Cardiopulmonary Bypass Suppresses Forkhead Box O3 and Downstream Autophagy in the Diabetic Human Heart.

BACKGROUND: Autophagy is an integral component of cellular homeostasis and metabolism. The exact mechanism of impaired autophagy in diabetes mellitus is unknown. Forkhead Box O3 (FOXO3α) is a key regulator of oxidative stress-related responses. We hypothesize FOXO3α is a direct upstream regulator of the autophagy pathway, and its upregulation is compromised in diabetic patients during stress of cardiopulmonary bypass (CPB). METHODS: The study enrolled 32 diabetic and 33 nondiabetic patients undergoing a cardiac surgical procedure on CPB. Right atrial tissue and serum samples were collected before and after CPB per protocol. A set of key components were quantitatively assessed and compared by microarray, immunoblotting, and immunohistochemistry studies. Data were analyzed using paired or unpaired student test. A P of <.05 or less was considered significant. RESULTS: Serum microarray showed FOXO3α was upregulated in the diabetic vs nondiabetic group after CPB (P = .033), autophagy-related 4B gene and Beclin 1 gene were greatly upregulated in the nondiabetic group (P = .028 and P = .002, respectively). On immunoblotting, there was upregulation of FOXO3α in the nondiabetic patients after CPB (P = .003). There were increased levels of Beclin-1, Bcl-2, and light chain 3B after CPB in the nondiabetic group only (P = .016, P = .005, P = .002, respectively). Sirtuin 1, Unc-51-like autophagy activating kinase 1 (ULK1), peroxisome proliferator-activated receptor gamma coactivator 1α (PGC1α), and mammalian target of rapamycin (mTOR) were not significantly changed in the nondiabetic group after CPB. CONCLUSIONS: Compared with nondiabetic patients, there was no significant upregulation of FOXO3α in diabetic patients, which could possibly explain the lack of upregulation of the autophagy process after CPB. FOXO3α could potentially serve as a therapeutic target to improve cellular homeostasis.

Impact of Left Atrial Appendage Exclusion on Short-Term Outcomes in Isolated Coronary Artery Bypass Graft Surgery.

BACKGROUND: The objective of this study was to evaluate the impact of left atrial appendage (LAA) exclusion on short-term outcomes in patients with atrial fibrillation undergoing isolated coronary artery bypass graft surgery. METHODS: We queried the 2010 to 2014 National Readmissions Database for patients who underwent coronary artery bypass graft repair with and without LAA ligation by using International Classification of Diseases, Ninth Revision, Clinical Modification procedure codes (International Classification of Diseases, Ninth Revision, Clinical Modification: 36.1xx). Only patients with a history of atrial fibrillation were included in our analysis. The primary outcome of our study was 30-day readmissions following discharge. Secondary outcomes were in-hospital mortality and stroke. To assess the postoperative outcomes, we used multivariate logistic regression models to adjust for clinical and demographic covariates. RESULTS: In total, we analyzed 253 287 patients undergoing coronary artery bypass graft surgery, 7.0% of whom received LAA closure. LAA exclusion was associated with a greater risk of postoperative respiratory failure (8.2% versus 6.2%, P<0.0001) and acute kidney injury (21.8% versus 18.5%, P<0.0001), but it did not significantly change the rate of blood transfusions or occurrence of cardiac tamponade. LAA exclusion was associated with a nonsignificant reduction in stroke (7.9% versus 8.6%, P=0.12), no difference in in-hospital mortality (2.2% versus 2.2% P=0.99), and a greater risk of 30-day readmission (16.0% versus 9.6%, P<0.0001). After covariate adjustment, LAA ligation remained a significant predictor of 30-day readmission (odds ratio, 1.640 [95% CI, 1.603-1.677], P<0.0001). CONCLUSIONS: LAA exclusion during isolated coronary artery bypass graft surgery in patients with atrial fibrillation is associated with a higher rate of 30-day readmission. Postoperative measures to mitigate the loss of the hormonal and hemodynamic effects of the LAA may increase the therapeutic benefit of this procedure.

Neuropeptide Y3-36 incorporated into PVAX nanoparticle improves angiogenesis in a murine model of myocardial ischemia.

