Hypercholesterolemia exacerbates in-stent restenosis in rabbits: Studies of the mitigating effect of stent surface modification with a CD47-derived peptide.

BACKGROUND AND AIMS: Hypercholesterolemia (HC) has previously been shown to augment the restenotic response in animal models and humans. However, the mechanistic aspects of in-stent restenosis (ISR) on a hypercholesterolemic background, including potential augmentation of systemic and local inflammation precipitated by HC, are not completely understood. CD47 is a transmembrane protein known to abort crucial inflammatory pathways. Our studies have examined the interrelation between HC, inflammation, and ISR and investigated the therapeutic potential of stents coated with a CD47-derived peptide (pepCD47) in the hypercholesterolemic rabbit model. METHODS: PepCD47 was immobilized on metal foils and stents using polybisphosphonate coordination chemistry and pyridyldithio/thiol conjugation. Cytokine expression in buffy coat-derived cells cultured over bare metal (BM) and pepCD47-derivatized foils demonstrated an M2/M1 macrophage shift with pepCD47 coating. HC and normocholesterolemic (NC) rabbit cohorts underwent bilateral implantation of BM and pepCD47 stents (HC) or BM stents only (NC) in the iliac location. RESULTS: A 40 % inhibition of cell attachment to pepCD47-modified compared to BM surfaces was observed. HC increased neointimal growth at 4 weeks post BM stenting. These untoward outcomes were mitigated in hypercholesterolemic rabbits treated with pepCD47-derivatized stents. Compared to NC animals, inflammatory cytokine immunopositivity and macrophage infiltration of peri-strut areas increased in HC animals and were attenuated in HC rabbits treated with pepCD47 stents. CONCLUSIONS: Augmented inflammatory responses underlie severe ISR morphology in hypercholesterolemic rabbits. Blockage of initial platelet and leukocyte attachment to stent struts through CD47 functionalization of stents mitigates the pro-restenotic effects of hypercholesterolemia.

Stability and bioactivity of pepCD47 attachment on stainless steel surfaces.

In-stent restenosis (ISR) and late stent thrombosis are the major complications associated with the use of metal stents and drug eluting stents respectively. Our lab previously investigated the use of peptide CD47 in improving biocompatibility of bare metal stents in a rat carotid stent model and our results demonstrated a significant reduction in platelet deposition and ISR. However, this study did not characterize the stability of the pepCD47 on metal surfaces post storage, sterilization and deployment. Thus, the objective of the present study was 1) to test the stability of the peptide post - storage, sterilization, exposure to shear and mechanical stress and 2) to begin to expand our current knowledge of pepCD47 coated metal surfaces into the preclinical large animal rabbit model. Our results show that the maximum immobilization density of pepCD47 on metal surfaces is approximately 350 ng/cm2. 100% of the pepCD47 was retained on the metal surface post 24 weeks of storage at 4 °C, exposure to physiological shear stress, and mechanical stress of stent expansion. The bioactivity of the pepCD47 was found to be intact post 24 weeks of storage and ethylene oxide sterilization. Finally our ex vivo studies demonstrated that compared to bare metal the rabbit pepCD47 coated surfaces showed - 45% reduced platelet adhesion, a 10-fold decrease in platelet activation, and 93% endothelial cell retention. Thus, our data suggests that pepCD47 coating on metal surfaces is stable and rabbit pepCD47 shows promising preliminary results in preventing thrombosis and not inhibiting the growth of endothelial cells. STATEMENT OF SIGNIFICANCE: Biocompatibility of bare metal stents is a major challenge owing to the significantly high rates of in-stent restenosis. Previously we demonstrated that peptide CD47 functionalization improves the biocompatibility of bare metal stents in rat model. A similar trend was observed in our ex vivo studies where rabbit blood was perfused over the rabbit pepCD47 functionalized surfaces. These results provide valuable proof of concept data for future in vivo rabbit model studies. In addition, we investigated stability of the pepCD47 on metal surface and observed that pepCD47 coating is stable over time and resistant to industrially relevant pragmatic challenges.

Non-invasive optical neuromonitoring of the temperature-dependence of cerebral oxygen metabolism during deep hypothermic cardiopulmonary bypass in neonatal swine.

