Behfar, Atta

Introduction: Baseline hemodynamic parameters have been shown to predict postoperative outcomes such as right ventricular failure (RVF) in LVAD patients. The pressure adjusted heart rate (PaHR) is a hemodynamic parameter that has not been reported in LVAD recipients. Hypothesis: Patients with an elevated PaHR at baseline will have an increased risk of adverse outcomes following LVAD implantation. Methods: Historical cohort study of 273 patients with preoperative invasive hemodynamic assessment before durable LVAD implantation from January 1 st , 2007 to April 10 th 2017. Baseline patient characteristics and hemodynamic parameters were assessed. The primary endpoint was a composite of 30 day mortality, stage 3 acute kidney injury (AKI), and postoperative RVF. Univariate analysis was used to identify predictors of the composite endpoint, which were entered into stepwise backwards multivariate logistic regression to determine independent predictors of the composite outcome. Results: The mean age was 59 and 79% of the patients were male. The median INTERMACS profile was 4 and 166 (60%) of LVADs placed were as destination therapy. The primary composite endpoint was reached by 74 (27%) patient, including 30-day mortality in 13 (5%), severe AKI in 48 (18%) and RVF in 53 (19%). Univariate predictors of the composite endpoint (p <0.05) included atrial fibrillation, INTERMACS profile, home inotropes, preoperative IABP, admission creatinine, baseline Vasoactive-Inotropic Score, mean right atrial pressure (mRAP), mRAP/wedge, mean arterial pressure/mRAP, mean pulmonary artery pressure/mRAP, right ventricular stroke work index (RVSWi), pulmonary artery pulsatility index, and the PaHR. Logistic regression identified PaHR (OR 0.96, 95% CI 0.93-0.99, p=.026), RVSWi (OR 1.002, 95% CI 1.001-1.004, p=.002), home inotropes (OR 0.46, 95% CI 0.22-0.94, p=.034), atrial fibrillation (OR 0.48, 95% CI 0.26-0.88, p=.019) and admission creatinine (OR 0.51, 95% CI 0.34-0.77, p=0.002) as predictors of the composite endpoint. Conclusions: The PaHR is a readily available, novel hemodynamic parameter, that when elevated on baseline hemodynamic assessment can predict those patients at increased risk of postoperative adverse outcomes after durable LVAD implantation.

Introduction: Patients at increased risk of complications following LVAD placement are admitted to the hospital for hemodynamic optimization prior to LVAD implantation, which can include adjustment of medical therapy and/or placement of an IABP. Hypothesis: Prior to LVAD placement patients treated with an IABP during hemodynamic optimization will have similar outcomes despite worse baseline characteristics compared with patients treated medically. Methods: This single-center study included 199 non-inotrope dependent patients who underwent durable LVAD implantation between January 1 st , 2007 and April 10 th 2017. Hemodynamic data was collected retrospectively. Patients who received an IABP were compared to those who did not. Stage 2 or 3 acute kidney injury, right ventricular failure, and 30 day mortality was compared between patients with and without and IABP. Results: The mean age was 62.7 and 82.9% were male; 72 (36.2%) received an IABP. Baseline characteristics between groups were similar. Patients treated with an IABP had worse INTERMACS profiles and worse baseline hemodynamic parameters. The incidence of the primary composite endpoint was similar between patients who had an IABP and those who did not (23.6% vs 19.7%; p=0.517), as were each of the individual endpoints: stage 2 or 3 acute kidney injury (18.1% vs 14.2%; p=0.472), right ventricular failure (13.9% vs 13.4%; p=0.796), and 30 day mortality (6.9 % vs 3.2%; p=0.226). Patients treated with an IABP had greater relative reductions in mean right atrial pressure (-24.1% vs -5.9%; p=0.044), pulmonary artery systolic (-11.7% vs +3.3%; p=<0.001), diastolic (-17.0% vs +12.0%; p=0.015), and mean pressures (-15.2% vs 0.5%; p=<0.001). Conclusions: Despite worse hemodynamic parameters and INTERMACS profile at baseline, ambulatory heart failure patients who received an IABP prior to LVAD implantation did not have an increased incident of stage 2 or 3 acute kidney injury, right ventricular failure, or 30 day mortality, and had more favorable reductions in right atrial and pulmonary artery pressures. These results suggest that the use of the IABP prior to LVAD implantation in non-inotrope dependent patients with poor baseline hemodynamics may mitigate the risk of postoperative complications.

