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Purpose: Cardiac allograft vasculopathy (CAV) continues to hinder the long-term success of heart transplant recipients. Redo-transplantation is currently the only definitive treatment for advanced CAV. We examined whether these patients are at similar CAV-risk with the second transplant. Methods: Heart recipients from 1985 to 2011 at the UTAH program were included in the study and those with CAV as an indication for redo-transplantation were identified. CAV diagnosis was made by coronary angiography and based on the 2010 ISHLT standardized nomenclature for CAV. Patient demographics, rejection history, and CAV incidence were analyzed. Results: Of the 1,169 eligible patients, 135 (11.5%) developed CAV post their first transplant; 78 cases within 10 years and 54 beyond 10 years. The mean time to CAV was 6.58 years. Of the 135 patients who developed CAV, only 21 (15.5%) ended up requiring a redo-transplant. Of the 21 retransplanted patients, 4 (19.0%) developed CAV again; 2 patients within 10 years and 2 patients beyond 10 years indicating a similar risk for CAV occurrence for first and redo-transplant. Conclusions: Our results indicate that CAV is as likely to develop in redo-transplants despite recent advances in immunosuppression and the standardized use of lipid-lowering agents. Although outcomes in redo-transplantation for the indication of CAV are favorable, efforts to better understand and minimize CAV are needed, especially in the face of scarce donor organs. [ABSTRACT FROM AUTHOR]

Background: Small-scale studies focused mainly on nonischemic cardiomyopathy (NICM) have shown that a subset of left ventricular assist device (LVAD) patients can achieve significant improvement of their native heart function, but the impact of ischemic cardiomyopathy (ICM) has not been specifically investigated. Many patients with acute myocardial infarction are discharged from their index hospitalization without heart failure (HF), only to return much later with overt HF syndrome, mainly caused by chronic remodeling of the noninfarcted region of the myocardium.Objectives: This study sought to prospectively investigate the effect of ICM HF etiology on LVAD-associated improvement of cardiac structure and function using NICM as control.Methods: Consecutive patients (n = 154) with documented chronic and dilated cardiomyopathy (ICM, n = 61; NICM, n = 93) requiring durable support with continuous-flow LVAD were prospectively evaluated with serial echocardiograms and right heart catheterizations.Results: In patients supported with LVAD for at least 6 months, we found that 5% of subjects with ICM and 21% of subjects with NICM achieved left ventricular ejection fraction ≥40% (p = 0.034). LV end-diastolic and end-systolic volumes and diastolic function were significantly and similarly improved in patients with ICM and NICM.Conclusions: LVAD-associated unloading for 6 months resulted in a substantial improvement in myocardial structure, and systolic and diastolic function in 1 in 20 ICM and 1 in 5 NICM patients. These specific incidence and timeline findings may provide guidance in clinical practice and research design for sequencing and prioritizing advanced HF and heart transplantation therapeutic options in patients with ICM and NICM. [ABSTRACT FROM AUTHOR]

Background Immune allosensitization can be triggered by continuous-flow left ventricular assist devices (CF LVAD). However, the effect of this type of allosensitization on post-transplant outcomes remains controversial. This study examined the post-transplant course in a contemporary cohort of patients undergoing transplantation with and without LVAD bridging. Methods We included consecutive patients who were considered for cardiac transplant from 2006 to 2015. Serum alloantibodies were detected with single-antigen beads on the Luminex platform (One Lambda Inc., Canoga Park, CA). Allosensitization was defined as calculated panel reactive antibody (cPRA) > 10%. cPRA was determined at multiple times. LVAD-associated allosensitization was defined as development of cPRA > 10% in patients with cPRA ≤ 10% before LVAD implantation. Post-transplant outcomes of interest were acute cellular rejection (ACR), antibody-mediated rejection (AMR), and survival. Results Allosensitization status was evaluated in 268 patients (20% female). Mean age was 52 ± 12 years, and 132 (49.3%) received CF LVADs. After LVAD implant, 30 patients (23%) became newly sensitized, and the level of sensitization appeared to diminish in many of these patients while awaiting transplant. During the study period, 225 of 268 patients underwent transplant, and 43 did not. A CF LVAD was used to bridge 50% of the transplant recipients. Compared with patients without new sensitization or those already sensitized at baseline, the patients with LVAD-associated sensitization had a higher risk of ACR ( p = 0.049) and higher risk of AMR ( p = 0.018) but a similar intermediate-term post-transplant survival. The patients who did not receive a transplant had higher level of allosensitization, with a baseline cPRA of 20% vs 6% in those who received an allograft and a high risk (40%) of death during follow-up. Conclusions New allosensitization takes place in > 20% of patents supported with CF LVADs. Among patients who undergo transplant, this results in a higher risk of ACR and AMR, but survival remains favorable, likely due to the efficacy of current management after transplant. However, mortality in sensitized patients who do not reach transplant remains high, and new approaches are necessary to meet the needs of this group of patients. [ABSTRACT FROM AUTHOR]