Management of deep hypothermic (DH) cardiopulmonary bypass (CPB), a critical neuroprotective strategy, currently relies on non-invasive temperature to guide cerebral metabolic suppression during complex cardiac surgery in neonates. Considerable inter-subject variability in temperature response and residual metabolism may contribute to the persisting risk for postoperative neurological injury. To characterize and mitigate this variability, we assess the sufficiency of conventional nasopharyngeal temperature (NPT) guidance, and in the process, validate combined non-invasive frequency-domain diffuse optical spectroscopy (FD-DOS) and diffuse correlation spectroscopy (DCS) for direct measurement of cerebral metabolic rate of oxygen (CMRO2). During CPB, n = 8 neonatal swine underwent cooling from normothermia to 18℃, sustained DH perfusion for 40 min, and then rewarming to simulate cardiac surgery. Continuous non-invasive and invasive measurements of intracranial temperature (ICT) and CMRO2 were acquired. Significant hysteresis (p < 0.001) between cooling and rewarming periods in the NPT versus ICT and NPT versus CMRO2 relationships were found. Resolution of this hysteresis in the ICT versus CMRO2 relationship identified a crucial insufficiency of conventional NPT guidance. Non-invasive CMRO2 temperature coefficients with respect to NPT (Q10 = 2.0) and ICT (Q10 = 2.5) are consistent with previous reports and provide further validation of FD-DOS/DCS CMRO2 monitoring during DH CPB to optimize management.

Effect of compression waveform and resuscitation duration on blood flow and pressure in swine: One waveform does not optimally serve.

BACKGROUND: Chest compression (CC) research primarily focuses on finding the 'optimum' compression waveform using a variety of compression efficacy metrics. Blood flow is rarely measured systematically with high fidelity. Using a programmable mechanical chest compression device, we studied the effect of inter-compression pauses in a swine model of cardiac arrest, testing the hypothesis that a single 'optimal' CC waveform exists based on measurements of resulting blood flow. METHODS: Hemodynamics were studied in 9 domestic swine (∼30 kg) using multiple flow probes and standard physiological monitoring. After 10 min of ventricular fibrillation, five mechanical chest compression waveforms (5.1 cm, varying inter-compression pauses) were delivered for 2 min each in a semi-random pattern, totaling 50 compression minutes. Linear Mixed Models were used to estimate the effect of compression waveform on hemodynamics. RESULTS: Blood flow and pressure decayed significantly with time in both arteries and veins. No waveform maximized blood flow in all vessels simultaneously and the waveform generating maximal blood flow in a specific vessel changed over time in all vessels. A flow mismatch between paired arteries and veins, e.g. abdominal aorta and inferior vena cava, also developed over time. The waveform with the slowest rate and shortest duty cycle had the smallest mismatch between flows after about 30 min of CPR. CONCLUSIONS: This data challenges the concept of a single optimal CC waveform. Time dependent physiological response to compressions and no single compression waveform optimizing flow in all vessels indicate that current descriptions of CPR don't reflect patient physiology.

A hemodynamic-directed approach to pediatric cardiopulmonary resuscitation (HD-CPR) improves survival.

AIM: Most pediatric in-hospital cardiac arrests (IHCAs) occur in ICUs where invasive hemodynamic monitoring is frequently available. Titrating cardiopulmonary resuscitation (CPR) to the hemodynamic response of the individual improves survival in preclinical models of adult cardiac arrest. The objective of this study was to determine if titrating CPR to systolic blood pressure (SBP) and coronary perfusion pressure (CoPP) in a pediatric porcine model of asphyxia-associated ventricular fibrillation (VF) IHCA would improve survival as compared to traditional CPR. METHODS: After 7min of asphyxia followed by VF, 4-week-old piglets received either hemodynamic-directed CPR (HD-CPR; compression depth titrated to SBP of 90mmHg and vasopressor administration to maintain CoPP ≥20mmHg); or Standard Care (compression depth 1/3 of the anterior-posterior chest diameter and epinephrine every 4min). All animals received CPR for 10min prior to the first defibrillation attempt. CPR was continued for a maximum of 20min. Protocolized intensive care was provided to all surviving animals for 4h. The primary outcome was 4-h survival. RESULTS: Survival rate was greater with HD-CPR (12/12) than Standard Care (6/10; p=0.03). CoPP during HD-CPR was higher compared to Standard Care (point estimate +8.1mmHg, CI95: 0.5-15.8mmHg; p=0.04). Chest compression depth was lower with HD-CPR than Standard Care (point estimate -14.0mm, CI95: -9.6 to -18.4mm; p<0.01). Prior to the first defibrillation attempt, more vasopressor doses were administered with HD-CPR vs. Standard Care (median 5 vs. 2; p<0.01). CONCLUSIONS: Hemodynamic-directed CPR improves short-term survival compared to standard depth-targeted CPR in a porcine model of pediatric asphyxia-associated VF IHCA.

