Publications by authors named "Ahmed Abdel-Latif"

147 Publications

A novel role of claudin-5 in prevention of mitochondrial fission against ischemic/hypoxic stress in cardiomyocytes.

Can J Cardiol 2021 Apr 7. Epub 2021 Apr 7.

Division of Cardiology, Department of Medicine, School of Medicine, University of California Irvine, Irvine, CA 92697, USA. Electronic address:

Background: Downregulation of claudin-5 in the heart is associated with the end-stage heart failure. However, the underlying mechanism of claudin-5 is unclear. Here we investigated the molecular actions of claudin-5 in perspective of mitochondria in cardiomyocytes to better understand the role of claudin-5 in cardioprotection during ischemia.

Methods And Results: Claudin-5 was detected in the murine heart tissue and the neonatal rat cardiomyocytes (NRCM). Its protein level was severely decreased after myocardial ischemia/reperfusion (I/R; 30 min/24 h) or hypoxia/reoxygenation (H/R; 24 h/4 h). Claudin-5 was present in the mitochondria of NRCM as determined by confocal microscopy. H/R-induced downregulation of claudin-5 was accompanied by mitochondrial fragmentation. The protein level of mitofusin 2 (Mfn2) was dramatically decreased while the expression of dynamin-related protein (Drp) 1 was significantly increased after H/R. H/R-induced mitochondrial swelling and fission were observed by transmission electron microscope (TEM). Overexpression of claudin-5 by adenoviral infection reversed these structural disintegration of mitochondria. The mitochondria-centered intrinsic pathway of apoptosis triggered by H/R and indicated by the expression of cytochrome c and cleaved caspase 3 in the cytoplasm of NRCMs was also reduced by overexpressing claudin-5. Overexpression of claudin-5 in mouse heart also significantly decreased cleaved caspase 3 expression and the infarct size in ischemic heart with improved systolic function.

Conclusion: We demonstrated for the first time the presence of claudin-5 in the mitochondria in cardiomyocytes and provided the firm evidence for the cardioprotective role of claudin-5 in the preservation of mitochondrial dynamics and cell fate against hypoxia- or ischemia-induced stress.
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http://dx.doi.org/10.1016/j.cjca.2021.03.021DOI Listing
April 2021

Immunomodulatory Effects of Azithromycin Revisited: Potential Applications to COVID-19.

Front Immunol 2021 12;12:574425. Epub 2021 Feb 12.

Department of Pharmacy Practice and Science, College of Pharmacy, University of Kentucky, Lexington, KY, United States.

The rapid advancement of the COVID-19 pandemic has prompted an accelerated pursuit to identify effective therapeutics. Stages of the disease course have been defined by viral burden, lung pathology, and progression through phases of the immune response. Immunological factors including inflammatory cell infiltration and cytokine storm have been associated with severe disease and death. Many immunomodulatory therapies for COVID-19 are currently being investigated, and preliminary results support the premise of targeting the immune response. However, because suppressing immune mechanisms could also impact the clearance of the virus in the early stages of infection, therapeutic success is likely to depend on timing with respect to the disease course. Azithromycin is an immunomodulatory drug that has been shown to have antiviral effects and potential benefit in patients with COVID-19. Multiple immunomodulatory effects have been defined for azithromycin which could provide efficacy during the late stages of the disease, including inhibition of pro-inflammatory cytokine production, inhibition of neutrophil influx, induction of regulatory functions of macrophages, and alterations in autophagy. Here we review the published evidence of these mechanisms along with the current clinical use of azithromycin as an immunomodulatory therapeutic. We then discuss the potential impact of azithromycin on the immune response to COVID-19, as well as caution against immunosuppressive and off-target effects including cardiotoxicity in these patients. While azithromycin has the potential to contribute efficacy, its impact on the COVID-19 immune response requires additional characterization so as to better define its role in individualized therapy.
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http://dx.doi.org/10.3389/fimmu.2021.574425DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7906979PMC
March 2021

Danger-associated molecular pattern molecules take unexpectedly a central stage in Nlrp3 inflammasome-caspase-1-mediated trafficking of hematopoietic stem/progenitor cells.

Leukemia 2021 Feb 23. Epub 2021 Feb 23.

Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA.

Like their homing after transplantation to bone marrow (BM), the mobilization of hematopoietic stem/progenitor cells (HSPCs) is still not fully understood, and several overlapping pathways are involved. Several years ago our group proposed that sterile inflammation in the BM microenvironment induced by pro-mobilizing agents is a driving force in this process. In favor of our proposal, both complement cascade (ComC)-deficient and Nlrp3 inflammasome-deficient mice are poor G-CSF and AMD3100 mobilizers. It is also known that the Nlrp3 inflammasome mediates its effects by activating caspase-1, which is responsible for proteolytic activation of interleukin-1β (IL-1β) and interleukin-18 (IL-18) and their release from cells along with several danger-associated molecular pattern molecules (DAMPs). We observed in the past that IL-1β and IL-18 independently promote mobilization of HSPCs. In the current work we demonstrated that caspase-1-KO mice are poor mobilizers, and, to our surprise, administration of IL-1β or IL-18, as in the case of Nlrp3-KO animals, does not correct this defect. Moreover, neither Caspase-1-KO nor Nlrp3-KO mice properly activated the ComC to execute the mobilization process. Interestingly, mobilization in these animals and activation of the ComC were both restored after injection of the DAMP cocktail eATP+HGMB1+S100A9, the components of which are normally released from cells in an Nlrp3 inflammasome-caspase-1-dependent manner. In addition, we report that caspase-1-deficient HSPCs show a decrease in migration in response to BM homing factors and engraft more poorly after transplantation. These results for the first time identify caspase-1 as an orchestrator of HSPC trafficking.
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http://dx.doi.org/10.1038/s41375-021-01158-9DOI Listing
February 2021

Hospital Volume and Outcomes of Coronary Atherectomy.

