An Adjuvant Stem Cell Patch with Coronary Artery Bypass Graft Surgery Improves Diastolic Recovery in Porcine Hibernating Myocardium.

Diastolic dysfunction persists despite coronary artery bypass graft surgery (CABG) in patients with hibernating myocardium (HIB). We studied whether the adjunctive use of a mesenchymal stem cells (MSCs) patch during CABG improves diastolic function by reducing inflammation and fibrosis. HIB was induced in juvenile swine by placing a constrictor on the left anterior descending (LAD) artery, causing myocardial ischemia without infarction. At 12 weeks, CABG was performed using the left-internal-mammary-artery (LIMA)-to-LAD graft with or without placement of an epicardial vicryl patch embedded with MSCs, followed by four weeks of recovery. The animals underwent cardiac magnetic resonance imaging (MRI) prior to sacrifice, and tissue from septal and LAD regions were collected to assess for fibrosis and analyze mitochondrial and nuclear isolates. During low-dose dobutamine infusion, diastolic function was significantly reduced in HIB compared to the control, with significant improvement after CABG + MSC treatment. In HIB, we observed increased inflammation and fibrosis without transmural scarring, along with decreased peroxisome proliferator-activated receptor-gamma coactivator (PGC1α), which could be a possible mechanism underlying diastolic dysfunction. Improvement in PGC1α and diastolic function was noted with revascularization and MSCs, along with decreased inflammatory signaling and fibrosis. These findings suggest that adjuvant cell-based therapy during CABG may recover diastolic function by reducing oxidant stress-inflammatory signaling and myofibroblast presence in the myocardial tissue.

NT-Pro BNP Predicts Myocardial Injury Post-vascular Surgery and is Reduced with CoQ10: A Randomized Double-Blind Trial.

BACKGROUND: NT-Pro BNP levels provide incremental value in perioperative risk assessment prior to major noncardiac surgery. Whether they can be pharmacologically modified in patients prior to an elective vascular operation is uncertain. METHODS: A double-blind, randomized controlled trial was implemented at a single institution. Patients were screened during their preoperative vascular clinic appointment and randomly assigned to CoQ10 (400 mg per day) versus Placebo for 3 days prior to surgery. Biomarkers, including NT-Pro BNP, troponin I and C-reactive protein were obtained prior to and following surgery for up to 48 hours. The primary endpoint was postoperative NT-Pro BNP levels, and secondary endpoint measures included myocardial injury, defined by an elevated cardiac troponin level and length of stay. RESULTS: One hundred and twenty-three patients were randomized to receive either CoQ10 (N = 62) versus Placebo (N = 61) for 3 days before vascular surgery. Preoperative cardiac risks included ischemic heart disease (N = 52), CHF (N = 12), stroke (N = 23), and diabetes mellitus (N = 48) and the planned vascular procedures were infrainguinal (N = 78), carotid (N = 36), and intraabdominal (N = 9). There were no intergroup differences in these clinical variables. NT-Pro BNP levels (median; IQs) in the CoQ10 and Placebo groups were 179 (75-347) and 217 (109-585) pg/ml, respectively, (P = 0.08) preoperatively, and 397 (211-686) and 591 (288-1,433) pg/ml respectively, (P = 0.01) at 24 hours following surgery. Patients with an elevated NT-Pro BNP had a higher incidence of myocardial injury, (58% vs. 20%; P < 0.01) and a longer hospital stay (4.4 ± 3.8 vs. 2.8 ± 3.2 days; P < 0.02) compared with individuals without an elevated NT-Pro BNP level. CONCLUSIONS: NT-Pro BNP levels predict adverse events post-vascular surgery and are lowered in those patients assigned to preoperative administration of CoQ10. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT03956017. Among patients undergoing elective vascular surgery, 123 patients were randomized to either CoQ10 (400 mg/day) versus placebo for three days preoperatively. NT-Pro BNP levels (median; IQs) in the CoQ10 and Placebo groups were 179 (75-347) and 217 (109-585) pg/ml, respectively, (P = 0.08) preoperatively, and 397 (211-686) and 591 (288-1,433) pg/ml, respectively, (P = 0.01) post-surgery. Patients with an elevated NT-Pro BNP had a higher incidence of myocardial injury (58% vs. 20%; P < 0.01) and a longer hospital stay (4.4 ± 3.8 vs. 2.8 ± 3.2 days; P < 0.02) compared with individuals without an NT-Pro BNP elevation. In conclusion, BNP predicts adverse outcomes and can be reduced with preoperative CoQ10.

