Behfar, Atta

Patients are admitted to the hospital for hemodynamic optimization before left ventricular assist device (LVAD) implantation. The aim of this study was to evaluate the clinical outcomes of hemodynamic optimization using an intra-aortic balloon pump (IABP) in ambulatory heart failure patients before LVAD placement. This retrospective single-center study included 199 noninotrope-dependent patients who underwent durable LVAD implantation between January 1, 2007 and April 10, 2017. Invasive hemodynamic as well as the primary composite end-point of stage 2 or 3 acute kidney injury, right ventricular failure, and 30-day mortality were compared between patients with and without an IABP. Median age was 64 (interquartile range [IQR], 57–71) years and 165 (82.9%) were male; 72 (36.2%) received an IABP. Patients treated with an IABP had worse baseline exercise capacity and hemodynamic parameters. Patients with an IABP had greater relative reduction in pulmonary artery mean pressure (−16% vs. −2%; p ≤ 0.001). The primary composite end-point was not different between patients who had an IABP and those who did not (20.8% vs. 20.5%; p = 0.952), as were each of the individual end-points. Despite worse baseline hemodynamic parameters and exercise capacity, ambulatory heart failure patients who received an IABP before LVAD implantation had more favorable reductions in pulmonary artery pressures without an increase in the composite end-point. These results suggest that IABP use before LVAD implantation may mitigate the risk of postoperative complications in ambulatory patients.

Abstract Introduction: Therapies for substrate-related arrhythmias include ablation or drugs targeted at altering conductive properties or disruption of slow zones in heterogeneous myocardium. Conductive compounds such as carbon nanotubes may provide a novel personalizable therapy for arrhythmia treatment by allowing tissue homogenization. Methods: A nanocellulose-carbon nanotube conductive hydrogel was developed to have conduction properties similar to normal myocardium. Ex vivo perfused canine hearts were studied. Electroanatomic activation mapping of the epicardial surface was performed at baseline, after radiofrequency ablation, and after uniform needle injections of the conductive hydrogel through the injured tissue. Gross histology was used to assess distribution of conductive hydrogel in the tissue. Results: The conductive hydrogel viscosity was optimized to decrease with increasing shear rate to allow expression through a syringe. The DC conductivity under aqueous conduction was 4.3·10-1 S/cm. In 4 canine hearts, when compared to the homogeneous baseline conduction, isochronal maps demonstrated sequential myocardial activation with a shift in direction of activation to surround the edges of the ablated region. After injection of conductive hydrogel, isochrones demonstrated conduction through the ablated tissue with activation similar to baseline in all 4 hearts. Gross specimen examination demonstrated retention of the hydrogel within the tissue. Conclusions: This proof-of-concept study demonstrates that conductive hydrogel can be injected into acutely disrupted myocardium to restore conduction. Future experiments should focus on evaluating long-term retention and biocompatibility of the hydrogel through in vivo experimentation.