Am J Cardiol 2021 05 19;146:140-141. Epub 2021 Feb 19.

Minneapolis Heart Institute at Abbott Northwestern Hospital and Minneapolis Heart Institute Foundation, Minneapolis, Minnesota. Electronic address:

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http://dx.doi.org/10.1016/j.amjcard.2021.02.004DOI Listing
May 2021

Cardiac Cell Therapy: Insights into the Mechanisms of Tissue Repair.

Int J Mol Sci 2021 Jan 26;22(3). Epub 2021 Jan 26.

Gill Heart and Vascular Institute and Division of Cardiovascular Medicine, University of Kentucky and The Lexington VA Medical Center, Lexington, KY 40508, USA.

Stem cell-based cardiac therapies have been extensively studied in recent years. However, the efficacy of cell delivery, engraftment, and differentiation post-transplant remain continuous challenges and represent opportunities to further refine our current strategies. Despite limited long-term cardiac retention, stem cell treatment leads to sustained cardiac benefit following myocardial infarction (MI). This review summarizes the current knowledge on stem cell based cardiac immunomodulation by highlighting the cellular and molecular mechanisms of different immune responses to mesenchymal stem cells (MSCs) and their secretory factors. This review also addresses the clinical evidence in the field.
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http://dx.doi.org/10.3390/ijms22031201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7865339PMC
January 2021

Comparative Effectiveness of Anti-Inflammatory Drug Treatments in Coronary Heart Disease Patients: A Systematic Review and Network Meta-Analysis.

Mediators Inflamm 2021 14;2021:5160728. Epub 2021 Jan 14.

Gill Heart Institute and Division of Cardiovascular Medicine, University of Kentucky and the Lexington VA Medical Center, Lexington, KY, USA.

Methods: We conducted a network meta-analysis of randomized controlled trials that studied the effects of anti-inflammatory medications on cardiovascular outcomes of coronary artery disease patients. We searched the electronic database until March 2020 for relevant studies.

Results: Nineteen trials examining the efficacy of eight anti-inflammatory medications (pexelizumab, anakinra, colchicine, darapladib, varespladib, canakinumab, inclacumab, and losmapimod) were selected for analysis. Overall, there is no statistically significant difference in all-cause mortality, cardiovascular mortality, revascularization, and major cardio and cerebrovascular events (MACCE) with the use of anti-inflammatory drugs. However, we found the use of colchicine significantly reduces the odds of developing stroke by approximately 75% (OR 0.26, CI 0.10-0.63). Colchicine use was also associated with a lower risk of revascularization and MACCE compared to the other agents. Our subgroup analyses comparing the timing of medication initiation (within 7 days vs. >7 days) and clinical presentation (ACS vs. non-ACS) revealed a significant reduction in the risk of recurrent MI in the group that received medication after seven days (OR 0.92, CI 0.86-0.99) and the non-ACS group (OR 0.88, CI 0.80-0.98).

Conclusion: Although many anti-inflammatory medications have failed to reduce adverse cardiovascular outcomes in the CAD population, selected medications show promise among subgroups of patients without ACS or after the first week following an acute ischemic event. Future studies examining the proper timing and targetable anti-inflammatory pathways are warranted.
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http://dx.doi.org/10.1155/2021/5160728DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7822705PMC
January 2021

Cangrelor in addition to standard therapy reduces cardiac damage and inflammatory markers in patients with ST-segment elevation myocardial infarction.

J Thromb Thrombolysis 2020 Nov 30. Epub 2020 Nov 30.

Cardiovascular Interventions, Coronary Artery Disease Center, Department of Cardiovascular Medicine, Heart, Vascular and Thoracic Institute, Cleveland Clinic, Cleveland, USA.

Although P2Y12 receptor blockers have become a standard, adjunctive therapy in patients with ST-segment elevation myocardial infarction (STEMI) undergoing percutaneous coronary intervention (PCI), the optimal regimen has not been established. We performed a prospective, open-label, randomized study to investigate the effect of cangrelor administration on platelet function and inflammation in patients with primary PCI (PPCI). Twenty-two patients were randomized to receive either cangrelor and ticagrelor or ticagrelor alone (standard group) before PPCI. Platelet reactivity was evaluated at baseline (before PCI), 10 min and the end of the procedure. At baseline, there was no significant difference in platelet reactivity between both groups, whereas platelets were significantly inhibited at 10 min after initiating cangrelor vs. standard (adenosine-diphosphate-induced aggregation 102.2 ± 24.88 vs. 333.4 ± 63.3, P < 0.05 and thrombin-receptor-activating-peptide-induced aggregation 285.8 ± 86.1 vs. 624.8 ± 106.0, P < 0.05). Lower platelet aggregation in the cangrelor group persisted but the difference was reduced by the end of the procedure. Circulating inflammatory cells, pro-inflammatory cytokines, total elastase, and surrogates of neutrophil extracellular traps (total elastase-myeloperoxidase complexes) were significantly lower in the cangrelor compared to the standard therapy group at 6 h after randomization. There was a trend towards reduction in cardiac damage in the cangrelor group as reflected by the changes in late gadolinium enhancement between 48 h and 3 months after STEMI. Early administration of cangrelor in STEMI patients was associated with more effective platelet inhibition during PPCI and significantly dampened the deleterious inflammatory response compared to standard therapy (NCT03043274).
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http://dx.doi.org/10.1007/s11239-020-02345-8DOI Listing
November 2020

Adhesive stem cell coatings for enhanced retention in the heart tissue.