Background Ventricular assist devices ( VADs) have a proven survival benefit in select patients with advanced heart failure, yet many patients considered for implantation are declined for various reasons. The outcome of these patients is obscure owing to their exclusion from recent VAD studies. We aim to compare the outcomes of patients who received a VAD to those who did not. Methods For this study, the Artificial Heart Program's database at Intermountain Medical Center was queried from 2006 to 2012 for patients referred for a VAD. Kaplan-Meier survival analysis was performed with log-rank test determining significance. Results Of 232 patients included, 118 patients received a VAD and 114 patients did not. The prevailing reason for VAD decline in eligible and willing patients was due to pre-existing illness (39%). Mortality was higher in non- VAD vs. VAD patients (58.8% vs. 35.6%, p < 0.001) with a median time-to-death of 67 ( IQR:12-314) and 301 ( IQR:136-694) d, respectively (p = 0.007). Conclusions In the current era of non-pulsatile VADs, mortality of patients who are considered but not implanted remains high. Additionally, mortality of these patients occurred much sooner. Educational efforts ensuring timely referral for VAD therapy are important to maximize the number of patients who may benefit. [ABSTRACT FROM AUTHOR]

Background Antibody-mediated rejection (AMR) in cardiac transplant recipients is a serious form of rejection with adverse patient outcomes. The International Society of Heart and Lung Transplantation (ISHLT) has published a consensus schema for the pathologic diagnosis of various grades of antibody-mediated rejection (pathology antibody-mediated rejection [pAMR]). We sought to determine whether the ISHLT pAMR grading schema correlates with patient outcomes. Methods Using our database, which contains a semi-quantitative scoring of all pathologic descriptors of pAMR, we retrospectively used these descriptors to convert the previous AMR categories to the current ISHLT pAMR categories. Cox proportional hazard models were fit with cardiovascular (CV) death or retransplant as the outcome. The pAMR value was included as a categorical variable, and cellular rejection (CR) values were included in a separate model. Results There were 13,812 biopsies from 1,014 patients analyzed. The pAMR grades of pAMR1h, pAMR1i, and pAMR2 conferred comparable increased risk for CV mortality. Significantly increased risk of CV mortality was conferred by biopsies graded as severe AMR (pAMR3). Conclusions The new ISHLT pAMR grading schema identifies patients at increased risk of CV mortality, consistent with risks published from several programs before 2011. The current schema is validated by this analysis in a large biopsy database. Because pAMR1h, pAMR1i, and pAMR2 have similar CV risks associated with them, the threshold for a positive diagnosis of pAMR should be re-evaluated in future iterations of the ISHLT schema. [ABSTRACT FROM AUTHOR]

Background The elevated baseline heart rate ( HR) of a heart transplant recipient has previously been considered inconsequential. However, we hypothesized that a resting HR above 100 beats per minute (bpm) may be associated with morbidity and mortality. Methods The U.T.A.H. Cardiac Transplant Program studied patients who received a heart transplant between 2000 and 2011. Outpatient HR values for each patient were averaged during the first year post-transplant. The study cohort was divided into two groups: the tachycardic ( TC) ( HR >100 bpm) and the non- TC group ( HR ≤100 bpm) in which mortality, incidence of rejection, and cardiac allograft vasculopathy were compared. Results Three hundred and ten patients were included as follows: 73 in the TC and 237 in the non- TC group. The TC group had a higher risk of a 10-yr all-cause mortality (p = 0.004) and cardiovascular mortality (p = 0.044). After adjustment for donor and recipient characteristics in multivariable logistic regression analysis, the hazard ratio was 3.9, (p = 0.03, CI: 1.2-13.2) and 2.6 (p = 0.02, CI: 1.2-5.5) for cardiovascular mortality and all-cause mortality, respectively. Conclusion Heart transplant recipients with elevated resting HR appear to have higher mortality than those with lower resting HR. Whether pharmacologically lowering the HR would result in better outcomes warrants further investigation. [ABSTRACT FROM AUTHOR]

