Sharif A. Sabe

Background: Patients with chronic hypertension have worse outcomes following on‐pump (cardioplegia and cardiopulmonary bypass [CP/CPB]) cardiac surgery. Altered vasomotor function of the coronary microvasculature to ET‐1 (endothelin‐1) and other agonists may underlie these differences. Methods: Heart samples were collected from 85 patients undergoing CP/CPB enrolled in this observational study. Ex vivo coronary microvascular responses to ET‐1, adenosine diphosphate, and sodium nitroprusside were assessed using video microscopy. Immunoblotting, immunohistochemistry, enzyme‐linked immunosorbent assay, and multiomics approaches were also used. Results: Coronary microvascular contractile response to ET‐1 in patients with uncontrolled hypertension was increased compared with the other 2 cohorts pre‐ and post‐CP/CPB ( P −10 to 10 ⁻⁷ mmol/L). Adenosine diphosphate‐induced coronary microvascular vasodilation was conversely decreased ( P −5 and 10 ⁻⁴ mmol/L). Post‐CP/CPB microvascular responses to ET‐1 and adenosine diphosphate were blunted overall ( P A receptor diminished contractile response ( P 2 0.95 pre‐CP/CPB, R ² 0.86 post‐CP/CPB), which, in turn, estimated change in ejection fraction pre‐ and post‐CP/CPB ( P P <0.05). Conclusions: Altered coronary microvascular vasomotor function in patients with uncontrolled hypertension may jeopardize myocardial perfusion. Hypertension status and cardiac mass may be used to prognosticate this physiology, which, in turn, estimates change in ejection fraction postoperatively. Perioperative endothelin receptor blockers may benefit patients with uncontrolled hypertension and thus warrant further investigation.

There is a significant body of literature to suggest that coronary artery disease (CAD) is a highly sex-specific disease. The study of sex-specific therapeutics and sex-specific responses to treatment for CAD remains underreported in the literature. Sodium-glucose transporter 2 (SGLT2) inhibitors are of growing interest in the treatment of ischemic heart disease and heart failure; however, the sex-specific response to SGLT2 inhibitors is unknown. We studied an SGLT2 inhibitor, canagliflozin, in a swine model of metabolic syndrome (MS) and chronic myocardial ischemia with emphasis on the sex-specific outcomes. Yorkshire swine (n = 21) were obtained at 6 weeks of age and fed a high-fat diet to induce MS. Left thoracotomy was performed on all swine at 11 weeks of age for the placement of an ameroid constrictor to model chronic myocardial ischemia. Swine recovered for two weeks, then were assigned to either the drug group, CAN 300 mg daily group (M = 5, F = 5), or the control group (CON, M = 5, F = 6). Both groups received 5 weeks of therapy. After completion of therapy, swine underwent functional assessment and terminal harvest. The male animals treated with CAN (CAN-M) had significant increases in stroke volume and cardiac output (p = 0.047, p < 0.001) compared to control males (CON-M), which were not seen in females treated with CAN (CAN-F) compared to control females (CON-F). Effective arterial elastance was decreased in CAN-M compared to CON-M. The CAN-F group had a significant increase in ischemic myocardial capillary density compared to CON-F (p = 0.04). There was no difference in capillary density between the CAN-M and CON-M groups. CAN treatment resulted in sex-specific changes in angiogenesis and myocardial function. The CAN-M group had significant improvements in cardiac function based on afterload reduction, stroke volume, and increased cardiac output not seen in the CAN-F group. The CAN-F group had increased ischemic myocardial capillary density. These findings provide a foundation for further investigation of the sex-specific effects of SGLT-2 inhibitors in humans.

Background: Coronary artery bypass grafting remains the standard of care for advanced and multifocal coronary artery disease; however, for patients that are surgical candidates, total arterial revascularization (TAR) remains underutilized due to concerns such as sternal wound infections and the learning curve. We present the results of a large cohort of mid-career surgeons transitioning to TAR, focusing on short-term outcomes and the learning curve. Methods: The surgeons transitioned to using TAR as the preferred revascularization technique in August of 2017. The Society of Thoracic Surgeons database was reviewed to identify all patients who underwent isolated non-emergent CABG performed by a single surgeon from January 2014 through January 2022. Patients were divided into two groups—those who had TAR and those who had traditional CABG using one internal mammary artery and vein grafts (IMA-SVG). Results: Eight hundred ninety-eight patients meet inclusion criteria (458 IMA-SVG and 440 TAR). The TAR group had slightly longer cardiopulmonary bypass time, cross clamp times, and operative times (all p < 0.05); however, ICU stay was shorter and 30-day readmission rate was lower for TAR compared to IMA-SVG (all p < 0.05). The TAR group also required fewer postoperative transfusions (p = 0.005). There was no difference in prolonged intubation, stroke, length of stay, mortality, or sternal wound complications between groups (all p > 0.05). The average TAR was 30 min longer; however, learning curves, stratified by number of grafts placed, showed no significant learning curve associated with TAR. Conclusions: An experienced surgeon transitioning from IMA-SVG to TAR slightly increases operative time, but decreases ICU stay, readmissions, and postoperative transfusions with no significant difference in rates of immediate post-operative complications or 30-day mortality, with a minimal learning curve.