ACS Appl Bio Mater 2020 May 22;3(5):2930-2939. Epub 2020 Apr 22.

Chemical and Materials Engineering, University of Kentucky, Lexington, Kentucky 40506-0046, United States.

Injection into the heart tissue is a direct route for optimally placing mesenchymal stem cells (MSC) to regulate local inflammation following a heart attack. The retention of MSCs at the injection site is severely limited by the fluid flows that rapidly wash cells away and minimize their capacity to modulate cardiac inflammation. To prevent this loss of MSCs and their function, antibody coatings were designed for the surface of MSCs to enhance their adhesion to the inflamed tissue. MSCs were biotinylated, and biotinylated antibodies against intercellular cell adhesion molecules were conjugated to the cell surface through an intermediate layer of streptavidin. MSC surfaces were modified with ~7,000 biotin/μm and ~23 antibodies/μm. The heart tissue injection of antibody-coated MSCs offered a 3-fold increase of cell retention in an infarcted heart over the injection of uncoated MSCs. We supported the mechanism of adhesion through analysis of MSC adhesion to inflamed endothelial cells and also surfaces of purified adhesion molecules on glass under microfluidic shear flow.
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http://dx.doi.org/10.1021/acsabm.9b01198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7679078PMC
May 2020

NT-proBNP Level Predicts Extent of Myonecrosis and Clinical Adverse Outcomes in Patients with ST-Elevation Myocardial Infarction: A Pilot Study.

Med Res Arch 2020 Feb 21;8(2). Epub 2020 Feb 21.

Division of Cardiovascular Medicine, Gill Heart & Vascular Institute, University of Kentucky, and Lexington VA Medical Center, Lexington, KY, USA.

Background And Hypothesis: The initial assessment of late gadolinium enhancement (LGE) on cardiac magnetic resonance imaging (CMR) reflects cardiac damage and is an important prognostic factor in patients with acute ST-elevation myocardial infarction (STEMI). N-Terminal prohormone of brain natriuretic peptide (NT-proBNP) is released following cardiomyocytes injury. However, the relationship between NT-proBNP levels, myocardial damage and clinical outcomes after STEMI has not been well defined.

Methods: Plasma levels of NT-proBNP, troponin I and creatinine kinase (CK) were assessed in 75 patients with STEMI. Echocardiography and CMR were performed prior to hospital discharge. Cardiac damage was quantified using peak biomarker levels and LGE. Patients were followed for a median of 975 days (IQR 823-1098 days) for major adverse cardiac events (MACE) (all-cause mortality, recurrent myocardial infraction, unplanned recurrent revascularization and recurrent hospitalization for heart failure).

Results: Plasma levels of NT-proBNP increased following STEMI to peak at 24 hours. The dynamic changes in plasma NT-proBNP were similar to those noted with troponin I and its delayed peak but not those observed with plasma CK levels. Peak NT-proBNP levels correlated positively with indices of myocardial damage such as peak troponin I (R =0.38, <0.001), peak CK (R =0.22, = 0.01) and LGE examination (R = 0.46, <0.001). Peak plasma level of NT- proBNP was strongly predictive of MACE during the follow-up period.

Conclusions: Peak levels of NT-proBNP following STEMI are predictive of the extent of myocardial damage and clinical outcomes. These results suggest an important prognostic role for NT-proBNP assessment in STEMI patients.
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http://dx.doi.org/10.18103/mra.v8i2.2039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7575211PMC
February 2020

Liposomal delivery of azithromycin enhances its immunotherapeutic efficacy and reduces toxicity in myocardial infarction.

Sci Rep 2020 10 6;10(1):16596. Epub 2020 Oct 6.

Gill Heart and Vascular Institute and Division of Cardiovascular Medicine, University of Kentucky, Lexington, KY, USA.

A growing body of evidence shows that altering the inflammatory response by alternative macrophage polarization is protective against complications related to acute myocardial infarction (MI). We have previously shown that oral azithromycin (AZM), initiated prior to MI, reduces inflammation and its negative sequelae on the myocardium. Here, we investigated the immunomodulatory role of a liposomal AZM formulation (L-AZM) in a clinically relevant model to enhance its therapeutic potency and avoid off-target effects. L-AZM (40 or 10 mg/kg, IV) was administered immediately post-MI and compared to free AZM (F-AZM). L-AZM reduced cardiac toxicity and associated mortality by 50% in mice. We observed a significant shift favoring reparatory/anti-inflammatory macrophages with L-AZM formulation. L-AZM use resulted in a remarkable decrease in cardiac inflammatory neutrophils and the infiltration of inflammatory monocytes. Immune cell modulation was associated with the downregulation of pro-inflammatory genes and the upregulation of anti-inflammatory genes. The immunomodulatory effects of L-AZM were associated with a reduction in cardiac cell death and scar size as well as enhanced angiogenesis. Overall, L-AZM use enhanced cardiac recovery and survival after MI. Importantly, L-AZM was protective from F-AZM cardiac off-target effects. We demonstrate that the liposomal formulation of AZM enhances the drug's efficacy and safety in an animal model of acute myocardial injury. This is the first study to establish the immunomodulatory properties of liposomal AZM formulations. Our findings strongly support clinical trials using L-AZM as a novel and clinically relevant therapeutic target to improve cardiac recovery and reduce heart failure post-MI in humans.
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http://dx.doi.org/10.1038/s41598-020-73593-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7538891PMC
October 2020

Autotaxin inhibition reduces cardiac inflammation and mitigates adverse cardiac remodeling after myocardial infarction.

