neurological survival after cardiac arrest.


Subject(s)
Cardiopulmonary Resuscitation/methods , Cerebrovascular Circulation/physiology , Heart Arrest/therapy , Neuroprotection , Animals , Disease Models, Animal , Heart Arrest/etiology , Heart Arrest/physiopathology , Humans , Swine , Treatment Outcome
13.
Resuscitation ; 110: 6-11, 2017 01.
Article in English | MEDLINE | ID: mdl-27771299

ABSTRACT

INTRODUCTION: Sodium nitroprusside (SNP) enhanced CPR (SNPeCPR) demonstrates increased vital organ blood flow and survival in multiple porcine models. We developed a new, coronary occlusion/ischemia model of prolonged resuscitation, mimicking the majority of out-of-hospital cardiac arrests presenting with shockable rhythms. HYPOTHESIS: SNPeCPR will increase short term (4-h) survival compared to standard 2015 Advanced Cardiac Life Support (ACLS) guidelines in an ischemic refractory ventricular fibrillation (VF), prolonged CPR model. METHODS: Sixteen anesthetized pigs had the ostial left anterior descending artery occluded leading to ischemic VF arrest. VF was untreated for 5min. Basic life support was performed for 10min. At minute 10 (EMS arrival), animals received either SNPeCPR (n=8) or standard ACLS (n=8). Defibrillation (200J) occurred every 3min. CPR continued for a total of 45min, then the balloon was deflated simulating revascularization. CPR continued until return of spontaneous circulation (ROSC) or a total of 60min, if unsuccessful. SNPeCPR animals received 2mg of SNP at minute 10 followed by 1mg every 5min until ROSC. Standard ACLS animals received 0.5mg epinephrine every 5min until ROSC. Primary endpoints were ROSC and 4-h survival. RESULTS: All SNPeCPR animals (8/8) achieved sustained ROSC versus 2/8 standard ACLS animals within one hour of resuscitation (p=0.04). The 4-h survival was significantly improved with SNPeCPR compared to standard ACLS, 7/8 versus 1/8 respectively, p=0.0019. CONCLUSION: SNPeCPR significantly improved ROSC and 4-h survival compared with standard ACLS CPR in a porcine model of prolonged ischemic, refractory VF cardiac arrest.


Subject(s)
Heart Arrest , Myocardial Ischemia , Nitroprusside/administration & dosage , Regional Blood Flow/drug effects , Ventricular Fibrillation/complications , Advanced Cardiac Life Support/methods , Advanced Cardiac Life Support/mortality , Animals , Cardiopulmonary Resuscitation/methods , Disease Models, Animal , Drug Administration Schedule , Drug Monitoring/methods , Electric Countershock/methods , Heart Arrest/etiology , Heart Arrest/therapy , Myocardial Ischemia/drug therapy , Myocardial Ischemia/etiology , Myocardial Ischemia/physiopathology , Survival Analysis , Swine , Time Factors , Treatment Outcome , Vasodilator Agents/administration & dosage , Ventricular Fibrillation/physiopathology , Ventricular Fibrillation/therapy
14.
JACC Basic Transl Sci ; 1(4): 224-234, 2016 Jun.
Article in English | MEDLINE | ID: mdl-27695713

ABSTRACT

BACKGROUND: Poloxamer 188 (P188) is a nonionic triblock copolymer believed to prevent cellular injury after ischemia and reperfusion. OBJECTIVES: This study compared intracoronary infusion of P188 immediately after reperfusion with delayed infusion through a peripheral intravenous catheter in a porcine model of ST segment elevation myocardial infarction (STEMI). Cellular and mitochondrial injury were assessed. METHODS: STEMI was induced in 55 pigs using 45 minutes of endovascular coronary artery occlusion. Pigs were then randomized to four groups: control, immediate intracoronary (IC) P188, delayed peripheral P188, and polyethylene glycol (PEG) infusion. Heart tissue was collected after 4 hours of reperfusion. Assessment of mitochondrial function or infarct size was performed. RESULTS: Mitochondrial yield improved significantly with IC P188 treatment compared to control animals (0.25% vs. 0.13%) suggesting improved mitochondrial morphology and survival. Mitochondrial respiration and calcium retention were also significantly improved with immediate IC P188 compared to controls (complex I RCI: 7.4 vs. 3.7 and calcium retention (nmol): 1152 vs. 386). This benefit was only observed with activation of complex I of the mitochondrial respiratory chain suggesting a specific impact of ischemia and reperfusion on this complex. Infarct size and serum troponin I were significantly reduced by immediate IC P188 infusion (infarct size: 13.9% vs. 41.1% and troponin I (µg/L): 19.2 vs. 77.4 µg/L). Delayed P188 and PEG infusion did not provide a significant benefit. CONCLUSIONS: Intracoronary infusion of P188 immediately upon reperfusion significantly reduces cellular and mitochondrial injury after ischemia and reperfusion in this clinically relevant porcine model of STEMI. The timing and route of delivery were critical to achieve the benefit.