Background Driveline exit site (DLES) infection is a major complication of ventricular assist devices (VADs). Differences in the sheath material interfacing with exit site tissue appear to affect healing time and infection risk more than site hygiene, but the mechanistic basis for this is not clear. Methods Health record data from Utah Artificial Heart Program patients with HeartMate II (HMII) devices implanted from 2008 to 2012 were retrospectively reviewed, with particular attention to interface type, incorporation (healing) time, and infections. Tissue samples from the DLES were collected at the time of VAD removal in a small subset. These samples were examined by routine histology and environmental scanning electron microscopy (ESEM). Results Among 57 patients with sufficient data, 15 had velour interfaces and 42 had silicone. Indications for and duration of support were similar between the groups. The silicone group had shorter incorporation time (45 ± 22 vs. 56 ± 34 days, P = .17) and fewer DLES infections (20% vs. 1.7%, P = .026, for patient infections and 0.0340 vs. 0.166, P = .16, for infections per patient-year). Tissues from five patients, three with velour, were examined. Velour interfaces demonstrated more hyperkeratosis, hypergranulosis, and dermal inflammation. By ESEM, the silicone driveline tracts appeared relatively smooth and flat, whereas the velour interface samples were irregular with deep fissures and globular material adhering to the surface. Conclusions Using the silicone portion of the HMII driveline at the DLES was associated with fewer infections and a trend toward faster healing in this small retrospective series. Whether the intriguing microscopic differences directly account for this needs further study on a larger scale. [ABSTRACT FROM AUTHOR]

Background: In animal models of heterotopic transplantation, mechanical unloading of the normal, nonhypertrophic heart results in atrophy. Primarily on the basis of these animal data, the notion that chronic left ventricular assist device (LVAD)-induced unloading will result in atrophy has dominated the clinical heart failure field, and anti-atrophic drugs have been used to enhance the cardiac recovery potential observed in some LVAD patients. However, whether unloading-induced atrophy in experimental normal heart models applies to failing and hypertrophic myocardium in heart failure patients unloaded by continuous-flow LVADs has not been studied.Objectives: The study examined whether mechanical unloading by continuous-flow LVAD leads to myocardial atrophy.Methods: We prospectively examined myocardial tissue and hemodynamic and echocardiographic data from 44 LVAD patients and 18 untransplanted normal donors.Results: Cardiomyocyte size (cross-sectional area) decreased after LVAD unloading from 1,238 ± 81 μm(2) to 1,011 ± 68 μm(2) (p = 0.001), but not beyond that of normal donor hearts (682 ± 56 μm(2)). Electron microscopy ultrastructural evaluation, cardiomyocyte glycogen content, and echocardiographic assessment of myocardial mass and left ventricular function also did not suggest myocardial atrophy. Consistent with these findings, t-tubule morphology, cytoplasmic penetration, and distance from the ryanodine receptor were not indicative of ongoing atrophic remodeling during LVAD unloading. Molecular analysis revealed no up-regulation of proatrophic genes and proteins of the ubiquitin proteasome system.Conclusions: Structural, ultrastructural, microstructural, metabolic, molecular, and clinical functional data indicated that prolonged continuous-flow LVAD unloading does not induce hypertrophy regression to the point of atrophy and degeneration. These findings may be useful in designing future investigations that combine LVAD unloading and pharmaceutical therapies as a bridge to recovery of the failing heart. [ABSTRACT FROM AUTHOR]

