D.B. Dyke

Immunosuppression: practice and trends

Over the past decade, immunosuppression therapy has undergone striking changes in the scale and pace by which new immunosuppressive molecules and antibodies have become incorporated into daily transplant medicine. An organ‐by‐organ review of data reveals several trends. The highest use of induction therapy (over 70% of patients) was reported for simultaneous pancreas kidney (SPK) and pancreas after kidney (PAK) transplants in 2002; use of induction therapy was less common in liver transplants (only 18%). Corticosteroids served as discharge maintenance immunosuppression in over 87% of the recipients of kidney, SPK, PAK and thoracic transplants, and in over 70% of pancreas transplant alone (PTA) recipients. Corticosteroid use in intestine transplants was reported in 64% of recipients in 2002. A shift in the calcineurin inhibitor used for maintenance immunosuppression from cyclosporine to tacrolimus for the majority of patients had occurred for kidney, PAK, SPK, PTA, liver, lung, and heart‐lung by 2001. For heart transplants, cyclosporine remained the calcineurin inhibitor of choice; tacrolimus remained the predominant calcineurin inhibitor agent for intestine (since 1994). Use of antibody treatment for rejection during the first post‐transplant year for most organs declined. Short‐term outcomes have improved, based on the observation that rates of rejection within the first year post‐transplant have diminished.

Renal and Hepatic Function Improve in Advanced Heart Failure Patients During Continuous-Flow Support With the HeartMate II Left Ventricular Assist Device

Background— The effects of continuous blood flow and reduced pulsatility on major organ function have not been studied in detail. Methods and Results— We evaluated renal (creatinine and blood urea nitrogen) and hepatic (aspartate transaminase, alanine transaminase, and total bilirubin) function in 309 (235 male, 74 female) advanced heart failure patients who had been supported with the HeartMate II continuous-flow left ventricular assist device for bridge to transplantation. To determine whether patients with impaired renal and hepatic function improve over time with continuous-flow left ventricular assist device support or whether there are any detrimental effects in patients with normal organ function, we divided patients into those with above-normal and normal laboratory values before implantation and measured blood chemistry over time during left ventricular assist device support. There were significant improvements over 6 months in all parameters in the above-normal groups, with values in the normal groups remaining in the normal range over time. Mean blood urea nitrogen and serum creatinine in the above-normal groups decreased significantly from 37±14 to 23±10 mg/dL (P<0.0001) and from 1.8±0.4 to 1.4±0.8 mg/dL (P<0.01), respectively. There were decreases in aspartate transaminase and alanine transaminase in the above-normal groups from 121±206 and 171±348 to 36±19 and 31±22 IU (P<0.001), respectively. Total bilirubin for the above-normal group was 2.1±0.9 mg/dL at baseline; after an acute increase at week 1, it decreased to 0.9±0.5 mg/dL by 6 months (P<0.0001). Both renal and liver values from patients in the normal groups remained normal during support with the left ventricular assist device. Conclusions— The HeartMate II continuous-flow left ventricular assist device improves renal and hepatic function in advanced heart failure patients who are being bridged to transplantation, without evidence of detrimental effects from reduced pulsatility over a 6-month time period. Clinical Trial Registration Information— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00121472.

Hemodynamic and exercise performance with pulsatile and continuous-flow left ventricular assist devices.

Background— Continuous-flow rotary pumps with axial design are increasingly used for left ventricular assist support. The efficacy of this design compared with pulsatile, volume displacement pumps, with respect to characteristics of left ventricular unloading, and exercise performance remains largely unstudied. Methods and Results— Thirty-four patients undergoing implantation with a pulsatile, volume displacement pump operating in a full-to-empty cycle (HeartMate XVE; Thoratec Inc, Pleasanton, Calif; n=16) or continuous-flow rotary pump with an axial design operating at a fixed rotor speed (HeartMate II; Thoratec Inc; n=18) were evaluated with right heart catheterization and echocardiography preoperatively and at 3 months postoperatively and cardiopulmonary exercise testing 3 months postoperatively. Support with either the XVE or II resulted in significant (P<0.05) increases in cardiac output and reduction in mean pulmonary artery and pulmonary wedge pressures. Exercise capacity at 3 months was similar between groups (% predicted peak o2−XVE: 46.8±10.2 versus II: 49.1±13.6). Echocardiography at 3 months demonstrated a significantly (P<0.05) greater reduction in left ventricular end-diastolic volume (−49±16% versus −35±20%), left ventricular end-systolic volume (−59±20 versus −37±21%), and percent mitral valve regurgitant volume (−99±2% versus −52±56%) for the XVE compared with II, respectively. Conclusions— The HeartMate XVE or II provided equivalent degrees of hemodynamic support and exercise capacity. The XVE was associated with greater left ventricular volume unloading. Characteristics of left ventricular pressure and volume unloading between these pump designs and mode of operation do not influence early exercise performance.

