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Mohammad T Alrefai,1–3 Divya Murali,4 Arghya Paul,4 Khalid M Ridwan,1,2 John M Connell,1,2 Dominique Shum-Tim1,2 1Division of Cardiac Surgery, 2Division of Surgical Research, McGill University Health Center, Montreal, QC, Canada; 3King Faisal Specialist Hospital and Research Center, Jeddah, Saudi Arabia; 4Department of Chemical and Petroleum Engineering, School of Engineering, University of Kansas, Lawrence, KS, USA Abstract: Stem cell therapy and tissue engineering represent a forefront of current research in the treatment of heart disease. With these technologies, advancements are being made into therapies for acute ischemic myocardial injury and chronic, otherwise nonreversible, myocardial failure. The current clinical management of cardiac ischemia deals with reestablishing perfusion to the heart but not dealing with the irreversible damage caused by the occlusion or stenosis of the supplying vessels. The applications of these new technologies are not yet fully established as part of the management of cardiac diseases but will become so in the near future. The discussion presented here reviews some of the pioneering works at this new frontier. Key results of allogeneic and autologous stem cell trials are presented, including the use of embryonic, bone marrow-derived, adipose-derived, and resident cardiac stem cells. Keywords: stem cells, cardiomyocytes, cardiac surgery, heart failure, myocardial ischemia, heart, scaffolds, organoids, cell sheet and tissue engineering

One of the major challenges in vascular tissue regeneration is effective wound healing that can be resolved by an innovative targeted nanoshuttle that delivers growth factors to blood vessels. This study investigates the production and efficacy of transforming growth factor-β1 (TGFβ1) gene delivery using poly(lactic- co -glycolic acid) (PLGA) baculovirus (BV) nanoshuttles (NSs). They exhibited an encapsulation efficiency of 86.23% ± 0.65% and a negative zeta potential of -29.57 ± 1.27 mV. In vitro studies in human umbilical vein endothelial cells (HUVECs) revealed that a 12 h incubation period optimized virus transduction. The safety and superior intracellular uptake of NSs and BVs in HUVECs were observed. The NSs carrying 100 and 400 MOI exhibited the highest cell proliferation rates in HUVECs. These sustained-release NSs significantly improved vascular cell migration and wound closure compared to free TGFβ1 carrying BV and can be a groundbreaking find in regenerative medicine, cardiovascular diseases, and chronic ulcer conditions., Competing Interests: The authors declare no competing financial interest., (© 2024 American Chemical Society.)

Biomechanics-based patient-specific modeling is a promising approach that has proved invaluable for its clinical potential to assess the adversities caused by ischemic heart disease (IHD). In the present study, we propose a framework to find the passive material properties of the myocardium and the unloaded shape of cardiac ventricles simultaneously in patients diagnosed with ischemic cardiomyopathy (ICM). This was achieved by minimizing the difference between the simulated and the target end-diastolic pressure-volume relationships (EDPVRs) using black-box Bayesian optimization, based on the finite element analysis (FEA). End-diastolic (ED) biventricular geometry and the location of the ischemia were determined from cardiac magnetic resonance (CMR) imaging. We employed our pipeline to model the cardiac ventricles of three patients aged between 57 and 66 years, with and without the inclusion of valves. An excellent agreement between the simulated and the target EDPVRs has been reached. Our results revealed that the incorporation of valvular springs typically leads to lower hyperelastic parameters for both healthy and ischemic myocardium, as well as a higher fiber Green strain in the viable regions compared to models without valvular stiffness. Furthermore, the addition of valve-related effects did not result in significant changes in myofiber stress after optimization. We concluded that more accurate results could be obtained when cardiac valves were considered in modeling ventricles. The present novel and practical methodology paves the way for developing digital twins of ischemic cardiac ventricles, providing a non-invasive assessment for designing optimal personalized therapies in precision medicine., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Coronary stents have saved millions of lives in the last three decades by treating atherosclerosis especially, by preventing plaque protrusion and subsequent aneurysms. They attenuate the vascular SMC proliferation and promote reconstruction of the endothelial bed to ensure superior revascularization. With the evolution of modern stent types, nanotechnology has become an integral part of stent technology. Nanocoating and nanosurface fabrication on metallic and polymeric stents have improved their drug loading capacity as well as other mechanical, physico-chemical, and biological properties. Nanofeatures can mimic the natural nanofeatures of vascular tissue and control drug-delivery. This review will highlight the role of nanotechnology in addressing the challenges of coronary stents and the recent advancements in the field of related medical devices. Different generations of stents carrying nanoparticle-based formulations like liposomes, lipid-polymer hybrid NPs, polymeric micelles, and dendrimers are discussed highlighting their roles in local drug delivery and anti-restenotic properties. Drug nanoparticles like Paclitaxel embedded in metal stents are discussed as a feature of first-generation drug-eluting stents. Customized precision stents ensure safe delivery of nanoparticle-mediated genes or concerted transfer of gene, drug, and/or bioactive molecules like antibodies, gene mimics via nanofabricated stents. Nanotechnology can aid such therapies for drug delivery successfully due to its easy scale-up possibilities. However, limitations of this technology such as their potential cytotoxic effects associated with nanoparticle delivery that can trigger hypersensitivity reactions have also been discussed in this review. This article is categorized under: Implantable Materials and Surgical Technologies > Nanotechnology in Tissue Repair and Replacement Therapeutic Approaches and Drug Discovery > Nanomedicine for Cardiovascular Disease Therapeutic Approaches and Drug Discovery > Emerging Technologies., (© 2024 The Authors. WIREs Nanomedicine and Nanobiotechnology published by Wiley Periodicals LLC.)

