Robert Sorabella

Outcomes after transplantation for “failed” Fontan: A single-institution experience

OBJECTIVE Despite the excellent outcomes in the current era after the Fontan procedure, it continues to have an inherent risk of failure. Cardiac transplantation provides 1 option for treating these patients; however, the indications for, timing of, and outcomes after, transplantation remain undefined. We examined our own institutional experience with transplantation for failed Fontan. METHODS The records of 155 patients transplanted for congenital heart disease at a single institution from June 1984 to September 2007 were reviewed. Of these patients, 43 had undergone a previous Fontan procedure (25 male, 15 female; median age, 14.5 years; range, 1-47; 23 classic Fontan, 13 lateral tunnel, 4 extracardiac conduit, and 3 revised to shunt). The predictors of short- and long-term survival were evaluated, and the Fontan patients were compared with all other patients with congenital heart disease (n = 129, 78 male, 51 female). RESULTS The most common indications for transplantation included protein-losing enteropathy (PLE) (39.5%), chronic heart failure (41.8%), and acute post-Fontan failure (9.3%). The transplants performed in Fontan patients were more likely to require pulmonary artery reconstruction (85.4% vs 42.9%; P < .0001) and had longer cardiopulmonary bypass times (278 vs 179 minutes; P < .0001). The 90-day mortality rate was greater in the Fontan group (35.0% vs 20.0%; P = .055). No correlation was observed between the interval from Fontan to transplantation and morality; however, renal failure was a strong predictor of early mortality (odds ratio, 10.8; 95% confidence interval, 1.5-75.7). CONCLUSIONS Transplantation is an acceptable treatment for patients with a failed Fontan. Clinical factors (instead of the indication for transplantation) appear to have the greatest correlation with early mortality.

Posttransplant survival is not diminished in heart transplant recipients bridged with implantable left ventricular assist devices

BACKGROUND The purpose of this study was to compare posttransplantation morbidity and mortality in orthotopic heart transplant recipients bridged to transplant with a left ventricular assist device with nonbridged recipients. To account for potential differences across device types, we stratified bridge-to-transplant recipients by type of ventricular assist device: extracorporeal (EXTRA), paracorporeal (PARA), and intracorporeal (INTRA). METHODS The United Network for Organ Sharing provided de-identified patient-level data. The study population included 10,668 orthotopic heart transplant recipients aged 18 years old or older and undergoing transplantation between January 1, 2001, and December 31, 2006. Follow-up data were provided through August 3, 2008, with a mean follow-up time of 3.17 +/- 2.15 years (range, 0-8.11 years). The primary outcome was actuarial posttransplant graft survival. Other outcomes of interest included infection, stroke, and dialysis during the transplant hospitalization; primary graft failure at 30 days; transplant hospitalization length of stay; and long-term complications including diabetes mellitus, transplant coronary artery disease, and chronic dialysis. Multivariable Cox proportional hazards regression (backward, P < .15) was used to determine the relationship between groups and overall graft survival, and multivariable logistic regression analysis (backward, P < .15) was used to determine the relationship between groups and secondary outcome measures. RESULTS In multivariable Cox regression analysis, when compared with the nonbridged group, risk-adjusted greater than 90-day graft survival was diminished among the EXTRA group (hazard ratio = 3.54, 2.28-5.51, P < .001), but not the INTRA group (1.04, 0.719-1.51, P = .834) or the PARA group (1.06, 0.642-1.76, P = .809). There were no significant differences in risk-adjusted graft survival across the 4 groups during the 90-days to 1-year or 1- to 5-year intervals. However, at more than 5 years, risk-adjusted graft survival in the INTRA group (0.389, 0.205-0.738, P = .004) was better than in the nonbridged group. The EXTRA, PARA, and INTRA groups all experienced increased risks of infection. The EXTRA group had increased risks of dialysis, stroke, and primary graft failure at 30 days, whereas neither the PARA nor the INTRA group differed from the nonbridged group. Long-term complications did not differ by group. CONCLUSION The use of implantable left ventricular assist devices as bridges to transplantation, including both intracorporeal and paracorporeal devices, is not associated with diminished posttransplant survival. However, 90-day survival was diminished in recipients bridged with extracorporeal devices.

Standard versus bicaval techniques for orthotopic heart transplantation: an analysis of the United Network for Organ Sharing database.