Neuropeptide-Y (NPY) leads to angiogenesis and remodeling of the ischemic myocardium. The objective of this study is to assess the therapeutic potential of NPY in a model of acute myocardial ischemia using a nanoparticles delivery system targeted to tissue with oxidative stress. NPY3-36 was loaded onto copolyoxalate containing vanillyl alcohol (PVAX) using a double emulsification strategy. Adult C57BL/J6 mice (n = 49) were randomly divided into PVAX-NPY3-36 (n = 22), Vehicle (Saline) (n = 16), and Sham (n = 11) groups. The ischemia to left anterior descending artery was induced in PVAX-NPY3-36 or vehicle groups. The tissue was collected at the end of two weeks after assessing the functional and echocardiographic data. There was a significant decrease in infarction size and mortality in PVAX-NPY3-36 group compared to the Vehicle group (P = 0.01 and P = 0.05). On echocardiography, there was significant improvement in contractility and diastolic parameters (P = 0.01). On pressure-volume loop there was significant increase in stroke volume (P = 0.01), cardiac output (P = 0.01) and ventricular stroke work (P = 0.01) in the PVAX-NPY3-36 group. On Western blot analysis, there was a significant increase in pro-angiogenic factors Ang-1, TGF-ß, PDGF- ß and its receptors and VEGF in the ischemic tissue treated with PVAX-NPY3-36 as compared to Vehicle ischemic tissue (P = 0.01, P = 0.0003, and P < 0.05 respectively). It may be possible to have targeted delivery of labile neurotransmitters NPY3-36 to the ischemic myocardium using nanoparticle PVAX and achieving angiogenesis and significant functional improvement.

Effect of Chloroquine, Hydroxychloroquine, and Azithromycin on the Corrected QT Interval in Patients With SARS-CoV-2 Infection.

BACKGROUND: The novel SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) is responsible for the global coronavirus disease 2019 pandemic. Small studies have shown a potential benefit of chloroquine/hydroxychloroquine±azithromycin for the treatment of coronavirus disease 2019. Use of these medications alone, or in combination, can lead to a prolongation of the QT interval, possibly increasing the risk of Torsade de pointes and sudden cardiac death. METHODS: Hospitalized patients treated with chloroquine/hydroxychloroquine±azithromycin from March 1 to the 23 at 3 hospitals within the Northwell Health system were included in this prospective, observational study. Serial assessments of the QT interval were performed. The primary outcome was QT prolongation resulting in Torsade de pointes. Secondary outcomes included QT prolongation, the need to prematurely discontinue any of the medications due to QT prolongation, and arrhythmogenic death. RESULTS: Two hundred one patients were treated for coronavirus disease 2019 with chloroquine/hydroxychloroquine. Ten patients (5.0%) received chloroquine, 191 (95.0%) received hydroxychloroquine, and 119 (59.2%) also received azithromycin. The primary outcome of torsade de pointes was not observed in the entire population. Baseline corrected QT interval intervals did not differ between patients treated with chloroquine/hydroxychloroquine (monotherapy group) versus those treated with combination group (chloroquine/hydroxychloroquine and azithromycin; 440.6±24.9 versus 439.9±24.7 ms, P=0.834). The maximum corrected QT interval during treatment was significantly longer in the combination group versus the monotherapy group (470.4±45.0 ms versus 453.3±37.0 ms, P=0.004). Seven patients (3.5%) required discontinuation of these medications due to corrected QT interval prolongation. No arrhythmogenic deaths were reported. CONCLUSIONS: In the largest reported cohort of coronavirus disease 2019 patients to date treated with chloroquine/hydroxychloroquine±azithromycin, no instances of Torsade de pointes, or arrhythmogenic death were reported. Although use of these medications resulted in QT prolongation, clinicians seldomly needed to discontinue therapy. Further study of the need for QT interval monitoring is needed before final recommendations can be made.

Immediate Preoperative Transthoracic Echocardiography for the Prediction of Postoperative Atrial Fibrillation in High-Risk Cardiac Surgery.