Introduction: Ventricular septal defect (VSD) is a mechanical complication of acute myocardial infarction (MI) with a very high mortality, despite advances in surgical and circulatory support. The tremendous hemodynamic disturbance and the severely fragile myocardium render surgical repair a great challenge. The optimal time of surgical repair with or without circulatory support is still controversial., Objective: The aim of this study is to review our experience with early surgical repair of post-MI VSD in a single major cardiac institution in China., Methods: From January 2013 to October 2020, 9consecutive patients presented to our emergency department with a diagnosis of post-MI VSD. Among them, 8 were male, and the mean age was 58 ± 7years. The mean VSD size was 22.5 ± 5.7 mm. In all patients, an intra-aortic balloon pump (IABP)was inserted immediately after admission to cardiac surgery service. All patients were operated at a mean of 3.3 ± 2.9 days, and 4 within 24 h of the rupture (range 1 to 9 days post-VSD). In 5 cases, the VSD was located superiorly, and 4 cases in the posterior septum., Results: The overall 30-day mortality was 11% (1/9). Coronary angiography was performed in all nine patients, four with single vessel disease had coronary stents implanted, and the other five received concomitant coronary artery bypass grafting during VSD repair surgery. There was no death in all 5 patients with anterior septal perforation. One patient with posterior septal perforation died in the operating room due to bleeding from the ventriculotomy site. Three survived patients were diagnosed with a small residual defect and mild left to right shunt post-repair. However, no further intervention was required, and patients remained asymptomatic (Killip II in 1 and III in 2)., Conclusion: In our experience, immediate insertion of IABP and hemodynamic stabilization with early surgical intervention of VSD repair and concomitant coronary revascularization provided an 89% survival rate., (© 2023. The Author(s).)

Nitric oxide synthase 3 (NOS3) eluting polyvinyl alcohol-based hydrogels have a large potential in medical applications and device coatings. NOS3 promotes nitric oxide and nitrate production and can effectively be delivered using insect cell viruses, termed baculoviruses. Nitric oxide is known for regulating cell proliferation, promoting blood vessel vasodilation, and inhibiting bacterial growth. The polyvinyl alcohol (PVA)-based hydrogels investigated here sustained baculovirus elution from five to 25 days, depending on the hydrogel composition. The quantity of viable baculovirus loaded significantly declined with each freeze-thaw from one to four (15.3 ± 2.9% vs. 0.9 ± 0.5%, respectively). The addition of gelatin to the hydrogels protected baculovirus viability during the freeze-thaw cycles, resulting in a loading capacity of 94.6 ± 1.2% with sustained elution over 23 days. Adding chitosan, PEG-8000, and gelatin to the hydrogels altered the properties of the hydrogel, including swelling, blood coagulation, and antimicrobial effects, beneficial for different therapeutic applications. Passive absorption of the baculovirus into PVA hydrogels exhibited the highest baculovirus loading (96.4 ± 0.6%) with elution over 25 days. The baculovirus-eluting hydrogels were hemocompatible and non-cytotoxic, with no cell proliferation or viability reduction after incubation. This PVA delivery system provides a method for high loading and sustained release of baculoviruses, sustaining nitric oxide gene delivery. This proof of concept has clinical applications as a medical device or stent coating by delivering therapeutic genes, improving blood compatibility, preventing thrombosis, and preventing infection., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Schaly et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Reduction of right ventricular (RV) function after cardiac surgery has been shown to impact outcomes. Conventional indices for right ventricular dysfunction are validated using transthoracic echocardiogram (TTE) which has limited use compared to transesophageal echocardiogram (TEE) in the perioperative settings. The aim of this study was to assess the agreement of RV systolic function assessment with TEE compared to TTE and assess the association of echocardiographic parameter with hemodynamic indices of RV dysfunction. This was a single center prospective observational study in an academic institution. Fifty adult patients undergoing elective cardiac surgery were included. TTE, TEE and stroke volume measurements pre-cardiopulmonary bypass (CPB) and post-CPB were performed. The variables of interest were anatomical M-mode tricuspid annular plane systolic excursion (AMM-TAPSE), fractional area change (FAC), tricuspid annular velocity (S') and myocardial performance index (MPI). FAC and AMM-TAPSE measured at the mid-esophageal 4 chamber view had substantial agreement with the TTE acquired parameters (Lin's concordance correlation coefficient (CCC) = 0.76, 95%CI 0.59-0.86 and CCC = 0.85, 95%CI 0.76-0.91). S' was significantly underestimated by TEE (CCC = 0.07, 95%CI 0.04-0.19) and MPI showed moderate agreement (CCC = 0.45 95%CI 0.19-0.65). Despite the significant changes in echocardiographic parameters, there were no corresponding changes in stroke volume (SV) or pulmonary artery pulsatility index at the post-CPB period. TEE acquired FAC and AMM-TAPSE had substantial agreement with pre-operative TTE values and no significant differences between the pre-CPB and post-CPB period. Systolic RV echocardiographic parameters decreased post-CPB but this was not accompanied by significant hemodynamic changes., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

Although the field of cardiac regeneration is relatively young, it is progressing rapidly with technological advancements. Genome editing tools are allowing researchers to creatively influence signaling pathways to be able to shed light on them and are important for addressing certain issues and limitations associated with in vitro and in vivo aspects of cardiac regeneration, such as imaging and immune rejection. In this chapter, the pathways involved in cardiac regeneration will be highlighted, and the role of gene-editing tools in endogenous and exogenous approaches to regenerate injured myocardium is discussed., (© 2023. The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd.)