Left ventricular assist device therapy improves utilization of donor hearts

OBJECTIVES We sought to determine the survival experiences of patients bridged to heart transplantation with either intravenous (IV) inotropes or an implantable left ventricular assist device (LVAD). BACKGROUND Because of the operative risks of LVAD implantation and the reported lower mortality associated with inotropic therapy, bridging to heart transplantation with inotropes is thought to be the preferred treatment option. METHODS Between April 1, 1996, and May 10, 2001, a total of 104 patients were bridged to heart transplantation with either IV inotropes (n = 38) or an implantable LVAD (n = 66; HeartMate). Survival was compared (Kaplan-Meier method) for three periods: survival to transplantation, post-transplantation survival and overall survival (i.e., survival from the onset of bridging to follow-up). RESULTS Survival to transplantation was 81 +/- 5% at three months for the LVAD group and 64 +/- 11% for the inotrope group (p = NS). Post-transplantation survival was 95 +/- 4% at three years for the LVAD group (two deaths) and 65 +/- 10% at three years for the inotrope group (nine deaths; p = 0.007). Overall survival was 77 +/- 6% at three years for the LVAD group and 44 +/- 9% at three years for the inotrope group (p = 0.01). CONCLUSIONS Overall survival for patients who were bridged to heart transplantation with an implantable LVAD was superior to that of patients who were bridged with inotropes. Bridging to transplantation with an implantable LVAD improves utilization of donor hearts.

Nosocomial Infections in Left Ventricular Assist Device Recipients

Infection remains a serious complication of left ventricular assist device (LVAD) implantation. We performed a cohort study to assess infections among patients who underwent LVAD implantation from October 1996 through May 1999. Thirty-six LVADs were implanted in 35 patients; the mean duration (+/- standard deviation) of LVAD use was 73+/-60 days (total for all patients, 2565 days). Sixteen patients developed surgical site infections (SSIs; rate, 6.2 infections per 1000 LVAD days); 9 were deep-tissue or organ/space infections and 7 were superficial. Other infections included 7 cases of pneumonia (rate, 2.7 cases per 1000 LVAD days), 6 venous infections (rate, 2.3 per 1000 LVAD days), 2 bloodstream infections (rate, cases 0.8 per 1000 LVAD days), 3 urinary tract infections, and 2 skin and soft-tissue infections. Deep SSIs were associated with the requirement for postoperative hemodialysis (P=.02). Overall use of antibiotics was extensive, and a trend toward infection with antibiotic-resistant organisms was noted. Infections were a frequent complication of LVAD implantation. Further studies of interventions for preventing infection in LVAD recipients are warranted.

Assessment of an extracorporeal life support to LVAD bridge to heart transplant strategy

BACKGROUND Extracorporeal life support (ECLS) is an effective technique for providing emergent circulatory assistance. However, its use in adult patients is associated with poor survival when myocardial function fails to recover. Due to the prolonged waiting times for heart transplantation, ECLS as a bridge to transplant is associated with poor survival. In addition, ECLS has been reported to be a significant risk factor for death after bridging to an implantable left ventricular assist device (LVAD). After acquisition of the HeartMate LVAD (Thermo Cardiosystems, Inc) in October 1996, we began using ECLS as a bridge to an implantable LVAD and subsequently transplantation in selected high-risk patients. METHODS From October 1, 1996 to December 1, 1999, 60 adult patients presenting with cardiogenic shock were evaluated for circulatory assistance. RESULTS Twenty-five patients (group 1) with cardiac arrest or severe hemodynamic instability and multiorgan failure were placed on ECLS. Eight patients survived to LVAD implant, 1 was bridged directly to transplant, and 4 weaned from ECLS. Nine patients in group 1 survived to discharge. Thirty patients (group 2) underwent LVAD implant without ECLS. Twenty-three were bridged to transplant, with 22 surviving to discharge. Five patients (group 3) were placed on extracorporeal ventricular assist with 3 bridged to transplant and all surviving to discharge. One-year actuarial survival from the initiation of circulatory support was 36% (group 1), 73% (group 2), and 60% (group 3). One-year actuarial survival from the time of LVAD implant in group 1, conditional on surviving ECLS, was 75% (p = NS compared with group 2). CONCLUSIONS In selected high-risk patients, LVAD survival after initial ECLS was not different from survival after LVAD support alone. An initial period of resuscitation with ECLS is an effective strategy to salvage patients with cardiac arrest or extreme hemodynamic instability and multiorgan injury.