Blood Pressure- and Coronary Perfusion Pressure-Targeted Cardiopulmonary Resuscitation Improves 24-Hour Survival From Ventricular Fibrillation Cardiac Arrest.

OBJECTIVES: Treatment algorithms for cardiac arrest are rescuer centric and vary little from patient to patient. The objective of this study was to determine if cardiopulmonary resuscitation-targeted to arterial blood pressure and coronary perfusion pressure rather than optimal guideline care would improve 24-hour survival in a porcine model of ventricular fibrillation cardiac arrest. DATA SOURCES: Preclinical animal laboratory using female 3-month-old swine. STUDY SELECTION: A randomized interventional study. DATA EXTRACTION: After induction of anesthesia and 7 minutes of untreated ventricular fibrillation, 16 female 3-month-old swine were randomized to 1) blood pressure care: titration of chest compression depth to a systolic blood pressure of 100 mm Hg and vasopressor dosing to maintain coronary perfusion pressure of greater than 20 mm Hg or 2) guideline care: chest compression depth targeted to 51 mm and standard guideline vasopressor dosing. Animals received manual cardiopulmonary resuscitation for 10 minutes before the first defibrillation attempt and standardized postresuscitation care for 24 hours. DATA SYNTHESIS: Twenty-four-hour survival was more likely with blood pressure care versus guideline care (0/8 vs 5/8; p < 0.03), and all survivors had normal neurologic examinations. Mean coronary perfusion pressure prior to defibrillation was significantly higher with blood pressure care (28 ± 3 vs 10 ± 6 mm Hg; p < 0.01). Chest compression depth was lower with blood pressure care (48 ± 0.4 vs 44 ± 0.5 mm Hg; p < 0.05), and the number of vasopressor doses was higher with blood pressure care (median, 3 [range, 1-7] vs 2 [range, 2-2]; p < 0.01). CONCLUSIONS: Individualized goal-directed hemodynamic resuscitation targeting systolic blood pressure of 100 mm Hg and coronary perfusion pressure of greater than 20 mm Hg improved 24-hour survival compared with guideline care in this model of ventricular fibrillation cardiac arrest.

A quantitative comparison of physiologic indicators of cardiopulmonary resuscitation quality: Diastolic blood pressure versus end-tidal carbon dioxide.

AIM: The American Heart Association (AHA) recommends monitoring invasive arterial diastolic blood pressure (DBP) and end-tidal carbon dioxide (ETCO2) during cardiopulmonary resuscitation (CPR) when available. In intensive care unit patients, both may be available to the rescuer. The objective of this study was to compare DBP vs. ETCO2 during CPR as predictors of cardiac arrest survival. METHODS: In two models of cardiac arrest (primary ventricular fibrillation [VF] and asphyxia-associated VF), 3-month old swine received either standard AHA guideline-based CPR or patient-centric, BP-guided CPR. Mean values of DBP and ETCO2 in the final 2min before the first defibrillation attempt were compared using receiver operating characteristic curves (area under curve [AUC] analysis). The optimal DBP cut point to predict survival was derived and subsequently validated in two independent, randomly generated cohorts. RESULTS: Of 60 animals, 37 (61.7%) survived to 45min. DBP was higher in survivors than in non-survivors (40.6±1.8mmHg vs. 25.9±2.4mmHg; p<0.001), while ETCO2 was not different (30.0±1.5mmHg vs. 32.5±1.8mmHg; p=0.30). By AUC analysis, DBP was superior to ETCO2 (0.82 vs. 0.60; p=0.025) in discriminating survivors from non-survivors. The optimal DBP cut point in the derivation cohort was 34.1mmHg. In the validation cohort, this cut point demonstrated a sensitivity of 0.78, specificity of 0.81, positive predictive value of 0.64, and negative predictive value of 0.89 for survival. CONCLUSIONS: In both primary and asphyxia-associated VF porcine models of cardiac arrest, DBP discriminates survivors from non-survivors better than ETCO2. Failure to attain a DBP >34mmHg during CPR is highly predictive of non-survival.

