Peter Eckman

Transplantation of Cultured Islets from Two-Layer Preserved Pancreases in Type 1 Diabetes with Anti-CD3 Antibody

We sought to determine whether or not optimizing pancreas preservation, islet processing, and induction immunosuppression would facilitate sustained diabetes reversal after single‐donor islet transplants. Islets were isolated from two‐layer preserved pancreata, purified, cultured for 2 days; and transplanted into six C‐peptide‐negative, nonuremic, type 1 diabetic patients with hypoglycemia unawareness. Induction immunosuppression, which began 2 days pretransplant, included the Fc receptor nonbinding humanized anti‐CD3 monoclonal antibody hOKT3γ1 (Ala‐Ala) and sirolimus. Immunosuppression was maintained with sirolimus and reduced‐dose tacrolimus. Of our six recipients, four achieved and maintained insulin independence with normal HbA1c levels and freedom from hypoglycemia; one had partial islet graft function; and one lost islet graft function 2 weeks post‐transplant. The four insulin‐independent patients showed prolonged CD4+ T‐cell lymphocytopenia; inverted CD4:CD8 ratios; and increases in the percentage of CD4+CD25+ T cells. These cells suppressed the in‐vitro proliferative response to donor cells and, to a lesser extent, to third‐party cells. Severe adverse events were limited to a transient rash in one recipient and to temporary neutropenia in three. Our preliminary results thus suggest that a combination of maximized viable islet yield, pretransplant islet culture, and preemptive immunosuppression can result in successful single‐donor islet transplants.

An analysis of pump thrombus events in patients in the HeartWare ADVANCE bridge to transplant and continued access protocol trial

BACKGROUND The HeartWare left ventricular assist device (HVAD, HeartWare Inc, Framingham, MA) is the first implantable centrifugal continuous-flow pump approved for use as a bridge to transplantation. An infrequent but serious adverse event of LVAD support is thrombus ingestion or formation in the pump. In this study, we analyze the incidence of pump thrombus, evaluate the comparative effectiveness of various treatment strategies, and examine factors pre-disposing to the development of pump thrombus. METHODS The analysis included 382 patients who underwent implantation of the HVAD as part of the HeartWare Bridge to Transplant (BTT) and subsequent Continued Access Protocol (CAP) trial. Descriptive statistics and group comparisons were generated to analyze baseline characteristics, incidence of pump thrombus, and treatment outcomes. A multivariate analysis was performed to assess significant risk factors for developing pump thrombus. RESULTS There were 34 pump thrombus events observed in 31 patients (8.1% of the cohort) for a rate of 0.08 events per patient-year. The incidence of pump thrombus did not differ between BTT and CAP. Medical management of pump thrombus was attempted in 30 cases, and was successful in 15 (50%). A total of 16 patients underwent pump exchange, and 2 underwent urgent transplantation. Five patients with a pump thrombus died after medical therapy failed, 4 of whom also underwent a pump exchange. Survival at 1 year in patients with and without a pump thrombus was 69.4% and 85.5%, respectively (p = 0.21). A multivariable analysis revealed that significant risk factors for pump thrombus included a mean arterial pressure > 90 mm Hg, aspirin dose ≤ 81 mg, international normalized ratio ≤ 2, and Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profile level of ≥ 3 at implant. CONCLUSIONS Pump thrombus is a clinically important adverse event in patients receiving an HVAD, occurring at a rate of 0.08 events per patient-year. Significant risk factors for pump thrombosis include elevated blood pressure and sub-optimal anti-coagulation and anti-platelet therapies. This suggests that pump thrombus event rates could be reduced through careful adherence to patient management guidelines.

Bleeding and Thrombosis in Patients With Continuous-Flow Ventricular Assist Devices

Because of the obligate intravascular location of contemporary continuous-flow ventricular assist devices (CF-VADs), it is not surprising that bleeding and thrombosis are among the most common and feared complications of this therapy, respectively. Although strides have been made in our understanding of the pathophysiology of continuous flow, intravascular CF-VADs have been widely used only in the last few years, and a great deal remains less well known (or unknown). Outcomes have improved significantly over the past decade, but a deeper understanding of how these devices perturb the delicate intrinsic balance of bleeding and thrombosis is critical to guide therapy and to overcome the current obstacles to achieving a long-term safety profile comparable to that of mechanical prosthetic valves. ### Hematologic Effect of CF-VADs The hematologic effects of CF-VADs are of significant interest and importance and have recently been reviewed in detail elsewhere.1,2 Hemocompatibility refers to the interaction of prosthetic material with blood and can be measured in terms of impact on hematologic, inflammatory, or immunologic parameters, which has been observed clinically as significant and prolonged activation of endothelial and coagulation systems after CF-VAD implantation, including intercellular adhesion molecule, E-selectin, and tissue factor, for example.3 Hemocompatibility has always been a goal in pump design, along with efforts to maximize blood flow without clinically significant hemolysis, areas of stasis, turbulent flow, or retrograde flow. It has been suggested that the major complications of thrombosis, bleeding, and infection could be related to the effects of blood interaction with the VAD surface,4,5 and further optimization of surface coatings presents an appealing strategy for additional exploration.6 A better understanding of the impact of blood–VAD surface interactions with the presently used CF-VAD devices, however, is essential to evaluating the impact of novel designs or materials. A few recent observations have provided some insight …