OBJECTIVE: The present study aimed to validate the utility of bedside cardiac ultrasound to identify patients for the risk of postoperative atrial fibrillation (POAF). DESIGN: A prospective cohort study of consecutive patients. SETTING: Single-center tertiary referral center. PARTICIPANTS: After Institutional Review Board consent, 169 patients undergoing elective cardiac surgery were enrolled in the study. INTERVENTIONS: A preoperative transthoracic echocardiographic interrogation assessing diastolic function was performed. Measurements were assessed offline with experienced echocardiographers blinded to clinical outcomes. MEASUREMENTS AND MAIN RESULTS: The primary outcome was POAF during the first 72 hours after surgery. A total of 169 patients completed the study, 44 of whom (26.0%) developed POAF, and 39 (25.2%) had diastolic dysfunction. Patients with POAF had a higher rate of postoperative heart failure, reintubation within 24 hours of surgery, and length of stay (p = 0.002, 0.01, and 0.0006, respectively). Predictors significant for POAF included increasing age, left atrial volume indexed to body surface area (LAVI), and diastolic dysfunction (p = 0.02, 0.0001, and 0.001, respectively). Multivariate spline regressions demonstrated a nonlinear correlation between increasing LAVI and risk of POAF. CONCLUSION: Left atrial volume can be assessed efficiently preoperatively to provide superior risk stratification over clinical factors and diastolic parameters alone for the prediction of POAF. Furthermore, the present study demonstrated that the cutoffs of chamber quantification currently used do not appropriately capture the increased risk of POAF. Thus, LAVI provides a simple measure to identify patients who are in need of targeted prophylaxis for POAF.

Three-Dimensional Printing and Transesophageal Echocardiographic Imaging of Patient-Specific Mitral Valve Models in a Pulsatile Phantom Model.

Three-dimensional printing is increasingly used in the health care industry. Making patient-specific anatomic task trainers has been one of the more commonly described uses of this technique specifically, allowing surgeons to perform complex procedures on patient-specific models in a nonoperative setting. With regard to transesophageal echocardiography (TEE) training, commercially available simulators have been increasingly used. Even though these simulators are haptic in nature and anatomically near realistic, they lack patient specificity and the training of the dynamic workflow and imaging protocol used in the operative setting. Herein a customized pulsatile left-sided heart model that uses patient-specific 3-dimensional printed valves under physiological intracardiac pressures as a TEE task trainer is described. With this model, dynamic patient-specific valvular anatomy can be visualized with actual TEE machines by trainees to familiarize themselves with the surgery equipment and the imaging protocol.

Decreased PGC-1α Post-Cardiopulmonary Bypass Leads to Impaired Oxidative Stress in Diabetic Patients.

BACKGROUND: The mechanism of mitochondrial dysfunction after cardiopulmonary bypass (CPB) in patients with diabetes mellitus lacks understanding. We hypothesized that impaired beta-oxidation of fatty acids leads to worsened stress response in this patient population after cardiac surgery. METHODS: After Institutional Review Board approval, right atrial tissue samples were collected from 35 diabetic patients and 33 nondiabetic patients before and after CPB. Patients with glycated hemoglobin of 6.0 or greater and a clinical diagnosis of diabetes mellitus were considered to be diabetic. Immunoblotting and microarray analysis were performed to assess protein and gene expression changes. Blots were quantified with ImageJ and analyzed using one-way analysis of variance with multiple Student's t test comparisons after normalization. All p values less than 0.05 were considered significant. Immunohistochemistry was performed for cellular lipid deposition assessment. RESULTS: Diabetic patients had significantly lower levels of PGC-1α before and after CPB (p < 0.01 for both) compared with nondiabetic patients. Several upstream regulators of PGC-1α (SIRT1 and CREB) were significantly higher in nondiabetic patients before CPB (p = 0.01 and 0.0018, respectively). Antioxidant markers (NOX4 and GPX4), angiogenic factors (TGF-ß, NT3, and Ang1), and the antiapoptotic factor BCL-xL were significantly lower in diabetic patients after CPB (p < 0.05). The expression of genes supporting mitochondrial energy production (CREB5 and SLC25A40) and angiogenic genes (p < 0.05) was significantly downregulated in diabetic patients after CPB. Immunohistochemistry results showed significantly increased lipid deposition in diabetic myocardial tissue. CONCLUSIONS: Decreased PGC-1α in diabetic patients may lead to impaired mitochondrial function and attenuated antiapoptotic and angiogenic responses after CPB. Therefore, PGC-1α and upstream regulators could serve as a target for improving beta-oxidation in diabetic patients.

Google Ranking of Plastic Surgeons Values Social Media Presence Over Academic Pedigree and Experience.