Volume infusion cooling increases end-tidal carbon dioxide and results in faster and deeper cooling during intra-cardiopulmonary resuscitation hypothermia induction.

BACKGROUND: Intra-arrest hypothermia induction may provide more benefit than inducing hypothermia after return of spontaneous circulation. However, little is understood about the interaction between patient physiology and hypothermia induction technology choice during ongoing chest compressions. METHODS: After 10 min of untreated ventricular fibrillation, mechanical chest compressions were provided for 60 min (100 CPM, 1.25" deep) in 26 domestic swine (30.5 ± 1.7 kg) with concurrent hypothermia induction using one of eight cooling methods. Four cooling methods included volume infusion with cold saline or an ice particulate slurry through the femoral vein or carotid artery (volume infusion cooling group, VC); three included cooling via an intra-vascular heat exchange catheter, nasal cooling, or surface ice bags (no volume cooling group, NVC); and the other was a control group with no cooling (no cooling group, NC). Physiological monitoring included end-tidal carbon dioxide, aortic pressure, right atrial pressure, brain temperature, esophageal temperature, and rectal temperature. RESULTS: During cardiopulmonary resuscitation (CPR), the volume infusion cooling group cooled faster and to lower temperatures than the other groups (VC vs. NVC or NC; ∆T = -5.6 vs. -2.1 °C or -0.6 °C; p < 0.01). The aortic pressure and right atrial pressure were higher in the volume cooling group than the other groups (VC vs. NVC or NC; AOP = 23.6 vs. 16.7 mmHg or 14.7 mmHg; p < 0.02). End-tidal carbon dioxide measurements during CPR were also higher in the volume cooling group (VC vs. NVC; EtCO2 = 23.4 vs. 13.1 mmHg; p < 0.05). Intra-corporeal temperature gradients larger than 3 °C were created by volume cooling during ongoing chest compressions. CONCLUSIONS: Volume infusion cooling significantly altered physiology relative to other cooling methods during ongoing chest compressions. Volume cooling led to faster cooling rates, lower temperatures, higher end-tidal carbon dioxide levels, and higher central vascular pressures. IACUC protocol numbers: UPenn (803178), CHOP (997).

Developing a kinematic understanding of chest compressions: the impact of depth and release time on blood flow during cardiopulmonary resuscitation.

BACKGROUND: Effective cardiopulmonary resuscitation is a critical component of the pre-hospital treatment of cardiac arrest victims. Mechanical chest compression (MCC) devices enable the delivery of MCC waveforms that could not be delivered effectively by hand. While chest compression generated blood flow has been studied for more than 50 years, the relation between sternum kinematics (depth over time) and the resulting blood flow have not been well described. Using a five parameter MCC model, we studied the effect of MCC depth, MCC release time, and their interaction on MCC generated blood flow in a highly instrumented swine model of cardiac arrest. METHODS: MCC hemodynamics were studied in 17 domestic swine (~30 kg) using multiple extra-vascular flow probes and standard physiological monitoring. After 10 min of untreated ventricular fibrillation, mechanical MCC were started. MCC varied such that sternal release occurred over 100, 200, or 300 ms. MCC were delivered at a rate of 100 per min and at a depth of 1.25″ (n = 9) or at a depth of 1.9″ (n = 8) for a total of 18 min. Transitions between release times occurred every 2 min and were randomized. Linear Mixed Models were used to estimate the effect of MCC depth, MCC release time, and the interaction between MCC depth and release time on physiological outcomes. RESULTS: Blood pressures were optimized by a 200 ms release. End tidal carbon dioxide (EtCO2) was optimized by a 100 ms release. Blood flows were significantly lower at a 300 ms release than at either a 100 or 200 ms release (p < 0.05). 1.9″ deep MCC improved EtCO2, right atrial pressure, coronary perfusion pressure, inferior vena cava blood flow, carotid blood flow, and renal vein blood flow relative to 1.25″ MCC. CONCLUSIONS: Deeper MCC improved several hemodynamic parameters. Chest compressions with a 300 ms release time generated less blood flow than chest compressions with faster release times. MCC release time is an important quantitative metric of MCC quality and, if optimized, could improve MCC generated blood flows and pressures.