The management of patients with heart failure focuses on halting the progression of disease. To date, no therapeutic approach has been able to restore cardiac function to its original baseline state. Cell therapies, such as cardiopoietic (CP) stem cells, have shown to be promising platforms to restore cardiac function. The CP platform enhances the cardioregenerative potency of mesenchymal stem cells (MSCs). CP cells are characterized by the robust expression and nuclear translocation of cardiac transcription factors such Mesoderm Posterior Basic Helix‐Loop‐Helix Transcription Factor 1 (MESP1), early cardiac transcription factor Nkx2.5, myocyte enhancer factor 2C (Mef2C), and zinc finger‐containing transcription factor GATA4. Clinical trials using CP cells showed signs of safety and efficacy in improving cardiac function in patients with heart failure. However, the costs, time, and complexities associated with the manufacturing process have precluded the adoption of the therapy as a large‐scale clinical practice. In response, we adopted a microencapsulated‐modified‐messenger RNA (M3RNA) platform as a cost‐effective and time‐saving alternative to induce high expression of cardiopoietic markers. We hypothesized that the transfection of human umbilical cord‐derived mesenchymal stem cells (hUC‐MSCs) with M3RNA encoding mesodermal and/or cardiac transcription factor(s) will induce the expression of cardiopoietic markers (MESP1, Nkx2.5, Mef2C, and GATA4). hUC‐MSCs were transfected with M3RNA encoding Brachyury (this protein plays a key role in cardiomyocyte differentiation) and MESP1, Nkx2.5, Mef2C, and GATA4 using the transfection reagent Lipofectamine STEM. Protein expression was measured and quantified using fluorescence microscopy and flow cytometry. hUC‐MSCs transfected with M3RNA encoding mesodermal and/or cardiac transcription factor(s) demonstrated rapid protein expression at 4 hours post‐transfection that reached peak levels between 24 hours and 48 hours post‐transfection. Immunocytochemistry demonstrated similar morphology between transfected and non‐transfected cells. Thus, hUC‐MSCs can be transfected with M3RNA with high efficiency to produce rapid and predictable protein expression in vitro. We here demonstrate a simple, cost‐effective, and time‐saving approach to induce the expression of cardiopoietic markers in UC‐MSCs using M3RNA, which can serve as a highly translatable platform to circumvent many burdens associated with current strategies and development of cell‐based therapies for future clinical trials and practice. Support or Funding Information Mayo Clinic Center for Regenerative Medicine, Van Cleve Cardiac Regenerative Medicine Program, Marriott Foundation, Michael S. and Mary Sue Shannon Family, NIH NHLBI HL134664, Mayo Clinic Regenerative Sciences Post‐Baccalaureate Training Program

There is a paucity of data describing the invasive assessment of afterload and influence on cardiac output in patients supported on left ventricular assist device (LVAD) therapy. From 2015 to 2018, patients on LVAD therapy were evaluated with simultaneous left/right heart catheterization ramp study for speed optimization. Hemodynamic parameters from 31 patients without significant aortic insufficiency were analyzed. Mean central aortic pressure (MAP) was elevated at 87 ± 13 mm Hg at baseline. No direct association between MAP and cardiac index (CI) was found (r = 0.11, p = 0.20). However, variable MAP provided vastly different patterns of cardiac output response to speed increments (positive correlation, p = 0.047 for MAP <80 mm Hg; negative trend, p = 0.25 for MAP > 100 mm Hg). Patients noted to be hypertensive (MAP > 90, n = 8) received nitrate therapy and experienced both improvement in biventricular filling pressures and a mean increase in CI from 2.4 to 2.9 L/min/m2 (+22%, p = 0.04) at a fixed revolutions per minute. High afterload is common in patients on LVAD therapy, is associated with poor response to ramp, and is ameliorated by nitrates. These findings serve as a foundation to evaluate the dynamic effects of high afterload and chronic vasodilator therapy in patients with durable LVADs.

Utilization of venoarterial extracorporeal membrane oxygenation (VA-ECMO) is expanding, but dual VA-ECMO circuits to treat cardiogenic shock with refractory hypoxemia is unreported. We describe the case of combined cardiogenic and distributive shock due to necrotizing pulmonary blastomycosis. After initial central VA-ECMO cannulation, acute respiratory distress syndrome (ARDS) with increasing shunt resulted in significant central hypoxemia due to progressive ventilation-perfusion mismatch. An additional circuit provided complete oxygenation of the high circulating volume. After 4 months on support, he underwent successful heart-lung-kidney transplantation. Dual ECMO circuits are technically feasible and may be advantageous in specific circumstances of high pulmonary shunting resulting in excessive hypoxemia unbalanced with appropriate oxygen delivery.