Pioglitazone increases PGC1-α signaling within chronically ischemic myocardium.

The peroxisome proliferator-activated receptor (PPAR)-γ drug pioglitazone (PIO) has been shown to protect tissue against oxidant stress. In a swine model of chronic myocardial ischemia, we tested whether PIO increases PGC1-α signaling and the expression of mitochondrial antioxidant peptides. Eighteen pigs underwent a thoracotomy with placement of a fixed constrictor around the LAD artery. At 8 weeks, diet was supplemented with either PIO (3 mg/kg) or placebo for 4 weeks. Regional myocardial function and blood flow were determined at the time of the terminal study. PGC1-α expression was quantified from nuclear membranes by gels and respiration, oxidant stress markers and proteomics by iTRAQ were determined from isolated mitochondria. In the chronically ischemic LAD region, wall thickening from the PIO and control groups was 42 ± 6 and 45 ± 5 %, respectively (NS) with no intergroup differences in basal blood flow (0.72 ± 0.04 versus 0.74 ± 0.04 ml/min g, respectively; NS). In the PIO group, the expression of nuclear bound PGC1-α was higher (11.3 ± 2.6 versus 4.4 ± 1.4 AU; P < 0.05) and the content of mitochondrial antioxidant peptides including superoxide dismutase 2, aldose reductase, glutathione S-transferase and thioredoxin reductase were greater than controls. Although isolated mitochondria from the PIO group showed lower state 3 respiration (102 ± 13 versus 161 ± 22 nmol/min mg; P < 0.05), no differences in oxidant stress were noted by protein carbonyl (1.7 ± 0.7 versus 1.1 ± 0.1 nmol/mg). Chronic pioglitazone does not reduce regional myocardial blood flow or function in a swine model of chronic myocardial ischemia, but may have an important role in increasing expression of antioxidant proteins through PGC1-α signaling.

A bioengineered artificial interstitium supports long-term islet xenograft survival in nonhuman primates without immunosuppression.

Cell-based therapies hold promise for many chronic conditions; however, the continued need for immunosuppression along with challenges in replacing cells to improve durability or retrieving cells for safety are major obstacles. We subcutaneously implanted a device engineered to exploit the innate transcapillary hydrostatic and colloid osmotic pressure generating ultrafiltrate to mimic interstitium. Long-term stable accumulation of ultrafiltrate was achieved in both rodents and nonhuman primates (NHPs) that was chemically similar to serum and achieved capillary blood oxygen concentration. The majority of adult pig islet grafts transplanted in non-immunosuppressed NHPs resulted in xenograft survival >100 days. Stable cytokine levels, normal neutrophil to lymphocyte ratio, and a lack of immune cell infiltration demonstrated successful immunoprotection and averted typical systemic changes related to xenograft transplant, especially inflammation. This approach eliminates the need for immunosuppression and permits percutaneous access for loading, reloading, biopsy, and recovery to de-risk the use of "unlimited" xenogeneic cell sources to realize widespread clinical translation of cell-based therapies.

Surgical Porcine Model of Chronic Myocardial Ischemia Treated by Exosome-laden Collagen Patch and Off-pump Coronary Artery Bypass Graft.