15.
Shock ; 44 Suppl 1: 96-102, 2015 08.
Article in English | MEDLINE | ID: mdl-25692250

ABSTRACT

Brain injury is a leading cause of death and disability in children and adults in their most productive years. Use of intrathoracic pressure regulation (IPR) to generate negative intrathoracic pressure during the expiratory phase of positive pressure ventilation improves mean arterial pressure and 24-h survival in porcine models of hemorrhagic shock and cardiac arrest and has been demonstrated to decrease intracranial pressure (ICP) and cerebral perfusion pressure (CPP) in these models. Application of IPR for 240 min in a porcine model of intracranial hypertension (ICH) will increase CPP when compared with controls. Twenty-three female pigs were subjected to focal brain injury by insertion of an epidural Foley catheter inflated with 3 mL of saline. Animals were randomized to treatment for 240 min with IPR set to a negative expiratory phase pressure of -12 cmH2O or no IPR therapy. Intracranial pressure, mean arterial pressure, CPP, and cerebral blood flow (CBF) were evaluated. Intrathoracic pressure regulation significantly improved mean CPP and CBF. Specifically, mean CPP after 90, 120, 180, and 240 min of IPR use was 43.7 ± 2.8 mmHg, 44.0 ± 2.7 mmHg, 44.5 ± 2.8 mmHg, and 43.1 ± 1.9 mmHg, respectively; a significant increase from ICH study baseline (39.5 ± 1.7 mmHg) compared with control animals in which mean CPP was 36.7 ± 1.4 mmHg (ICH study baseline) and then 35.9 ± 2.1 mmHg, 33.7 ± 2.8 mmHg, 33.9 ± 3.0 mmHg, and 36.0 ± 2.7 mmHg at 90, 120, 180, and 240 min, respectively (P < 0.05 for all time points). Cerebral blood flow, as measured by an invasive CBF probe, increased in the IPR group (34 ± 4 mL/100 g-min to 49 ± 7 mL/100 g-min at 90 min) but not in controls (27 ± 1 mL/100 g-min to 25 ± 5 mL/100 g-min at 90 min) (P = 0.01). Arterial pH remained unchanged during the entire period of IPR compared with baseline values and control values. In this anesthetized pig model of ICH, treatment with IPR significantly improved CPP and CBF. This therapy may be of clinical value by noninvasively improving cerebral perfusion in states of compromised cerebral perfusion.


Subject(s)
Brain Injuries/physiopathology , Cerebrovascular Circulation , Intracranial Pressure , Animals , Blood Flow Velocity , Blood Pressure , Catheters , Disease Models, Animal , Female , Perfusion , Random Allocation , Swine , Time Factors
16.
Resuscitation ; 87: 38-43, 2015 Feb.
Article in English | MEDLINE | ID: mdl-25447353