J Mol Cell Cardiol 2020 12 2;149:95-114. Epub 2020 Oct 2.

Gill Heart Institute and Division of Cardiovascular Medicine, University of Kentucky and the Lexington VA Medical Center, Lexington, KY, USA. Electronic address:

Objective: Acute myocardial infarction (AMI) initiates pathological inflammation which aggravates tissue damage and causes heart failure. Lysophosphatidic acid (LPA), produced by autotaxin (ATX), promotes inflammation and the development of atherosclerosis. The role of ATX/LPA signaling nexus in cardiac inflammation and resulting adverse cardiac remodeling is poorly understood.

Approach And Results: We assessed autotaxin activity and LPA levels in relation to cardiac and systemic inflammation in AMI patients and C57BL/6 (WT) mice. Human and murine peripheral blood and cardiac tissue samples showed elevated levels of ATX activity, LPA, and inflammatory cells following AMI and there was strong correlation between LPA levels and circulating inflammatory cells. In a gain of function model, lipid phosphate phosphatase-3 (LPP3) specific inducible knock out (Mx1-Plpp3) showed higher systemic and cardiac inflammation after AMI compared to littermate controls (Mx1-Plpp3); and a corresponding increase in bone marrow progenitor cell count and proliferation. Moreover, in Mx1- Plpp3 mice, cardiac functional recovery was reduced with corresponding increases in adverse cardiac remodeling and scar size (as assessed by echocardiography and Masson's Trichrome staining). To examine the effect of ATX/LPA nexus inhibition, we treated WT mice with the specific pharmacological inhibitor, PF8380, twice a day for 7 days post AMI. Inhibition of the ATX/LPA signaling nexus resulted in significant reduction in post-AMI inflammatory response, leading to favorable cardiac functional recovery, reduced scar size and enhanced angiogenesis.

Conclusion: ATX/LPA signaling nexus plays an important role in modulating inflammation after AMI and targeting this mechanism represents a novel therapeutic target for patients presenting with acute myocardial injury.
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http://dx.doi.org/10.1016/j.yjmcc.2020.09.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7744112PMC
December 2020

Emerging roles of neutrophil-borne S100A8/A9 in cardiovascular inflammation.

Pharmacol Res 2020 11 28;161:105212. Epub 2020 Sep 28.

Division of Cardiac Surgery, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH, USA. Electronic address:

Elevated neutrophil count is associated with higher risk of major adverse cardiac events including myocardial infarction and early development of heart failure. Neutrophils contribute to cardiac damage through a number of mechanisms, including attraction of other immune cells and release of inflammatory mediators. Recently, a number of independent studies have reported a causal role for neutrophil-derived alarmins (i.e. S100A8/A9) in inducing inflammation and cardiac injury following myocardial infarction (MI). Furthermore, a positive correlation between serum S100A8/A9 levels and major adverse cardiac events (MACE) in MI patients was also observed implying that targeting neutrophils or their inflammatory cargo could be beneficial in reducing heart failure. However, contradictory to this idea, neutrophils and neutrophil-derived S100A8/A9 also seem to play a vital role in the resolution of inflammation. Thus, a better understanding of how neutrophils balance these seemingly contrasting functions would allow us to develop effective therapies that preserve the inflammation-resolving function while restricting the damage caused by inflammation. In this review, we specifically discuss the mechanisms behind neutrophil-derived S100A8/A9 in promoting inflammation and resolution in the context of MI. We also provide a perspective on how neutrophils could be potentially targeted to ameliorate cardiac inflammation and the ensuing damage.
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http://dx.doi.org/10.1016/j.phrs.2020.105212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7755830PMC
November 2020

CYP2C19 Genotyping to Guide Antiplatelet Therapy After Percutaneous Coronary Interventions: One Size Rarely Fits All.

JAMA 2020 08;324(8):747-749

Gill Heart Institute, Division of Cardiovascular Medicine, University of Kentucky, Lexington.

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http://dx.doi.org/10.1001/jama.2020.13094DOI Listing
August 2020

Nlrp3 Inflammasome Signaling Regulates the Homing and Engraftment of Hematopoietic Stem Cells (HSPCs) by Enhancing Incorporation of CXCR4 Receptor into Membrane Lipid Rafts.

Stem Cell Rev Rep 2020 Oct;16(5):954-967

Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, 500 S. Floyd Street, Rm. 107, Louisville, KY, 40202, USA.

Fast and efficient homing and engraftment of hematopoietic stem progenitor cells (HSPCs) is crucial for positive clinical outcomes from transplantation. We found that this process depends on activation of the Nlrp3 inflammasome, both in the HSPCs to be transplanted and in the cells in the recipient bone marrow (BM) microenvironment. For the first time we provide evidence that functional deficiency in the Nlrp3 inflammasome in transplanted cells or in the host microenvironment leads to defective homing and engraftment. At the molecular level, functional deficiency of the Nlrp3 inflammasome in HSPCs leads to their defective migration in response to the major BM homing chemoattractant stromal-derived factor 1 (SDF-1) and to other supportive chemoattractants, including sphingosine-1-phosphate (S1P) and extracellular adenosine triphosphate (eATP). We report that activation of the Nlrp3 inflammasome increases autocrine release of eATP, which promotes incorporation of the CXCR4 receptor into membrane lipid rafts at the leading surface of migrating cells. On the other hand, a lack of Nlrp3 inflammasome expression in BM conditioned for transplantation leads to a decrease in expression of SDF-1 and danger-associated molecular pattern molecules (DAMPs), which are responsible for activation of the complement cascade (ComC), which in turn facilitates the homing and engraftment of HSPCs.
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http://dx.doi.org/10.1007/s12015-020-10005-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456406PMC
October 2020

Increased yield of gelatin coated therapeutic cells through cholesterol insertion.