BACKGROUND: Patients increasingly rely on online resources to make healthcare decisions. Google dominates the search engine market; first-page results receive most of the web traffic and therefore serve as an important indicator of consumer reach. OBJECTIVES: Our objective was to analyze the respective importance of physician academic pedigree, experience, and social media presence on plastic surgeon Google first-page search result placement. METHODS: A Google.com search was conducted in the top 25 United States metropolitan areas to identify the top 20 websites of board-certified plastic surgeons. Social media presence was quantified by tracking the number of followers on Facebook, Twitter, and Instagram for every surgeon as well as medical school and year of graduation. The primary outcome was website ranking in the first page of Google search results. To identify the independent predictors of presence on the front page, we performed a multivariate logistic regression. RESULTS: Total number of social medial followers was associated with Google front-page placement (P < 0.001), whereas medical school ranking and years in practice were not (P = 0.17 and 0.39, respectively). A total 19.6% of plastic surgeon practices in our study cohort still had no social media accounts whatsoever. CONCLUSIONS: For the past few decades, plastic surgery practices relied on referrals, word of mouth, and the surgeon's reputation and academic pedigree to attract new patients. It is now clear that this practice-building model is being rapidly supplanted by a new paradigm based on social media presence to reach potential patients.

Multifactorial risk index for prediction of intraoperative blood transfusion in endovascular aneurysm repair.

BACKGROUND: In some institutions, the current blood ordering practice does not discriminate minimally invasive endovascular aneurysm repair (EVAR) from open procedures, with consequent increasing costs and likelihood of blood product wastage for EVARs. This limitation in practice can possibly be addressed with the development of a reliable prediction model for transfusion risk in EVAR patients. We used the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) database to create a model for prediction of intraoperative blood transfusion occurrence in patients undergoing EVAR. Afterward, we tested our predictive model on the Vascular Study Group of New England (VSGNE) database. METHODS: We used the ACS NSQIP database for patients who underwent EVAR from 2011 to 2013 (N = 4709) as our derivation set for identifying a risk index for predicting intraoperative blood transfusion. We then developed a clinical risk score and validated this model using patients who underwent EVAR from 2003 to 2014 in the VSGNE database (N = 4478). RESULTS: The transfusion rates were 8.4% and 6.1% for the ACS NSQIP (derivation set) and VSGNE (validation) databases, respectively. Hemoglobin concentration, American Society of Anesthesiologists class, age, and aneurysm diameter predicted blood transfusion in the derivation set. When it was applied on the validation set, our risk index demonstrated good discrimination in both the derivation and validation set (C statistic = 0.73 and 0.70, respectively) and calibration using the Hosmer-Lemeshow test (P = .27 and 0.31) for both data sets. CONCLUSIONS: We developed and validated a risk index for predicting the likelihood of intraoperative blood transfusion in EVAR patients. Implementation of this index may facilitate the blood management strategies specific for EVAR.

Plastic Surgery-Related Hashtag Utilization on Instagram: Implications for Education and Marketing.

BACKGROUND: Recent data suggest patients are seeking aesthetic surgery to improve their appearance on Instagram and other social media. Despite the rising influence of Instagram in plastic surgery, few academic publications address Instagram, let alone evaluate its utilization in plastic surgery. OBJECTIVES: We set out to answer the following three questions: 1) what plastic surgery-related content is being posted to Instagram; 2) who is posting this content; and 3) what specific hashtags are they using? METHODS: Our study queried 21 Instagram plastic surgery-related hashtags. Content analysis was used to qualitatively evaluate each of the nine "top" posts associated with each hashtag (189 posts). Duplicate posts and those not relevant to plastic surgery were excluded. RESULTS: A total of 1,789,270 posts utilized the 21 hashtags sampled in this study. Of the top 189 posts for these 21 queried hashtags, 163 posts met inclusion criteria. Plastic surgeons eligible for membership in American Society for Aesthetic Plastic Surgery (ASAPS) accounted for only 17.8% of top posts, whereas noneligible physicians accounted for 26.4%. All nonplastic surgery trained physicians marketed themselves as "cosmetic surgeons." Nine top posts (5.5%) were by nonphysicians, including dentists, spas with no associated physician, and a hair salon. The majority of these posts were self-promotional (67.1%) as opposed to educational (32.9%). Board-certified plastic surgeons were significantly more likely to post educational content to Instagram as compared to nonplastic surgeons (62.1% vs 38.1%, P = 0.02). CONCLUSIONS: ASAPS eligible board-certified plastic surgeons are underrepresented amongst physicians posting top plastic surgery-related content to Instagram.

Preoperative asymptomatic leukocytosis and postoperative outcome in cardiac surgery patients.