AbstractRamp studies are utilized for speed optimization of continuous flow left ventricular assist devices (CF‐LVADs). We here report the utility of combined left and right heart catheterization during a ramp study to ensure a comprehensive understanding of the hemodynamic implications on both ventricles. Pressure‐volume loop (PV loop) monitoring uncovered compromised systolic and mildly compromised right ventricular function with increasing LVAD speeds, despite improvement in left ventricular unloading. These findings informed patient management and highlight the potential utility of PV loop monitoring as an adjunct to left and right heart catheterization during ramp studies of next‐generation LVADs.

The purpose of this study was to evaluate the biodistribution of a platelet-derived exosome product (PEP), previously shown to promote regeneration in the setting of wound healing, in a porcine model delivered through various approaches. Exosomes were labeled with DiR far-red lipophilic dye to track and quantify exosomes in tissue, following delivery via intravenous, pulmonary artery balloon catheter, or nebulization in sus scrofa domestic pigs. Following euthanasia, far-red dye was detected by Xenogen IVUS imaging, while exosomal protein CD63 was detected by Western blot and immunohistochemistry. Nebulization and intravenous delivery both resulted in global uptake of exosomes within the lung parenchyma. However, nebulization resulted in the greatest degree of exosome uptake. Pulmonary artery balloon catheter-guided delivery provided the further ability to localize pulmonary delivery. No off-target absorption was noted in the heart, spleen, or kidney. However, the liver demonstrated uptake primarily in nebulization-treated animals. Nebulization also resulted in uptake in the trachea, without significant absorption in the esophagus. Overall, this study demonstrated the feasibility of pulmonary delivery of exosomes using nebulization or intravenous infusion to accomplish global delivery or pulmonary artery balloon catheter-guided delivery for localized delivery.

The purpose of this study was to evaluate left ventricular (LV) unloading strategies in patients supported with peripheral venoarterial extracorporeal membrane oxygenation (VA-ECMO). A retrospective review was conducted of all consecutive patients requiring VA-ECMO support for any indication, who underwent novel LV unloading strategies with either direct left atrial venoarterial (LAVA) cannulation or pulmonary artery venoarterial (PAVA) venting, in comparison to Impella and intra-aortic balloon pump (IABP). The primary outcome was successful bridge to transplant, LV assist device, or myocardial recovery. Forty-six patients (63% male, mean age 52.8 ± 17.6 years) were included. Fourteen patients (30%) underwent novel unloading with either LAVA or PAVA, 11 patients (24%) underwent IABP placement, and 21 patients (46%) underwent Impella insertion. In the novel LV unloading cohort, 10 patients (71%) survived to hospital discharge. Four patients (29%) were weaned from ECMO and eight patients (57%) underwent cardiac transplantation. Although a trend favoring cannula-based unloading for the primary outcome was noted, the cohort was too small for statistical significance (79% LAVA/PAVA, 57% Impella, 45% IABP; p = 0.21). However, probability of survival was greater in the LAVA/PAVA cohort compared to Impella and IABP (p < 0.05). Thus, we demonstrate the efficacy of LA and PA cannulation as an alternative LV unloading strategy for patients supported with peripheral VA-ECMO.

AbstractBackgroundGastrointestinal bleeding (GIB) in patients with continuous flow left ventricular assist devices (CF‐LVADs) is often related to GI angiodysplasia (GIAD). We previously reported data on VEGF inhibition with IV bevacizumab in the treatment of LVAD‐associated GIAD bleeding, and now present follow‐up data on patients treated with IV bevacizumab and/or low‐dose oral pazopanib.MethodsAll consecutive adult patients with LVAD‐associated GIB from GIAD treated with bevacizumab or pazopanib, from July 20, 2017 to June 22, 2022, were included in the analysis. Data on hospitalizations, GI endoscopic procedures, and blood transfusions were obtained from first admission for GIB up to a median of 35.7 months following treatment initiation (range 1.3–59.8 months).ResultsEleven patients (91% male, mean 69.5 ± 8.9 years) were included. Eight patients (73%) received IV bevacizumab, two patients (18%) received oral pazopanib, and one patient (9%) received bevacizumab followed by pazopanib therapy. We observed a significantly decreased number of annualized hospitalizations for GIB (median difference − 2.87, p = 0.002), blood transfusions (median difference − 20.9, p = 0.01), and endoscopies (median difference − 6.95, p = 0.007) in patients pre‐ and post‐anti‐angiogenic therapy (bevacizumab and/or pazopanib). Similarly, a significant improvement in these clinical outcomes was noted in the bevacizumab group with decreased annualized hospitalizations (median difference − 2.75, p = 0.014), blood transfusions (median difference − 24.5, p = 0.047), and number of endoscopies (median differences −6.88, p = 0.006).ConclusionAnti‐angiogenic therapy with IV bevacizumab and/or low‐dose oral pazopanib appears to provide benefits in patients with LVAD‐associated GIB with reduced hospitalizations, blood transfusions, and need for GI endoscopic procedures.