Hydrogel wound dressings are effective in their ability to provide a wound-healing environment but are limited by their ability to promote later stages of revascularization. Here, a biosafe recombinant baculovirus expressing VEGFA tagged with EGFP is encapsulated in chitosan-coated alginate hydrogels using ionic cross-linking. The VEGFA, delivered by the baculovirus, significantly improves cell migration and angiogenesis to assist with the wound-healing process and revascularization. Moreover, the hydrogels have an encapsulation efficiency of 99.9%, no cytotoxicity, antimicrobial properties, good blood compatibility, promote hemostasis, and enable sustained delivery of baculoviruses over eight days. These hydrogels sustain baculovirus delivery and may have clinical implications in wound dressings or future gene therapy applications.

Background: This study sought to compare characteristics and outcomes of patients who underwent surgical aortic valve replacement (SAVR) after being referred to a heart team (HT), to those of patients referred directly for SAVR., Methods: An analysis of patients who underwent SAVR from 2015 to 2020 was conducted. Patients were categorized into 3 groups, as follows: (i) H-HT: patients referred to the HT from 2015 to 2017 (historical cohort); (ii) C-HT: patients referred to the HT from 2018 to 2020 (contemporary cohort); and (iii) No-HT: patients referred directly to cardiac surgery from 2018 to 2020. Two subanalyses were performed: H-HT vs C-HT patients, and C-HT vs No-HT patients. The primary outcome was a composite of in-hospital mortality, prolonged intubation, reoperation, sternal wound infection, and stroke., Results: This study consisted of 288 patients, distributed as follows: H-HT (n = 45); C-HT (n = 51); and No-HT (n = 192). The mean ages of H-HT, C-HT, and No-HT patients was 76.3 ± 6.9 years, 73.3 ± 7.6 years, and 69.6 ± 9.7 years, respectively ( P  = 0.0001). H-HT, C-HT, and No-HT patients had average Society of Thoracic Surgeons scores of 4.8 ± 2.2, 3.2 ± 1.6, and 4.2 ± 2 ( P  = 0.002), respectively. The composite outcome rate was more than 5 times higher among H-HT patients compared to that among the C-HT patients (20.0 vs 3.9%, P  = 0.02), and was numerically higher in No-HT compared to C-HT patients (13.0 vs 3.9%, P  = 0.07)., Conclusions: Referral to an HT appears to be primarily driven by higher chronological age rather than overall risk profile. Patients assessed by the HT prior to undergoing SAVR have a low incidence of complications, comparable to that among patients referred directly to cardiac surgery., (© 2022 The Authors.)

Background: The COVID-19 pandemic has had a major impact on cardiac surgery patients. Significant reductions in access to surgical treatment have forced surgeons to prioritise patients and follow strict COVID-19 protocols to protect surgeons, staff, and patients. Adult cardiac surgery and the COVID-19 pandemic: aggressive infection mitigation strategies are necessary in the operating room and surgical recovery. Nosocomial infections among cardiac surgery patients have been reported and are associated with a high mortality rate. As a COVID-19 tertiary care centre and a tertiary cardiac centre, we tried to balance the need to operate on urgent cardiac cases while protecting patients and staff from COVID-19., Methods: During the first wave of the pandemic, we performed 579 surgeries. We report findings from an outbreak of 4 nosocomial infections., Results: All patients tested negative within 24 hours of surgery or admission. Three patients were positive after surgery, suggesting an overall nosocomial rate during the first wave of 0.5% (3/579). One patient admitted for evaluation tested positive during mass screening. Two of the 4 patients died after respiratory complications. No health care worker (HCW) or family member with direct contact with these patients tested positive for COVID-19. Nosocomial COVID-19 infection is uncommon when adhering to safety protocols. Although uncommon, the mortality rate is high (50%) in our series., Conclusions: As widespread vaccination of HCWs and high-risk individuals susceptible to COVID-19 is in progress, we suggest that cardiac surgery patients, when feasible, be vaccinated before surgery given this could prevent excess mortality, protect HCWs and reduce resource use., (© 2021 The Authors.)

Congestive heart failure, a prominent cardiovascular disease results primarily from myocardial infarction or ischemia. Milrinone (MRN), a widely used clinical drug for heart failure, improves myocardial contractility and cardiac function through its inotropic and vasodilatory effects. However, lacking target specificity, it exhibits low bioavailability and lower body retention time. Therefore, in this study, angiotensin II (AT1) peptide conjugated human serum albumin nanoparticles (AT1-HSA-MRN-NPs) have been synthesized for targeted delivery of MRN to the myocardium, overexpressing AT1 receptors under heart failure. The NPs were surface functionalized through a covalent conjugation reaction between HSA and AT1. Nanoparticle size was 215.2±4.7 nm and zeta potential -28.8±2.7 mV and cumulative release of MRN was ~72% over 24 hrs. The intracellular uptake of nanoparticles and cell viability was studied in H9c2 cells treated with AT1-MRN-HSA-NPs vs the control non-targeted drug, MRN Lactate under normal, hypoxic and hypertrophic conditions. The uptake of AT1-HSA-MRN-NPs in H9c2 cells was significantly higher as compared to non-targeted nanoparticles, and the viability of H9c2 cells treated with AT1-MRN-HSA-NPs vs MRN Lactate was 73.4±1.4% vs 44.9±1.4%, respectively. Therefore, AT1-HSA-MRN-NPs are safe for in vivo use and exhibit superior targeting and drug delivery characteristics for treatment of heart failure., Competing Interests: The authors declare no competing interests.

