Tajinder P. Singh

Waiting List Mortality Among Children Listed for Heart Transplantation in the United States

Background— Children listed for heart transplantation face the highest waiting list mortality in solid-organ transplantation medicine. We examined waiting list mortality since the pediatric heart allocation system was revised in 1999 to determine whether the revised allocation system is prioritizing patients optimally and to identify specific high-risk populations that may benefit from emerging pediatric cardiac assist devices. Methods and Results— We conducted a multicenter cohort study using the US Scientific Registry of Transplant Recipients. All children <18 years of age who were listed for a heart transplant between 1999 and 2006 were included. Among 3098 children, the median age was 2 years (interquartile range 0.3 to 12 years), and median weight was 12.3 kg (interquartile range 5 to 38 kg); 1294 (42%) were nonwhite; and 1874 (60%) were listed as status 1A (of whom 30% were ventilated and 18% were on extracorporeal membrane oxygenation). Overall, 533 (17%) died, 1943 (63%) received transplants, and 252 (8%) recovered; 370 (12%) remained listed. Multivariate predictors of waiting list mortality include extracorporeal membrane oxygenation support (hazard ratio [HR] 3.1, 95% confidence interval [CI] 2.4 to 3.9), ventilator support (HR 1.9, 95% CI 1.6 to 2.4), listing status 1A (HR 2.2, 95% CI 1.7 to 2.7), congenital heart disease (HR 2.2, 95% CI 1.8 to 2.6), dialysis support (HR 1.9, 95% CI 1.2 to 3.0), and nonwhite race/ethnicity (HR 1.7, 95% CI 1.4 to 2.0). Conclusions— US waiting list mortality for pediatric heart transplantation remains unacceptably high in the current era. Specific high-risk subgroups can be identified that may benefit from emerging pediatric cardiac assist technologies. The current pediatric heart-allocation system captures medical urgency poorly. Further research is needed to define the optimal organ-allocation system for pediatric heart transplantation.

Vascular function and carotid intimal-medial thickness in children with insulin-dependent diabetes mellitus

OBJECTIVES The objective of this study was to evaluate endothelium-dependent vasodilation and carotid intimal-medial thickness (IMT) in children with insulin-dependent diabetes mellitus. BACKGROUND Diabetes mellitus is an established risk factor for atherosclerosis. Vascular complications of diabetes are not clinically evident in diabetic children. However, preclinical atherosclerosis is more common in young subjects exposed to cardiovascular risk factors. Endothelial function and carotid IMT, known to be abnormal in preclinical atherosclerosis, have not been studied concurrently in a pediatric population exposed to a risk factor for atherosclerosis. METHODS We studied 31 diabetic teenagers (age 15.0 +/- 2.4 years; duration of diabetes 6.8 +/- 3.9 years) and 35 age-matched healthy children (age 15.7 +/- 2.7 years). Using high-resolution vascular ultrasound, we compared carotid IMT and brachial artery responses to reactive hyperemia (endothelium-dependent vasodilation) and to sublingual nitroglycerin (endothelium-independent vasodilation). RESULTS There was no difference in baseline brachial artery diameter between the two groups. Endothelium-dependent vasodilation was significantly lower in diabetic children compared with healthy children (4.2 +/- 3.8% vs. 8.2 +/- 4.2%, p < 0.001). There was no difference in endothelium-independent vasodilation (17 +/- 6% vs. 18 +/- 6%, p = NS) or mean carotid IMT between the groups (0.33 +/- 0.05 vs. 0.32 +/- 0.08 mm, p = NS). Endothelium-dependent brachial vasodilation correlated with blood glucose levels (r = 0.58, p = 0.001) and was weakly and inversely related to the duration of diabetes (r = -0.4, p = 0.02), total cholesterol, and low-density lipoprotein cholesterol levels. CONCLUSIONS Endothelial function is impaired in children with diabetes mellitus within the first decade of its onset and precedes an increase in carotid IMT. The relative timing of these events is important in the evaluation of strategies to prevent progression of atherosclerosis and other vascular complications in this patient population.