Chronic myocardial ischemia resulting from progressive coronary artery stenosis leads to hibernating myocardium (HIB), defined as myocardium that adapts to reduced oxygen availability by reducing metabolic activity, thereby preventing irreversible cardiomyocyte injury and infarction. This is distinct from myocardial infarction, as HIB has the potential for recovery with revascularization. Patients with significant coronary artery disease (CAD) experience chronic ischemia, which puts them at risk for heart failure and sudden death. The standard surgical intervention for severe CAD is coronary artery bypass graft surgery (CABG), but it has been shown to be an imperfect therapy, yet no adjunctive therapies exist to recover myocytes adapted to chronic ischemia. To address this gap, a surgical model of HIB using porcine that is amenable to CABG and mimics the clinical scenario was used. The model involves two surgeries. The first operation involves implanting a 1.5 mm rigid constrictor on the left anterior descending (LAD) artery. As the animal grows, the constrictor gradually causes significant stenosis resulting in reduced regional systolic function. Once the stenosis reaches 80%, the myocardial flow and function are impaired, creating HIB. An off-pump CABG is then performed with the left internal mammary artery (LIMA) to revascularize the ischemic region. The animal recovers for one month to allow for optimal myocardial improvement prior to sacrifice. This allows for physiologic and tissue studies of different treatment groups. This animal model demonstrates that cardiac function remains impaired despite CABG, suggesting the need for novel adjunctive interventions. In this study, a collagen patch embedded with mesenchymal stem cell (MSC)-derived exosomes was developed, which can be surgically applied to the epicardial surface distal to LIMA anastomosis. The material conforms to the epicardium, is absorbable, and provides the scaffold for the sustained release of signaling factors. This regenerative therapy can stimulate myocardial recovery that does not respond to revascularization alone. This model translates to the clinical arena by providing means of physiological and mechanistic explorations regarding recovery in HIB.

Stem cell-derived exosome patch with coronary artery bypass graft restores cardiac function in chronically ischemic porcine myocardium.

OBJECTIVE: This study aimed to investigate whether or not the application of a stem cell-derived exosome-laden collagen patch (EXP) during coronary artery bypass grafting (CABG) can recover cardiac function by modulating mitochondrial bioenergetics and myocardial inflammation in hibernating myocardium (HIB), which is defined as myocardium with reduced blood flow and function that retains viability and variable contractile reserve. METHODS: In vitro methods involved exposing H9C2 cardiomyocytes to hypoxia followed by normoxic coculture with porcine mesenchymal stem cells. Mitochondrial respiration was measured using Seahorse assay. GW4869, an exosomal release antagonist, was used to determine the effect of mesenchymal stem cells-derived exosomal signaling on cardiomyocyte recovery. Total exosomal RNA was isolated and differential micro RNA expression determined by sequencing. In vivo studies comprised 48 Yorkshire-Landrace juvenile swine (6 normal controls, 17 HIB, 19 CABG, and 6 CABG + EXP), which were compared for physiologic and metabolic changes. HIB was created by placing a constrictor on the proximal left anterior descending artery, causing significant stenosis but preserved viability by 12 weeks. CABG was performed with or without mesenchymal stem cells-derived EXP application and animals recovered for 4 weeks. Before terminal procedure, cardiac magnetic resonance imaging at rest, and with low-dose dobutamine, assessed diastolic relaxation, systolic function, graft patency, and myocardial viability. Tissue studies of inflammation, fibrosis, and mitochondrial morphology were performed posttermination. RESULTS: In vitro data demonstrated improved cardiomyocyte mitochondrial respiration upon coculture with MSCs that was blunted when adding the exosomal antagonist GW4869. RNA sequencing identified 8 differentially expressed micro RNAs in normoxia vs hypoxia-induced exosomes that may modulate the expression of key mitochondrial (peroxisome proliferator-activator receptor gamma coactivator 1-alpha and adenosine triphosphate synthase) and inflammatory mediators (nuclear factor kappa-light-chain enhancer of activated B cells, interferon gamma, and interleukin 1ß). In vivo animal magnetic resonance imaging studies demonstrated regional systolic function and diastolic relaxation to be improved with CABG + EXP compared with HIB (P = .02 and P = .02, respectively). Histologic analysis showed increased interstitial fibrosis and inflammation in HIB compared with CABG + EXP. Electron microscopy demonstrated increased mitochondrial area, perimeter, and aspect ratio in CABG + EXP compared with HIB or CABG alone (P < .0001). CONCLUSIONS: Exosomes recovered cardiomyocyte mitochondrial respiration and reduced myocardial inflammation through paracrine signaling, resulting in improved cardiac function.