AbstractFlexor tendon injuries and tendinopathy are very common but remain challenging in clinical treatment. Exosomes‐based cell‐free therapy appears to be a promising strategy for tendon healing, while limited studies have evaluated its impacts on tenocyte biology. The objective of this study was to characterize a novel purified exosome product (PEP) derived from plasma, as well as to explore its cellular effects on canine tenocyte biology. The transmission electron microscope revealed that exosomes of PEP present cup‐shaped structures with the diameters ranged from 80 to 141 nm, and the NanoSight report presented that their size mainly concentrated around 100 nm. The enzyme‐linked immunosorbent assay kits analysis showed that PEP was positive for CD63 and AChE expression, and the cellular uptake of exosomes internalized into tenocyte cytoplasm was observed. The cell growth assays displayed that tenocyte proliferation ability was enhanced by PEP solution in a dose‐dependent manner. Tenogenic phenotype was preserved as is evident by that tendon‐related genes expression (SCX, COL1A, COL3A1, TNMD, DCN, and MKX) were expressed insistently in a high level, while tenocytes were treated with 5% PEP solution. Furthermore, migration capability was maintained and total collagen deposition was increased. More interesting, dexamethasone‐induced cellular apoptosis was attenuated during the incubation of tenocytes with a 5% PEP solution. These findings will provide the basic understandings about the PEP, and support the potential use of this biological strategy for tendon healing.

Background The presence of a durable left ventricular assist device ( LVAD ) is associated with increased risk of vasoplegia in the early postoperative period following heart transplantation ( HT ). However, preoperative predictors of vasoplegia and its impact on survival after HT are unknown. We sought to examine predictors and outcomes of patients who develop vasoplegia after HT following bridging therapy with an LVAD . Methods and Results We identified 94 patients who underwent HT after bridging with continuous‐flow LVAD from 2008 to 2018 at a single institution. Vasoplegia was defined as persistent low vascular resistance requiring ≥2 intravenous vasopressors within 48 hours after HT for >24 hours to maintain mean arterial pressure >70 mm Hg. Overall, 44 patients (46.8%) developed vasoplegia after HT . Patients with and without vasoplegia had similar preoperative LVAD , echocardiographic, and hemodynamic parameters. Patients with vasoplegia were significantly older; had longer LVAD support, higher preoperative creatinine, longer cardiopulmonary bypass time, and higher Charlson comorbidity index; and more often underwent combined organ transplantation. In a multivariate logistic regression model, older age (odds ratio: 1.08 per year; P =0.010), longer LVAD support (odds ratio: 1.06 per month; P =0.007), higher creatinine (odds ratio: 3.9 per 1 mg/dL; P =0.039), and longer cardiopulmonary bypass time (odds ratio: 1.83 per hour; P =0.044) were independent predictors of vasoplegia. After mean follow‐up of 4.0 years after HT , vasoplegia was associated with increased risk of all‐cause mortality (hazard ratio: 5.20; 95% CI, 1.71–19.28; P =0.003). Conclusions Older age, longer LVAD support, impaired renal function, and prolonged intraoperative CPB time are independent predictors of vasoplegia in patients undergoing HT after LVAD bridging. Vasoplegia is associated with worse prognosis; therefore, detailed assessment of these predictors can be clinically important.

Following implantation of continuous-flow left ventricular assist devices, mechanical off-loading results in improved resting hemodynamics; however, peak exercise capacity generally does not increase substantially. This study evaluated patients supported by continuous-flow left ventricular assist devices who were invasively monitored during exercise to define parameters that underpin exercise capacity and outcomes. A review of all patients supported by continuous-flow left ventricular assist devices who underwent supine bicycle ergometry exercise testing with measurement of pulmonary gas exchange during right heart catheterization for evaluation of dyspnea at one institution between 2007 and 2018 was performed (n = 22). The primary outcome of this investigation was death or heart failure hospitalization. Although resting filling pressures were relatively preserved, resting cardiac index (Fick) was low (2.1 ± 0.5 mL/kg/min). An impaired cardiac output reserve was present in 75% of patients. On univariate modeling, patients with supine exercise–induced hypoxemia (O 2 saturation <90%) experienced significantly diminished hospitalization-free survival (unadjusted hazard ratio = 11.0, confidence interval = 2.4–57.2, p = 0.003), which persisted despite adjustment for right heart catheterization peak VO 2 and peak cardiac output (adjusted hazard ratio = 25, confidence interval = 3.6–322, p = 0.001). Our findings suggest that supine exercise testing provides additional prognostic utility in the continuous-flow left ventricular assist device population.