Introduction: Platelets are heavily implicated in angiogenesis; however, the underlying mechanism remains relatively uncharacterized. The goal of this study was to evaluate the angiogenic potency of a platelet-derived regenerative exosome product (PEP) in an effort to develop a novel treatment for peripheral arterial disease. Here, we evaluated the mechanistic basis of PEP in angiogenesis and it’s use In Vivo in a rodent hind limb ischemia model. Methods/Results: Under Current Good Manufacturing Practices, conditioned medium from apheresis platelet cultures was purified to acquire the exosomes. PEP, enriched in exosome markers CD63, CD9 and Flotillin, induced human umbilical vein endothelial cell (HUVEC) proliferation, migration, and vascular tube formation In Vitro. Proteomic evaluation of PEP highlighted receptor tyrosine kinase (RTK) pathways and western blot validation demonstrated induction of phospho-MAPK and phospho-AKT following PEP treatment of HUVECs. Systematic evaluation of RTK receptor involvement was performed using small molecule inhibitors and receptor knock-down in HUVECs, ruling out RTK activation as a mode of action. However, small molecule inhibition of PI3 kinase demonstrated elimination of PEP-induced AKT phosphorylation and reduction in PEP-induced angiogenesis In Vitro measured by HUVEC proliferation and migration. In Vivo, evaluation of angiogenesis was performed in a rodent model of hindlimb ischemia treated with PEP embedded in fibrin glue (PEP/TISSEEL). Blood flow was evaluated by SPY angiography on day 0 pre- and post-operation, day 21, and day 28. Animals treated with PEP/TISSEEL showed a significant increase in blood flow compared to sham and TISSEEL treated animals (percent perfusion at 28 days: sham 40.9%, TISSEEL 44.3%, PEP/TISSEEL 100.2%), with significant increase in vascular area on histology (at 28 days vascular area (μm 2 )/muscle area(μm 2 ): healthy control 12.71, sham 4.66, TISSEEL 4.76, PEP/TISSEEL 15.54). Conclusions: Exosome driven activation of PI3 kinase can induce angiogenesis both In Vitro and In Vivo. PEP provides a novel, clinical-grade, off-the-shelf therapy to promote angiogenesis for the treatment of peripheral arterial disease.

Introduction: Patients with coronary artery disease (CAD) not amenable to revascularization are reported to have a 3-year mortality >14%. Advances in treatment modalities including medical management, rotational atherectomy, balloon lithotripsy, and drug-eluting stents work for focal disease but poorly treat diffuse CAD. In a porcine model of in-stent restenosis, we here evaluated whether a pro-angiogenic platelet-derived exosome product (PEP) could be delivered into the perivascular space to foster collateral vessel formation. Methods/Results: Cobalt chromium stents were placed and were oversized by 1 mm in the left anterior descending (LAD) and posterior descending arteries (PDA) of sus scrofa domesticus pigs. In-stent restenosis was angiographically visualized at the 2-month timepoint, with hemodynamic significance documented with fractional flow reserve (FFR) of <0.8. To document feasibility of PEP delivery into the perivascular space, exosomes were labeled with a far-red fluorescent tag and delivered into the perivascular bed. Here, the Bullfrog® micro-infusion catheter was positioned either in the great cardiac vein or the middle cardiac vein and PEP was delivered with the microneedle pointed towards the LAD or the PDA. Biodistribution demonstrated exosome retention and uptake around cardiac veins. Using the Bullfrog® technique, PEP was delivered in the perivascular space adjacent to areas of significant coronary stenosis. Initial results 1-month post-treatment demonstrated improved FFR of treated stenotic vessels (from 0.68 to 0.85), while untreated vessels demonstrate no change from previous FFR measurement (from 0.79 to 0.78). Conclusions: Here, exosome-mediated angiogenesis in the perivascular space improved coronary blood flow, distal to areas of stenosis. In patients with diffuse CAD, delivery of biotherapy in cardiac veins running anatomically parallel to stenosed epicardial arteries provides a novel therapeutic opportunity to supplement the existing armamentarium of therapies available for in-stent restenosis.