Congestive heart failure is a fatal cardiovascular disease resulting in tissue necrosis and loss of cardiac contractile function. Inotropic drugs such as milrinone are commonly used to improve the myocardial contractility and heart function. However, milrinone is associated with severe side effects and lower circulation time. In this article, a novel protein nanoparticle formulation for heart-targeted delivery of milrinone has been designed and tested. The formulation was prepared using albumin protein conjugated with the targeting ligand, angiotensin II peptide to form nanoparticles following the ethanol desolvation method. The formulation was characterized for size, charge, and morphology and tested in a rat model of congestive heart failure to study pharmacokinetics, biodistribution, and efficacy. The overall cardiac output parameters were evaluated comparing the formulation with the control non-targeted drug, milrinone lactate. This formulation exhibited improved pharmacokinetics with a mean retention time of 123.7 min, half-life of 101.3 min, and clearance rate of 0.24 L/(kg*h). The targeted formulation also significantly improved ejection fraction and fractional shortening parameters thus improving cardiac function. This study demonstrates a new approach in delivering inotropic drugs such as milrinone for superior treatment of congestive heart failure.

Aims: Diabetes is a conventional risk factor for atherosclerotic cardiovascular disease and myocardial infarction (MI) is the most common cause of death among these patients. Mesenchymal stromal cells (MSCs) in patients with type 2 diabetes mellitus (T2DM) and atherosclerosis have impaired ability to suppress activated T-cells (i.e. reduced immunopotency). This is mediated by an inflammatory shift in MSC-secreted soluble factors (i.e. pro-inflammatory secretome) and can contribute to the reduced therapeutic effects of autologous T2DM and atherosclerosis-MSC post-MI. The signalling pathways driving the altered secretome of atherosclerosis- and T2DM-MSC are unknown. Specifically, the effect of IκB kinase β (IKKβ) modulation, a key regulator of inflammatory responses, on the immunopotency of MSCs from T2DM patients with advanced atherosclerosis has not been studied., Methods and Results: MSCs were isolated from adipose tissue obtained from patients with (i) atherosclerosis and T2DM (atherosclerosis+T2DM MSCs, n = 17) and (ii) atherosclerosis without T2DM (atherosclerosis MSCs, n = 17). MSCs from atherosclerosis+T2DM individuals displayed an inflammatory senescent phenotype and constitutively expressed active forms of effectors of the canonical IKKβ nuclear factor-κB transcription factors inflammatory pathway. Importantly, this constitutive pro-inflammatory IKKβ signature resulted in an altered secretome and impaired in vitro immunopotency and in vivo healing capacity in an acute MI model. Notably, treatment with a selective IKKβ inhibitor or IKKβ knockdown (KD) (clustered regularly interspaced short palindromic repeats/Cas9-mediated IKKβ KD) in atherosclerosis+T2DM MSCs reduced the production of pro-inflammatory secretome, increased survival, and rescued their immunopotency both in vitro and in vivo., Conclusions: Constitutively active IKKβ reduces the immunopotency of atherosclerosis+T2DM MSC by changing their secretome composition. Modulation of IKKβ in atherosclerosis+T2DM MSCs enhances their myocardial repair ability., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Background: The paracrine effects of multipotent mesenchymal stromal cells (MSCs) are mediated by their secretome composed by soluble factors (i.e., cytokines, growth factors, hormones) and extracellular vesicles (EVs). EVs promote intercellular communication, and the EV cargoes [e.g., proteins, soluble factors, microRNAs (miRNAs), messenger RNA (mRNA), DNA] reflect the molecular and functional characteristics of their parental cells. MSC-derived EVs (MSC-EVs) are currently evaluated as subcellular therapeutics. A key function of the MSC secretome is its ability to promote immune tolerance (i.e., immunopotency), a property that is enhanced by priming approaches (e.g., cytokines, hypoxia, chemicals) and inversely correlates with the age of the MSC donors. We evaluated mechanisms underlying MSC vesiculation and the effects of inflammation and aging on this process., Methods: We evaluated the effects of interferon gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α) on human adipose-derived MSC: (a) vesiculation (custom RT 2 Profiler PCR Array), (b) EV profiles (Nanoparticle Tracking Analysis and Nanoparticle Flow Cytometry), (c) EV cargo (proteomic analysis and Western blot analysis), and (d) immunopotency (standard MSC:CD4 T cell proliferation inhibition assay). We confirmed the role of RAB27B on MSC vesiculation (RAB27B siRNA) and assessed its differential contribution to vesiculation in adult and pediatric MSCs (qPCR)., Results: Cytokine priming upregulated RAB27B in adipose-derived MSCs increasing their secretion of exosome-like small EVs (sEVs; < 200 nm) containing two key mediators of immunopotency: A20 and TSG-6. These EVs inhibited T cell proliferation in a dose-dependent manner. RAB27B siRNA inhibited MSC vesiculation. Adipose-derived MSCs isolated from pediatric donors exhibited higher RAB27B expression and secreted more sEVs than adult MSCs., Conclusions: Cytokine priming is a useful strategy to harvest anti-inflammatory MSC-sEVs for clinical applications. Of relevance, donor age should be considered in the selection of MSC-sEVs for clinical applications.

