John W. MacArthur

Minimally invasive approach provides at least equivalent results for surgical correction of mitral regurgitation: A propensity-matched comparison

OBJECTIVE Minimally invasive approaches to mitral valve surgery are increasingly used, but the surgical approach must not compromise the clinical outcome for improved cosmesis. We examined the outcomes of mitral repair performed through right minithoracotomy or median sternotomy. METHODS Between January 2002 and October 2011, 1011 isolated mitral valve repairs were performed in the University of Pennsylvania health system (455 sternotomies, 556 right minithoracotomies). To account for key differences in preoperative risk profiles, propensity scores identified 201 well-matched patient pairs with mitral regurgitation of any cause and 153 pairs with myxomatous disease. RESULTS In-hospital mortality was similar between propensity-matched groups (0% vs 0% for the degenerative cohort; 0% vs 0.5%, P = .5 for the overall cohort; in minimally invasive and sternotomy groups, respectively). Incidence of stroke, infection, myocardial infarction, exploration for postoperative hemorrhage, renal failure, and atrial fibrillation also were comparable. Transfusion was less frequent in the minimally invasive groups (11.8% vs 20.3%, P = .04 for the degenerative cohort; 14.0% vs 22.9%, P = .03 for the overall cohort), but time to extubation and discharge was similar. A 99% repair rate was achieved in patients with myxomatous disease, and a minimally invasive approach did not significantly increase the likelihood of a failed repair resulting in mitral valve replacement. Patients undergoing minimally invasive mitral repair were more likely to have no residual post-repair mitral regurgitation (97.4% vs 92.1%, P = .04 for the degenerative cohort; 95.5% vs 89.6%, P = .02 for the overall cohort). In the overall matched cohort, early readmission rates were higher in patients undergoing sternotomies (12.6% vs 4.4%, P = .01). Over 9 years of follow-up, there was no significant difference in long-term survival between groups (P = .8). CONCLUSIONS In appropriate patients with isolated mitral valve disease of any cause, a right minithoracotomy approach may be used without compromising clinical outcome.

Sustained Release of Engineered Stromal Cell–Derived Factor 1-α From Injectable Hydrogels Effectively Recruits Endothelial Progenitor Cells and Preserves Ventricular Function After Myocardial Infarction

Background— Exogenously delivered chemokines have enabled neovasculogenic myocardial repair in models of ischemic cardiomyopathy; however, these molecules have short half-lives in vivo. In this study, we hypothesized that the sustained delivery of a synthetic analog of stromal cell–derived factor 1-&agr; (engineered stromal cell–derived factor analog [ESA]) induces continuous homing of endothelial progenitor cells and improves left ventricular function in a rat model of myocardial infarction. Methods and Results— Our previously designed ESA peptide was synthesized by the addition of a fluorophore tag for tracking. Hyaluronic acid was chemically modified with hydroxyethyl methacrylate to form hydrolytically degradable hydrogels through free-radical–initiated crosslinking. ESA was encapsulated in hyaluronic acid hydrogels during gel formation, and then ESA release, along with gel degradation, was monitored for more than 4 weeks in vitro. Chemotactic properties of the eluted ESA were assessed at multiple time points using rat endothelial progenitor cells in a transwell migration assay. Finally, adult male Wistar rats (n=33) underwent permanent ligation of the left anterior descending (LAD) coronary artery, and 100 µL of saline, hydrogel alone, or hydrogel+25 µg ESA was injected into the borderzone. ESA fluorescence was monitored in animals for more than 4 weeks, after which vasculogenic, geometric, and functional parameters were assessed to determine the therapeutic benefit of each treatment group. ESA release was sustained for 4 weeks in vitro, remained active, and enhanced endothelial progenitor cell chemotaxis. In addition, ESA was detected in the rat heart >3 weeks when delivered within the hydrogels and significantly improved vascularity, ventricular geometry, ejection fraction, cardiac output, and contractility compared with controls. Conclusions— We have developed a hydrogel delivery system that sustains the release of a bioactive endothelial progenitor cell chemokine during a 4-week period that preserves ventricular function in a rat model of myocardial infarction.

