Christoph Bara

Acquired von Willebrand Syndrome in Patients with an Axial Flow Left Ventricular Assist Device

Background—Rotary blood pumps used as left ventricular assist devices (LVADs) allow for long-term support and may become suitable alternatives to heart transplantation. Effects of this technology on the coagulation system are not completely understood, leading to controversial anticoagulation protocols. Thus, we investigated the primary hemostasis in patients with chronic LVAD therapy. Methods and Results—Twenty-six outpatients received axial flow LVAD (HeartMate II; Thoratec) for a median support time of 4.5 months. In a cross-sectional protocol, platelet aggregation in response to ADP and epinephrine, von Willebrand antigen (vWF:AG), and collagen-binding capacity (vWF:CB) were obtained. Von Willebrand factor (vWF) multimer analyses were performed, and patients were screened for bleeding events. This analysis was repeated after removal of the device for transplantation or recovery (n=12) and after a median of 15.5 months in ongoing patients (n=11). In all patients on devices, severe impairment of platelet aggregation as well as a loss of large vWF multimers were found. In 10 patients, a decreased vWF:CB/vWF:AG ratio was observed. Bleeding episodes occurred with an incidence of 0.17 per patient-year. After removal of the device, normal patterns of platelet aggregation, multimer analysis, and vWF:CB/vWF:AG ratio were recorded. In the second analysis of ongoing patients, impairment of platelet aggregation and loss of large vWF multimers were verified. Conclusions—A diagnosis of von Willebrand syndrome type 2 was established in all patients after LVAD implantation, and bleeding events confirmed this finding. Reversibility of this condition was found after removal of the device.

Ribavirin treatment of acute and chronic hepatitis E: a single-centre experience.

The role of ribavirin for treatment of severe acute or chronic hepatitis E virus (HEV) infection is not well defined.

Hepatitis E virus (HEV)‐specific T‐cell responses are associated with control of HEV infection

Hepatitis E virus (HEV) infection is usually self‐limited but may lead to acute hepatitis and rarely to fulminant hepatic failure. Persistent HEV infections have recently been described in organ transplant recipients receiving immunosuppressive medications, suggesting that HEV is controlled by adaptive immune responses. However, only few studies have investigated HEV‐specific T‐cell responses and immune correlates for the failure to clear HEV infection have not been established so far. We investigated T‐cell responses against HEV in 38 subjects including anti‐HEV‐positive (exposed, n = 9) and anti‐HEV‐negative (n = 10) healthy controls, 12 anti‐HEV‐positive but HEV RNA‐negative organ transplant recipients, and seven transplant recipients with chronic hepatitis E. Proliferation as well as cytokine production of CD4+ and CD8+ T cells was studied after stimulation with overlapping peptides spanning all proteins encoded by HEV‐open reading frame (ORF)2 and HEV‐ORF3. We show that (1) strong and multispecific HEV‐specific T‐cell responses are present in exposed healthy controls, and to a lesser extent also in recovered patients after transplantation; (2) that these responses are absent in patients with chronic hepatitis E but become detectable after viral clearance; and (3) that HEV‐specific T‐cell responses can be restored in vitro by blocking the PD‐1 or CTLA‐4 pathways. However, a combination of PD‐1 and CTLA‐4 blockade had no synergistic effects. We conclude that chronic hepatitis E is associated with impaired HEV‐specific T‐cell responses and suggest that enhancing adaptive cellular immunity against HEV might prevent persistent HEV infections. (HEPATOLOGY 2012)

Health-related quality of life and exercise tolerance in recipients of heart transplants and left ventricular assist devices: A prospective, comparative study