BACKGROUND: Despite showing a prognostic value in general surgical patients, preoperative asymptomatic elevated white blood cell (WBC) count is not considered a risk factor for cardiac surgery. Whereas there is sporadic evidence of its value as a preoperative risk marker, it has not been looked at methodically as a specific index of outcome during cardiac surgery. Using a national database we sought to determine the relationship between preoperative WBC count and postoperative outcome in cardiac surgical patients. METHODS: Cardiac surgeries were extracted from the 2007-2013 American College of Surgeons National Surgical Quality Improvement Program database. Leukocytosis was defined by a preoperative WBC count greater than 11,000 cells/µL. A univariate analysis compared the incidence of adverse outcomes for patients with and without leukocytosis. A multivariate logistic regression model was constructed in order to test whether leukocytosis was an independent predictor of morbidity and mortality. RESULTS: Out of a total of 10,979 cardiac surgery patients 863 (7.8%) had preoperative leukocytosis. On univariate analysis, patients with leukocytosis experienced greater incidences of 30-day mortality, wound complications, and medical complications. Wound complications included surgical site infection as well as wound dehiscence. The medical complications included all other non-surgical causes of increased morbidity and infection leading to urinary tract infection, pneumonia, ventilator dependence, sepsis and septic shock. After stepwise model adjustment, leukocytosis was a strong predictor of medical complications (OR 1.22, 95% CI: 1.09-1.36, p = 0.002) with c-statistic of 0.667. However, after stepwise model adjustment leukocytosis was not a significant predictor of 30-day mortality and wound complications. CONCLUSION: Preoperative leukocytosis is associated with adverse postoperative outcome after cardiac surgery and is an independent predictor of infection-related postoperative complications.

Dynamic Three-Dimensional Geometry of the Aortic Valve Apparatus-A Feasibility Study.

OBJECTIVE: To provide (1) an overview of the aortic valve (AV) apparatus anatomy and nomenclature, and (2) data regarding the normal AV apparatus geometry and dynamism during the cardiac cycle obtained from three-dimensional transesophageal echocardiography (3D TEE). DESIGN: Retrospective feasibility study. SETTING: A single-center university teaching hospital. PARTICIPANTS: The study was performed on data of 10 patients with a nonregurgitant, nonstenotic aortic valve undergoing cardiac surgery. INTERVENTIONS: Intraoperative 3D TEE was performed on all the participants using the Siemens ACUSON SC2000 ultrasound system and Z6Ms transducer (Siemens Medical Systems, Mountainview, CA). MEASUREMENTS AND MAIN RESULTS: Dynamic offline analyses were performed with Siemens eSie valve analytical software in a semiautomated fashion. Forty-five parameters were exported of which 13 were selected and analyzed. The cardiac cycle was divided into 4 quartiles to account for frame-rate variations. The annulus, sinus of Valsalva (SoV) and sinotubular junction (STJ) areas, diameter, perimeter and height, aortic leaflet height, leaflet coaptation height, and aortic valve-mitral valve angle changed significantly during the cardiac cycle (p < 0.001). STJ expanded more than both the annulus and the SoV (p < 0.001). The maximum aortic valve leaflet height change was greater in the left and right versus noncoronary leaflet (p < 0.001). CONCLUSIONS: The semiautomated AV apparatus dynamic assessment using eSie valve software is a clinically feasible technique and can be performed readily in the operating room. It has the potential to significantly impact intraoperative decision-making in cases suitable for AV repair. The AV apparatus is a dynamic structure and demonstrates significant changes during the cardiac cycle.

Racial Disparities in Comorbidities, Complications, and Maternal and Fetal Outcomes in Women With Preeclampsia/eclampsia.

OBJECTIVE: The mechanisms leading to worse outcomes in African-American (AA) women with preeclampsia/eclampsia remain unclear. Our objective was to identify racial differences in maternal comorbidities, peripartum characteristics, and maternal and fetal outcomes. METHODS/RESULTS: When compared to white women with preeclampsia/eclampsia, AA women had an increased unadjusted risk of inpatient maternal mortality (OR 3.70, 95% CI: 2.19-6.24). After adjustment for covariates, in-hospital mortality for AA women remained higher than that for white women (OR 2.85, 95% CI: 1.38-5.53), while the adjusted risk of death among Hispanic women did not differ from that for white women. We also found an increased risk of intrauterine fetal death (IUFD) among AA women. When compared to white women with preeclampsia, AA women had an increased unadjusted odds of IUFD (OR 2.78, 95% CI: 2.49-3.11), which remained significant after adjustment for covariates (adjusted OR 2.45, 95% CI: 2.14-2.82). In contrast, IUFD among Hispanic women did not differ from that for white women after adjusting for covariates. CONCLUSIONS AND RELEVANCE: Our data suggest that African-American women are more likely to have risk factors for preeclampsia and more likely to suffer an adverse outcome during peripartum care. Future research should examine whether controlling co-morbidities and other risk factors will help to alleviate racial disparities in outcomes in this cohort of women.