Persistent diastolic dysfunction in chronically ischemic hearts following coronary artery bypass graft.

OBJECTIVE: A porcine model was used to study diastolic dysfunction in hibernating myocardium (HM) and recovery with coronary artery bypass surgery (CABG). METHODS: HM was induced in Yorkshire-Landrace juvenile swine (n = 30) by placing a c-constrictor on left anterior descending artery causing chronic myocardial ischemia without infarction. At 12 weeks, animals developed the HM phenotype and were either killed humanely (HIB group; n = 11) or revascularized with CABG and allowed 4 weeks of recovery (HIB+CABG group; n = 19). Control pigs were matched for weight, age, and sex to the HIB group. Before the animals were killed humanely, cardiac magnetic resonance imaging (MRI) was done at rest and during a low-dose dobutamine infusion. Tissue was obtained for histologic and proinflammatory biomarker analyses. RESULTS: Diastolic peak filling rate was lower in HIB compared with control (5.4 ± 0.7 vs 6.7 ± 1.4 respectively, P = .002), with near recovery with CABG (6.3 ± 0.8, P = .06). Cardiac MRI confirmed preserved global systolic function in all groups. Histology confirmed there was no transmural infarction but showed interstitial fibrosis in the endomysium in both the HIB and HIB+CABG groups compared with normal myocardium. Alpha-smooth muscle actin stain identified increased myofibroblasts in HM that were less apparent post-CABG. Cytokine and proteomic studies in HM showed decreased peroxisome proliferator-activator receptor gamma coactivator 1-alpha (PGC1-α) expression but increased expression of granulocyte-macrophage colony-stimulating factor and nuclear factor kappa-light-chain enhancer of activated B cells (NFκB). Following CABG, PGC1-α and NFκB expression returned to control whereas granulocyte-macrophage colony-stimulating factor, tumor necrosis factor-α, and interferon gamma remained increased. CONCLUSIONS: In porcine model of HM, increased NFκB expression, enhanced myofibroblasts, and collagen deposition along with decreased PGC1-α expression were observed, all of which tended toward normal with CABG. Estimates of impaired relaxation with MRI within HM during increased workload persisted despite CABG, suggesting a need for adjuvant therapies during revascularization.

Preventing Myocardial Injury Following Non-Cardiac Surgery: A Potential Role for Preoperative Antioxidant Therapy with Ubiquinone.

Over 240 million non-cardiac operations occur each year and are associated with a 15-20% incidence of adverse perioperative cardiovascular events. Unfortunately, preoperative therapies that have been useful for chronic ischemic heart diseases, such as coronary artery revascularization, antiplatelet agents, and beta-blockers have failed to improve outcomes. In a pre-clinical swine model of ischemic heart disease, we showed that daily administration of ubiquinone (coenzyme Q10, CoQ10) enhances the antioxidant status of mitochondria within chronically ischemic heart tissue, potentially via a PGC1α-dependent mechanism. In a randomized controlled trial, among high-risk patients undergoing elective vascular surgery, we showed that NT Pro-BNP levels are an important means of risk-stratification during the perioperative period and can be lowered with administration of CoQ10 (400 mg/day) for 3 days prior to surgery. The review provides background information for the role of oxidant stress and inflammation during high-risk operations and the potential novel application of ubiquinone as a preoperative antioxidant therapy that might reduce perioperative adverse cardiovascular outcomes.

Recovery of hibernating myocardium using stem cell patch with coronary bypass surgery.