Aortic valve pathophysiology during left ventricular assist device support

The increased applicability and excellent results with left ventricular assist devices (LVADs) have revolutionized the available treatment options for patients with advanced heart failure. Pre-existing valve abnormalities are common in this population, and subsequent development of valve abnormalities after LVAD placement is also often noted. Although native mitral and tricuspid valve disease is more common in heart failure patients before LVAD placement, aortic valves are much more likely to generate abnormal pathophysiology in the LVAD patient during as well as after LVAD placement. The aim of this comprehensive review is to review aortic valve function in LVAD patients and highlight the consideration of pre-existing valve disease on patient treatment at the time of LVAD implant. The basis for structural changes leading to valve pathophysiology during and after LVAD placement will be described, providing a basis for improved clinical understanding and new strategies to prevent these conditions.

Clinical, molecular, and genomic changes in response to a left ventricular assist device

The use of left ventricular assist devices in treating patients with end-stage heart failure has increased significantly in recent years, both as a bridge to transplantation and as destination therapy in those who are ineligible for cardiac transplantation. This increase is based largely on the results of several recently completed clinical trials with the new second-generation continuous-flow devices that showed significant improvements in survival, functional capacity, and quality of life. Additional information on the use of the first- and second-generation left ventricular assist devices has come from a recently released report spanning the years 2006 to 2009, from the Interagency Registry for Mechanically Assisted Circulatory Support, a National Heart, Lung, and Blood Institute-sponsored collaboration between the U.S. Food and Drug Administration, the Centers for Medicare and Medicaid Services, and the scientific community. The authors review the latest clinical trials and data from the registry, with tight integration of the landmark molecular, cellular, and genomic research that accompanies the reverse remodeling of the human heart in response to a left ventricular assist device and functional recovery that has been reported in a subset of these patients.

Continuous Flow Left Ventricular Assist Device Outcomes in Commercial Use Compared With the Prior Clinical Trial

BACKGROUND A multicenter clinical trial conducted from 2005 to 2008 of a continuous flow left ventricular assist device (LVAD) resulted in Food and Drug Administration approval for bridge to transplantation. The purpose of this analysis was to determine changes in posttrial outcomes in widespread commercial use since the clinical trial. METHODS We compared outcomes of 486 patients who received a continuous flow LVAD as a bridge to transplantation at 36 centers during the clinical trial (March 2005 to April 2008) with outcomes of 1,496 posttrial patients who received a continuous flow LVAD at 83 centers (April 2008 to September 2010 as reported to the Interagency Registry for Mechanically Assisted Circulatory Support). RESULTS Baseline data were comparable between groups. Cumulative follow-up was 511 and 1,082 patient-years for trial and posttrial patients, respectively, and average support duration was 12.6 ± 14.0 and 8.7 ± 7.1 months. Kaplan-Meier survival improved at 1 year from 76% (trial) to 85% (posttrial). The percentage of patients undergoing transplantation in the first year decreased from 48% in the trial period to 39% in the posttrial period. Quality of life metrics improved by 3 months in both groups. CONCLUSIONS The survival rate of a large group of continuous flow LVAD patients in a real-world setting after Food and Drug Administration market approval for bridge to transplantation has improved since the clinical trial. These data show that excellent outcomes have been maintained with dissemination of new LVAD technology from a clinical trial phase to more broad based use in the period after market approval.

Lessons Learned From Experience With Over 100 Consecutive HeartMate II Left Ventricular Assist Devices

BACKGROUND Continuous-flow left ventricular assist devices (LVADs) such as the HeartMate II have become the therapy of choice in patients with end-stage heart failure. The aim of this study is to report the outcomes in patients receiving the HeartMate II LVAD at a single center and review the lessons learned from this experience. METHODS From June 2005 to June 2010, 130 consecutive patients received the HeartMate II LVAD. Of these, 102 were bridge-to-transplant (BTT), 17 destination therapy, and 11 exchanges for failed HeartMate XVE. This study focuses on the 102 BTT patients. The HeartMate II was approved by the US Food and Drug Administration (FDA) as BTT in April 2008 and 64 patients received this device as BTT since that date. We review our experience with the device as BTT and report on patient survival and adverse events as well as the impact of FDA approval on outcomes. RESULTS Overall, mean age was 52.6 ± 12.8 years; 26 (25.5%) were female. Disease etiology was ischemic in 58, nonischemic in 36, and other in 8. Overall, 30-day, 6-month, and 1-year survival for the BTT patients was 95.1%, 83.5%, and 78.8%, respectively. The 6-month survival in 38 patients in the clinical trial (pre-FDA) was 88.8% and was not statistically significant compared with the 76.2% 6-month survival in the 64 patients in the post-FDA approval period (p value = 0.1). Major adverse events among the 102 BTT patients included right ventricular failure in 5 (4.9%), LVAD driveline infections in 25 (24.5%), neurologic events in 10 (9.8%), and gastrointestinal bleeding in 18 (17.6%) patients. In addition, 1 patient (0.98%) had pump thrombus requiring device replacement. CONCLUSIONS Despite significant morbidity, use of the HeartMate II LVAD as BTT provides excellent hemodynamic support and is associated with excellent survival and low mortality. In addition, there needs to be improvement and focused strategies in the areas of gastrointestinal bleeding, driveline infections, and adverse neurologic events for these devices to be able to provide a real long-term alternative to heart transplantation.