Background In animal models of heterotopic transplantation, mechanical unloading of the normal, nonhypertrophic heart results in atrophy. Primarily on the basis of these animal data, the notion that chronic left ventricular assist device (LVAD)-induced unloading will result in atrophy has dominated the clinical heart failure field, and anti-atrophic drugs have been used to enhance the cardiac recovery potential observed in some LVAD patients. However, whether unloading-induced atrophy in experimental normal heart models applies to failing and hypertrophic myocardium in heart failure patients unloaded by continuous-flow LVADs has not been studied. Objectives The study examined whether mechanical unloading by continuous-flow LVAD leads to myocardial atrophy. Methods We prospectively examined myocardial tissue and hemodynamic and echocardiographic data from 44 LVAD patients and 18 untransplanted normal donors. Results Cardiomyocyte size (cross-sectional area) decreased after LVAD unloading from 1,238 ± 81 μm 2 to 1,011 ± 68 μm 2 (p = 0.001), but not beyond that of normal donor hearts (682 ± 56 μm 2 ). Electron microscopy ultrastructural evaluation, cardiomyocyte glycogen content, and echocardiographic assessment of myocardial mass and left ventricular function also did not suggest myocardial atrophy. Consistent with these findings, t-tubule morphology, cytoplasmic penetration, and distance from the ryanodine receptor were not indicative of ongoing atrophic remodeling during LVAD unloading. Molecular analysis revealed no up-regulation of proatrophic genes and proteins of the ubiquitin proteasome system. Conclusions Structural, ultrastructural, microstructural, metabolic, molecular, and clinical functional data indicated that prolonged continuous-flow LVAD unloading does not induce hypertrophy regression to the point of atrophy and degeneration. These findings may be useful in designing future investigations that combine LVAD unloading and pharmaceutical therapies as a bridge to recovery of the failing heart. [ABSTRACT FROM AUTHOR]

Objectives: This study sought to prospectively investigate the longitudinal effects of continuous-flow left ventricular assist device (LVAD) unloading on myocardial structure and systolic and diastolic function. Background: The magnitude, timeline, and sustainability of changes induced by continuous-flow LVAD on the structure and function of the failing human heart are unknown. Methods: Eighty consecutive patients with clinical characteristics consistent with chronic heart failure requiring implantation of a continuous-flow LVAD were prospectively enrolled. Serial echocardiograms (at 1, 2, 3, 4, 6, 9, and 12 months) and right heart catheterizations were performed after LVAD implant. Cardiac recovery was assessed on the basis of improvement in systolic and diastolic function indices on echocardiography that were sustained during LVAD turn-down studies. Results: After 6 months of LVAD unloading, 34% of patients had a relative LV ejection fraction increase above 50% and 19% of patients, both ischemic and nonischemic, achieved an LV ejection fraction ≥40%. LV systolic function improved as early as 30 days, the greatest degree of improvement was achieved by 6 months of mechanical unloading and persisted over the 1-year follow up. LV diastolic function parameters also improved as early as 30 days after LVAD unloading, and this improvement persisted over time. LV end-diastolic and end-systolic volumes decreased as early as 30 days after LVAD unloading (113 vs. 77 ml/m2, p < 0.01, and 92 vs. 60 ml/m2, p < 0.01, respectively). LV mass decreased as early as 30 days after LVAD unloading (114 vs. 95 g/m2, p < 0.05) and continued to do so over the 1-year follow-up but did not reach values below the normal reference range, suggesting no atrophic remodeling after prolonged LVAD unloading. Conclusions: Continuous-flow LVAD unloading induced in a subset of patients, both ischemic and nonischemic, early improvement in myocardial structure and systolic and diastolic function that was largely completed within 6 months, with no evidence of subsequent regression. [Copyright &y& Elsevier]

The article discusses a study on the use of Left ventricular (LV) assist devices (LVADs) as a tool for end-stage heart failure (HF) patients to heart transplantation or as a permanent therapy. It mentions that increase in clinical use of LVADs presents a key opportunity for in-depth investigations of the biology of the failing human heart. It also informs that trough biological and clinical outcomes it is possible to identify new therapeutic strategies of myocardial recovery and regeneration.

Background: Growing evidence suggests worse cardiac allograft vasculopathy and mortality in patients with asymptomatic antibody-mediated rejection (AMR). Debate continues about whether therapeutic intervention is warranted to avoid adverse outcomes. In this study we examine the course of individual episodes of untreated asymptomatic AMR on follow-up endomyocardial biopsy (EMB). Methods: The U.T.A.H. Cardiac Transplant Program database was queried for transplant recipients between 1985 and 2009 who survived beyond 1 year and had at least 1 episode of lone AMR with a follow-up EMB. All EMBs were screened for AMR by immunofluorescence and graded for severity. Data were analyzed based on time from transplant (early, ≤12 months; late, >12 months). Results: Nine hundred fifty-eight patients with a total of 15,448 biopsies qualified for the study. Average age at transplant was 46.7 years; 13% of the patients were female. Within the first year post-transplant, asymptomatic AMR was diagnosed in 13.6% of biopsies compared with 5.2% beyond 1 year. AMR resolved in 65% (early) vs 75% (late) on follow-up EMB. More severe AMR was less likely to improve regardless of time from transplant. Furthermore, after an episode of AMR had resolved, the recurrence rate at 3, 6 and 12 months was 44%, 50.1% and 56.2%, respectively. Conclusions: The incidence of AMR is higher in the first year post-transplant and the likelihood of resolution is less on follow-up EMB, especially when more severe. A small but significant number of cases became worse or did not change. These new findings may be helpful in planning future studies that test whether therapeutic interventions on asymptomatic AMR favorably impact outcomes. [Copyright &y& Elsevier]