OBJECTIVE Most studies of anastomotic technique have been underpowered to detect subtle differences in survival. We analyzed the United Network for Organ Sharing database for trends in use and outcomes after either bicaval or traditional (biatrial) anastomoses for heart implantation. METHODS Review of United Network for Organ Sharing data identified 20,999 recipients of heart transplants from 1997 to 2007. Patients were stratified based on the technique of atrial anastomosis: standard biatrial (atrial group, n = 11,919, 59.3%), bicaval (caval group, n = 7661, 38.1%), or total orthotopic (total group, n = 519, 2.6%). RESULTS The use of the bicaval anastomosis is increasing, but many transplantations continue to use a biatrial anastomosis (1997, 0.2% vs 97.6%; 2007, 62.0% vs 34.7%; P < .0001). Atrial group patients required permanent pacemaker implantation more often (odds ratio, 2.6; 95% confidence interval, 2.2-3.1). Caval group patients had a significant advantage in 30-day mortality (odds ratio, 0.83; 95% confidence interval, 0.75-0.93), and Cox regression analysis confirmed the decreased long-term survival in the atrial group (hazard ratio, 1.11; 95% confidence interval, 1.04-1.19). CONCLUSIONS Heart transplantations performed with bicaval anastomoses require postoperative permanent pacemaker implantation at lower frequency and have a small but significant survival advantage compared with biatrial anastomoses. We recommend that except where technical considerations require a biatrial technique, bicaval anastomoses should be performed for heart transplantation.

Cardiac Donor Risk Factors Predictive of Short-Term Heart Transplant Recipient Mortality: An Analysis of the United Network for Organ Sharing Database.

INTRODUCTION To address the shortage of donor hearts for transplantation, there is significant interest in liberalizing donor acceptance criteria. Therefore, the aim of this study was to evaluate cardiac donor characteristics from the United Network for Organ Sharing (UNOS) database to determine their impact on posttransplantation recipient outcomes. METHODS Adult (≥18 years) patients undergoing heart transplantation from July 1, 2004, to December 31, 2012, in the UNOS Standard Transplant Analysis and Research (STAR) database were reviewed. Patients were stratified by 1-year posttransplantation status; survivors (group S, n = 13,643) and patients who died or underwent cardiac retransplantation at 1-year follow-up (group NS/R = 1785). Thirty-three specific donor variables were collected for each recipient, and independent donor predictors of recipient death or retransplantation at 1 year were determined using multivariable logistic regression analysis. RESULTS Overall 1-year survival for the entire cohort was 88.4%. Mean donor age was 31.5 ± 11.9 years, and 72% were male. On multivariable logistic regression analysis, donor age >40 years (odds ratio [OR] 1.44, 95% confidence interval [CI] 1.27 to 1.64), graft ischemic time >3 hours (OR 1.32, 1.16 to 1.51), and the use of cardioplegia (OR 1.17, 1.01 to 1.35) or Celsior (OR 1.21, 1.06 to 1.38) preservative solution were significant predictors of recipient death or retransplantation at 1 year posttransplantation. Male donor sex (OR 0.83, 0.74 to 0.93) and the use of antihypertensive agents (OR 0.88, 0.77 to 1.00) or insulin (OR 0.84, 0.76 to 0.94) were protective from adverse outcomes at 1 year. CONCLUSIONS These data suggest that donors who are older, female, or have a long projected ischemic time pose greater risk to heart transplant recipients in the short term. Additionally, certain components of donor management protocols, including antihypertensive and insulin administration, may be protective to recipients.

Comparison of Outcomes After Heart Replacement Therapy in Patients Over 65 Years Old

BACKGROUND There are currently no well-defined, evidence-based guidelines for management of end-stage heart failure in patients over 65, and the decisions to use mechanical circulatory support with left ventricular assist device (LVAD), either as a bridge to transplantation or destination therapy, or isolated heart transplantation (HTx) remain controversial. We aimed to compare the outcomes after the implementation of three heart replacement strategies in this high-risk population. METHODS We conducted a retrospective cohort study of all patients between the ages of 65 and 72 receiving a continuous-flow LVAD as bridge to transplantation or destination therapy or isolated HTx at our center between 2005 and 2012. The patients were stratified according to treatment strategy into three groups: group D (destination LVAD, n = 23), group B (bridge to transplantation LVAD, n = 43), and group H (HTx alone, n = 47). The primary outcomes of interest were survival to discharge and 2-year overall survival. RESULTS The patients in group D were significantly older, had a higher prevalence of ischemic cardiomyopathy, and had a higher pulmonary vascular resistance than did patients in groups B or H. There were no significant differences between groups in survival to discharge (87% D vs 83.7% B vs 87.2% H, p = 0.88) or 2-year overall survival (75.7% D vs 68.7% B vs 80.9% H, log-rank p = 0.47). The incidence rates of readmission were 1.1 events/patient·year in group D and 0.5 events/patient·year in group H. CONCLUSIONS There was no significant difference in perioperative, short-term, and medium-term survival between the treatment groups. However, the LVAD patients had a higher incidence of readmission. Larger trials are needed to refine differences in long-term survival, quality of life, and resource utilization for elderly patients requiring heart replacement therapy.