Natural history of coexistent tricuspid regurgitation in patients with degenerative mitral valve disease: implications for future guidelines.

OBJECTIVE The management of coexistent tricuspid regurgitation in patients with mitral regurgitation remains controversial. We sought to define the incidence and natural history of coexistent tricuspid regurgitation in patients undergoing isolated mitral surgery for degenerative mitral regurgitation, as well as the effect of late secondary tricuspid regurgitation on cardiovascular symptom burden and survival. METHODS To minimize confounding, analysis was limited to 495 consecutive patients who underwent isolated mitral surgery for degenerative mitral valve disease between 2002 and 2011. Patients with coexistent severe tricuspid regurgitation were excluded because such patients typically undergo concomitant tricuspid intervention. RESULTS Grade 1 to 3 coexistent tricuspid regurgitation was present in 215 patients (43%) preoperatively. Actuarial freedom from grade 3 to 4 tricuspid regurgitation 1, 5, and 9 years after surgery was 100% ± 0%, 90% ± 2%, and 64% ± 7%, respectively. Older age (P < .001) and grade of preoperative tricuspid regurgitation (P = .006) independently predicted postoperative progression of tricuspid regurgitation on multivariable analysis. However, when limited to patients with mild or absent tricuspid regurgitation, indexed tricuspid annular diameter was the only significant risk factor for late tricuspid regurgitation (P = .04). New York Heart Association functional class and long-term survival did not worsen with development of late secondary tricuspid regurgitation (P = .4 and P = .6, respectively). However, right ventricular dysfunction was significantly more common in patients with more severe late tricuspid regurgitation (P = .007). CONCLUSIONS Despite durable correction of degenerative mitral regurgitation, less than severe tricuspid regurgitation is likely to progress after surgery if uncorrected. Given the low incremental risk of tricuspid annuloplasty, a more aggressive strategy of concomitant tricuspid repair may be warranted.

Continuous Flow Left Ventricular Assist Device Implant Significantly Improves Pulmonary Hypertension, Right Ventricular Contractility, and Tricuspid Valve Competence

Continuous flow left ventricular assist devices (CF LVAD) are being implanted with increasing frequency for end‐stage heart failure. At the time of LVAD implant, a large proportion of patients have pulmonary hypertension, right ventricular (RV) dysfunction, and tricuspid regurgitation (TR). RV dysfunction and TR can exacerbate renal dysfunction, hepatic dysfunction, coagulopathy, edema, and even prohibit isolated LVAD implant. Repairing TR mandates increased cardiopulmonary bypass time and bicaval cannulation, which should be reserved for the time of orthotopic heart transplantation. We hypothesized that CF LVAD implant would improve pulmonary artery pressures, enhance RV function, and minimize TR, obviating need for surgical tricuspid repair.

Computational Protein Design to Reengineer Stromal Cell–Derived Factor-1α Generates an Effective and Translatable Angiogenic Polypeptide Analog

Background— Experimentally, exogenous administration of recombinant stromal cell–derived factor-1&agr; (SDF) enhances neovasculogenesis and cardiac function after myocardial infarction. 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 modeling was used to engineer an SDF polypeptide analog (engineered SDF 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. Endothelial progenitor cells (EPCs) in ESA gradient, assayed by Boyden chamber, showed significantly increased migration compared with both SDF and control gradients. EPC receptor activation was evaluated by quantification of phosphorylated AKT, and cells treated with ESA yielded significantly greater phosphorylated AKT levels than SDF and control cells. Angiogenic growth factor assays revealed a distinct increase in angiopoietin-1 expression in the ESA- and SDF-treated hearts. In addition, CD-1 mice (n=30) underwent ligation of the left anterior descending coronary artery and peri-infarct intramyocardial injection of ESA, SDF-1&agr;, or saline. At 2 weeks, echocardiography demonstrated a significant gain in ejection fraction, cardiac output, stroke volume, and fractional area change in mice treated with ESA compared with controls. Conclusions— Compared with native SDF, a novel engineered SDF polypeptide analog (ESA) more efficiently induces EPC migration and improves post–myocardial infarction cardiac function and thus offers a more clinically translatable neovasculogenic therapy.

