Background Right ventricular (RV) failure after left ventricular assist device (LVAD) placement is a serious complication and is difficult to predict. In the era of destination therapy and the total artificial heart, predicting post-LVAD RV failure requiring mechanical support is extremely important. Methods We reviewed patient characteristics, laboratory values, and hemodynamic data from 266 patients who underwent LVAD placement at the University of Pennsylvania from April 1995 to June 2007. Results Of 266 LVAD recipients, 99 required RV assist device (BiVAD) placement (37%). We compared 36 parameters between LVAD (n=167) and BiVAD patients (n=99) to determine preoperative risk factors for RV assist device (RVAD) need. By univariate analysis, 23 variables showed statistically significant differences between the two groups (P ≤ 0.05). By multivariate logistic regression, cardiac index ≤ 2.2 L/min·m2 (odds ratio [OR] 5.7), RV stroke work index ≤ 0.25 mmHg·mL/m2 (OR 5.1), severe preoperative RV dysfunction (OR 5.0), preoperative creatinine ≥ 1.9 mg/dL (OR 4.8), previous cardiac surgery (OR 4.5), and systolic blood pressure ≤ 96 mmHg (OR 2.9) were the best predictors of RVAD need. Conclusions The most significant predictors for RVAD need were cardiac index, RV stroke work index, severe preoperative RV dysfunction, creatinine, previous cardiac surgery, and systolic blood pressure. Using these, we constructed an algorithm which can predict which LVAD patients will require RVAD with greater than 80% sensitivity and specificity.

Objective It is generally accepted that patients who require biventricular mechanical support (BiVAD) have poorer outcomes than those requiring isolated left ventricular support (LVAD). However, it is unknown how the timing of BiVAD insertion affects outcomes. We hypothesized that planned BiVAD insertion improves survival compared to delayed conversion of LVAD to BiVAD. Methods We reviewed and compared outcomes of 266 patients undergoing LVAD or BiVAD placement at the University of Pennsylvania from April 1995 to June 2007. We subdivided BiVAD patients into planned BiVAD (P-BiVAD) and delayed BiVAD (D-BiVAD) groups, based on the timing of RVAD insertion. We defined D-BiVAD as any failure of isolated LVAD support. Results Of 266 LVAD patients, 99 required BiVAD (37%). We compared preoperative characteristics, successful bridging to transplant, survival to hospital discharge, and Kaplan-Meier one-year survival between P-BiVAD (n=71) and D-BiVAD (n=28) groups. Preoperative comparison showed that patients who ultimately require biventricular support have similar preoperative status. LVAD (n=167) outcomes in all categories exceeded both P-BiVAD and D-BiVAD outcomes. Further, P-BiVAD patients had superior survival to discharge than D-BiVAD patients (51% v 29% p<0.05). One-year and long-term Kaplan-Meier survival distribution confirmed this finding. There was also a trend towards improved bridging to transplant in P-BiVAD (n=55) vs. D-BiVAD (n=22) patients (65% v 45% p=0.10). Conclusion When patients at risk for isolated LVAD support failure are identified, proceeding directly to BiVAD implantation is advised, as early institution of biventricular support results in dramatic improvement in survival.

Background Myocardial ischemia causes cardiomyocyte death, adverse ventricular remodeling, and ventricular dysfunction. Endothelial progenitor cells (EPC) have been shown to ameliorate this process, particularly when activated with stromal cell-derived factor-1α (SDF). We hypothesized that implantation of a tissue engineered extracellular matrix scaffold seeded with EPCs primed with SDF could induce neovasculogenesis, prevent adverse remodeling, and preserve ventricular function after myocardial infarction (MI). Methods and Results Lewis rats (n=82) underwent left anterior descending artery ligation to induce MI. EPCs were cultured on a vitronectin/collagen scaffold, and primed with SDF to generate the activated EPC matrix (EPCM). EPCM was sutured to the anterolateral left ventricular (LV) wall including the region of ischemia.. At four weeks, when compared to controls, borderzone myocardial tissue demonstrated increased levels of VEGF in the EPCM group. Vessel density as assessed by immunohistochemical microscopy was significantly increased in the EPCM group (4.1 vs 6.2 vessels/high-powered field, p<0.001), and microvascular perfusion measured by lectin microangiography was enhanced four-fold (0.7 vs. 2.7% vessel volume/section volume, p=0.04). Ventricular geometry and scar fraction assessed by analysis of sectioned hearts exhibited significantly preserved LV internal diameter (9.7mm vs. 8.6mm, p=0.005) and decreased infarct scar expressed as percent of total section area (16% vs. 7%, p=0.002) when compared to all other groups. In addition, EPCM animals showed a significant preservation of function as measured by echocardiography, pressure volume-conductance, and Doppler flow. Conclusions Extracellular matrix seeded with EPCs primed with SDF induces borderzone neovasculogenesis, attenuates adverse ventricular remodeling, and preserves ventricular function after MI.

BACKGROUND After ischemic injury, cardiac secretion of the potent endothelial progenitor stem cell (EPC) chemokine SDF stimulates endogenous neovascularization and myocardial repair, a process insufficiently robust to repair major infarcts. Experimentally, exogenous administration of recombinant SDF enhances neovasculogenesis and cardiac function after MI. However, SDF has a short half-life, is bulky, and very expensive. Smaller analogs of SDF may provide translational advantages including enhanced stability and function, ease of synthesis, lower cost, and potential modulated delivery via engineered biomaterials. In this study, computational protein design was used to create a more efficient evolution of the native SDF protein. METHODS and RESULTS Protein structure model was used to engineer an SDF polypeptide analog (ESA) that splices the N-terminus (activation and binding) and C-terminus (extracellular stabilization) with a diproline segment designed to limit the conformational flexibility of the peptide backbone and retain the relative orientation of these segments observed in the native structure of SDF. EPCs in ESA gradient, assayed by Boyden chamber, showed significantly increased migration compared to both SDF and control gradients (ESA 567±74 cells/HPF vs SDF 438±46 p=0.037; vs Control 156±45 p=0.001). EPC receptor activation was evaluated by quantifying phosphorylated AKT. ESA had significantly greater pAKT levels than SDF and control (1.64±0.24 vs 1.26±0.187, p=0.01; vs. 0.95±0.08, p<0.001). Angiogenic growth factor assays revealed a distinct increase in Angiopoietin-1 expression in the ESA and SDF treated hearts. Also, CD-1 mice (n=30) underwent LAD ligation and peri-infarct intramyocardial injection of ESA, SDF-1α, or saline. At 2 weeks, echocardiography demonstrated a significant gain in EF, CO, SV, and Fractional Area Change (FAC) in mice treated with ESA when compared to controls and significant improvement in FAC when compared to SDF treated mice. CONCLUSION When compared to native SDF, a novel engineered SDF polypeptide analog (ESA) more efficiently induces EPC migration and improves post-MI cardiac function, and thus offers a more clinically translatable neovasculogenic therapy.