Ventura PA, Alharethi R, Budge D, Reid BB, Horne BD, Mason NO, Stoker S, Caine WT, Rasmusson B, Doty J, Clayson SE, Kfoury AG. Differential impact on post-transplant outcomes between pulsatile- and continuous-flow left ventricular assist devices. Clin Transplant 2011: 25: E390-E395. © 2011 John Wiley & Sons A/S. Abstract: Background: The HeartMate II (HMII) left ventricular assist device (LVAD) has proven reliable and durable and has become the preferred choice for bridge to transplant therapy (BTT) when compared with the pulsatile HeartMate XVE (XVE). In this study, we compared the post-transplant (PTx) outcomes between XVE and HMII using a large national data registry. Methods: The Organ Procurement and Transplantation Network (OPTN)/United Network for Organ Sharing (UNOS) Thoracic Registry database was queried for all patients implanted with either an XVE or an HMII as BTT during 2004-2009. Statistical analysis between XVE and HMII were performed using Kaplan-Meier survival analysis and Cox regression analyses. Results: A total of 673 patients were implanted with the XVE and 484 with HMII. When adjusted for age, gender, ethnicity, intra-aortic balloon pump, ventilator, inotropes, dialysis, body mass index, creatinine, bilirubin, transfusion, pulmonary capillary wedge, and pulmonary arterial pressures, the HMII had similar one- and three-yr survival (hazard ratio = 0.95, CI = 0.64, 1.42) and rejection-free survival PTx compared to XVE. The XVE group had more early incidences of allograft rejection (AR) and hospitalization for infection (HI). Conclusions: Compared to XVE, patients with HMII have similar one- and three-yr survival after heart transplantation with less risk of early graft rejection and significant infection. With a strong shift toward use of continuous-flow LVADs, PTx outcomes are expected to continue to improve. [ABSTRACT FROM AUTHOR]

Background: Recent efforts are being undertaken to update and refine current diagnostic criteria for antibody-mediated rejection (AMR) in heart transplantation. We believe that the appropriate reactants are those that best predict the adverse consequences of AMR and therefore tested various models using different reactants to find the best predictors of cardiovascular mortality in pathologically defined AMR. Methods: The study group included only patients in whom all immunofluorescence antibodies of interest had been tested on biopsy specimens obtained after 2002 when C4d was routinely added. We analyzed our data using 3 Cox proportional hazard models with time-varying covariates using an end point of cardiovascular mortality, as previously defined. Results: In 3,712 biopsy specimens from 422 patients, the 2-antibody model achieved a value of R 2 = 0.930 using C3d and C4d antibodies alone. A model that used 4 antibodies—C3d, C4d, human leukocyte antigen-D related (HLA-DR) and fibrin—was superior (R 2 = 0.988). The model that best predicted cardiovascular mortality included all 6 antibodies: HLA-DR, immunoglobulin (Ig) G, IgM, C3d, C4d, and fibrin (R 2 = 0.989). The models using 4 or 6 antibodies were significantly superior to the model using only C3d and C4d (for each interaction, p < 0.0001). Conclusions: The combination of complement components, HLA-DR and fibrin, is valuable in defining AMR in patients at risk for allograft loss from cardiovascular causes. Fibrin is particularly important for detecting the presence of severe AMR, with a high likelihood of poor long-term patient outcome. [ABSTRACT FROM AUTHOR]