Ventricular assist device implant in the elderly is associated with increased, but respectable risk: a multi-institutional study.

BACKGROUND There are an increasing number of elderly patients with end-stage heart failure. Destination mechanical circulatory support is often the only therapy available for these patients who are not transplant candidates. The outcomes after continuous flow left ventricular assist device (CF LVAD) implant in older patients remains unclear. We undertook this multi-institutional study to quantify short-term and midterm outcomes after CF LVAD implant in the elderly. METHODS We retrospectively analyzed all patients in the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) national registry that underwent implant of a CF LVAD (June 2006 to April 2012). Patients were divided into 2 cohorts based upon age (<70 years [n = 4,439] and ≥ 70 years (n = 590]). Preoperative, intraoperative, and postoperative variables were analyzed. The primary endpoint, survival, was compared between cohorts. RESULTS Patients age 70 and older were more hemodynamically stable pre-VAD implant as evidenced by INTERMACS profile and inotrope dependence. Perioperative outcomes, including median bypass time (89 vs 89 minutes) and length of stay (0.657 vs 0.657 months) were similar between cohorts (p = not significant). Kaplan-Meier analysis revealed a significant difference in 2-year survival between patients aged 70 years or greater (63%) and less than 70 (71%, p < 0.001). Multivariable Cox proportional hazard analysis revealed age as an independent predictor of mortality during follow-up (p < 0.001). Nonetheless, midterm cumulative survival in the older cohort was still reasonable (63% at 2 years). CONCLUSIONS Multi-institutional analysis revealed advanced age as a predictor of increased mortality after CF LVAD implantation. Careful patient selection is critical in the elderly to optimize long-term outcomes after CF LVAD implantation.

Tissue Engineered, Hydrogel-Based Endothelial Progenitor Cell Therapy Robustly Revascularizes Ischemic Myocardium and Preserves Ventricular Function

OBJECTIVES Cell-based angiogenic therapy for ischemic heart failure has had limited clinical impact, likely related to low cell retention (<1%) and dispersion. We developed a novel, tissue-engineered, hydrogel-based cell-delivery strategy to overcome these limitations and provide prolonged regional retention of myocardial endothelial progenitor cells at high cell dosage. METHODS Endothelial progenitor cells were isolated from Wistar rats and encapsulated in fibrin gels. In vitro viability was quantified using a fluorescent live-dead stain of transgenic enhanced green fluorescent protein(+) endothelial progenitor cells. Endothelial progenitor cell-laden constructs were implanted onto ischemic rat myocardium in a model of acute myocardial infarction (left anterior descending ligation) for 4 weeks. Intramyocardial cell injection (2 × 10(6) endothelial progenitor cells), empty fibrin, and isolated left anterior descending ligation groups served as controls. Hemodynamics were quantified using echocardiography, Doppler flow analysis, and intraventricular pressure-volume analysis. Vasculogenesis and ventricular geometry were quantified. Endothelial progenitor cell migration was analyzed by using endothelial progenitor cells from transgenic enhanced green fluorescent protein(+) rodents. RESULTS Endothelial progenitor cells demonstrated an overall 88.7% viability for all matrix and cell conditions investigated after 48 hours. Histologic assessment of 1-week implants demonstrated significant migration of transgenic enhanced green fluorescent protein(+) endothelial progenitor cells from the fibrin matrix to the infarcted myocardium compared with intramyocardial cell injection (28 ± 12.3 cells/high power field vs 2.4 ± 2.1 cells/high power field, P = .0001). We also observed a marked increase in vasculogenesis at the implant site. Significant improvements in ventricular hemodynamics and geometry were present after endothelial progenitor cell-hydrogel therapy compared with control. CONCLUSIONS We present a tissue-engineered, hydrogel-based endothelial progenitor cell-mediated therapy to enhance cell delivery, cell retention, vasculogenesis, and preservation of myocardial structure and function.