Objective: Although both clinical data and animal models suggest cardiovascular benefits following administration of Dipeptidyl Peptidase 4 (DPP-4) inhibitors, the underlying mechanisms remain unclear. We therefore sought to evaluate the effect of the DPP-4 inhibitor sitagliptin on myocardial fibrosis, and insulin signaling in chronic myocardial ischemia using a swine model. An ameroid constrictor placement on the left coronary circumflex artery of thirteen Yorkshire swine to model chronic myocardial ischemia. After two weeks of recovery, swine were assigned to one of two groups: control (CON, n = 8), or sitagliptin 100mg daily (SIT, n = 5). After 5 weeks of treatment, the swine underwent terminal harvest with collection of myocardial tissue. Fibrosis was quantified using Masson’s trichrome. Protein expression was quantified by Immunoblotting. Trichrome stain demonstrated a significant decrease in perivascular and interstitial fibrosis in the SIT group relative to CON (all p<0.05). Immunoblot showed a reduction in Jak2, the pSTAT3 to STAT 3 Ratio, pSMAD 2/3, and SMAD 2/3, and an increase in STAT 3 in the SIT group relative to CON (all p<0.05). SIT treatment was associated with increased expression of insulin receptor one and decreased expression of makers for insulin resistance, including phospho-PKC- alpha, RBP-4, SIRT1, and PI3K (p<0.05). Sitagliptin results in a reduction in perivascular and interstitial fibrosis and increased insulin sensitivity in chronically ischemic swine myocardium. This likely contributes to the improved cardiovascular outcomes seen with DPP-4 inhibitors.

Background: Sodium–glucose cotransporter-2 (SGLT2) inhibitors are known to be cardioprotective independent of glucose control, but the mechanisms of these benefits are unclear. We previously demonstrated improved cardiac function and decreased fibrosis in a swine model of chronic myocardial ischemia. The goal of this study is to use high-sensitivity proteomic analyses to characterize specific molecular pathways affected by SGLT-2 inhibitor canagliflozin (CAN) therapy in a swine model of chronic myocardial ischemia. Methods: Chronic myocardial ischemia was induced in sixteen Yorkshire swine via the placement of an ameroid constrictor to the left circumflex coronary artery. After two weeks of recovery, swine received either 300 mg of CAN daily (n = 8) or a control (n = 8). After five weeks of therapy, the group of swine were euthanized, and left ventricular tissue was harvested and sent for proteomic analysis. Results: Total proteomic analysis identified a total of 3256 proteins between the CAN and control groups. Three hundred and five proteins were statistically different. This included 55 proteins that were downregulated (p < 0.05, fold change p < 0.05, fold change >2) with CAN treatment. Pathway analysis demonstrated the upregulation of several proteins involved in metabolism and redox activity in the CAN-treated group. The CAN group also exhibited a downregulation of proteins involved in motor activity and cytoskeletal structure. Conclusions: In our swine model of chronic myocardial ischemia, CAN therapy alters several proteins involved in critical molecular pathways, including redox regulation and metabolism. These findings provide additional mechanistic insights into the cardioprotective effects of canagliflozin.

The past several decades have borne witness to several breakthroughs and paradigm shifts within the field of cardiovascular medicine, but one component that has remained constant throughout this time is the need for accurate animal models for the refinement and elaboration of the hypotheses and therapies crucial to our capacity to combat human disease. Numerous sophisticated and high-throughput molecular strategies have emerged, including rational drug design and the multi-omics approaches that allow extensive characterization of the host response to disease states and their prospective resolutions, but these technologies all require grounding within a faithful representation of their clinical context. Over this period, our lab has exhaustively tested, progressively refined, and extensively contributed to cardiovascular discovery on the basis of one such faithful representation. It is the purpose of this paper to review our porcine model of chronic myocardial ischemia using ameroid constriction and the subsequent myriad of physiological and molecular–biological insights it has allowed our lab to attain and describe. We hope that, by depicting our methods and the insight they have yielded clearly and completely—drawing for this purpose on comprehensive videographic illustration—other research teams will be empowered to carry our work forward, drawing on our experience to refine their own investigations into the pathogenesis and eradication of cardiovascular disease.

