Erika D. Feller

A Randomized, Controlled Trial of the Renal Effects of Ultrafiltration as Compared to Furosemide in Patients With Acute Decompensated Heart Failure

OBJECTIVES This study was designed to evaluate the consequences of ultrafiltration (UF) and standard intravenous diuretic (furosemide) therapy on glomerular filtration rate (GFR) and renal plasma flow in patients with acute decompensated heart failure. BACKGROUND It has been hypothesized that treatment with diuretics may worsen renal function as the result of systemic neurohormonal activation and direct renal vascular effects. UF also removes fluid, but its actions on intrarenal hemodynamics, and therefore renal function, are unknown. METHODS Patients hospitalized for acute decompensated heart failure with an ejection fraction less than 40% and two or more signs of hypervolemia were randomized to receive UF or intravenous diuretics. Urine output, GFR (as measured by iothalamate), and renal plasma flow (as measured by para-aminohippurate) were assessed before fluid removal and after 48 hours. RESULTS Nineteen patients (59 +/- 16 years, 68% were male) were randomized to receive UF (n = 9) or intravenous diuretics (n = 10). The change in GFR (-3.4 +/- 7.7 mL/min vs. -3.6 +/- 11.5 mL/min; P = .966), renal plasma flow (26.6 +/- 62.7 mL/min vs. 16.1 +/- 42.0 mL/min; P = .669), and filtration fraction (-6.9 +/- 13.6 mL/min vs. -3.9 +/- 13.6 mL/min; P = .644) after treatment were not significantly different between the UF and furosemide treatment groups, respectively. There was no significant difference in net 48-hour fluid removal between the groups (-3211 +/- 2345 mL for UF and -2725 +/- 2330 mL for furosemide, P = .682). UF removed 3666 +/- 2402 mL. Urine output during 48 hours was significantly greater in the furosemide group (5786 +/- 2587 mL) compared with the UF group (2286 +/- 915 mL, P < .001). CONCLUSIONS During a 48-hour period, UF did not cause any significant differences in renal hemodynamics compared with the standard treatment of intravenous diuretics.

Allograft Inflammatory Factor-1 Expression Correlates With Cardiac Rejection and Development of Cardiac Allograft Vasculopathy

Background—Standard morphological features of endomyocardial biopsy specimens do not necessarily correlate with the efficacy of immunotherapy or development of cardiac allograft vasculopathy (CAV). We hypothesized that expression of allograft inflammatory factor-1 (AIF-1), a cytokine-inducible, calcium-binding protein associated with vascular smooth muscle cell proliferation, would be associated with allograft rejection and development of CAV. Methods and Results—A total of 157 endomyocardial biopsy specimens from 26 patients with heart transplants were examined for expression of AIF-1 mRNA by semiquantitative reverse transcription–polymerase chain reaction. A significant relation was found between the International Society for Heart and Lung Transplantation rejection grade and expression of AIF-1 (P <0.001). The calculated odds ratio indicates that a biopsy has 2.5 times the chance of AIF-1 expression per grade of rejection. The relative concentrations of AIF-1 and GAPDH mRNA were calculated and the resulting ratios indicated that the amount of AIF-1 mRNA expression is relative to the rejection grade (P <0.02). In grade 1 biopsy specimens, AIF-1 was localized to infiltrating immune cells. In grade 3 biopsy specimens, AIF-1 was observed in immune cells and myocytes. AIF-1 is expressed in vascular and immune cells in coronary arteries with CAV, and persistent expression of AIF-1 in the allograft correlates with development of CAV (P <0.002). Conclusions—Expression of AIF-1 in cardiac allografts correlates with rejection, and the amount of AIF-1 expressed correlates with the severity of rejection. AIF-1 is expressed in coronary arteries with CAV, and persistent expression of AIF-1 in the cardiac allograft is associated with development of CAV.

FDG PET/CT imaging for LVAD associated infections.