Aortic valve stenosis (AVS) is a prevailing and life-threatening cardiovascular disease in adults over 75 years of age. However, the molecular mechanisms governing the pathogenesis of AVS are yet to be fully unraveled. With accumulating evidence that Wnt signaling plays a key role in the development of AVS, the involvement of Wnt molecules has become an integral study target in AVS pathogenesis. Thus, we hypothesized that the Wnt/β-catenin pathway mediators, SFRP2, DVL2, GSK3β and β-catenin are dysregulated in patients with AVS. Using immunohistochemistry, Real-Time qPCR and Western blotting, we investigated the presence of SFRP2, GSK-3β, DVL2, and β-catenin in normal and stenotic human aortic valves. Markedly higher mRNA and protein expression of GSK-3β, DVL2, β-catenin and SFRP2 were found in stenotic aortic valves. This was further corroborated by observation of their abundant immunostaining, which displayed strong immunoreactivity in diseased aortic valves. Proteomic analyses of selective GSK3b inhibition in calcifying human aortic valve interstitial cells (HAVICs) revealed enrichment of proteins involved organophosphate metabolism, while reducing the activation of pathogenic biomolecular processes. Lastly, use of the potent calcification inhibitor, Fetuin A, in calcifying HAVICs significantly reduced the expression of Wnt signaling genes Wnt3a, Wnt5a, Wnt5b, and Wnt11. The current findings of altered expression of canonical Wnt signaling in AVS suggest a possible role for regulatory Wnts in AVS. Hence, future studies focused on targeting these molecules are warranted to underline their role in the pathogenesis of the disease., (Copyright © 2020 Khan, Yu, Kiwan, Shalal, Filimon, Cipro, Shum-Tim, Cecere and Schwertani.)

Degenerative aortic stenosis is the most common valvular disease worldwide; however, its physiopathology remains poorly understood. Although, developments in prevention of this disease have remained relatively stagnant, the last decade has brought about innovative treatment options incorporating different percutaneous and surgical approaches. These advances have allowed physicians to offer relief to high-risk patients, previously deemed nonsurgical. Increasingly, there is a shift toward offering percutaneous valve replacement to moderate and low-risk patients with aortic stenosis. Enthusiasm for a new treatment option must always be tempered by caution; as defining appropriate patient selection is essential to achieve optimal outcomes.

Objectives: Surgery triggers a stress response that produces insulin resistance and hyperglycemia. During cardiac surgery, the administration of high-dose insulin along with dextrose titration maintains normoglycemia, but dramatically decreases plasma amino acids (AAs) compared with preoperative fasting levels. Hypoaminoacidemia limits protein synthesis and prevents anabolic responses after surgery. We investigated whether parenteral infusion of AAs during and immediately after cardiac surgery would prevent hypoaminoacidemia in patients who receive high-dose insulin therapy., Methods: Sixteen patients undergoing coronary artery bypass grafting surgery were randomly allocated to receive AAs with % kcal equivalent to either 20% (n = 8) or 35% (n = 8) of their measured resting energy expenditure (REE). Insulin was infused at a constant rate of 5 mU/(kg × min), whereas dextrose was titrated to maintain normoglycemia during and until 5 h after surgery. Plasma AA concentrations were measured at baseline before and after surgery., Results: Compared with the 20% AA group after surgery, AA concentrations were significantly higher in the 35% AA group for 12 of 20 AAs (P < 0.032), including all branched-chain AAs. In the 20% AA group, total essential AAs decreased by 21% and nonessential AAs decreased by 14% after surgery compared with preoperative fasting levels. In contrast, giving 35% AAs prevented this unfavorable decrease in AAs, and in fact allowed for a 23% and 12% increase in essential and nonessential AAs, respectively., Conclusions: AA supplementation at 35% REE, but not 20% REE, can effectively prevent hypoaminoacidemia caused by high-dose insulin therapy during cardiac surgery., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Introduction: Few bioprosthetic valved conduits for aortic root surgery are commercially available. Long-term Warfarin therapy (mechanical), potential root calcification (xeno- or homograft valves), and the need for additional ascending aorta grafts are concerns associated with currently used valved conduits. A simplified, self-assembled bioroot conduit comprising currently available materials that facilitates future intervention and exhibits advantages of a bioprosthesis was used., Methods: From November 2015 to January 2017, 17 consecutive patients underwent urgent or elective aortic root surgery. A bioroot conduit, constructed using 28 or 30 mm of sinus of Valsalva Gelweave tube graft and a 3 to 5 mm smaller bioprosthetic Trifecta valve sewn into the sinus of Valsalva base, was preconstructed in the operating room before sternotomy. The size of the valved conduit was based on the distal ascending aorta or proximal arch and not aortic annular dimension. The bioroot was sutured to the native aortic annulus at the level of the bottom skirt of the Valsalva graft without contacting the sewing cuff of the bioprosthetic valve., Results: All patients survived the operation and were discharged home without long-term anticoagulation therapy. The mean age was 65 ± 12 years, and 13 patients were male. The cardiopulmonary bypass duration was 169 ± 84 minutes, and the cross-clamp (XC) duration was 110 ± 32 minutes. The operation was elective in 12 patients, urgent/emergent in five, and redo in three., Conclusion: A simplified self-assembled bioroot Bentall conduit is appropriate for aortic root reconstruction. Use of a patient-tailored valved conduit will not prolong the cardiac ischemic time and will facilitate future valve replacement., (© 2019 Wiley Periodicals, Inc.)