ABSTRACT

INTRODUCTION: Cerebral perfusion is compromised during cardiopulmonary resuscitation (CPR). We hypothesized that beneficial effects of gravity on the venous circulation during CPR performed in the head-up tilt (HUT) position would improve cerebral perfusion compared with supine or head-down tilt (HDT). METHODS: Twenty-two pigs were sedated, intubated, anesthetized, paralyzed and placed on a tilt table. After 6min of untreated ventricular fibrillation (VF) CPR was performed on 14 pigs for 3min with an automated CPR device called LUCAS (L) plus an impedance threshold device (ITD), followed by 5min of L-CPR+ITD at 0° supine, 5min at 30° HUT, and then 5min at 30° HDT. Microspheres were used to measure organ blood flow in 8 pigs. L-CPR+ITD was performed on 8 additional pigs at 0°, 20°, 30°, 40°, and 50° HUT. RESULTS: Coronary perfusion pressure was 19±2mmHg at 0° vs. 30±3 at 30° HUT (p<0.001) and 10±3 at 30° HDT (p<0.001). Cerebral perfusion pressure was 19±3 at 0° vs. 35±3 at 30° HUT (p<0.001) and 4±4 at 30° HDT (p<0.001). Brain-blood flow was 0.19±0.04mlmin(-1)g(-1) at 0° vs. 0.27±0.04 at 30° HUT (p=0.01) and 0.14±0.06 at 30° HDT (p=0.16). Heart blood flow was not significantly different between interventions. With 0, 10, 20, 30, 40 and 50° HUT, ICP values were 21±2, 16±2, 10±2, 5±2, 0±2, -5±2 respectively, (p<0.001), CerPP increased linearly (p=0.001), and CPP remained constant. CONCLUSION: During CPR, HDT decreased brain flow whereas HUT significantly lowered ICP and improved cerebral perfusion. Further studies are warranted to explore this new resuscitation concept.


Subject(s)
Brain , Cerebrovascular Circulation/physiology , Heart Arrest , Patient Positioning , Animals , Brain/blood supply , Brain/physiopathology , Gravitation , Heart Arrest/etiology , Heart Arrest/therapy , Humans , Patient Positioning/adverse effects , Patient Positioning/methods , Regional Blood Flow , Swine , Ventricular Fibrillation/complications
17.
Resuscitation ; 87: 7-13, 2015 Feb.
Article in English | MEDLINE | ID: mdl-25447036

ABSTRACT

OBJECTIVE: Ischemic postconditioning (stutter CPR) and sevoflurane have been shown to mitigate the effects of reperfusion injury in cardiac tissue after 15min of ventricular fibrillation (VF) cardiac arrest. Poloxamer 188 (P188) has also proven beneficial to neuronal and cardiac tissue during reperfusion injury in human and animal models. We hypothesized that the use of stutter CPR, sevoflurane, and P188 combined with standard advanced life support would improve post-resuscitation cardiac and neurologic function after prolonged VF arrest. METHODS: Following 17min of untreated VF, 20 pigs were randomized to Control treatment with active compression/decompression (ACD) CPR and impedance threshold device (ITD) (n=8) or Bundle therapy with stutter ACD CPR+ITD+sevoflurane+P188 (n=12). Epinephrine and post-resuscitation hypothermia were given in both groups per standard protocol. Animals that achieved return of spontaneous circulation (ROSC) were evaluated with echocardiography, biomarkers, and a blinded neurologic assessment with a cerebral performance category score. RESULTS: Bundle therapy improved hemodynamics during resuscitation, reduced need for epinephrine and repeated defibrillation, reduced biomarkers of cardiac injury and end-organ dysfunction, and increased left ventricular ejection fraction compared to Controls. Bundle therapy also improved rates of ROSC (100% vs. 50%), freedom from major adverse events (50% vs. 0% at 48h), and neurologic function (42% with mild or no neurologic deficit and 17% achieving normal function at 48h). CONCLUSIONS: Bundle therapy with a combination of stutter ACD CPR, ITD, sevoflurane, and P188 improved cardiac and neurologic function after 17min of untreated cardiac arrest in pigs. All studies were performed with approval from the Institutional Animal Care Committee of the Minneapolis Medical Research Foundation (protocol #12-11).