Persistently Altered Brain Mitochondrial Bioenergetics After Apparently Successful Resuscitation From Cardiac Arrest.

BACKGROUND: Although advances in cardiopulmonary resuscitation have improved survival from cardiac arrest (CA), neurologic injury persists and impaired mitochondrial bioenergetics may be critical for targeted neuroresuscitation. The authors sought to determine if excellent cardiopulmonary resuscitation and postresuscitation care and good traditional survival rates result in persistently disordered cerebral mitochondrial bioenergetics in a porcine pediatric model of asphyxia-associated ventricular fibrillation CA. METHODS AND RESULTS: After 7 minutes of asphyxia, followed by ventricular fibrillation, 5 female 1-month-old swine (4 sham) received blood pressure-targeted care: titration of compression depth to systolic blood pressure of 90 mm Hg and vasopressor administration to a coronary perfusion pressure >20 mm Hg. All animals received protocol-based vasopressor support after return of spontaneous circulation for 4 hours before they were killed. The primary outcome was integrated mitochondrial electron transport system (ETS) function. CA animals displayed significantly decreased maximal, coupled oxidative phosphorylating respiration (OXPHOSCI + CII) in cortex (P<0.02) and hippocampus (P<0.02), as well as decreased phosphorylation and coupling efficiency (cortex, P<0.05; hippocampus, P<0.05). Complex I- and complex II-driven respiration were both significantly decreased after CA (cortex: OXPHOSCI P<0.01, ETSCII P<0.05; hippocampus: OXPHOSCI P<0.03, ETSCII P<0.01). In the hippocampus, there was a significant decrease in maximal uncoupled, nonphosphorylating respiration (ETSCI + CII), as well as a 30% reduction in citrate synthase activity (P<0.04). CONCLUSIONS: Mitochondria in both the cortex and hippocampus displayed significant alterations in respiratory function after CA despite excellent cardiopulmonary resuscitation and postresuscitation care in asphyxia-associated ventricular fibrillation CA. Analysis of integrated ETS function identifies mitochondrial bioenergetic failure as a target for goal-directed neuroresuscitation after CA. IACUC Protocol: IAC 13-001023.

Patient-centric blood pressure-targeted cardiopulmonary resuscitation improves survival from cardiac arrest.

RATIONALE: Although current resuscitation guidelines are rescuer focused, the opportunity exists to develop patient-centered resuscitation strategies that optimize the hemodynamic response of the individual in the hopes to improve survival. OBJECTIVES: To determine if titrating cardiopulmonary resuscitation (CPR) to blood pressure would improve 24-hour survival compared with traditional CPR in a porcine model of asphyxia-associated ventricular fibrillation (VF). METHODS: After 7 minutes of asphyxia, followed by VF, 20 female 3-month-old swine randomly received either blood pressure-targeted care consisting of titration of compression depth to a systolic blood pressure of 100 mm Hg and vasopressors to a coronary perfusion pressure greater than 20 mm Hg (BP care); or optimal American Heart Association Guideline care consisting of depth of 51 mm with standard advanced cardiac life support epinephrine dosing (Guideline care). All animals received manual CPR for 10 minutes before first shock. Primary outcome was 24-hour survival. MEASUREMENTS AND MAIN RESULTS: The 24-hour survival was higher in the BP care group (8 of 10) compared with Guideline care (0 of 10); P = 0.001. Coronary perfusion pressure was higher in the BP care group (point estimate +8.5 mm Hg; 95% confidence interval, 3.9-13.0 mm Hg; P < 0.01); however, depth was higher in Guideline care (point estimate +9.3 mm; 95% confidence interval, 6.0-12.5 mm; P < 0.01). Number of vasopressor doses before first shock was higher in the BP care group versus Guideline care (median, 3 [range, 0-3] vs. 2 [range, 2-2]; P = 0.003). CONCLUSIONS: Blood pressure-targeted CPR improves 24-hour survival compared with optimal American Heart Association care in a porcine model of asphyxia-associated VF cardiac arrest.

Hemodynamic directed CPR improves cerebral perfusion pressure and brain tissue oxygenation.