Heart failure is a major cause of morbidity and mortality, particularly among patients with advanced disease and no access to cardiac transplantation. Owing to the constant shortage of donor hearts, the role of left ventricular assist device (LVAD) has been expanding in the management of these

Oxidative Stress, DNA Damage and Repair in Heart Failure Patients after Implantation of Continuous Flow Left Ventricular Assist Devices

Objective: To study the status of oxidative stress and DNA damage repair in circulating blood leukocytes of heart failure patients supported by continuous flow left ventricular assist devices (LVADs). Materials and methods: Ten HF patients implanted with LVAD as bridge to transplant or destination therapy were enrolled in the study and 10 age and sex matched volunteers were recruited as the study control. Reactive oxygen species (ROS) in blood leukocytes and superoxide dismutase (SOD) in erythrocytes were measured by flow cytometry/immunofluorescence microscopy and spectrophotometry, respectively. ELISA was used to measure oxidized low density lipoproteins (oxLDL) in plasma. Markers of DNA damage (γ-H2AX) and repairs (Mre11, DNA ligase IV, Ku70, and Ku80) were quantified in blood lymphocytes by immunocytochemistry. Results: Levels of ROS and oxLDL were significantly higher in HF patients with LVAD than baseline as well as the control group; moreover, SOD levels were decreased with increasing post-operative periods. All the changes indicated enhanced oxidative stress among LVAD recipients. Significantly higher γ-H2AX foci in lymphocytes confirmed DNA double strand breaks in LVAD recipients. γ-H2AX foci numbers in lymphocytes were positively correlated with the ROS and oxLDL and negatively with SOD levels (p<0.0001). Expressions of DNA ligase IV, Ku70 and Ku80 proteins were highest after one week and Mre11 protein after 3 months of LVAD transplantation; indicated abnormal DNA repair. Conclusions: The study, for the first time shows that, continuous flow LVAD implanted HF patients not only exhibit elevated oxidative stress and DNA damage in blood leukocytes but also have abnormalities in DNA repair pathways.

The promise of protein-based and gene-based clinical markers in heart transplantation: from bench to bedside

Advances in immunosuppression, guided by invasive endomyocardial biopsy for the assessment of graft rejection, have ushered heart transplantation into the clinical arena by the demonstration of acceptable 1-year outcomes. Further decreases in the risk of malignancy and cardiac allograft vasculopathy that improve long-term outcomes, are, however, still desired. Attention has become directed towards the use of markers that can be detected noninvasively to provide insight into underlying molecular and cellular events associated with the immune response and graft function. Various candidate, protein-based markers have been identified: those of alloimmune activation; those of microvascular injury, such as cardiac-specific troponins; those of inflammation, including C-reactive protein; and surrogate markers of cardiac function, including natriuretic peptides such as brain natriuretic peptide. In the realm of genomics, it is becoming increasingly clear that a single molecular marker is unlikely to prove to be useful, but rather that multiple genes from a number of pathways are needed to capture biological complexity and overcome variability in the general population. Thus, the field of protein-based and gene-based biomarkers is advancing rapidly to define its place in clinical therapeutics and to guide immunosuppression according to molecular mechanisms of disease. We discuss here the main findings for the more-successful protein markers identified so far, and the genomic molecular approaches being used to improve heart transplant outcomes.

University of Maryland Surgical Experience With the Jarvik 2000 Axial Flow Ventricular Assist Device

BACKGROUND The Jarvik 2000, an axial flow ventricular assist device (VAD), is currently under investigation for bridge to transplant (BTT) indications. The principal advantage of the Jarvik device is intraventricular pump placement. This eliminates the inflow cannula and pump pocket and allows for uncomplicated left ventricular implantation without sternotomy. Here we describe the evolution of our surgical implantation and explantation technique. METHODS Data for all patients undergoing implantation of a left VAD (LVAD) (n=35) at the University of Maryland between September 2002 and September 2010 were retrospectively reviewed. Preoperative patient demographics and clinical status and operative technique and outcomes were reviewed. RESULTS A simple technique for enclosing the pump and outflow graft greatly simplifies the explantation procedure and reduces the risk of lung adhesions and injury. Off-pump implantation reduces operative time and intraoperative red cell transfusions but carries a risk of incomplete ventricular coring, which may precipitate pump thrombosis. The benefits of the left thoracotomy approach were seen in the reduced need for intraoperative red cell transfusion and reduced total intensive care unit (ICU) stay for patients who had undergone previous sternotomy. CONCLUSIONS The Jarvik 2000 has several distinctive features that simplify surgical management and permit flexible application in an expanded range of candidates for LVAD implantation, particularly in patients who have undergone previous sternotomy.