Subject(s)
Cardiopulmonary Resuscitation , Heart Arrest , Ischemic Postconditioning/methods , Methyl Ethers/pharmacology , Myocardial Reperfusion Injury/prevention & control , Anesthetics, Inhalation/pharmacology , Animals , Cardiopulmonary Resuscitation/adverse effects , Cardiopulmonary Resuscitation/methods , Coronary Circulation , Disease Models, Animal , Female , Heart/physiopathology , Heart Arrest/etiology , Heart Arrest/therapy , Hemodynamics , Humans , Male , Neurologic Examination , Sevoflurane , Stroke Volume , Swine , Time Factors , Treatment Outcome , Ventricular Fibrillation/complications
18.
Crit Care Med ; 43(4): 849-55, 2015 Apr.
Article in English | MEDLINE | ID: mdl-25525755

ABSTRACT

OBJECTIVES: The aim of this study was to assess the effect of sodium nitroprusside-enhanced cardiopulmonary resuscitation on heat exchange during surface cooling. We hypothesized that sodium nitroprusside-enhanced cardiopulmonary resuscitation would decrease the time required to reach brain temperature less than 35°C compared to active compression-decompression plus impedance threshold device cardiopulmonary resuscitation alone, in the setting of intra-cardiopulmonary resuscitation cooling. We further hypothesized that the addition of epinephrine during sodium nitroprusside-enhanced cardiopulmonary resuscitation would mitigate heat exchange. DESIGN: Prospective randomized animal investigation. SETTING: Preclinical animal laboratory. SUBJECTS: Female farm pigs (n=28). INTERVENTIONS: After 10 minutes of untreated ventricular fibrillation, animals were randomized to three different protocols: sodium nitroprusside-enhanced cardiopulmonary resuscitation (n=8), sodium nitroprusside-enhanced cardiopulmonary resuscitation plus epinephrine (n=10), and active compression-decompression plus impedance threshold device alone (control, n=10). All animals received surface cooling at the initiation of cardiopulmonary resuscitation. Sodium nitroprusside-enhanced cardiopulmonary resuscitation included active compression-decompression plus impedance threshold device plus abdominal binding and 2 mg of sodium nitroprusside at 1, 4, and 8 minutes of cardiopulmonary resuscitation. No epinephrine was used during cardiopulmonary resuscitation in the sodium nitroprusside-enhanced cardiopulmonary resuscitation group. Control and sodium nitroprusside-enhanced cardiopulmonary resuscitation plus epinephrine groups received 0.5 mg of epinephrine at 4.5 and 9 minutes of cardiopulmonary resuscitation. Defibrillation occurred after 10 minutes of cardiopulmonary resuscitation. After return of spontaneous circulation, an Arctic Sun (Medivance, Louiseville, CO) was applied at maximum cooling on all animals. The primary endpoint was the time required to reach brain temperature less than 35°C beginning from the time of cardiopulmonary resuscitation initiation. Data are presented as mean±SEM. MEASUREMENTS AND MAIN RESULTS: The time required to reach a brain temperature of 35°C was decreased with sodium nitroprusside-enhanced cardiopulmonary resuscitation versus control or sodium nitroprusside-enhanced cardiopulmonary resuscitation plus epinephrine (24±6 min, 63±8 min, and 50±9 min, respectively; p=0.005). Carotid blood flow was higher during cardiopulmonary resuscitation in the sodium nitroprusside-enhanced cardiopulmonary resuscitation group (83±15 mL/min vs 26±7 mL/min and 35±5 mL/min in the control and sodium nitroprusside-enhanced cardiopulmonary resuscitation plus epinephrine groups, respectively; p=0.001). CONCLUSIONS: This study demonstrates that sodium nitroprusside-enhanced cardiopulmonary resuscitation facilitates intra-cardiopulmonary resuscitation hypothermia. The addition of epinephrine to sodium nitroprusside-enhanced cardiopulmonary resuscitation during cardiopulmonary resuscitation reduced its improvement in heat exchange.