Background: The use of left ventricular assist devices (LVADs) as destination therapy (DT) is increasing and has proven beneficial in prolonging survival and improving quality of life in select patients with end-stage heart failure. Nonetheless, end-of-life (EOL) issues are inevitable and how to approach them underreported. Methods: Our DT data registry was queried for eligible patients, defined as those individuals who actively participated in EOL decision making. The process from early EOL discussion to palliation and death was reviewed. We recorded the causes leading to EOL discussion, time from EOL decision to withdrawal and from withdrawal to death, and location. Primary caregivers were surveyed to qualify their experience and identify themes relevant to this process. Results: Between 1999 and 2009, 92 DT LVADs were implanted in 69 patients. Twenty patients qualified for inclusion (mean length of support: 833 days). A decrease in quality of life from new/worsening comorbidities usually prompted EOL discussion. Eleven patients died at home, 8 in the hospital and 1 in a nursing home. Time from EOL decision to LVAD withdrawal ranged from <1 day to 2 weeks and from withdrawal until death was <20 minutes in all cases. Palliative care was provided to all patients. Ongoing assistance from the healthcare team facilitated closure and ensured comfort at EOL. Conclusions: With expanding indications and improved technology, more DT LVADs will be implanted and for longer durations, and more patients will face EOL issues. A multidisciplinary team approach with protocols involving DT patients and their families in EOL decision making allows for continuity of care and ensures dignity and comfort at EOL. [ABSTRACT FROM AUTHOR]

Objectives: This study investigates alterations in myocardial microvasculature, fibrosis, and hypertrophy before and after mechanical unloading of the failing human heart. Background: Recent studies demonstrated the pathophysiologic importance and significant mechanistic links among microvasculature, fibrosis, and hypertrophy during the cardiac remodeling process. The effect of left ventricular assist device (LVAD) unloading on cardiac endothelium and microvasculature is unknown, and its influence on fibrosis and hypertrophy regression to the point of atrophy is controversial. Methods: Hemodynamic data and left ventricular tissue were collected from patients with chronic heart failure at LVAD implant and explant (n = 15) and from normal donors (n = 8). New advances in digital microscopy provided a unique opportunity for comprehensive whole-field, endocardium-to-epicardium evaluation for microvascular density, fibrosis, cardiomyocyte size, and glycogen content. Ultrastructural assessment was done with electron microscopy. Results: Hemodynamic data revealed significant pressure unloading with LVAD. This was accompanied by a 33% increase in microvascular density (p = 0.001) and a 36% decrease in microvascular lumen area (p = 0.028). We also identified, in agreement with these findings, ultrastructural and immunohistochemical evidence of endothelial cell activation. In addition, LVAD unloading significantly increased interstitial and total collagen content without any associated structural, ultrastructural, or metabolic cardiomyocyte changes suggestive of hypertrophy regression to the point of atrophy and degeneration. Conclusions: The LVAD unloading resulted in increased microvascular density accompanied by increased fibrosis and no evidence of cardiomyocyte atrophy. These new insights into the effects of LVAD unloading on microvasculature and associated key remodeling features might guide future studies of unloading-induced reverse remodeling of the failing human heart. [Copyright &y& Elsevier]

Right ventricular failure (RVF) after left ventricular assist device (LVAD) implantation appears to be associated with increased mortality. However, the determination of which patients are at greater risk of developing postoperative RVF remains controversial and relatively unknown. We sought to determine the preoperative risk factors for the development of RVF after LVAD implantation. The data were obtained for 175 consecutive patients who had received an LVAD. RVF was defined by the need for inhaled nitric oxide for ≥48 hours or intravenous inotropes for >14 days and/or right ventricular assist device implantation. An RVF risk score was developed from the β coefficients of the independent variables from a multivariate logistic regression model predicting RVF. Destination therapy (DT) was identified as the indication for LVAD implantation in 42% of our patients. RVF after LVAD occurred in 44% of patients (n = 77). The mortality rates for patients with RVF were significantly greater at 30, 180, and 365 days after implantation compared to patients with no RVF. By multivariate logistic regression analysis, 3 preoperative factors were significantly associated with RVF after LVAD implantation: (1) a preoperative need for intra-aortic balloon counterpulsation, (2) increased pulmonary vascular resistance, and (3) DT. The developed RVF risk score effectively stratified the risk of RV failure and death after LVAD implantation. In conclusion, given the progressively growing need for DT, the developed RVF risk score, derived from a population with a large percentage of DT patients, might lead to improved patient selection and help stratify patients who could potentially benefit from early right ventricular assist device implantation. [Copyright &y& Elsevier]