BACKGROUND The aim of this study was to evaluate and compare health-related quality of life (HRQoL) and physical exercise tolerance in patients after heart transplantation (HTx) or implantation of a left ventricular assist device (LVAD). METHODS A prospective, comparative design was used to characterize changes over time in HRQoL (SF-36) and exercise tolerance in patients after HTx (n = 54) and during LVAD support (n = 36). Nine LVAD patients were lost for follow-up. The majority of patients in both groups were male (97%); the LVAD cohort tended to be younger (p = 0.06). RESULTS HRQoL improved significantly in HTx patients in the SF-36 physical (p = 0.02), but not in the psychosocial (p = 0.27) component score during follow-up. In the LVAD group, HRQoL showed improvements for both the SF-36 physical and psychosocial component scores (both p = 0.04). Between-group comparisons revealed better HRQoL for the HTx cohort than the LVAD cohort for 2 of 8 SF-36 subscales. Age-, gender- and body mass index (BMI)-adjusted exercise tolerance (workload; VO(2max)) showed significant improvements for both HTx (p = 0.01) and LVAD (p = 0.01) patients. Adjusted maximum oxygen consumption was higher for HTx patients (p = 0.05) relative to LVAD patients at 8 ± 1 months after implant. CONCLUSION HRQoL and exercise capacity increased in both groups over the time-course of the study. After adjusting for relevant variables, HTx patients showed a higher exercise tolerance compared with the LVAD group during follow-up. Thus, future large-scale intervention studies should emphasize the specific needs of these patient cohorts.

Multidisciplinary Insights on Clinical Guidance for the Use of Proliferation Signal Inhibitors in Heart Transplantation

Proliferation signal or mammalian target-of-rapamycin inhibitors (PSI/mTOR inhibitors), everolimus and sirolimus, provide attractive options for use in heart transplantation because they are immunosuppressive and anti-proliferative. PSI/mTOR inhibitors work synergistically with calcineurin inhibitors (CNIs) and thus permit the minimization of CNIs without compromising efficacy. This approach is advantageous for the majority of heart transplant recipients and might provide particular benefit in specific cases, such as patients with cardiac allograft vasculopathy, malignancies and renal dysfunction, or in patients intolerant to other immunosuppressive agents. Drawing on the expertise of transplant cardiologists, cardiac surgeons and nephrologists, we addressed the assessment of renal function; management of adverse events associated with this class of drugs; and clinical guidance, specifically for the use of everolimus, including patient selection, indications for treatment and practicalities of drug initiation and monitoring.

A lower incidence of cytomegalovirus infection in de novo heart transplant recipients randomized to everolimus.

Background. Cytomegalovirus (CMV) infection in recipients of cardiac transplants is associated with higher rates of morbidity. A recent phase III trial showed highly significantly (P<0.001) lower CMV rates with the proliferation signal inhibitor everolimus compared to azathioprine (AZA). To better define this association, data on CMV risk factors were collected retrospectively and analyzed. Methods. Data on CMV risk factors from a multicenter phase III trial on de novo heart transplant recipients (n=634) receiving a triple immunosuppressive regimen randomized to everolimus 1.5 mg/day (group 1), everolimus 3 mg/day (group 2), or AZA (group 3) were merged with prospectively collected CMV-related outcome data and analyzed. Results. CMV-positive donors (D+) and CMV-negative recipients (R−) were evenly distributed across groups 1–3 at 36/209 (17.2%), 48/211 (22.7%), and 38/214 (17.8%), respectively. CMV prophylaxis had been given for a mean (SD) of 175 (127.8), 183 (137.1), and 177 (132.9) days, respectively. In the high-risk D+/R− subgroup with prophylaxis, the proportions of patients with CMV infection compared with group 3 (12/29 [41.4%]) were 3/25 (12.0%) in group 1 (P=0.031) and 6/36 (16.7%) in group 2 (P=0.049). In D+/R+ subgroups either with or without prophylaxis, the everolimus groups had less CMV disease (P<0.001). The incidence of CMV syndrome, organ involvement, and laboratory evidence was lower with everolimus use compared to AZA. Conclusions. Everolimus is associated with lower rates of CMV infection, syndrome, or organ involvement, suggesting an additional advantage from the use of everolimus in cardiac transplant recipients.

Acquired von Willebrand syndrome after exchange of the HeartMate XVE to the HeartMate II ventricular assist device

Instead of pulsatile ventricular assist devices an increasing number of nonpulsatile ventricular assist devices are introduced to clinical practice. The different flow characteristics of this new technique lead to alteration in shear stress on blood components, which may affect the coagulation system. Repeated von Willebrand factor analyses were performed in a patient who first was implanted with a pulsatile ventricular assist device (Thoratec HeartMate XVE), which had to be replaced after 405 days with an axial flow device (HeartMate II). During support with the pulsatile ventricular assist device there was no sign of any coagulation disorder. However, on the axial flow device acquired von Willebrand syndrome Type 2 developed. Inhibition of platelet function was also observed, which may be in part due to the von Willebrand syndrome. The HeartMate II axial flow device may induce von Willebrand syndrome, which was not observed in HeartMate XVE pulsatile ventricular assist device. Patients put on continuous flow devices should be screened for acquired von Willebrand syndrome.