Effect of cardiogenic shock hospital volume on mortality in patients with cardiogenic shock.

BACKGROUND: Cardiogenic shock (CS) is associated with significant morbidity, and mortality rates approach 40% to 60%. Treatment for CS requires an aggressive, sophisticated, complex, goal-oriented, therapeutic regimen focused on early revascularization and adjunctive supportive therapies, suggesting that hospitals with greater CS volume may provide better care. The association between CS hospital volume and inpatient mortality for CS is unclear. METHODS AND RESULTS: We used the Nationwide Inpatient Sample to examine 533 179 weighted patient discharges from 2675 hospitals with CS from 2004 to 2011 and divided them into quartiles of mean annual hospital CS case volume. The primary outcome was in-hospital mortality. Multivariate adjustments were performed to account for severity of illness, relevant comorbidities, hospital characteristics, and differences in treatment. Compared with the highest volume quartile, the adjusted odds ratio for inpatient mortality for persons admitted to hospitals in the lowest-volume quartile (≤27 weighted cases per year) was 1.27 (95% CI 1.15 to 1.40), whereas for admission to hospitals in the low-volume and medium-volume quartiles, the odds ratios were 1.20 (95% CI 1.08 to 1.32) and 1.12 (95% CI 1.01 to 1.24), respectively. Similarly, improved survival was observed across quartiles, with an adjusted inpatient mortality incidence of 41.97% (95% CI 40.87 to 43.08) for hospitals with the lowest volume of CS cases and a drop to 37.01% (95% CI 35.11 to 38.96) for hospitals with the highest volume of CS cases. Analysis of treatments offered between hospital quartiles revealed that the centers with volumes in the highest quartile demonstrated significantly higher numbers of patients undergoing coronary artery bypass grafting, percutaneous coronary intervention, or intra-aortic balloon pump counterpulsation. A similar relationship was demonstrated with the use of mechanical circulatory support (ventricular assist devices and extracorporeal membrane oxygenation), for which there was significantly higher use in the higher volume quartiles. CONCLUSIONS: We demonstrated an association between lower CS case volume and higher mortality. There is more frequent use of both standard supportive and revascularization techniques at the higher volume centers. Future directions may include examining whether early stabilization and transfer improve outcomes of patients with CS who are admitted to lower volume centers.

Local infiltration of neuropeptide Y as a potential therapeutic agent against apoptosis and fibrosis in a swine model of hypercholesterolemia and chronic myocardial ischemia.

While the angiogenic effects of Neuropeptide Y (NPY) in myocardial ischemia and hypercholesterolemia have been studied, its effects on altering oxidative stress, fibrosis and cell death are not known. We hypothesized that local infiltration of NPY in a swine model of chronic myocardial ischemia and hypercholesterolemia will induce nerve growth and cell survival, while reducing oxidative stress and fibrosis. Yorkshire mini-swine (n=15) were fed a high cholesterol diet for 5 weeks. Three weeks after surgical induction of focal myocardial ischemia, an osmotic pump was implanted, which delivered NPY (n=8, high cholesterol treated, HCT) or the vehicle (n=7, high cholesterol control, HCC) for 5 weeks. Then myocardium was harvested for analysis. Assessment of myocardial function and perfusion was made the last intervention. Immunoblotting demonstrated significantly decreased levels of MMP-9 (p=0.001) and TGF-ß (p=0.05) and significantly increased levels of Ang-1 (p=0.002), MnSOD (p=0.006) and NGF (p=0.01) in HCT. Immunohistochemistry results revealed significantly decreased TUNEL staining (p=0.005) and GLUT4 translocation (p=0.004) in HCT. The functional data showed significantly improved blood flow reserve (p=0.02) and improved diastolic function -dP/dt (p=0.009) in the treated animals. Local infiltration of NPY results in positive remodeling in ischemic myocardium in the setting of hypercholesterolemia. By initiating angio and neurogenesis, NPY infiltration improves blood flow reserve and restoration of fatty acid metabolism. The associated increased cell survival and decreased fibrosis result in improved myocardial diastolic function. NPY may have a potential therapeutic role in patients with hypercholesterolemia associated coronary artery disease.