Introduction: At the forefront of post-heart transplant care is early detection of transplant rejection. However, the current gold standard for detecting acute cellular transplant rejection is recurrent invasive endomyocardial biopsies (EMB). We aimed at developing a non-invasive biomarker for acute cellular heart transplant rejection (ACR) using a plasma extracellular vesicle (EV) platform. Methods: Peripheral and coronary sinus plasma samples were prospectively collected from 183 (31.7% female) patients from 2020 to 2023 during routine surveillance EMB. A discovery cohort comprised five patients who displayed ISHLT 0-1R biopsy followed by an ISHLT 2R grade rejection event. Plasma EVs were isolated from the baseline (0-1R) and rejection (2R) time points. Subsequently, integrative analysis of plasma EV proteomic, miRNomic, and metabolomics was performed pairwise with the samples. Results: The study collected 943 sample time points from 183 patients. Of these sample collections, 43 (4.5%) cases were 2R rejections. Our proteomic analysis of the plasma EVs identified 28 proteins found explicitly during a grade 2R rejection and 87 differentially expressed proteins during a 2R rejection event. An Ingenuity Pathway Analysis (IPA) analysis of the upregulated proteins highlighted EVs mediated mTOR signaling and antigen presentation as central to rejection events. Although all patients in the discovery cohort were negative for antibody-mediated rejection (AMR), the proteomic findings also revealed increased B-cell receptor signaling, implying a mechanistic intersection of ACR and AMR. Conclusions: A distinct set of proteins were found in plasma EVs during ACR events, providing potentially specific and sensitive biomarkers to reduce the need for EMB that could be exploited for ACR diagnosis. The proteins identified formed an immune signaling network that suggests a novel role for EVs in ACR pathogenesis.

Introduction: Left ventricular assist devices (LVAD) with magnetically levitated impellers have become standard due to hemocompatibility and survival profile. To optimize LVAD speeds, we previously introduced simultaneous right and left heart (RH/LH) catheterization during ramp studies. Here, we report pairing of this approach with pressure-volume (PV) assessment in a patient with a HeartMate 3 LVAD with mitral regurgitation (MR). The combined approach evaluated left ventricular (LV) hemodynamics and right ventricular (RV) PV-relationships during ramp testing. Methods: A 68-year-old male with ischemic cardiomyopathy, two years following HeartMate3 implantation, presented with NYHA class III symptoms. To evaluate for dyspnea, he underwent a RH/LH catheterization ramp study. RV PV-loops were created by use of a conductance catheter system, allowing creation of PV loops. Results: At the baseline LVAD speed of 5300 rotations per minute (RPM), right atrial pressure was elevated at 16 mmHg and pulmonary artery (PA) pressure of 26 mmHg. Left-end diastolic pressure (LVEDP) was elevated (16mmHg). Baseline cardiac index (CI) was 2.01 L/min/m 2 . Ramp testing was performed, increasing speeds from 5300 to 5800 RPM. Progressive LV unloading was observed with a 5 mmHg drop in LVEDP and a 3 mmHg drop in PA pressure. However, RV PV loop monitoring revealed a negative impact on RV contractility with the maximal elastance (Emax) slope demonstrating a 22% reduction. Furthermore, a 17% reduction in RV stroke volume was documented, while diastolic function remained unchanged. Thus, despite excellent LV offloading and diminishment of RV afterload, the significant negative impact on Emax resulted in no net increase in CI (+0.04 L/min/m 2 ) during the ramp evaluation. Inotrope therapy was initiated for RV function with increased LVAD RPM to outcompete MR. Conclusions: While RH/LH catheterization provides a real-time perspective of the interventricular relationship during ramp, the impact of increasing LVAD speeds on RV function has yet to be directly measured. Here, the RV PV loop relationship during LVAD ramp showed that although LVAD speed increases in the setting of MR may facilitate LV unloading, a drop in RV afterload did not compensate for reduction in RV contractility.