Background: Thrombus formation on or near the aortic valve has been reported in HeartMate II (Thoratec, Pleasanton, CA) left ventricular assist device (LVAD) patients whose aortic valves do not open. With an akinetic valve, thrombogenesis is more likely. Thrombus formation may lead to neurologic events, placing the patient at greater risk. Aortic valve stenosis and/or regurgitation have also been observed with akinetic aortic valves. Assessing aortic valve opening is crucial when optimizing rotations per minute (rpm) to minimize embolic risk and aortic valve stenosis but presently relies solely on echocardiography, intermittent decreases in rpms to force aortic valve opening, and monitoring of pulse pressure. We hypothesized the electrical current waveforms of the HeartMate II would reveal whether the aortic valve was opening due to pressure changes in the left ventricle to allow for continuous monitoring and control of aortic valve opening ratios. Methods: Electrical HeartMate II current waveforms of patients from 2008 to 2009 that were recorded at the time of echocardiograph procedures were analyzed using a modified Karhunen-Loève transformation with a training set of electrical waveforms from 8,860 HeartMate II electrical current recordings from 2001 to 2009. Results: The study included 6 patients. The electrical current magnitude of the projection of the electrical current waveforms onto the training set''s eigenvectors was statistically significantly greater in 4 of the 6 patients when the aortic valve was closed, confirmed by echocardiography. The 2 patients who did not have a large increase in the magnitude had mild aortic valve regurgitation. Conclusion: Electrical current analysis for rotary non-pulsatile pumps is a means to develop a physiologic feedback algorithm for an auto-mode, which currently does not exist. Constant regulation and optimization of rotary non-pulsatile LVADs would minimize patients'' risk for neurologic events and aortic valve stenosis. [Copyright &y& Elsevier]

Left ventricular assist device (LVAD) implantation before heart transplantation has been associated with formation of antibodies directed against human leukocyte antigens (HLA), often referred to as sensitization. This study investigated whether prior sensitization or LVAD type affected the degree of post-implantation sensitization. The records of consecutive HeartMate (HM) I and HM II LVAD patients were reviewed. Panel reactive antibody (PRA) was assessed before LVAD implantation and biweekly thereafter. Sensitization was defined as PRA > 10%, and high-degree sensitization was defined as PRA > 90%. An HM LVAD was implanted in 64 patients, and 11 received a HM II LVAD as a bridge to transplant. Ten HM I patients (16%) were sensitized before LVAD implantation (HM I-S), and 54 (84%) were not (HM I-Non-S). Nine HM I-S patients (90%) became highly sensitized (PRA > 90%) compared with 9 HM I-Non-S patients (16.7%; p < 0.001). The PRA remained elevated (> 90%) in 8 of the 9 (88.9%) highly sensitized HM I-S patients vs 5 of the 9 (55.6%) HM I-Non-S highly sensitized patients. The PRA levels in the rest of the HM I-S highly sensitized patients declined from 93% ± 4% to 55% ± 15% (p = 0.01). Among the 11 HM II patients, 1 (9%) was sensitized before LVAD implantation (PRA, 40%) and the PRA moderately increased to 80%. No other HM II patient became sensitized after implantation. Thus, 1 of 11 (9%) HM II patients became sensitized compared with 29 of 64 (45%) HM I patients (p = 0.04). Pre-sensitized patients are at higher risk for becoming and remaining highly HLA-allosensitized after LVAD implantation. The HeartMate II LVAD appears to cause less sensitization than HeartMate I. [Copyright &y& Elsevier]

Background: Little has been reported on the clinical significance of asymptomatic antibody-mediated rejection (AMR) alone or mixed rejection (MR), defined as concurrent cellular rejection (CR) and AMR in heart transplantation. In this study, we examined whether a differential impact on cardiovascular mortality (CVM) existed when comparing asymptomatic AMR, to stable MR or CR. Methods: The Utah Transplantation Affiliated Hospitals (UTAH) Cardiac Transplant Program pathology database of all heart transplant recipients between 1985 and 2004 was queried. Patients were classified as cellular, antibody-mediated, or mixed rejectors based on their predominant pattern of rejection type in the first three months post-transplant. Kaplan-Meier survival curves were fit to each of the three groups and analyses were adjusted for age at the time of transplant, gender, and underlying primary cardiac disease. Results: Eight hundred and sixty nine heart transplant recipients qualified for analysis. Over the study period, patients with asymptomatic AMR or stable MR patterns had significantly worse CVM when compared to patients with stable CR pattern (AMR, 21.2%; MR, 18.0%; CR, 12.6%; AMR vs. CR, p = 0.009; MR vs. CR, p = 0.001). In contrast, CVM was comparable in patients with asymptomatic AMR or stable MR patterns (p = 0.9). Conclusions: Asymptomatic or subclinical AMR and MR are clinically relevant, should be recognized, and deserve consideration for therapeutic intervention in hopes of avoiding adverse outcomes. [Copyright &y& Elsevier]