Spatially Oriented, Temporally Sequential Smooth Muscle Cell-Endothelial Progenitor Cell Bi-Level Cell Sheet Neovascularizes Ischemic Myocardium

Background— Endothelial progenitor cells (EPCs) possess robust therapeutic angiogenic potential, yet may be limited in the capacity to develop into fully mature vasculature. This problem might be exacerbated by the absence of a neovascular foundation, namely pericytes, with simple EPC injection. We hypothesized that coculturing EPCs with smooth muscle cells (SMCs), components of the surrounding vascular wall, in a cell sheet will mimic the native spatial orientation and interaction between EPCs and SMCs to create a supratherapeutic angiogenic construct in a model of ischemic cardiomyopathy. Methods and Results— Primary EPCs and SMCs were isolated from Wistar rats. Confluent SMCs topped with confluent EPCs were spontaneously detached from the Upcell dish to create an SMC-EPC bi-level cell sheet. A rodent ischemic cardiomyopathy model was created by ligating the left anterior descending coronary artery. Rats were then immediately divided into 3 groups: cell-sheet transplantation (n=14), cell injection (n=12), and no treatment (n=13). Cocultured EPCs and SMCs stimulated an abundant release of multiple cytokines in vitro. Increased capillary density and improved blood perfusion in the borderzone elucidated the significant in vivo angiogenic potential of this technology. Most interestingly, however, cell fate–tracking experiments demonstrated that the cell-sheet EPCs and SMCs directly migrated into the myocardium and differentiated into elements of newly formed functional vasculature. The robust angiogenic effect of this cell sheet translated to enhanced ventricular function as demonstrated by echocardiography. Conclusions— Spatially arranged EPC-SMC bi-level cell-sheet technology facilitated the natural interaction between EPCs and SMCs, thereby creating structurally mature, functional microvasculature in a rodent ischemic cardiomyopathy model, leading to improved myocardial function.

The Effect of Island Area on Population Densities

Bird population densities on the island of Canas, Pearl Archipelago, Panama, were estimated by regression analysis of mist net captures of resident birds. The Canas mist net capture rate is very similar to those from adjacent Puercos, which is one seventh as big but otherwise similar. This not only confirms the main results of the Puercos study but also seems to rule out the action on these birds of the boundary phenomena described for mice by Krebs et al. in which confined populations greatly increased in density because of the small enclosure. The results are consistent with observations made by Diamond on southwest Pacific birds. See full-text article at JSTOR

Combined Heart and Liver Transplantation Can Be Safely Performed With Excellent Short- and Long-Term Results

BACKGROUND Heart transplant has become the gold standard therapy for end-stage heart failure. Short- and long-term outcomes after orthotopic heart transplant have been excellent. Many patients with heart failure manifest hepatic failure as a result of a chronically elevated central venous pressure. Concomitant hepatic failure has been a contraindication to heart transplant in most centers. A few select institutions are currently performing combined heart-liver transplantation to treat dual organ failure. The outcomes after dual organ transplant are largely unknown, with limited data from a few select centers. We undertook this study to analyze our large experience with combined heart-liver transplant and determine the short-term and long-term outcomes associated with this procedure. METHODS We have performed 1,050 heart transplants at our center to date. Of these patients, 26 underwent combined heart and liver transplant (largest single-center experience). We reviewed demographic, perioperative, and short- and long-term outcomes after this combined procedure. RESULTS All 26 patients underwent successful dual organ transplant, without any episodes of primary graft dysfunction. Average length of intensive care unit stay was 10 ± 5 days, and average hospital stay was 25 ± 11 days. Kaplan-Meier analysis demonstrated excellent short-term survival (1 year, 87% ± 7%) and long-term survival (5 years, 83% ± 8%). Interestingly, only 3 patients (11%) demonstrated any evidence of rejection long-term by myocardial biopsy, suggesting that concomitant hepatic transplantation may provide immunologic protection for the cardiac allograft. CONCLUSIONS We present the largest single-center series of combined heart and liver transplant. This dual organ strategy is highly feasible, with excellent long-term survival. Concomitant liver transplant may confer immunologic protection for the cardiac allograft.