Objectives: Cell-based therapies have demonstrated variable degrees of success in the management of myocardial infarction and heart failure. By inducing a myocardial infarction in a rat model, the effects of secretome from human induced pluripotent stem cells (HiPSCs) and human mesenchymal stem cells (hMSCs) on cardiac function and remodeling were investigated., Methods: HiPSCs and hMSCs were cultured and after 12 cycles, secretome was collected. The quantification of stem cell growth factors was measured using the ELISA test. Thirty female Lewis rats underwent surgical ligation of the left coronary artery. The rats were then randomized (n=10/group) to receive one of three treatments injected into the peri-infarct area; normal saline, HiPSC and hMSC. Left ventricular ejection fraction (LVEF), fractional shortening (FS), histology and serum proteomics were evaluated in a blinded fashion both pre-operatively and at 2, 4 and 6 weeks., Results: ELISA studies revealed, Platelet-derived growth factor (PDGF) concentration of 3.35± 0.031 ng/ml (0.68± 0.027ng/ml) for MSC-CM group, 3.44± 0.042 ng/ml (0.78± 0.03 ng/ml) for the HiPSC-CM group, 3.2± 0.107 ng/ml (0.64±0.013 ng/ml) for the MSC-pre-group, 3.1± 0.075 ng/ml (0.71± 0.013 ng/ml) for the HiPSC-pre group and 3.3± 0.047 ng/ml (0.71± 0.014ng/ml) for the HiPSC-pre-r group at 60 min in comparison to at (0 min).Compared to non-treated (NT), HiPSC and hMSC, treated rats demonstrated significant improvement in LVEF and FS, and significant reduction in scar size (p<0.05) at 4 and 6 weeks. Proteomic analysis detected the presence of Vascular endothelial growth factor (VEGF) in the serum of rats receiving HiPSC, which was absent in the NT and hMSC groups., Conclusion: The current study demonstrated a significant improvement of cardiac function and remodeling in response to secretome from HiPSCs and hMSCs. These findings suggest that secretome from HiPSCs may have potential therapy for acute myocardial infarction (MI) without the need of stem cell harvesting and implantation.

Cardiovascular diseases are the leading causes of mortality across the globe. Over the years, various drug formulations and delivery methods have been tested for cardiac repair. Milrinone (MRN) is a widely known cardiac inotrope drug used for the treatment of congestive heart failure in patients, however, its efficacy is limited. This study is the first to report the design of a novel MRN-nanoformulation using human serum albumin nanoparticles (HSA-NPs). The HSA-NPs exhibit promising drug delivery characteristics, such as target specificity, nonimmunogenicity, biocompatibility, and enhanced bioavailability. This article describes a MRN-nanoformulation design for in vitro drug release, cellular uptake, biocompatibility, and other features. The MRN-nanoformulation was prepared by the ethanol desolvation technique and key parameters were optimized to obtain a desired particle size of 154.2 ± 5.8 nm, zeta potential of -29.5 ± 2.9 mV, and a drug encapsulation efficiency of 41.1 ± 1.7%. Molecular docking studies have revealed that MRN binds in the hydrophobic cavity of HSA, which has also been indicated by circular dichroism and enzyme-mediated drug release studies in the presence of trypsin, pepsin, proteinase K, protease, and cathepsin D. The intracellular uptake of fluorescently tagged MRN-HSA-NPs using HUVEC and H9c2 cells was evaluated by flow cytometry. The nanoparticle toxicity results indicated that MRN-HSA-NPs show significantly lower cytotoxicity and higher cell viability ( P < 0.0001) as compared to the MRN-lactate drug in HUVEC (61.6 ± 3.7% vs 36.2 ± 2.9%) and H9c2 (58.8 ± 5.7% vs 18.8 ± 4.9%) cells. These studies indicate that the novel MRN-nanoformulation offers better drug delivery procedures than currently used methods and has potential in treatment of congestive heart failure and other cardiovascular diseases.

The intra-aortic balloon pump (IABP) is frequently used to support severely compromised ventricles in critically ill patients. Its relatively affordability and ease of insertion has cemented its position as the first line of treatment for hemodynamic support in cardiogenic shock. Accordingly, the current ACC/AHA recommendations maintain a Class 2A for the use of IABP in shock. However, a review of the current literature suggests that the evidence supporting the American College of Cardiology and American Heart Association (ACC/AHA) guidelines are equivocal. Alternative uses for IABP such as perioperative support during high-risk cardiac surgery, treatment of left ventricular distention on extracorporeal membrane oxygenation, and as bridge to transplant have been proposed. The effectiveness of the IABP in these clinical situations remains largely unproven, due to the paucity of available data.

Rationale: Mesenchymal stromal cells (MSCs) are promising therapeutic strategies for coronary artery disease; however, donor-related variability in cell quality is a main cause of discrepancies in preclinical studies. In vitro, MSCs from individuals with coronary artery disease have reduced ability to suppress activated T-cells. The mechanisms underlying the altered immunomodulatory capacity of MSCs in the context of atherosclerosis remain elusive., Objective: The aim of this study was to assess the role of mitochondrial dysfunction in the impaired immunomodulatory properties of MSCs from patients with atherosclerosis., Methods and Results: Adipose tissue-derived MSCs were isolated from atherosclerotic (n=38) and nonatherosclerotic (n=42) donors. MSCs:CD4 + T-cell suppression was assessed in allogeneic coculture systems. Compared with nonatherosclerotic-MSCs, atherosclerotic-MSCs displayed higher levels of both intracellular ( P =0.006) and mitochondrial ( P =0.03) reactive oxygen species reflecting altered mitochondrial function. The increased mitochondrial reactive oxygen species levels of atherosclerotic-MSCs promoted a phenotypic switch characterized by enhanced glycolysis and an altered cytokine secretion (interleukin-6 P <0.0001, interleukin-8/C-X-C motif chemokine ligand 8 P =0.04, and monocyte chemoattractant protein-1/chemokine ligand 2 P =0.01). Furthermore, treatment of atherosclerotic-MSCs with the reactive oxygen species scavenger N-acetyl-l-cysteine reduced the levels of interleukin-6, interleukin-8/C-X-C motif chemokine ligand 8, and monocyte chemoattractant protein-1/chemokine ligand 2 in the MSC secretome and improved MSCs immunosuppressive capacity ( P =0.03)., Conclusions: An impaired mitochondrial function of atherosclerotic-MSCs underlies their altered secretome and reduced immunopotency. Interventions aimed at restoring the mitochondrial function of atherosclerotic-MSCs improve their in vitro immunosuppressive ability and may translate into enhanced therapeutic efficiency., (© 2017 American Heart Association, Inc.)