J Biomed Mater Res A 2021 Mar 20;109(3):326-335. Epub 2020 Jun 20.

Department of Chemical and Materials Engineering, University of Kentucky, Lexington, Kentucky, USA.

Gelatin coatings are effective in increasing the retention of MSCs injected into the heart and minimizing the damage from acute myocardial infarction (AMI), but early studies suffered from low fractions of the MSCs coated with gelatin. Biotinylation of the MSC surface is a critical first step in the gelatin coating process, and in this study, we evaluated the use of biotinylated cholesterol "lipid insertion" anchors as a substitute for the covalent NHS-biotin anchors to the cell surface. Streptavidin-eosin molecules, where eosin is our photoinitiator, can then be bound to the cell surface through biotin-streptavidin affinity. The use of cholesterol anchors increased streptavidin density on the surface of MSCs further driving polymerization and allowing for an increased fraction of MSCs coated with gelatin (83%) when compared to NHS-biotin (52%). Additionally, the cholesterol anchors increased the uniformity of the coating on the MSC surface and supported greater numbers of coated MSCs even when the streptavidin density was slightly lower than that of an NHS-biotin anchoring strategy. Critically, this improvement in gelatin coating efficiency did not impact cytokine secretion and other critical MSC functions. Proper selection of the cholesterol anchor and the biotinylation conditions supports cellular function and densities of streptavidin on the MSC surface of up to ~10 streptavidin molecules/μm . In all, these cholesterol anchors offer an effective path towards the formation of conformal coatings on the majority of MSCs to improve the retention of MSCs in the heart following AMI.
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http://dx.doi.org/10.1002/jbm.a.37025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710926PMC
March 2021

The Nlrp3 inflammasome as a "rising star" in studies of normal and malignant hematopoiesis.

Leukemia 2020 06 20;34(6):1512-1523. Epub 2020 Apr 20.

Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA.

Recent investigations indicate that hematopoiesis is coregulated by innate immunity signals and by pathways characteristic of the activation of innate immunity cells that also operate in normal hematopoietic stem progenitor cells (HSPCs). This should not be surprising because of the common developmental origin of these cells from a hemato/lymphopoietic stem cell. An important integrating factor is the Nlrp3 inflammasome, which has emerged as a major sensor of changes in body microenvironments, cell activation, and cell metabolic activity. It is currently the best-studied member of the inflammasome family expressed in hematopoietic and lymphopoietic cells, including also HSPCs. It is proposed as playing a role in (i) the development and expansion of HSPCs, (ii) their release from bone marrow (BM) into peripheral blood (PB) in stress situations and during pharmacological mobilization, (iii) their homing to BM after transplantation, and (iv) their aging and the regulation of hematopoietic cell metabolism. The Nlrp3 inflammasome is also involved in certain hematological pathologies, including (i) myelodysplastic syndrome, (ii) myeloproliferative neoplasms, (iii) leukemia, and (iv) graft-versus-host disease (GvHD) after transplantation. The aim of this review is to shed more light on this intriguing intracellular protein complex that has become a "rising star" in studies focused on both normal steady-state and pathological hematopoiesis.
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http://dx.doi.org/10.1038/s41375-020-0827-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7266743PMC
June 2020

Contemporary Meta-Analysis of Extended Direct-Acting Oral Anticoagulant Thromboprophylaxis to Prevent Venous Thromboembolism.

Am J Med 2020 09 6;133(9):1074-1081.e8. Epub 2020 Mar 6.

Gill Heart & Vascular Institute, University of Kentucky, Lexington.

Background: Medically ill patients remain at risk of venous thromboembolism for up to 6 weeks after hospital discharge due to factors such as immobilization and inflammation.

Methods: We conducted a meta-analysis and systematic review of Phase III randomized controlled trials comparing extended use of direct oral anticoagulation (DOAC) post discharge for venous thromboembolism prophylaxis with placebo.

Results: The primary efficacy outcome (composite of venous thromboembolism and mortality) occurred in 373/13,099 patients in the DOAC group (2.9%) and 477/13,309 patients in the placebo group (3.6%), with an odds ratio (OR) of 0.79 (95% confidence interval [CI], 0.69-0.91). The secondary efficacy outcome (nonfatal symptomatic venous thromboembolism) occurred in 75/15,573 patients in the DOAC group (0.48%) and 120/15,599 in the placebo group (0.77%) with an OR of 0.62 (95% CI, 0.47-0.83). The primary safety outcome (major bleeding) occurred in 90/15,474 patients in the DOAC group (0.58%) and in 47/15,418 patients in the placebo group (0.3%) with an OR of 1.92 (95% CI, 1.35-2.73). The secondary safety (clinically relevant nonmajor bleeding) outcome occurred in 333/15,474 patients in the DOAC group (2.2%) and 191/15,418 patients in the placebo group (1.2%) with an OR of 1.75 (95% CI, 1.46-2.1). The extended use of venous thromboembolism prophylaxis post discharge results in decreased venous thromboembolism events but increased bleeding risk. Our cost-effective analysis of extended DOAC use vs placebo showed superiority of the DOAC group.

Conclusion: In conclusion, given the mortality benefit and cost benefit, extended thromboprophylaxis is a beneficial strategy to efficiently reduce the risk of venous thromboembolism.
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http://dx.doi.org/10.1016/j.amjmed.2020.01.037DOI Listing
September 2020

Role of Heparin-Binding Epidermal Growth Factor-Like Growth Factor in Oxidative Stress-Associated Metabolic Diseases.