Sex and Age Dimorphism of Myocardial Gene Expression in Nonischemic Human Heart Failure

Background—We report the first comprehensive analysis of gene expression differences by sex and age in left ventricular samples from 102 patients with dilated cardiomyopathy. Methods and Results—Gene expression data (HG-U133A gene chip, Affymetrix) were analyzed from 30 females and 72 males from 3 separate centers. More than 1800 genes displayed sexual dimorphism in the heart (adjusted P value <0.05). A significant number of these genes were highly represented in gene ontology pathways involved in ion transport and G-protein-coupled receptor signaling. Localization of these genes revealed enrichment on both the sex chromosomes as well as chromosomes 3, 4, and 14. The second goal of this study was to determine the effect of age on gene expression. Within the female cohort, >140 genes were differentially expressed in the <55 years age group compared with the >55 years age group. These genes were highly represented in gene ontology pathways involved in DNA damage. In contrast, zero genes in the male cohort <55 years met statistical significance when compared with the >55 years age group. Conclusions—Gene expression in dilated cardiomyopathy displayed evidence of sexual dimorphism similar to other somatic tissues and age dimorphism within the female cohort.

The effect of transplant center volume on survival after heart transplantation: A multicenter study

OBJECTIVE Few studies have examined the association between procedural volume and clinical outcomes in heart transplantation. This retrospective study was performed on a contemporary cohort of heart transplant recipients to better elucidate the effect of transplant center volume on 1-year mortality. METHODS Data from the Scientific Registry of Transplant Recipients were used to analyze the relationship between transplant center volume and short-term survival. Center volume designation (very low, low, medium, and high) was assigned on the basis of quartiles with approximately equal numbers of patients per group. Survival differences were explored using Cox proportional hazards modeling to adjust for differences in variables between volume groups and to determine variables associated with 1-year mortality. RESULTS Between January 1, 1999, and May 31, 2005, 13,230 heart transplantations were performed at 147 transplant centers in the United States. Although most recipient and donor characteristics were similar across quartiles, larger volume centers were more likely to perform transplantations in older candidates and accept organs from older donors with longer cold ischemia times. A statistically significant relationship between transplant center volume and 1-year mortality was observed. Compared with the reference group (very low volume), the hazard ratios for the low, medium, and high-volume quartiles were 0.71, 0.64, and 0.56, respectively (P < .001 for each group compared with the reference). CONCLUSION There was a significant association between transplant center volume and 1-year survival. Patients who undergo cardiac transplantation at very low-volume centers are at higher risk for early mortality than those who undergo transplantation in higher-volume centers.

Successful Treatment of Vancomycin Resistant Enterococcus faecium Mediastinitis Associated With Left Ventricular Assist Devices

We present 2 cases of vancomycin-resistant Enterococcus faecium mediastinitis associated with left ventricular assist devices in the setting of heart transplantation. Despite complicated operative courses and deep infection secondary to antimicrobial resistant organisms, both patients were successfully treated and have remained infection free in the long term.

Changes in serial B-type natriuretic peptide level independently predict cardiac allograft rejection

BACKGROUND Despite positive associations with rejection, the clinical value of B-type natriuretic peptide (BNP) monitoring in heart transplant recipients has not been established. We sought to determine the predictive value of changes in serial BNP level for identifying patients with acute allograft rejection. METHODS BNP, hemodynamics and biopsies were obtained for 205 transplant recipients who underwent a total of 4,007 endomyocardial biopsy procedures. Samples analyzed were collected ≥ 180 days post-transplant, without evidence of rejection on the immediately preceding biopsy. Using a repeated-measures multivariate model, we assessed the association of change in BNP with Grade ≥ 3A (2R) rejection. We also determined predictive values of various cut-off thresholds of change in serial BNP levels to predict Grade ≥ 3A rejection. RESULTS There were 47 episodes of Grade ≥ 3A rejection among the 1,350 samples analyzed. Median change in serial BNP (ΔBNP) for those with Grade ≥ 3A rejection was 20 pg/ml (IQR -26 to 169 pg/ml) and among those with Grade <3A rejection was -4 pg/ml (IQR -34 to 22 pg/ml, p = 0.003). On multivariate analysis, ΔBNP remained the most potent independent predictor of Grade ≥ 3A rejection (p = 0.001). ΔBNP >100 pg/ml predicted increased risk of Grade ≥ 3A rejection (OR = 5.3, p < 0.001) with high specificity (93.3%) and positive predictive value (13.0%) and excellent negative predictive value (97.3%). CONCLUSIONS Change in serial BNP level is an independent predictor of cardiac allograft rejection. With wide availability, rapid turnaround, low cost, favorable positive predictive value and excellent negative predictive value, serial BNP monitoring has several advantages for non-invasive monitoring of heart transplant recipients for acute cardiac allograft rejection.