AIM: Advances in cardiopulmonary resuscitation (CPR) have focused on the generation and maintenance of adequate myocardial blood flow to optimize the return of spontaneous circulation and survival. Much of the morbidity associated with cardiac arrest survivors can be attributed to global brain hypoxic ischemic injury. The objective of this study was to compare cerebral physiological variables using a hemodynamic directed resuscitation strategy versus an absolute depth-guided approach in a porcine model of ventricular fibrillation (VF) cardiac arrest. METHODS: Intracranial pressure and brain tissue oxygen tension probes were placed in the frontal cortex prior to induction of VF in 21 female 3-month-old swine. After 7 min of VF, animals were randomized to receive one of three resuscitation strategies: (1) hemodynamic directed care (CPP-20): chest compressions (CCs) with depth titrated to a target systolic blood pressure of 100 mmHg and titration of vasopressors to maintain coronary perfusion pressure (CPP)>20 mmHg; (2) depth 33 mm (D33): target CC depth of 33 mm with standard American Heart Association (AHA) epinephrine dosing; or (3) depth 51 mm (D51): target CC depth of 51 mm with standard AHA epinephrine dosing. RESULTS: Cerebral perfusion pressures (CerePP) were significantly higher in the CPP-20 group compared to both D33 (p<0.01) and D51 (p=0.046), and higher in survivors compared to non-survivors irrespective of treatment group (p<0.01). Brain tissue oxygen tension was also higher in the CPP-20 group compared to both D33 (p<0.01) and D51 (p=0.013), and higher in survivors compared to non-survivors irrespective of treatment group (p<0.01). Subjects with a CPP>20 mmHg were 2.7 times more likely to have a CerePP>30 mmHg (p<0.001). CONCLUSIONS: Hemodynamic directed resuscitation strategy targeting coronary perfusion pressure>20 mmHg following VF arrest was associated with higher cerebral perfusion pressures and brain tissue oxygen tensions during CPR.

Hemodynamic-directed cardiopulmonary resuscitation during in-hospital cardiac arrest.

Cardiopulmonary resuscitation (CPR) guidelines assume that cardiac arrest victims can be treated with a uniform chest compression (CC) depth and a standardized interval administration of vasopressor drugs. This non-personalized approach does not incorporate a patient's individualized response into ongoing resuscitative efforts. In previously reported porcine models of hypoxic and normoxic ventricular fibrillation (VF), a hemodynamic-directed resuscitation improved short-term survival compared to current practice guidelines. Skilled in-hospital rescuers should be trained to tailor resuscitation efforts to the individual patient's physiology. Such a strategy would be a major paradigm shift in the treatment of in-hospital cardiac arrest victims.

Hemodynamic directed cardiopulmonary resuscitation improves short-term survival from ventricular fibrillation cardiac arrest.

OBJECTIVES: During cardiopulmonary resuscitation, adequate coronary perfusion pressure is essential for establishing return of spontaneous circulation. Current American Heart Association guidelines recommend standardized interval administration of epinephrine for patients in cardiac arrest. The objective of this study was to compare short-term survival using a hemodynamic directed resuscitation strategy versus chest compression depth-directed cardiopulmonary resuscitation in a porcine model of cardiac arrest. DESIGN: Randomized interventional study. SETTING: Preclinical animal laboratory. SUBJECTS: Twenty-four 3-month-old female swine. INTERVENTIONS: After 7 minutes of ventricular fibrillation, pigs were randomized to receive one of three resuscitation strategies: 1) Hemodynamic directed care (coronary perfusion pressure-20): chest compressions with depth titrated to a target systolic blood pressure of 100 mm Hg and titration of vasopressors to maintain coronary perfusion pressure greater than 20 mm Hg; 2) Depth 33 mm: target chest compression depth of 33 mm with standard American Heart Association epinephrine dosing; or 3) Depth 51 mm: target chest compression depth of 51 mm with standard American Heart Association epinephrine dosing. All animals received manual cardiopulmonary resuscitation guided by audiovisual feedback for 10 minutes before first shock. MEASUREMENTS AND MAIN RESULTS: Forty-five-minute survival was higher in the coronary perfusion pressure-20 group (8 of 8) compared to depth 33 mm (1 of 8) or depth 51 mm (3 of 8) groups; p equals to 0.002. Coronary perfusion pressures were higher in the coronary perfusion pressure-20 group compared to depth 33 mm (p = 0.004) and depth 51 mm (p = 0.006) and in survivors compared to nonsurvivors (p < 0.01). Total epinephrine dosing and defibrillation attempts were not different. CONCLUSIONS: Hemodynamic directed resuscitation targeting coronary perfusion pressures greater than 20 mm Hg during 10 minutes of cardiopulmonary resuscitation for ventricular fibrillation cardiac arrest improves short-term survival, when compared to resuscitation with depth of compressions guided to 33 mm or 51 mm and standard American Heart Association vasopressor dosing.