Background: Small conductance calcium‐activated potassium (SK) channels are largely responsible for endothelium‐dependent coronary arteriolar relaxation. Endothelial SK channels are downregulated by the reduced form of nicotinamide adenine dinucleotide (NADH), which is increased in the setting of diabetes, yet the mechanisms of these changes are unclear. PKC (protein kinase C) is an important mediator of diabetes‐induced coronary endothelial dysfunction. Thus, we aimed to determine whether NADH signaling downregulates endothelial SK channel function via PKC. Methods and Results: SK channel currents of human coronary artery endothelial cells were measured by whole cell patch clamp method in the presence/absence of NADH, PKC activator phorbol 12‐myristate 13‐acetate, PKC inhibitors, or endothelial PKC _α /PKC _β knockdown by using small interfering RNA. Human coronary arteriolar reactivity in response to the selective SK activator NS309 was measured by vessel myography in the presence of NADH and PKC _β inhibitor LY333531. NADH (30–300 μmol/L) or PKC activator phorbol 12‐myristate 13‐acetate (30–300 nmol/L) reduced endothelial SK current density, whereas the selective PKC _ᵦ inhibitor LY333531 significantly reversed the NADH‐induced SK channel inhibition. PKC _β small interfering RNA, but not PKC _α small interfering RNA, significantly prevented the NADH‐ and phorbol 12‐myristate 13‐acetate–induced SK inhibition. Incubation of human coronary artery endothelial cells with NADH significantly increased endothelial PKC activity and PKC _β expression and activation. Treating vessels with NADH decreased coronary arteriolar relaxation in response to the selective SK activator NS309, and this inhibitive effect was blocked by coadministration with PKC _β inhibitor LY333531. Conclusions: NADH‐induced inhibition of endothelial SK channel function is mediated via PKC _β . These findings may provide insight into novel therapeutic strategies to preserve coronary microvascular function in patients with metabolic syndrome and coronary disease.

Introduction: Patients with advanced coronary artery disease (CAD) who are not eligible for stenting or surgical bypass procedures have limited treatment options. Extracellular vesicles (EVs) have emerged as a potential therapeutic target for the treatment of advanced CAD. These EVs can be conditioned to modify their contents. In our previous research, we demonstrated increased perfusion, decreased inflammation, and reduced apoptosis with intramyocardial injection of hypoxia-conditioned EVs (HEVs). The goal of this study is to further understand the function of HEVs by examining their impact on oxidative stress using our clinically relevant and extensively validated swine model of chronic myocardial ischemia. Methods: Fourteen Yorkshire swine underwent a left thoracotomy for the placement of an ameroid constrictor on the left circumflex coronary artery to model chronic myocardial ischemia. After two weeks of recovery, the swine underwent a redo thoracotomy with injection of either HEVs (n = 7) or a saline control (CON, n = 7) into the ischemic myocardium. Five weeks after injection, the swine were subjected to terminal harvest. Protein expression was measured using immunoblotting. OxyBlot analysis and 3-nitrotyrosine staining were used to quantify total oxidative stress. Results: There was a significant increase in myocardial expression of the antioxidants SOD 2, GPX-1, HSF-1, UCP-2, catalase, and HO-1 (all p ≤ 0.05) in the HEV group when compared to control animals. The HEVs also exhibited a significant increase in pro-oxidant NADPH oxidase (NOX) 1, NOX 3, p47phox, and p67phox (all p ≤ 0.05). However, no change was observed in the expression of NFkB, KEAP 1, and PRDX1 (all p > 0.05) between the HEV and CON groups. There were no significant differences in total oxidative stress as determined by OxyBlot and 3-nitrotyrosine staining (p = 0.64, p = 0.32) between the groups. Conclusions: Administration of HEVs in ischemic myocardium induces a significant increase in pro- and antioxidant proteins without a net change in total oxidative stress. These findings suggest that HEV-induced changes in redox signaling pathways may play a role in increased perfusion, decreased inflammation, and reduced apoptosis in ischemic myocardium. Further studies are required to determine if HEVs alter the net oxidative stress in ischemic myocardium at an earlier time point of HEV administration.

Background and Aim of the Study. While several studies have suggested a relationship between adverse postoperative outcomes and systemic lupus erythematosus (SLE) in major surgical settings, no study to date has explored postoperative outcomes of SLE patients undergoing coronary artery bypass grafting (CABG). This study aimed to compare the characteristics and outcomes of SLE patients compared to non-SLE patients undergoing CABG. Methods. We utilized the Nationwide Inpatient Sample (NIS) data from 20082018 for CABG patients 18years old. Patients were divided into two groups based on SLE status (confirmed SLE diagnosis or no SLE present). Primary outcomes were in-hospital mortality, favorable discharge, and length of stay (LOS). Secondary outcomes included acute kidney injury (AKI), acute liver injury (ALI), hemodialysis, acute myocardial infarction (AMI), and cardiogenic shock. Patient characteristics including age, sex, race, and preexisting comorbidities were considered. Multivariable models, adjusting for confounding variables, were utilized. Results. Data from a total of 352,772 patients who underwent CABG were analyzed. 980 patients had a diagnosis code for SLE. SLE and non-SLE patients had similar rates of in-hospital mortality (OR=0.92, [0.631.35]), nonhome discharge (OR=1.09, [0.951.24]), and LOS (OR=1.02, [0.991.06]). SLE patients developed AKI at a higher rate (OR=1.50, [1.051.48]) and ALI at a lower rate (OR=0.35, [0.160.74]). Both groups had similar rates of hemodialysis (OR=1.19, [0.981.44]), AMI (OR=0.93, [0.811.06]), and cardiogenic shock (OR=0.8, [0.611.05]). Conclusion. These findings suggest that SLE patients undergoing CABG have similar mortality, discharge disposition, and LOS compared to non-SLE patients. However, SLE patients are at increased risk of AKI and decreased risk of ALI than non-SLE patients. These associations warrant further investigation to elucidate their physiologic basis.