Metab Syndr Relat Disord 2020 05 20;18(4):186-196. Epub 2020 Feb 20.

Saha Cardiovascular Research Center, University of Kentucky College of Medicine, Lexington, Kentucky, USA.

Heparin-binding EGF-like growth factor (HB-EGF) is an EGF family member that interacts with epidermal growth factor receptor (EGFR) and ERBB4. Since HB-EGF was first identified as a novel growth factor secreted from a human macrophage cell line, numerous pathological and physiological functions related to cell proliferation, migration, and inflammation have been reported. Notably, the expression of HB-EGF is sensitively upregulated by oxidative stress in the endothelial cells and functions for auto- and paracrine-EGFR signaling. Overnutrition and obesity cause elevation of HB-EGF expression and EGFR signaling in the hepatic and vascular systems. Modulations of HB-EGF signaling showed a series of protections against phenotypes related to metabolic syndrome and advanced metabolic diseases, suggesting HB-EGF as a potential target against metabolic diseases.
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http://dx.doi.org/10.1089/met.2019.0120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7196370PMC
May 2020

Isolation Methods for Human CD34 Subsets Using Fluorescent and Magnetic Activated Cell Sorting: an In Vivo Comparative Study.

Stem Cell Rev Rep 2020 04;16(2):413-423

Department of Chemical and Materials Engineering, University of Kentucky, Lexington, KY, USA.

Introduction: Acute myocardial infarction (AMI) and resulting cardiac damage and heart failure are leading causes of morbidity and mortality worldwide. Multiple studies have examined the utility of CD34 cells for the treatment of acute and ischemic heart disease. However, the optimal strategy to enrich CD34 cells from clinical sources is not known. We examined the efficacy of fluorescence activated cell sorting (FACS) and magnetic beads cell sorting (MACS) methods for CD34 cell isolation from mobilized human mononuclear peripheral blood cells (mhPBMNCs).

Methods: mhPBCs were processed following acquisition using FACS or MACS according to clinically established protocols. Cell viability, CD34 cell purity and characterization of surface marker expression were assessed using a flow cytometer. For in vivo characterization of cardiac repair, we conducted LAD ligation surgery on 8-10 weeks female NOD/SCID mice followed by intramyocardial transplantation of unselected mhPBMNCs, FACS or MACS enriched CD34 cells.

Results: Both MACS and FACS isolation methods achieved high purity rates, viability, and enrichment of CD34 cells. In vivo studies following myocardial infarction demonstrated retention of CD34 in the peri-infarct region for up to 30 days after transplantation. Retained CD34 cells were associated with enhanced angiogenesis and reduced inflammation compared to unselected mhPBMNCs or PBS treatment arms. Cardiac scar and fibrosis as assessed by immunohistochemistry were reduced in FACS and MACS CD34 treatment groups. Finally, reduced scar and augmented angiogenesis resulted in improved cardiac functional recovery, both on the global and regional function and remodeling assessments by echocardiography.

Conclusion: Cell based therapy using enriched CD34 cells sorted by FACS or MACS result in better cardiac recovery after ischemic injury compared to unselected mhPBMNCs. Both enrichment techniques offer excellent recovery and purity and can be equally used for clinical applications.
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http://dx.doi.org/10.1007/s12015-019-09939-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469922PMC
April 2020

Neutrophil-Derived S100A8/A9 Amplify Granulopoiesis After Myocardial Infarction.

Circulation 2020 03 16;141(13):1080-1094. Epub 2020 Jan 16.

Department of Surgery (G.S., B.A., P.R.N.), Ohio State University Wexner Medical Center, Columbus.

Background: Myocardial infarction (MI) triggers myelopoiesis, resulting in heightened production of neutrophils. However, the mechanisms that sustain their production and recruitment to the injured heart are unclear.

Methods: Using a mouse model of the permanent ligation of the left anterior descending artery and flow cytometry, we first characterized the temporal and spatial effects of MI on different myeloid cell types. We next performed global transcriptome analysis of different cardiac cell types within the infarct to identify the drivers of the acute inflammatory response and the underlying signaling pathways. Using a combination of genetic and pharmacological strategies, we identified the sequelae of events that led to MI-induced myelopoiesis. Cardiac function was assessed by echocardiography. The association of early indexes of neutrophilia with major adverse cardiovascular events was studied in a cohort of patients with acute MI.

Results: Induction of MI results in rapid recruitment of neutrophils to the infarct, where they release specific alarmins, S100A8 and S100A9. These alarmins bind to the Toll-like receptor 4 and prime the nod-like receptor family pyrin domain-containing 3 inflammasome in naïve neutrophils and promote interleukin-1β secretion. The released interleukin-1β interacts with its receptor (interleukin 1 receptor type 1) on hematopoietic stem and progenitor cells in the bone marrow and stimulates granulopoiesis in a cell-autonomous manner. Genetic or pharmacological strategies aimed at disruption of S100A8/A9 and their downstream signaling cascade suppress MI-induced granulopoiesis and improve cardiac function. Furthermore, in patients with acute coronary syndrome, higher neutrophil count on admission and after revascularization correlates positively with major adverse cardiovascular disease outcomes.

Conclusions: Our study provides novel evidence for the primary role of neutrophil-derived alarmins (S100A8/A9) in dictating the nature of the ensuing inflammatory response after myocardial injury. Therapeutic strategies aimed at disruption of S100A8/A9 signaling or their downstream mediators (eg, nod-like receptor family pyrin domain-containing 3 inflammasome, interleukin-1β) in neutrophils suppress granulopoiesis and may improve cardiac function in patients with acute coronary syndrome.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.119.043833DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7122461PMC
March 2020

A Randomized Study Comparing the Short-Term Neurocognitive Outcome of Electroconvulsive Therapy Versus Repetitive Transcranial Magnetic Stimulation in the Treatment of Patients With Depression.