Hemodynamic directed CPR improves short-term survival from asphyxia-associated cardiac arrest.

AIM: Adequate coronary perfusion pressure (CPP) during cardiopulmonary resuscitation (CPR) is essential for establishing return of spontaneous circulation. The objective of this study was to compare short-term survival using a hemodynamic directed resuscitation strategy versus an absolute depth-guided approach in a porcine model of asphyxia-associated cardiac arrest. We hypothesized that a hemodynamic directed approach would improve short-term survival compared to depth-guided care. METHODS: After 7 min of asphyxia, followed by induction of ventricular fibrillation, 19 female 3-month old swine (31±0.4 kg) were randomized to receive one of three resuscitation strategies: (1) hemodynamic directed care (CPP-20): chest compressions (CCs) with depth titrated to a target systolic blood pressure of 100 mmHg and titration of vasopressors to maintain CPP>20 mmHg; (2) depth 33 mm (D33): target CC depth of 33 mm with standard American Heart Association (AHA) epinephrine dosing; or (3) depth 51 mm (D51): target CC depth of 51 mm with standard AHA epinephrine dosing. All animals received manual CPR guided by audiovisual feedback for 10 min before first shock. RESULTS: 45-Min survival was higher in the CPP-20 group (6/6) compared to D33 (1/7) or D51 (1/6) groups; p=0.002. Coronary perfusion pressures were higher in the CPP-20 group compared to D33 (p=0.011) and D51 (p=0.04), and in survivors compared to non-survivors (p<0.01). Total number of vasopressor doses administered and defibrillation attempts were not different. CONCLUSIONS: Hemodynamic directed care targeting CPPs>20 mmHg improves short-term survival in an intensive care unit porcine model of asphyxia-associated cardiac arrest.

Increased cardiac myocyte progenitors in failing human hearts.

BACKGROUND: Increasing evidence, derived mainly from animal models, supports the existence of endogenous cardiac renewal and repair mechanisms in adult mammalian hearts that could contribute to normal homeostasis and the responses to pathological insults. METHODS AND RESULTS: Translating these results, we isolated small c-kit+ cells from 36 of 37 human hearts using primary cell isolation techniques and magnetic cell sorting techniques. The abundance of these cardiac progenitor cells was increased nearly 4-fold in patients with heart failure requiring transplantation compared with nonfailing controls. Polychromatic flow cytometry of primary cell isolates (<30 microm) without antecedent c-kit enrichment confirmed the increased abundance of c-kit+ cells in failing hearts and demonstrated frequent coexpression of CD45 in these cells. Immunocytochemical characterization of freshly isolated, c-kit-enriched human cardiac progenitor cells confirmed frequent coexpression of c-kit and CD45. Primary cardiac progenitor cells formed new human cardiac myocytes at a relatively high frequency after coculture with neonatal rat ventricular myocytes. These contracting new cardiac myocytes exhibited an immature phenotype and frequent electric coupling with the rat myocytes that induced their myogenic differentiation. CONCLUSIONS: Despite the increased abundance and cardiac myogenic capacity of cardiac progenitor cells in failing human hearts, the need to replace these organs via transplantation implies that adverse features of the local myocardial environment overwhelm endogenous cardiac repair capacity. Developing strategies to improve the success of endogenous cardiac regenerative processes may permit therapeutic myocardial repair without cell delivery per se.

Reduced sarcoplasmic reticulum Ca(2+) load mediates impaired contractile reserve in right ventricular pressure overload.