OBJECTIVE: This study aims to investigate the utility of mesenchymal stem cells (MSCs) applied as an epicardial patch during coronary artery bypass graft (CABG) to target hibernating myocardium; that is, tissue with persistently decreased myocardial function, in a large animal model. METHODS: Hibernating myocardium was induced in juvenile swine (n = 12) using a surgically placed constrictor on the left anterior descending artery, causing stenosis without infarction. After 12 weeks, single-vessel CABG was performed using left internal thoracic artery to left anterior descending artery graft. During CABG, an epicardial patch was applied to the hibernating myocardium region consisting either of MSCs grown onto a polyglactin mesh (n = 6), or sham polyglactin mesh without MSCs (n = 6). Four weeks after CABG and patch placement, cardiac magnetic resonance imaging was performed and cardiac tissue was examined by gross inspection, including coronary dilators for vessel stenosis and patency, electron microscopy, protein assays, and proteomic analysis. RESULTS: CABG + MSC myocardium showed improvement in contractile function (78.24% ± 19.6%) compared with sham patch (39.17% ± 5.57%) during inotropic stimulation (P < .05). Compared with sham patch control, electron microscopy of CABG + MSC myocardium showed improvement in mitochondrial size, number, and morphology; protein analysis similarly showed increases in expression of the mitochondrial biogenesis marker peroxisome proliferator-activated receptor gamma coactivator 1-alpha (0.0022 ± 0.0009 vs 0.023 ± 0.009) (P < .01) along with key components of the electron transport chain, including succinate dehydrogenase (complex II) (0.06 ± 0.02 vs 0.14 ± 0.03) (P < .05) and adenosine triphosphate synthase (complex V) (2.7 ± 0.4 vs 4.2 ± 0.26) (P < .05). CONCLUSIONS: In hibernating myocardium, placement of a stem cell patch during CABG shows promise in improving myocardial function by improving mitochondrial morphology and function.

Serum cytokine profiles in healthy nonhuman primates are blunted by sedation and demonstrate sexual dimorphism as detected by a validated multiplex immunoassay.

Cytokine profiling is a valuable tool for monitoring immune responses associated with disease and treatment. This study assessed the impact of sex and sedation on serum cytokines in healthy nonhuman primates (NHPs). Twenty-three cytokines were measured from serum using a bead-based multiplex assay. Assay validation for precision, sensitivity, recovery, linearity, and stability was performed. Samples from male and female cynomolgus and rhesus macaques either cooperating or sedated were compared. All cytokines except TNFα demonstrated acceptable sensitivity and precision, with variable recovery and linearity. IFNγ, IL-2, IL-5, IL-6, IL-8, IL-12/23 (p40), IL-13, IL-15, MCP-1, TGFα, VEGF met acceptance criteria; G-CSF, IL-4, IL-10, MIP1α, sCD40L were marginal. Higher cytokine levels were observed in females and cytokine levels were blunted in sedated NHPs when compared to awake cooperating NHPs. Significant differences observed in cytokines related to sex, species, or imposed by handling highlight the importance of model design on translational relevance for clinical settings.

A nonhuman primate model of vertical sleeve gastrectomy facilitates mechanistic and translational research in human obesity.

The obesity epidemic significantly contributes to overall morbidity and mortality. Bariatric surgery is the gold standard treatment for obesity and metabolic dysfunction, yet the mechanisms by which it exerts metabolic benefit remain unclear. Here, we demonstrate a model of vertical sleeve gastrectomy (VSG) in nonhuman primates (NHP) that mimics the complexity and outcomes in humans. We also show that VSG confers weight loss and durable metabolic benefit, where equivalent caloric intake in shams resulted in significant weight gain following surgery. Furthermore, we show that VSG is associated with early, weight-independent increases in bile acids, short-chain fatty acids, and reduced visceral adipose tissue (VAT) inflammation with a polarization of VAT-resident immunocytes toward highly regulatory myeloid cells and Tregs. These data demonstrate that this strongly translational NHP model can be used to interrogate factors driving successful intervention to unravel the interplay between physiologic systems and improve therapies for obesity and metabolic syndrome.

CoQ10 enhances PGC1α and increases expression of mitochondrial antioxidant proteins in chronically ischemic swine myocardium.