Subject(s)
Cardiopulmonary Resuscitation/methods , Hypothermia, Induced , Nitroprusside/pharmacology , Ventricular Fibrillation/therapy , Animals , Blood Gas Analysis , Body Temperature , Carotid Arteries , Disease Models, Animal , Echocardiography , Epinephrine/pharmacology , Female , Hemodynamics , Prospective Studies , Random Allocation , Swine , Ventricular Fibrillation/diagnostic imaging , Ventricular Function, Left
19.
Resuscitation ; 85(12): 1745-51, 2014 Dec.
Article in English | MEDLINE | ID: mdl-25281906

ABSTRACT

BACKGROUND: Anaesthetic postconditioning (APoC) attenuates myocardial injury following coronary ischaemia/reperfusion. We hypothesised that APoC at the initiation of cardiopulmonary resuscitation (CPR) will improve post resuscitation myocardial function along with improved mitochondrial function in a pig model of prolonged untreated ventricular fibrillation. METHODS: In 32 pigs isoflurane anaesthesia was discontinued prior to induction of ventricular fibrillation that was left untreated for 15 min. At the initiation of CPR, 15 animals were randomised to controls (CON), and 17 to APoC with 2 vol% sevoflurane during the first 3 min CPR. Pigs were defibrillated after 4 min of CPR. After return of spontaneous circulation (ROSC), isoflurane was restarted at 0.8-1.5 vol% in both groups. Systolic and diastolic blood pressures were measured continuously. Of the animals that achieved ROSC, eight CON and eight APoC animals were randomised to have their left ventricular ejection fraction (LVEF%) assessed by echocardiography at 4h. Seven CON and nine APoC were randomised to euthanasia 15 min after ROSC to isolate mitochondria from the left ventricle for bioenergetic studies. RESULTS: ROSC was achieved in 10/15 CON and 15/17 APoC animals. APoC improved haemodynamics during CPR and post-CPR LVEF%. Mitochondrial ATP synthesis, coupling of oxidative phosphorylation and calcium retention capacity were improved in cardiac mitochondria isolated after APoC. CONCLUSIONS: In a porcine model of prolonged untreated cardiac arrest, APoC with inhaled sevoflurane at the initiation of CPR, is associated with preserved mitochondrial function and improved post resuscitation myocardial dysfunction. Approved by the Institutional Animal Care Committee of the Minneapolis Medical Research Foundation of Hennepin County Medical Center (protocol number 11-05).


Subject(s)
Anesthesia/methods , Anesthetics/pharmacology , Heart Arrest/physiopathology , Mitochondria, Heart/physiology , Resuscitation/methods , Ventricular Fibrillation/physiopathology , Ventricular Function, Left/physiology , Animals , Disease Models, Animal , Female , Heart Arrest/etiology , Heart Arrest/therapy , Swine , Ventricular Fibrillation/complications
20.
Curr Opin Crit Care ; 20(3): 242-9, 2014 Jun.
Article in English | MEDLINE | ID: mdl-24751810

ABSTRACT

PURPOSE OF REVIEW: Despite decades of advances in prehospital and in-hospital medical care, patients with out-of-hospital cardiac arrest continue to have poor neurologic and cardiac function following otherwise successful resuscitation. This review examines the mechanisms and therapeutic strategies currently under development to activate the post-conditioning pathways and thereby improve survival and function. RECENT FINDINGS: Post-conditioning utilizes the reperfusion injury salvage kinase (RISK) and survivor activating factor enhancement (SAFE) pathways as common avenues to promote cell survival and function. Ischemic post-conditioning and multiple medications activate these pathways resulting in improved cardiac and neurological function in animal models of cardiac arrest. SUMMARY: Detailed knowledge of the RISK and SAFE pathways can be used for further drug development. Human studies are now underway to test some of these strategies, but further clinical trials are necessary to translate these therapies to clinical practice.


Subject(s)
Cardiopulmonary Resuscitation , Mitochondria, Heart/drug effects , Myocardial Reperfusion Injury/drug therapy , Out-of-Hospital Cardiac Arrest/therapy , Adenosine/therapeutic use , Analgesics, Opioid/therapeutic use , Anti-Arrhythmia Agents/therapeutic use , Cardiopulmonary Resuscitation/methods , Cyclosporine/therapeutic use , Guanidines/therapeutic use , Humans , Myocardial Reperfusion Injury/mortality , Myocardial Reperfusion Injury/prevention & control , Out-of-Hospital Cardiac Arrest/mortality , Out-of-Hospital Cardiac Arrest/physiopathology , Reactive Oxygen Species , Risk Assessment , Sulfones/therapeutic use , Survival Analysis , Time Factors , Treatment Outcome
SELECTION OF CITATIONS
SEARCH DETAIL
...