Thrombus formation in a HeartMate II left ventricular assist device

doi:10.1016/j.jtcvs.2007.08.048 M ajor limitations of ventricular assist devices have been the high incidence of thromboembolic events, the requirement for systemic anticoagulation, and the mechanical stability and duration of the device. The successful use of axial flow pumps for left ventricular (LV) assistance has been limited by thromboembolic events and pump thrombosis. Therefore, imaging of the devices is crucial. The HeartMate II axial flow pump (Thoratec, Pleasanton, Calif) has shown a low incidence of thromboembolic events and proper long-term mechanical function. Pump thrombosis has not been reported. We report a case of thrombus formation 4 months after HeartMate II implantation.

Lung transplantation for severe pulmonary hypertension--awake extracorporeal membrane oxygenation for postoperative left ventricular remodelling.

Background Bilateral lung transplantation (BLTx) is an established treatment for end-stage pulmonary hypertension (PH). Ventilator weaning failure and death are more common as in BLTx for other indications. We hypothesized that left ventricular (LV) dysfunction is the main cause of early postoperative morbidity or mortality and investigated a weaning strategy using awake venoarterial extracorporeal membrane oxygenation (ECMO). Methods In 23 BLTx for severe PH, ECMO used during BLTx was continued for a minimum of 5 days (BLTx-ECMO group). Echocardiography, left atrial (LA) and Swan-Ganz catheters were used for monitoring. Early extubation after transplantation was attempted under continued ECMO. Results Preoperatively, all patients had severely reduced cardiac index (mean, 2.1 L/min/m2). On postoperative day 2, reduction of ECMO flow resulted in increasing LA and decreasing systemic blood pressures. On the day of ECMO explantation (median, postoperative day 8), LV diameter had increased; LA and blood pressures remained stable. Survival rates at 3 and 12 months were 100% and 96%, respectively. Data were compared to two historic control groups of BLTx without ECMO (BLTx ventilation) or combined heart-lung transplantation for severe PH. Conclusion Early after BLTx for severe PH, the LV may be unable to handle normalized LV preload. This can be effectively bridged with awake venoarterial ECMO.

Transplanted human cord blood-derived unrestricted somatic stem cells improve left-ventricular function and prevent left-ventricular dilation and scar formation after acute myocardial infarction

Objective: Functional improvement after acute myocardial ischaemia (MI) has been achieved by transplantation of different adult stem and progenitor cell types. It is controversial whether these cell types are able to form novel functional myocardium. Alternatively, graft-related or immune-related paracrine mechanisms may preserve existing myocardium, improve neovascularisation, affect tissue remodelling or induce endogenous de novo formation of functional myocardium. We have applied an alternative somatic cell type, human cord-blood-derived unrestricted somatic stem cells (USSCs) in a porcine model of acute MI. Methods: USSCs were transplanted into the acutely ischaemic lateral wall of the left ventricle (LV). LV dimension and function were assessed by transoesophageal echocardiography (TEE) pre-MI, immediately post-MI, 48 hours and 8 weeks after USSC injection. Additionally, apoptosis, mitosis and recruitment of macrophages were examined 48 hours post-engraftment. Results: Gender-specific and species-specific FISH/immunostaining failed to detect engrafted donor cells 8 weeks post-MI. Nevertheless, cell treatment effectively preserved natural myocardial architecture. Global left ventricular ejection fraction (LVEF) before MI was 60% (7%). Post-MI, LVEF decreased to 34% (8%). After 8 weeks, LVEF had further decreased to 27% (6%) in the control group and recovered to 52% (2%) in the USSC group (p<0.01). Left-ventricular end-diastolic volume (LVEDV) before MI was 28 (2) ml. 8 weeks post-MI, LVEDV had increased to 77 (4) ml in the control group. No LV dilation was detected in the USSC group (LVEDV: 26 (2) ml, p<0.01). Neither apoptosis nor recruitment of macrophages and mitosis were different in either groups. Conclusions: Transplantation of USSCs significantly improved LV function and prevented scar formation as well as LV dilation. Since differentiation, apoptosis and macrophage mobilisation at infarct site were excluded as underlying mechanisms, paracrine effects are most likely to account for the observed effects of USSC treatment.