Macrophage inhibitor, Semapimod, reduces tumor necrosis factor-alpha in myocardium in a rat model of ischemic heart failure

Pharmaceutical agents aimed at reducing tumor necrosis factor-alpha (TNF-α) levels appeared to be attractive possibilities in the medical management of heart failure, as heart failure was shown to be associated with high TNF-α levels. However, therapies specifically targeting TNF-α failed to show any survival benefit. We examined whether a broad inhibition of inflammatory cytokine production secondary to macrophage inhibition would be more effective at improving cardiac function in the setting of heart failure. To this end, we studied Semapimod (formerly known as CNI-1493), a synthetic guanylhydrazone that inhibits macrophage activation and the production of several inflammatory cytokines. Left anterior descending coronary ligation surgery was performed on each animal to induce a myocardial infarction. After confirming heart failure by echocardiography, the animals were randomly assigned to one of four groups: (1) rats with myocardial infarct receiving high-dose Semapimod, 10 mg/kg/d (MI-H, N = 13); (2) rats with myocardial infarct receiving low-dose Semapimod, 3 mg/kg/d (MI-L, N = 9); (3) rats with myocardial infarct receiving vehicle treatment, 2.5% mannitol in water (MI-0, N = 9); and (4) control rats with sham operation and vehicle treatment (Sham, N = 10). Both Semapimod and vehicle treatments were administered by daily tail vein injections over a course of five days. Echoes were repeated at 2, 5, and 9 weeks following treatment. At 9 weeks, hemodynamic data were collected and the animals were euthanized. Trichrome staining was done to assess infarct, and immunohistochemistry was performed to assess TNF-α levels. Prior to drug administration, serum was taken from 5 random rats. No detectable level of TNF-α was seen (lower limit of detection for the assay used = 12.5 pg/mL). Also prior to any treatment, echocardiography confirmed significant cardiac impairment of rats undergoing LAD ligation as compared with sham. Over the course of the 9 weeks, there were 4 deaths, all in the MI-H group. There was no difference between Semapimod-treated animals and vehicle-treated MI animals in any echocardiographic or hemodynamic parameter. TNF-α staining in the noninfarcted region was evident only in the MI groups, not the sham group. When blindly compared on a semiquantitative scale (ie, 0 = no visible staining to 3 = marked staining), a significant difference in staining was observed between MI-0 versus MI-H (1.19 ± 0.32 versus 0.33 ± 0.14; P = 0.03) and between MI-0 and MI-L (1.19 ± 0.32 versus 0.39 ± 0.22; P = 0.05). In this setting, despite the fact that Semapimod treatment decreased tissue TNF-α levels, it did not improve cardiac function, and at high doses it was associated with higher mortality. These results in a rodent model confirm the results of clinical trials with etanercept and infliximab (ie, that decreasing TNF levels in plasma or tissues does not improve cardiac function and may actually increase mortality).

6 Months of “Temporary” Support by Levitronix Left Ventricular Assist Device

An otherwise healthy 47-year-old man presented to the emergency department in cardiogenic shock after suffering a massive myocardial infarction due to left main occlusion. He was initially supported by extracorporeal membrane oxygenation and subsequently was converted to paracorporeal support with a Levitronix left ventricular assist device. He experienced multiple postoperative complications including renal failure, respiratory failure, retroperitoneal hematoma requiring suspension of anticoagulation, and fungal bloodstream infection precluding transition to an implantable device. He was reconditioned and successfully underwent orthotopic heart transplant 183 days after presentation. A discussion of the relevant issues is included.

Aortic Root Replacement in Octogenarians Offers Acceptable Perioperative and Late Outcomes