J Psychiatr Pract 2020 01;26(1):23-36

LATIF, NASRELDIN, FATHY, MOUSSA, ELSHEIKH, and MADBOULY: Department of Psychiatry, Cairo University, Cairo, Egypt KADER, BASHEER: Department of Neurophysiology, Cairo University, Cairo, Egypt.

Background: Studies have compared electroconvulsive therapy (ECT) and repetitive transcranial magnetic stimulation (rTMS) with regard to their clinical efficacy in the treatment of depression, but only a few studies have addressed their differential impact on cognition. The purpose of this study was to compare the neurocognitive side effects of both treatment modalities.

Methods: In this comparative study, 40 patients with major depressive disorder referred for ECT were randomly assigned either to a course of 25 sessions of rTMS to the left dorsolateral prefrontal cortex or to a course of ECT ranging from 4 to 8 sessions. The primary outcome measures were the results of a cognitive battery that assessed different aspects of cognitive functioning. The cognitive battery comprised the Digit Span Subtest from the Wechsler Adult Intelligence Scale, the Stroop Color-Word Test-Victoria version, the Color Trails Test Trials 1 and 2, and the Rey-Osterrieth Complex Figure Test.

Results: At the end of treatment, scores on the Digit Span Subtest, the Stroop Color-Word Test-Victoria version, and the Color Trails Test showed statistically significant better results in the rTMS group compared with the ECT group.

Conclusions: rTMS was well tolerated with less negative impact on cognitive functioning than ECT.
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http://dx.doi.org/10.1097/PRA.0000000000000436DOI Listing
January 2020

Cellular Therapy for Ischemic Heart Disease: An Update.

Adv Exp Med Biol 2019 ;1201:195-213

Gill Heart and Vascular Institute and Division of Cardiovascular Medicine, University of Kentucky and the Lexington VA Medical Center, Lexington, KY, USA.

Ischemic heart disease (IHD), which includes heart failure (HF) induced by heart attack (myocardial infarction, MI), is a significant cause of morbidity and mortality worldwide (Benjamin, et al. Circulation 139:e56-e66, 2019). MI occurs at an alarmingly high rate in the United States (approx. One case every 40 seconds), and the failure to repair damaged myocardium is the leading cause of recurrent heart attacks, heart failure (HF), and death within 5 years of MI (Benjamin, et al. Circulation 139:e56-e66, 2019). At present, HF represents an unmet need with no approved clinical therapies to replace the damaged myocardium. As the population ages, the number of heart failure patients is projected to increase, doubling the annual cost by 2030 (Benjamin, et al. Circulation 139:e56-e66, 2019). In the past decades, stem cell therapy has become a promising strategy for cardiac regeneration. However, stem cell-based therapy yielded modest success in human clinical trials. This chapter examines the types of cells examined in cardiac therapy in the setting of IHD, with a brief introduction to ongoing research aiming at enhancing the therapeutic potential of transplanted cells.
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http://dx.doi.org/10.1007/978-3-030-31206-0_10DOI Listing
February 2020

Identification of Human Very Small Embryonic like Stem Cells (VSELS) in Human Heart Tissue Among Young and Old Individuals.

Stem Cell Rev Rep 2020 02;16(1):181-185

Saha Cardiovascular Research Center, University of Kentucky, Lexington, KY, USA.

Very Small Embryonic-Like (VSEL) stem cells are a proposed pluripotent population, residing in adult tissues. VSELs have been described in multiple tissues including bone marrow, cord blood, and gonads. They exhibit multiple characteristics of embryonic stem cells including the ability to differentiate into cellular lineages of all three germ layers, including cardiomyocytes and vascular endothelial cells. However, their presence in adult solid organs such as heart in humans has not been established. VSELs are valuable source of stem cells for tissue regeneration and replacement of cells for turnover and usual wear-and-tear. The purpose of our study was to explore the existence of human VSELs (huVSELs) in human heart tissue and examine the changes in their prevalence with aging and cardiac disease. Human heart tissue, collected from healthy and ischemic heart disease subjects was examined for the prevalence of VSELS, defined as CD45-/CD133+/SSEA4+. Both epicardial and endocardial tissues were examined comparing VSEL numbers across different age groups. Our data confirm the existence of huVSELs in adult hearts with decreasing prevalence during aging. This is the first evidence of huVSELs in adult cardiac tissue. Cardiac huVSELs could be further explored in future studies to characterize their primitive potential and therapeutic potential in regenerative studies.
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http://dx.doi.org/10.1007/s12015-019-09923-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7027381PMC
February 2020

Treatment Bias in Management of HIV Patients Admitted for Acute Myocardial Infarction: Does It Still Exist?

J Gen Intern Med 2020 01 11;35(1):57-62. Epub 2019 Nov 11.

Division of Cardiovascular Medicine, University of Kentucky, Lexington, KY, USA.

Introduction: Previous studies have reported lower rates of coronary angiography and revascularization, and significantly higher mortality among patients infected with human immunodeficiency virus (HIV) presenting with acute myocardial infarction (AMI). This observational study was designed to evaluate characteristics and inpatient outcomes of patients with seropositive HIV infection presenting with AMI.