Myocardial contractile reserve is significantly attenuated in patients with advanced heart failure. The aim of this study was to identify mechanisms of impaired contractile reserve in a large animal model that closely mimics human myocardial failure. Progressive right ventricular hypertrophy and failure were induced by banding the pulmonary artery in kittens. Isometric contractile force was measured in right ventricular trabeculae (n=115) from age-matched Control and Banded feline hearts. Rapid cooling contractures (RCC) were used to determine sarcoplasmic reticulum (SR) Ca(2+) load while assessing the ability of changes in rate, adrenergic stimulation and bath Ca(2+) to augment contractility. The positive force-frequency relationship and robust pre- and post-receptor adrenergic responses observed in Control trabeculae were closely paralleled by increases in RCC amplitude and the RCC2/RCC1 ratio. Conversely, the severely blunted force-frequency and adrenergic responses in Banded trabeculae were paralleled by an unchanged RCC amplitude and RCC2/RCC1 ratio. Likewise, supraphysiologic levels of bath Ca(2+) were associated with severely reduced contractility and RCC amplitude in Banded trabeculae compared to Controls. There were no differences in myofilament Ca(2+) sensitivity or length-dependent increases in contractility between Control and Banded trabeculae. There was a significant decrease in SR Ca(2+)-ATPase pump abundance and phosphorylation of phospholamban and ryanodine receptor in Banded trabeculae compared with Controls. A reduced ability to increase SR Ca(2+) load is the primary mechanism of reduced contractile reserve in failing feline myocardium. The similarity of impaired contractile reserve phenomenology in this feline model and transplanted hearts suggests mechanistic relevance to human myocardial failure.

Impaired contractile reserve in severe mitral valve regurgitation with a preserved ejection fraction.

BACKGROUND: Impaired contractile reserve in chronic MR results from load-independent, myocyte contractile abnormalities. AIMS: Investigate the mechanisms of contractile dysfunction in chronic mitral valve regurgitation (MR). METHODS: Mild MR was produced in eight dogs followed by pacing induced left ventricular (LV) dilatation over eight months. In-vivo LV dP/dt was measured at several pacing rates. Contractile function was measured in isolated LV trabeculae and myocytes at several stimulation rates and during changes in extracellular [Ca2+]. Identical studies were performed with six control dogs. RESULTS: Chronic MR resulted in a preserved ejection fraction with decreased dP/dt (p<0.01). LV trabeculae demonstrated significantly lower developed force and a negative force-frequency relation with chronic MR (p<0.05). Myocytes exhibited a negative shortening-frequency relationship in both groups with a greater decline with chronic MR (p<0.001) paralleled by decreases in peak [Ca2+](i) transients. Increases in extracellular [Ca2+] abrogated the defects in force generation in trabeculae from animals with chronic MR. CONCLUSION: Even with a preserved EF, chronic severe MR results in a significant reduction in intrinsic contractile function and reserve. Functional impairment was load-independent reflecting a predominant defect in calcium cycling rather than impaired peak force generating capacity due to myofibrillar attenuation.

Subvalvular alterations promote increased mitral valve regurgitation in progressive dilated cardiomyopathy.

BACKGROUND: Alterations in transmitral pressure, valve structure, subvalvular geometry, and abnormal myocardial function have all been implicated in the pathophysiology of functional/progressive mitral valve regurgitation (MR). In this study, we hypothesized that a relatively small structural lesion to the mitral valve apparatus predisposes to severe MR in the setting of progressive left ventricular dilation. While examining this hypothesis, an additional purpose of this study was to determine the extent of papillary muscle (PM) distortion and mitral annular dilation with increasing MR resulting from progressive dilated cardiomyopathy. METHODS AND RESULTS: Mild MR was produced via a limited, fixed structural lesion to the mitral valve apparatus of 8 dogs (20 to 22 kg). Incremental tachypacing induced left ventricular dilation over an 8-month period. The pacer was deactivated and the dogs followed for an additional 6 weeks. Echocardiographic measurements demonstrated significant cardiac remodeling (left ventricular end diastolic diameter) and MR progression with a 54% increase in left ventricular end diastolic diameter and a 44% increase in MR jet area (P < .05). Tachypacing induced decreases in left ventricular ejection fraction recovered nearly to baseline levels by 6 weeks after pacing cessation. Nevertheless, left ventricular dilation persisted and MR remained severe after pacing cessation. There was a significant increase in the short axis PM segment length and PM angular separation from baseline (6.28 +/- 0.83 versus 4.02 +/- 0.56 cm and 99.7 +/- 2.6 versus 90.1 +/- 3.2 deg, respectively, P < .05) with no change in mitral annulus circumference (8.71 +/- 0.70 versus 8.15 +/- 0.35 cm, P = NS). CONCLUSION: Progressive MR severity in nonischemic dilated cardiomyopathy resulted from changes in left ventricular shape and altered papillary muscle geometries and does not require mitral annulus dilation or a reduced left ventricular ejection fraction.