Lipoprotein(a), or Lp(a), significantly increased alkaline phosphatase activity, release of phosphate, calcium deposition, hydroxyapatite, cell apoptosis, matrix vesicle formation, and phosphorylation of signal transduction proteins; increased expression of chondro-osteogenic mediators; and decreased SOX9 and matrix Gla protein (p < 0.001). Inhibition of MAPK38 and GSK3β significantly reduced Lp(a)-induced calcification of human aortic valve interstitial cells (p < 0.001). There was abundant presence of Lp(a) and E06 immunoreactivity in diseased human aortic valves. The present study demonstrates a causal effect for Lp(a) in aortic valve calcification and suggests that interfering with the Lp(a)pathway could provide a novel therapeutic approach in the management of this debilitating disease.

Inflammation plays a pivotal role in the initiation and progression of atherosclerosis (ATH). Due to their potent immunomodulatory properties, mesenchymal stromal cells (MSCs) are evaluated as therapeutic tools in ATH and other chronic inflammatory disorders. Aging reduces MSCs immunopotency potentially limiting their therapeutic utility. The mechanisms that mediate the effect of age on MSCs immune-regulatory function remain elusive and are the focus of this study. Human adipose tissue-derived MSCs were isolated from patients undergoing coronary artery bypass graft surgery. MSCs:CD4 + T-cell suppression, a readout of MSCs' immunopotency, was assessed in allogeneic coculture systems. MSCs from elderly subjects were found to exhibit a diminished capacity to suppress the proliferation of activated T cells. Soluble factors and, to a lesser extent, direct cell-cell contact mechanisms mediated the MSCs:T-cell suppression. Elderly MSCs exhibited a pro-inflammatory secretome with increased levels of interleukin-6 (IL-6), IL-8/CXCL8, and monocyte chemoattractant protein-1 (MCP-1/CCL2). Neutralization of these factors enhanced the immunomodulatory function of elderly MSCs. In summary, our data reveal that in contrast to young MSCs, MSCs from elderly individuals with ATH secrete high levels of IL-6, IL-8/CXCL8 and MCP-1/CCL2 which mediate their reduced immunopotency. Consequently, strategies aimed at targeting pro-inflammatory cytokines/chemokines produced by MSCs could enhance the efficacy of autologous cell-based therapies in the elderly. Stem Cells Translational Medicine 2017;6:1132-1140., (© 2017 The Authors Stem Cells Translational Medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.)

Objective: The mechanisms underlying the pathogenesis of aortic valve calcification remain unclear. With accumulating evidence demonstrating that valve calcification recapitulates bone development, the crucial roles of noncanonical Wnt ligands WNT5a, WNT5b, and WNT11 in osteogenesis make them critical targets in the study of aortic valve calcification., Approach and Results: Using immunohistochemistry, real-time qPCR, Western blotting, and tissue culture, we examined the tissue distribution of WNT5a, WNT5b, and WNT11 in noncalcified and calcified aortic valves and their effects on human aortic valve interstitial cells (HAVICs). Only focal strong immunostaining for WNT5a was seen in and around areas of calcification. Abundant immunostaining for WNT5b and WNT11 was seen in inflammatory cells, fibrosis, and activated myofibroblasts in areas of calcified foci. There was significant correlation between WNT5b and WNT11 overall staining and presence of calcification, lipid score, fibrosis, and microvessels ( P <0.05). Real-time qPCR and Western blotting revealed abundant expression of both Wnts in stenotic aortic valves, particularly in bicuspid valves. Incubation of HAVICs from noncalcified valves with the 3 noncanonical Wnts significantly increased cell apoptosis and calcification ( P <0.05). Treatment of HAVICs with the mitogen-activated protein kinase-38β and GSK3β inhibitors significantly reduced their mineralization ( P <0.01). Raman spectroscopy identified the inorganic phosphate deposits as hydroxyapatite and showed a significant increase in hydroxyapatite deposition in HAVICs in response to WNT5a and WNT11 ( P <0.05). Similar crystallinity was seen in the deposits found in HAVICs treated with Wnts and in calcified human aortic valves., Conclusions: These findings suggest a potential role for noncanonical Wnt signaling in the pathogenesis of aortic valve calcification., (© 2016 American Heart Association, Inc.)