BACKGROUND As the proportion of the population more than 80 years of age increases, cardiac surgeons will increasingly be consulted to operate on this high-risk patient group. The aim of this study is to evaluate the perioperative and late outcomes of octogenarians undergoing aortic root replacement in comparison with younger patients. METHODS All patients undergoing aortic root replacement at our institution between 2005 and 2012 (n = 592) were retrospectively reviewed. Patients were stratified according to their age at surgery: patients less than 80 years old (group LT80, n = 558) and octogenarians (group OG, n = 34). Primary outcomes of interest were inhospital mortality and perioperative complication rate. RESULTS Patients in the OG group had significantly higher rates of preoperative stroke history, atrial fibrillation, and coronary artery disease. Indication for surgery was type A aortic dissection in 62 (10.5%), thoracic aortic aneurysm in 514 (86.8%), and endocarditis in 11 (1.9%), with no intergroup differences. Inhospital mortality was not significantly different between groups (5.9% OG versus 2.3% LT80, p = 0.21), and postoperative atrial fibrillation was more common in OG (60.6% OG versus 38.5% LT80, p = 0.01). Type A dissection, diabetes mellitus, and prior cardiac surgery were independent predictors of inhospital mortality or postoperative stroke. CONCLUSIONS Octogenarians can safely undergo aortic root replacement with moderately worse but acceptable perioperative mortality and late survival. Further studies are necessary to determine which subset of octogenarians are at the highest operative risk and may benefit from a conservative approach.

Patient-specific characteristics determine success of surgical atrial fibrillation ablation in patients with persistent atrial fibrillation.

Surgical atrial fibrillation ablation (SAFA) has not achieved the efficacy of Coxs original maze procedure, although technical improvements continue to be made. It is possible that biologic factors determine SAFA success. Therefore we examined how patient-specific characteristics affected SAFA success in 353 atrial fibrillation (AF) patients who underwent SAFA at a single institution. Among these, 257 (72.8%) had continuous AF and 96 (27.2%) had intermittent AF. For 297 patients (84.1%) postoperative follow-up was > 3 months. We compared SAFA success in patients whose procedure involved only pulmonary vein isolation with those whose procedure involved extensive lesion sets. Multivariate analysis included AF duration, left atrial size, preoperative atrial flutter, concomitant procedures, lesion sets, and energy source. Early SAFA success was classified as freedom from AF between postoperative months 3 and 6, and intermediate success between postoperative months 6 and 12. Receiver-operating characteristic (ROC) curves and stratum-specific likelihood ratios (SSLR) were generated to compare intermediate failure by left atrial size (LAS) thresholds. SAFA was more successful in the intermittent than the continuous AF group (n = 66, 86% vs n = 165, 71%; P = .014). When pulmonary vein isolation was compared only to more extensive lesion sets, there was no difference in success in the intermittent (34, 91% vs 32, 81%; P = .24) or continuous groups (67, 73% vs. 98, 69%; P = .603). Success for intermittent AF patients was not correlated with variables considered; in continuous AF patients, predictors included presence of concomitant mitral valve repair/replacement (P = .075), decreasing LAS (P = .025) and absence of preoperative atrial flutter (P = .001). In the continuous AF group, ROC curves and corresponding areas under the curve (AUC) were 0.60 (0.50-0.71) for failure at 6 months to 1 year. SSLR analysis generated 2 strata for LAS: < 8 cm with SSLR = 0.87 (0.74-1.0) and < or = 8 cm SSLR = 2.98 (1.07-8.3). In patients with intermittent AF, SAFA achieved acceptable results regardless of tested preoperative and intraoperative variables. In continuous AF, patient-specific characteristics affected success more than intraoperative variables. Failure was more than 3-fold greater in continuous AF patients with an LAS < or = 8 cm. In both patient types, more extensive lesion sets were not shown to improve outcomes. Future improvements in SAFA may depend on pharmacologic and/or surgical substrate modification.

Nkx2.5 is essential to establish normal heart rate variability in the zebrafish embryo

Heart rate variability (HRV) has become an important clinical marker of cardiovascular health and a research measure for the study of the cardiac conduction system and its autonomic controls. While the zebrafish (Danio rerio) is an ideal vertebrate model for understanding heart development, HRV has only recently been investigated in this system. We have previously demonstrated that nkx2.5 and nkx2.7, two homologues of Nkx2-5 expressed in zebrafish cardiomyocytes, play vital roles in maintaining cardiac chamber-specific characteristics. Given observed defects in ventricular and atrial chamber identities in nkx2.5-/- embryos coupled with conduction system abnormalities in murine models of Nkx2.5 insufficiency, we postulated that reduced HRV would serve as a marker of poor cardiac health in nkx2.5 mutants and in other zebrafish models of human congenital heart disease. Using live video image acquisition, we derived beat-to-beat intervals to compare HRV in wild-type and nkx2.5-/- embryos. Our data illustrate that the nkx2.5 loss-of-function model exhibits increased heart rate and decreased HRV when compared with wild type during embryogenesis. These findings validate HRV analysis as a useful quantitative tool for assessment of cardiac health in zebrafish and underscore the importance of nkx2.5 in maintaining normal heart rate and HRV during early conduction system development.