Effects on pre- and posttransplant pulmonary hemodynamics in patients with continuous-flow left ventricular assist devices

OBJECTIVE Pulsatile left ventricular assist devices have been shown to effectively reduce pulmonary hypertension in patients with end-stage heart failure. However, it remains to be seen whether newer continuous-flow left ventricular assist devices have a similar effect on pulmonary hypertension. The objective of this study was to determine whether the HeartMate II (Thoratec Corp, Pleasanton, Calif), a continuous-flow left ventricular assist device, is effective in improving pulmonary hemodynamics in the period after left ventricular assist device support and posttransplant. METHODS Fifty patients with end-stage heart failure underwent HeartMate II left ventricular assist device placement as a bridge to transplant. We evaluated their pulmonary hemodynamics with right-sided heart catheterization at baseline, after left ventricular assist device placement, and after heart transplant. RESULTS The mean age of patients was 53.7 +/- 13.5 years. Ischemic etiology was present in 60% of the patients. After left ventricular assist device placement (mean duration, 135 +/- 60 days), mean systolic and diastolic pulmonary artery pressures decreased significantly from a baseline of 55.2 +/- 13.4 mm Hg and 27.3 +/- 6.8 mm Hg, respectively, to 35.9 +/- 10.8 mm Hg and 15.8 +/- 6.5 mm Hg, respectively (P < .001). Similarly, mean pulmonary vascular resistance decreased significantly from a baseline of 3.6 +/- 1.9 Woods units to 2.1 +/- 0.8 Woods units (P < .001). Posttransplant pulmonary hemodynamics also remained within normal limits, even in patients with previously severe pulmonary hypertension. CONCLUSION Continuous-flow left ventricular assist devices effectively improve pulmonary hemodynamics associated with end-stage heart failure. Moreover, pulmonary hemodynamics remain within normal limits in the posttransplant period, even in patients with severe pulmonary hypertension. Therefore, adequate left ventricular decompression achieved with newer left ventricular assist devices can reverse significant pulmonary hypertension in patients with end-stage heart failure, making them eligible for cardiac transplantation.

Successful Treatment of Early Thrombosis of HeartWare Left Ventricular Assist Device With Intraventricular Thrombolytics

In the last few years, left ventricular assist devices (LVADs) have moved to the forefront in the management of patients with advanced heart failure. Pumps have gradually become smaller and more efficient and have clearly demonstrated survival benefits and improvement in functional status and quality of life in patients with advanced heart failure. Despite impressive advances in device technology, risk of severe complications remains, such as device thrombosis. A 62-year-old man who underwent HeartWare LVAD implantation as a bridge to cardiac transplant was admitted 18 days after device implantation with severe shortness of breath, fatigue and lethargy; he was found to have increased pump flows with high power demands and evidence of cardiogenic shock. An echocardiogram showed an echo density at the inflow cannula that was suggestive of thrombosis. Laboratory data showed evidence of hemolysis. He was treated successfully with intraventricular tissue plasminogen activator with rapid resolution of his symptoms and return of LVAD flow and power consumption to baseline. The patient was discharged with no complications or recurrence of thrombosis and received a successful transplant 1 month later.

Current State of Ventricular Assist Devices

Left ventricular assist device (LVAD) support is an accepted treatment of patients with end-stage heart failure. The increased applicability and excellent results with LVADs have revolutionized the treatment options available for such patients. Success with LVADs as bridge-to-transplant therapy has led to their successful use as an alternate to a transplant (ie, as destination therapy [DT]). The use of these devices as DT represents a relatively newer but growing indication. Until recently, most patients who have undergone LVAD implantation have been supported by pulsatile devices. Newer continuous-flow (CF) pumps have resulted in superior outcomes, including significantly reduced complication rates with improved durability over first-generation pulsatile design pumps. However, as with all new technology, the newer LVADs have introduced management challenges that were either unimportant or absent with pulsatile LVADs. This article reviews the current state of left ventricular devices, focusing on the CF pumps that currently dominate the field, including clinical outcomes, the physiologic and pathologic effects that are associated with CF pumps, and their unique management issues and complications.