Intraplatelet reactive oxygen species, mitochondrial damage and platelet apoptosis augment non-surgical bleeding in heart failure patients supported by continuous-flow left ventricular assist device

Abstract Non-surgical bleeding (NSB) is the most common clinical complication among heart failure (HF) patients supported by continuous-flow left ventricular assist devices (CF-LVADs). Understanding the role of platelet functionality contributing to NSB after CF-LVAD implantation is crucial for prevention and management of this adverse event. The aim of this study was to examine the role of intraplatelet reactive oxygen species (ROS) and platelet damage on the incidence of bleeding events after CF-LVAD implantation in HF patients. We recruited 25 HF patients implanted with CF-LVADs and 11 healthy volunteers as the control. Intraplatelet ROS generation, platelet mitochondrial damage and platelet apoptosis were quantified by flow cytometry. Among 25 patients, 8 patients developed non-surgical bleeding within one month after CF-LVAD implantation. Intraplatelet ROS, depolarized and apoptotic platelet were found to be pre-existing conditions in all baseline samples of the 25 HF patients when compared to the healthy volunteers. There was no significant difference in the levels of ROS between the non-bleeder and the bleeder groups prior to CF-LVAD implantation, although we noticed 2-fold and 1.5-fold rise in depolarized and apoptotic platelets, respectively, in the bleeder group compared to those in the non-bleeder group. Post implant levels of intraplatelet ROS, depolarized and apoptotic platelets increased and remained elevated in the bleeder group, whereas periodic decreases were noticed in the non-bleeder group, suggesting the potential role of platelet damage on bleeding incidence. ROS generation after CF-LVAD implantation positively associated with platelet apoptosis (ρ = 0.4263, p = 0.0023) and depolarized platelets (ρ = 0.4774, p = 0.0002), especially the latter. In conclusion, elevated intraplatelet ROS and platelet damage may be linked to the NSB among HF patients supported by CF-LVAD. These results provide mechanistic insights into the bleeding complication in patients with CF-LVAD support.

Comparison of intraplatelet reactive oxygen species, mitochondrial damage, and platelet apoptosis after implantation of three continuous flow left ventricular assist devices: HeartMate II, Jarvik 2000, and HeartWare.

Differences in device design may have an effect on platelet damage and associated clinical complications. We aimed to compare device-specific platelet functionality in 26 heart failure patients supported with three continuous-flow left ventricular assist devices: HeartMate II (n = 8), Jarvik 2000 (n = 9), and HeartWare (n = 9). Intraplatelet reactive oxygen species (ROS) generation, mitochondrial damage, and platelet apoptosis were compared between device types before and after the implantation at every week up to 1 month. Overall, the baseline characteristics, demographics, routine laboratory values were comparable between the three device groups. Intraplatelet ROS, mitochondrial damage, and platelet apoptosis significantly elevated in the HeartWare group in comparison with the other two device groups after implantation. The major bleeding, infections, systemic inflammatory response syndrome, and right ventricular failure were found to be more common among the HeartWare group than others. Intraplatelet ROS and platelet damage levels were returned to baseline in both the HeartMate II and the Jarvik groups, whereas in HeartWare group they remained elevated. The patients with the Jarvik and the HeartMate II experienced less clinical complications and the platelet functionality is not compromised by these devices. Data from this study suggests that the continuous-flow left ventricular assist devices design may exert different effects on platelet function.