Cardiac surgery triggers an inflammatory stress response, leading to protein catabolism, a process that even high-dose insulin therapy alone cannot reverse. To determine whether hyperinsulinemic-normoglycemic clamp and perioperative amino acid (AA) supplementation improves whole body protein balance, 20 patients scheduled for elective coronary artery bypass grafting surgery were randomly assigned to have intra- and postoperative hyperinsulinemic-normoglycemic clamp, with or without intravenous AA supplementation. Primed continuous infusions of [6,6- 2 H 2 ]glucose and l-[1- 13 C]leucine were used to quantify whole body protein and glucose metabolism before and after surgery. Adipose tissue and serum cytokines were also analyzed to measure their responsiveness to the anabolic effect of AA administration. During hyperinsulinemic-normoglycemic clamp, AA supplementation successfully stimulated whole body protein synthesis, resulting in a positive whole body protein balance after surgery (insulin: -13.6 ± 4.5 vs. insulin + AA: 2.1 ± 5.4 μmol·kg -1 ·h -1 , P < 0.001). Endogenous glucose production was equally suppressed in both groups (insulin: 0.0 ± 3.8 vs. insulin + AA 1.6 ± 1.6 μmol·kg -1 ·min -1 , P = 0.230). AA supplementation led to significant changes in serum and tissue IL-6 (insulin: 246.6 ± 111.2 vs. insulin + AA: 124.5 ± 79.3 pg/ml, P = 0.011). In conclusion, hyperinsulinemic-normoglycemic clamp technique, together with AA supplementation, can induce an anabolic state after open-heart surgery, as quantified by a positive whole body protein balance., (Copyright © 2016 the American Physiological Society.)

Human serum albumin nanoparticles (HSA-NPs) are widely-used drug delivery systems with applications in various diseases, like cancer. For intravenous administration of HSA-NPs, the particle size, surface charge, drug loading and in vitro release kinetics are important parameters for consideration. This study focuses on the development of stable HSA-NPs containing the anti-cancer drug paclitaxel (PTX) via the emulsion-solvent evaporation method using a high-pressure homogenizer. The key parameters for the preparation of PTX-HSA-NPs are: the starting concentrations of HSA, PTX and the organic solvent, including the homogenization pressure and its number cycles, were optimized. Results indicate a size of 143.4 ± 0.7 nm and 170.2 ± 1.4 nm with a surface charge of -5.6 ± 0.8 mV and -17.4 ± 0.5 mV for HSA-NPs and PTX-HSA-NPs (0.5 mg/mL of PTX), respectively. The yield of the PTX-HSA-NPs was ~93% with an encapsulation efficiency of ~82%. To investigate the safety and effectiveness of the PTX-HSA-NPs, an in vitro drug release and cytotoxicity assay was performed on human breast cancer cell line (MCF-7). The PTX-HSA-NPs showed dose-dependent toxicity on cells of 52%, 39.3% and 22.6% with increasing concentrations of PTX at 8, 20.2 and 31.4 μg/mL, respectively. In summary, all parameters involved in HSA-NPs' preparation, its anticancer efficacy and scale-up are outlined in this research article.

Hematopoietic stem and progenitor cell (HSPC) homeostasis declines with age, leading to impaired hematopoiesis. Mesenchymal stromal cells (MSC) are critical components of the bone marrow niche and key regulators of the balance between HSPC proliferation and quiescence. Accrual of DNA damage, a hallmark of cellular aging, occurs in aged MSC. Whether MSC aging alters the bone marrow niche triggering HSPC dysfunction is unknown. Using a human MSC-HSPC co-culture system, we demonstrated that DNA damaged MSC have impaired capacity to maintain CD34+CD38- HSPC quiescence. Furthermore, human MSC from adult donors display some hallmarks of cellular senescence and have a decreased capacity to maintain HSPC quiescence and the most primitive CD34+CD38- subset compared to MSC from pediatric donors. IL-6 neutralization restores the MSC-HPSC crosstalk in senescent and adult MSC-HSPC co-cultures highlighting the relevance of the local microenvironment in maintaining HSPC homeostasis. These results provide new evidence implicating components of the MSC secretome in HSPC aging.

To this end human MSCs were isolated from adipose tissue and the MSC:CD4(+) T-cell suppression was assessed in a co-culture system. In summary, this study demonstrates that advanced age, atherosclerosis and type 2 diabetes mellitus reduce the functional potency of MSCs. Optimizing the criteria for the selection of MSC donors could enhance the results of cell-based therapies.

We investigated the effect of insulin administered as part of a hyperinsulinemic-normoglycemic clamp on protein metabolism after coronary artery bypass grafting (CABG) surgery. Eighteen patients were studied, with nine patients in the control group receiving standard metabolic care and nine patients receiving insulin (5 mU·kg(-1)·min(-1)). Whole body glucose production, protein breakdown, synthesis, and oxidation were determined using stable isotope tracer kinetics (l-[1-(13)C]leucine, [6,6-(2)H2]glucose) before and 6 h after the procedure. Plasma amino acids, cortisol, and lactate were also measured. Endogenous glucose production (preoperatively 10.0 ± 1.6, postoperatively 3.7 ± 2.5 μmol·kg(-1)·min(-1); P = 0.0001), protein breakdown (preoperatively 105.3 ± 9.8, postoperatively 85.2 ± 9.2 mmol·kg(-1)·h(-1); P = 0.0005) and synthesis (preoperatively 88.7 ± 8.7, postoperatively 72.4 ± 8.4 mmol·kg(-1)·h(-1); P = 0.0005) decreased in the presence of hyperinsulinemia, whereas both parameters remained unchanged in the control group. A positive correlation between endogenous glucose production and protein breakdown was observed in the insulin group (r(2) = 0.385). Whole body protein oxidation and balance decreased after surgery in patients receiving insulin without reaching statistical significance. In the insulin group the plasma concentrations of 13 of 20 essential and nonessential amino acids decreased to a significantly greater extent than in the control group. In summary, supraphysiological hyperinsulinemia, while maintaining normoglycemia, decreased whole body protein breakdown and synthesis in patients undergoing CABG surgery. However, net protein balance remained negative., (Copyright © 2014 the American Physiological Society.)