Background: The role of coronary microvascular disease and its impact on functional and energetic reserve in heart failure with preserved ejection fraction (HFpEF) remains unclear. We hypothesized that in response to submaximal pharmacologic stress (dobutamine), patients with HFpEF have impairment in left ventricular (LV) myocardial mechanical (external work [EW]), energetic (myocardial O 2 consumption [MVO 2 ]), and myocardial blood flow (MBF) reserve. We further assessed whether coupling of MBF to EW is impaired in HFpEF and associated with compensatory increases or pathological decreases in myocardial O 2 extraction. Lastly, we assessed whether coupling of MVO 2 to EW (mechanical efficiency) was impaired in HFpEF. Methods and Results: In prospectively enrolled patients with HFpEF (n=19) and age/sex-matched healthy controls (n=19), we performed 11 C-acetate positron emission tomography assessing MVO 2 and MBF at rest and during dobutamine infusion. EW was calculated as stroke volume (echo)×end-systolic pressure×heart rate. At rest, compared with controls, patients with HFpEF had higher LV EW, MVO 2 , and MBF. With dobutamine, LV EW, MVO 2 , and MBF increased in both HFpEF and controls; however, the magnitude of increases was significantly smaller in HFpEF. In both groups, MBF increased in relation to EW, but in HFpEF, the slope of the relationship was significantly smaller than in controls. Myocardial O 2 extraction was increased in HFpEF. Mechanical efficiency was similar in HFpEF and controls. In a post hoc analysis, HFpEF patients with LV hypertrophy (n=10) had significant reductions in LV mechanical efficiency relative to controls. Conclusions: In HFpEF during submaximal dobutamine stress, there is myocardial mechanical-, energetic- and flow-reserve dysfunction with impaired coupling of blood flow to demand and slight increases in myocardial O 2 extraction. These findings provide evidence that coronary microvascular dysfunction is present in HFpEF, limits O 2 supply relative to demand, and is associated with reserve dysfunction.

Abstract Background Clinical trials utilizing mesenchymal stem cells (MCSs) for the treatment of perianal Crohn disease are expanding. Most enrolled Crohn patients are being actively treated with corticosteroids, immunomodulators, and biologic therapy for their luminal and perianal disease at the time of enrollment and treatment. Aim We sought to broaden the understanding of the effect of corticosteroids, immunomodulators, and biologic therapy on the viability and function of MCSs. This information is important for tailoring inclusion and exclusion criteria of clinical trials. Methods Human adipose–derived mesenchymal stem cells (hAMCSs) were harvested and isolated from healthy patient donors. At Passage 3, hAMCSs were treated with 7 commonly used immunosuppressive therapies used to treat Crohn disease at increasing concentrations: dexamethasone, methotrexate, azathioprine, 6-mercaptopurine, infliximab, vedolizumab, and ustekinumab. Cell proliferation, migration, and cytokine secretion were analyzed at Day 4. Results Dexamethasone and azathioprine and 6-mercaptopurien affected cell proliferation and migration. Dexamethasone even resulted in cell death at high physiologic concentrations. The same drugs also had the most profound impacts on IL-6, IL-8, and monocyte chemoattractant protein-1 secretion profiles. Biologic therapies, including anti-tumor necrosis factor, anti-interleukin, and anti-integrins, had the smallest impact on hAMSC proliferation, migration, and cytokine secretion profile. Conclusions In clinical trials with MCSs, a washout period may be recommended for corticosteroids and immunomodulators to minimize any effect of systemic immunosuppression on MSC function and efficacy.