BACKGROUND: Expression of mitochondrial proteins is reduced within hibernating myocardium (HM). It is unclear whether dietary supplementation with CoQ10 can increase expression of mitochondrial electron transport chain (ETC) and antioxidant proteins within this tissue. In a swine model of HM, we tested whether dietary administration of CoQ10 for four weeks enhances the expression of ETC and antioxidant proteins within the mitochondria via increased PGC1α signaling. METHODS: 12 swine were instrumented with a fixed constrictor around the LAD artery to induce gradual stenosis. At three months, transthoracic ECHO was performed to confirm the presence of a wall motion abnormality in the anterior wall. Animals were then randomly assigned to receive daily dietary supplements of either CoQ10 (10 mg/kg/day) or placebo for four weeks. At this time, animals underwent a final ECHO and terminal procedure. Expression of nuclear-bound PGC1α (Western blots) and mitochondrial proteins (Tandem Mass Tag) were determined. RESULTS: Mitochondrial and nuclear membranes were isolated from the LAD region. Nuclear-bound PGC1α levels were > 200-fold higher with administration of four weeks of CoQ10 treatment (p = 0.016). Expression of ETC proteins was increased in those animals that received CoQ10. Compared with mitochondria in the LAD region from placebo-treated pigs, CoQ10-treated pigs had higher levels of Complex I (p = 0.03), Complex IV (p = 0.04) and Complex V (p = 0.028) peptides. CONCLUSIONS: Four weeks of dietary CoQ10 in HM pigs enhances active, nuclear-bound PGC1α and increases the expression of ETC proteins within mitochondria of HM tissue.

Gulf War Illness-associated increases in blood levels of interleukin 6 and C-reactive protein: biomarker evidence of inflammation.

OBJECTIVE: Gulf War Illness is a chronic multisymptom disorder severely impacting the health and well-being of many Veterans of the 1990-1991 Gulf War. Symptoms that define the disease include pain, fatigue, mood and memory impairments, gastrointestinal problems, lung disorders, and skin rashes. In our previous biomarker study, we discovered Gulf War Illness-associated proinflammatory blood biomarkers. Therefore, we hypothesized that chronic inflammation causes the symptoms that define this disorder. Testing the chronic inflammation hypothesis is the objective of this study. RESULTS: The biomarker fingerprint of Gulf War Illness is the end-product of a cascade of proinflammatory cytokine signals. In particular, the observed increase in C-reactive protein predicts a corresponding increase in interleukin 6, the cytokine that stimulates hepatocytes to produce C-reactive protein. Therefore, in this study we measured potential upstream cytokine signals in plasma samples from Gulf War Veterans. As predicted, a positive correlation between interleukin 6 and C-reactive protein was observed.

Surgical Swine Model of Chronic Cardiac Ischemia Treated by Off-Pump Coronary Artery Bypass Graft Surgery.

Chronic cardiac ischemia that impairs cardiac function, but does not result in infarct, is termed hibernating myocardium (HM). A large clinical subset of coronary artery disease (CAD) patients have HM, which in addition to causing impaired function, puts them at higher risk for arrhythmia and future cardiac events. The standard treatment for this condition is revascularization, but this has been shown to be an imperfect therapy. The majority of pre-clinical cardiac research focuses on infarct models of cardiac ischemia, leaving this subset of chronic ischemia patients largely underserved. To address this gap in research, we have developed a well-characterized and highly reproducible model of hibernating myocardium in swine, as swine are ideal translational models for human heart disease. In addition to creating this unique disease model, we have optimized a clinically relevant treatment model of coronary artery bypass surgery in swine. This allows us to accurately study the effects of bypass surgery on heart disease, as well as investigate additional or alternate therapies. This model surgically induces single vessel stenosis by implanting a constrictor on the left anterior descending (LAD) artery in a young pig. As the pig grows, the constrictor creates a gradual stenosis, resulting in chronic ischemia with impaired regional function, but preserving tissue viability. Following the establishment of the hibernating myocardium phenotype, we perform off-pump coronary artery bypass graft surgery to revascularize the ischemic region, mimicking the gold-standard treatment for patients in the clinic.

Magnetic resonance imaging assessment of cardiac function in a swine model of hibernating myocardium 3 months following bypass surgery.