Methods: Using the National Inpatient Sample (NIS) database, we identified patients (admissions) with a primary diagnosis of myocardial infarction and a co-occurring HIV. We described baseline characteristics and outcomes. Our primary outcomes of interest were prevalence of coronary angiography, revascularization (percutaneous coronary intervention (PCI) or CABG), and mortality.

Results: From 2010 to 2014, of about 2,977,387 patients with a primary diagnosis of AMI, 10,907 (0.4%) were HIV seropositive. Patients with HIV were younger and more likely to be African American or Hispanic. Coronary angiography and revascularization were performed more frequently in the HIV population. The higher prevalence of revascularization was driven by a higher incidence of PCI. In a multivariable model, patients with HIV were no more likely to undergo revascularization than the general population. This was also the case for PCI. Unadjusted all-cause mortality was lower among patients with HIV. After controlling for confounders, this finding was not significant (OR 0.97, 95% CI 0.75-1.25, p = 0.79). The length of stay between both groups was comparable.

Conclusion: In this current analysis, we did not note any treatment bias or difference in the rate of in-hospital total mortality for HIV-seropositive patients presenting with AMI compared with the general population.
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http://dx.doi.org/10.1007/s11606-019-05416-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6957660PMC
January 2020

Left ventricular dysfunction postsurgical patent ductus arteriosus ligation in children: predictor factors analysis.

J Cardiothorac Surg 2019 Sep 18;14(1):168. Epub 2019 Sep 18.

Department of cardiothoracic surgery, Qena Faculty of Medicine, South Valley University, Safaga Road, Qena, 83523, Egypt.

Objective: To identify the predictor factors of left ventricular (LV) dysfunction following patent ductus arteriosus (PDA) surgical ligation.

Background: PDA is viewed as a noticeable amongst the most widely recognized congenital heart defects in children and its closure is responsible for many hemodynamic changes that require intervention and care.

Methods: A retrospective study included fifty children with isolated PDA treated by surgical ligation from June 2015 to June 2018. The LV dimensions and systolic function were assessed by two-dimensional echocardiography pre and post PDA ligation. All cases were followed-up on the first-day, 1 month and 6 months post ligation.

Results: The mean age of cases was 15.78 ± 7.58 months and 72% were females. The mean duct size was 4.08 ± 1.25 mm. There was a marked decrease in LVEDd, LA/Ao, EF and FS in the first-day post ligation contrasted with pre ligation values. Moreover, an amazing decline in LVEDd and LA/Ao ratio was observed 1 month post ligation contrasted with the early post ligation status with asynchronous improvement of FS and EF at one and 6 months postoperatively.

Conclusion: PDA ligation is associated with a noteworthy LV systolic dysfunction within the first day post ligation; that in a significant number of patients may require anti-failure measures, prolong the hospital stay and necessitate a regular follow up and monitoring of LV function. PDA size, age, preoperative LVEDd and FS can be considered as predictor factors for suspicion of acute decrease in the LV systolic function early post PDA ligation.

Trial Registration: ClinTrial.Gov NCT04018079 .
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http://dx.doi.org/10.1186/s13019-019-0990-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6751680PMC
September 2019

Ischemic Stroke After Percutaneous Coronary Intervention: Rare, But Devastating.

JACC Cardiovasc Interv 2019 08;12(15):1507-1509

Gill Heart and Vascular Institute and Division of Cardiovascular Medicine, University of Kentucky, Lexington, Kentucky.

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http://dx.doi.org/10.1016/j.jcin.2019.05.013DOI Listing
August 2019

Prognostic Role of Elevated Myeloperoxidase in Patients with Acute Coronary Syndrome: A Systemic Review and Meta-Analysis.

Mediators Inflamm 2019 25;2019:2872607. Epub 2019 Jun 25.

Gill Heart Institute and Division of Cardiovascular Medicine, University of Kentucky and the Lexington VA Medical Center, Lexington, KY, USA.

Background: Myocardial inflammation following acute ischemic injury has been linked to poor cardiac remodeling and heart failure. Many studies have linked myeloperoxidase (MPO), a neutrophil and inflammatory marker, to cardiac inflammation in the setting of acute coronary syndrome (ACS). However, the prognostic role of MPO for adverse clinical outcomes in ACS patients has not been well established.

Methods: MEDLINE and Cochrane databases were searched for studies from 1975 to March 2018 that investigated the prognostic value of serum MPO in ACS patients. Studies which have dichotomized patients into a high MPO group and a low MPO group reported clinical outcomes accordingly and followed up patients for at least 30 days to be eligible for enrollment. Data were analyzed using random-effects model. Sensitivity analyses were conducted for quality control.

Results: Our meta-analysis included 13 studies with 9090 subjects and a median follow-up of 11.4 months. High MPO level significantly predicted mortality (odds ratio (OR) 2.03; 95% confidence interval (CI): 1.40-2.94; < 0.001), whereas it was not significantly predictive of major adverse cardiac events and recurrent myocardial infarction (MI) (OR 1.28; CI: 0.92-1.77, = 0.14 and OR 1.23; CI: 0.96-1.58, = 0.101, respectively). Hypertension, diabetes mellitus, and age did not affect the prognostic value of MPO for clinical outcomes, whereas female gender and smoking status have a strong influence on the prognostic value of MPO in terms of mortality and recurrent MI (metaregression coefficient -8.616: 95% CI -14.59 to -2.633, = 0.0048 and 4.88: 95% CI 0.756 to 9.0133, = 0.0204, respectively).

Conclusions: Our meta-analysis suggests that high MPO levels are associated with the risk of mortality and that MPO can be incorporated in risk stratification models that guide therapy of high-risk ACS patients.
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http://dx.doi.org/10.1155/2019/2872607DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6614978PMC
February 2020