An increasing number of patients are living with ventricular assist devices (VADs). Many of these patients will require noncardiac surgery for conditions not directly related to their VADs. The aim of this study was to assess the risks and outcomes of noncardiac surgery in these patients. Perioperative and follow-up data from patients with VADs who underwent noncardiac surgery from 1993 to 2006 were analyzed. In that period, 184 VADs were implanted in 155 patients. Thirty-seven patients (24%) subsequently underwent 59 noncardiac surgeries. The mean duration of VAD support before surgery was 229 days. Bleeding was the most common postsurgical complication (10%), necessitating reexploration in 20% of abdominal surgeries. Thirty-day mortality was 12%. No deaths were caused by direct complications of surgery. Successful transplantation occurred in 72% of bridge to transplantation patients who required noncardiac surgery, compared with 71% of these patients who did not require noncardiac surgery (relative risk 1.0, p = 0.9). The average duration of VAD support after noncardiac surgery for destination therapy patients was 324 days, most of which time was spent at home. In conclusion, outcomes after noncardiac surgery in patients with VADs are favorable, and most patients continue to benefit from the intended purpose of mechanical circulatory support after recovering from noncardiac surgery. [Copyright &y& Elsevier]

Background: The current International Society for Heart and Lung Transplantation (ISHLT) diagnostic criteria for antibody-mediated rejection (AMR) designate AMR as either absent (AMR 0) or present (AMR 1), without grading its severity. Yet, the extent of histologic and immunofluorescence (IF) findings of AMR varies across endomyocardial biopsies (EMBs). In this study, we hypothesized that the severity of AMR, as assessed on EMBs, correlates with cardiovascular mortality in heart transplant recipients. Methods: All EMBs from 1985 to 2005 were evaluated. Biopsy specimens were uniformly studied by light microscopy and IF early post-transplant. A comprehensive vascular score (V1: no AMR, to V5: severe AMR) was prospectively assigned to each EMB, based on severity of both histologic and IF findings. Univariate Cox proportional hazards regressions were performed using indicators of vascular scores alone, combined, and cumulatively. Results: Nine hundred six patients were transplanted and included in the study. Mean age was 46.6 ± 15.5 years and 82% were male. A total of 26,236 EMBs comprised the study data. As expected, histologic and immunopathologic findings of AMR varied in severity. An incremental risk of cardiovascular mortality was found with more severe AMR whether vascular scores were analyzed individually (p = 0.001), in combination (p = 0.01) or cumulatively (p = 0.006). Conclusions: The severity of AMR on EMBs correlates with an incremental cardiovascular mortality risk after heart transplantation, suggesting that AMR should be viewed as a spectrum rather than just as present or absent. Supplementing the ISHLT AMR diagnostic guidelines with a consensus severity scale is warranted. [Copyright &y& Elsevier]

Background: The International Society for Heart and Lung Transplantation (ISHLT) recently established a diagnostic scheme for antibody-mediated rejection (AMR). Currently, however, confirmatory immunohistochemistry studies are recommended only if AMR is clinically or histologically suspected. In this study, we examine whether a pattern of repetitive AMR occurred early enough after transplantation to warrant prospective immunohistochemistry screening in all recently transplanted recipients. Methods: We queried our pathology database of adult and pediatric endomyocardial biopsies (EMBs) from 1985 to 2005. All EMB specimens were prospectively studied by immunofluorescence in the early post-operative period. AMR was defined as the presence of complement and immunoglobulin deposits on frozen section. Only patients classified as antibody-mediated rejectors (≥3 episodes of AMR) were included. Cumulative incidence and time from transplant to first and third AMR episodes were obtained. Results: Three hundred seventy-five of 870 heart transplant recipients had ≥3 episodes of AMR. Mean age of recipients was 45.6 years and 78% were male. A total of 19,569 EMBs comprised the study data. By 100 days post-transplant, 85% of patients had their first and 54% their third AMR. In addition, patients showed a clear trend of early clustering of AMR-positive biopsies. Results were similar regardless of whether or not muromonab-CD3 (Orthoclone OKT3) induction was used. Conclusions: We advocate early immunohistochemical surveillance testing for AMR to supplement the diagnostic algorithm established by the ISHLT, because a pattern of AMR becomes manifest soon after transplantation. This change will allow earlier detection of asymptomatic AMR and may prompt changes in immunosuppression strategies to avoid adverse outcomes. [Copyright &y& Elsevier]