OBJECTIVE: Clinical studies demonstrate delayed recovery of hibernating myocardium (HM) following coronary artery bypass graft (CABG) surgery. Cardiac magnetic resonance (CMR) imaging is effective in identifying HM in clinical settings. Our animal model of HM shows partial but incomplete functional recovery 1 month following CABG using echocardiography. This study uses CMR imaging to determine completeness of recovery 3 months post-CABG. METHODS: Swine (N = 12) underwent left anterior descending artery (LAD) 1.5-cm constrictor placement creating a territory of HM over 12 weeks. CMR at 12 weeks confirmed hibernation without infarction (N = 12). Off-pump left internal thoracic artery (LITA) to the LAD was performed in 9 animals. Three animals were killed as HM controls. CMR imaging was repeated in revascularized animals before death at 1 (n = 4) or 3 months (n = 5). CMR imaging was performed at baseline and with dobutamine infusion (5 µg/kg/min). RESULTS: Twelve weeks after constrictor placement, CMR imaging confirmed viability in LAD region and LAD stenosis in all animals. In HM, wall thickening is reduced at baseline but with contractile reserve present during dobutamine infusion. Following revascularization, CMR imaging confirmed patent LITA graft (n = 9). Analysis of baseline regional function shows incomplete recovery of HM following CABG, with reduced contractile reserve at both 1 and 3 months post-CABG. CONCLUSIONS: CMR imaging provides accurate spatial resolution of regional contractile function and confirms the presence of HM at 12 weeks following instrumentation of the LAD. Three months following CABG, partial recovery of HM with contractile reserve is present in the single LAD territory.

Cardiac Strain in a Swine Model of Regional Hibernating Myocardium: Effects of CoQ10 on Contractile Reserve Following Bypass Surgery.

There is conflicting clinical evidence whether administration of coenzyme Q10 (CoQ10) improves function following coronary artery bypass graft surgery (CABG). Using a swine model of hibernating myocardium, we tested whether daily CoQ10 would improve contractile function by MRI at 4-week post-CABG. Twelve pigs underwent a thoracotomy and had a constrictor placed on the left anterior descending (LAD). At 12 weeks, they underwent off-pump bypass and received daily dietary supplements of either CoQ10 (10 mg/kg/day) or placebo. At 4-week post-CABG, circumferential strain measurements in the hibernating LAD region from placebo and CoQ10 groups were not different and increased to a similar extent with dobutamine (-14.7 ± 0.6 versus -14.8 ± 0.1, respectively (NS)). Post-sacrifice, oxidant stress markers were obtained in the mitochondrial isolates and protein carbonyl in the placebo, and CoQ10 groups were 6.14 ± 0.36 and 5.05 ± 0.32 nmol/mg, respectively (NS). In summary, CoQ10 did not improve contractile reserve or reduce oxidant stress at 4-week post-CABG.

Amelioration of Ischemic Brain Injury in Rats With Human Umbilical Cord Blood Stem Cells: Mechanisms of Action.

Despite the high prevalence and devastating outcome, there remain a few options for treatment of ischemic stroke. Currently available treatments are limited by a short time window for treatment and marginal efficacy when used. We have tested a human umbilical cord blood-derived stem cell line that has been shown to result in a significant reduction in stroke infarct volume as well as improved functional recovery following stroke in the rat. In the present study we address the mechanism of action and compared the therapeutic efficacy of high- versus low-passage nonhematopoietic umbilical cord blood stem cells (nh-UCBSCs). Using the middle cerebral arterial occlusion (MCAo) model of stroke in Sprague-Dawley rats, we administered nh-UCBSC by intravenous (IV) injection 2 days following stroke induction. These human cells were injected into rats without any immune suppression, and no adverse reactions were detected. Both behavioral and histological analyses have shown that the administration of these cells reduces the infarct volume by 50% as well as improves the functional outcome of these rats following stroke for both high- and low-passaged nh-UCBSCs. Flow cytometry analysis of immune cells present in the brains of normal rats, rats with ischemic brain injury, and ischemic animals with nh-UCBSC treatment confirmed infiltration of macrophages and T cells consequent to ischemia and reduction to normal levels with nh-UCBSC treatment. Flow cytometry also revealed a restoration of normal levels of microglia in the brain following treatment. These data suggest that nh-UCBSCs may act by inhibiting immune cell migration into the brain from the periphery and possibly by inhibition of immune cell activation within the brain. nh-UCBSCs exhibit great potential for treatment of stroke, including the fact that they are associated with an increased therapeutic time window, no known ill-effects, and that they can be expanded to high numbers for, and stored for, treatment.