Extracorporeal Membrane Oxygenation for Bridge to Heart Transplantation Among Children in the United States Analysis of Data From the Organ Procurement and Transplant Network and Extracorporeal Life Support Organization Registry

Background— Extracorporeal membrane oxygenation (ECMO) has served for >2 decades as the standard of care for US children requiring mechanical support as a bridge to heart transplantation. Objective data on the safety and efficacy of ECMO for this indication are limited. We describe the outcomes of ECMO as a bridge to heart transplantation to serve as performance benchmarks for emerging miniaturized assist devices intended to replace ECMO. Methods and Results— Data from the Extracorporeal Life Support Organization Registry and the Organ Procurement Transplant Network database were merged to identify children supported with ECMO and listed for heart transplantation from 1994 to 2009. Independent predictors of wait-list and posttransplantation in-hospital mortality were identified. Objective performance goals for ECMO were developed. Of 773 children, the median age was 6 months (interquartile range, 1 to 44 months); 28% had cardiomyopathy; and in 38%, a bridge to transplantation was intended at ECMO initiation. Overall, 45% of subjects reached transplantation, although one third of those transplanted died before discharge; overall survival to hospital discharge was 47%. Wait-list mortality was independently associated with congenital heart disease, cardiopulmonary resuscitation before ECMO, and renal dysfunction. Posttransplantation mortality was associated with congenital heart disease, renal dysfunction, ECMO duration of >14 days, and initial ECMO indication as a bridge to recovery. In the objective performance goal cohort (n=485), patients with cardiomyopathy had the highest survival to hospital discharge (63%), followed by patients with myocarditis (59%), 2-ventricle congenital heart disease (44%) and 1-ventricle congenital heart disease (33%). Conclusion— Although ECMO is effective for short-term circulatory support, it is not reliable for the long-term circulatory support necessary for children awaiting heart transplantation. Fewer than half of patients bridged with ECMO survive to hospital discharge. More effective modalities for chronic circulatory support in children are urgently needed.

Extracorporeal Membrane Oxygenation for Bridge to Heart Transplantation Among Children in the United States

Background— Extracorporeal membrane oxygenation (ECMO) has served for >2 decades as the standard of care for US children requiring mechanical support as a bridge to heart transplantation. Objective data on the safety and efficacy of ECMO for this indication are limited. We describe the outcomes of ECMO as a bridge to heart transplantation to serve as performance benchmarks for emerging miniaturized assist devices intended to replace ECMO. Methods and Results— Data from the Extracorporeal Life Support Organization Registry and the Organ Procurement Transplant Network database were merged to identify children supported with ECMO and listed for heart transplantation from 1994 to 2009. Independent predictors of wait-list and posttransplantation in-hospital mortality were identified. Objective performance goals for ECMO were developed. Of 773 children, the median age was 6 months (interquartile range, 1 to 44 months); 28% had cardiomyopathy; and in 38%, a bridge to transplantation was intended at ECMO initiation. Overall, 45% of subjects reached transplantation, although one third of those transplanted died before discharge; overall survival to hospital discharge was 47%. Wait-list mortality was independently associated with congenital heart disease, cardiopulmonary resuscitation before ECMO, and renal dysfunction. Posttransplantation mortality was associated with congenital heart disease, renal dysfunction, ECMO duration of >14 days, and initial ECMO indication as a bridge to recovery. In the objective performance goal cohort (n=485), patients with cardiomyopathy had the highest survival to hospital discharge (63%), followed by patients with myocarditis (59%), 2-ventricle congenital heart disease (44%) and 1-ventricle congenital heart disease (33%). Conclusion— Although ECMO is effective for short-term circulatory support, it is not reliable for the long-term circulatory support necessary for children awaiting heart transplantation. Fewer than half of patients bridged with ECMO survive to hospital discharge. More effective modalities for chronic circulatory support in children are urgently needed.

Risk factors for recurrent rejection in pediatric heart transplantation: a multicenter experience.

BACKGROUND Cardiac allograft rejection remains as a primary cause of death in the first 3 years after pediatric heart transplantation. Multiple episode of acute rejection in adult heart transplant recipients may accelerate the development of graft vasculopathy. We sought to quantify the time-related probability of recurrent rejection and identify risk factors for the development of recurrent rejection. METHODS We analyzed data from 847 pediatric recipients who underwent transplantation between January 1, 1993 and December 31, 1998 at 22 centers in the Pediatric Heart Transplant Study (PHTS). Recurrent rejection and risk factors were evaluated using univariate and multivariate analyses. RESULTS Five hundred fifty two patients had 1,072 rejection events and were the subject of the analyses. The highest risk of recurrent rejection occurs within 1 month after resolution of a previous rejection episode. Risk factors for recurrent rejection include the number of previous rejection events, the elapsed time since a previous rejection episode, and subjects of either Hispanic or African-American descent. Rejection associated with hemodynamic compromise and late rejection is associated with higher mortality. CONCLUSIONS Recurrent rejection is a risk factor for mortality, especially in the presence of hemodynamic compromise. This association appears independent of the time post-transplantation. Use of surveillance biopsies appears warranted throughout the life of the transplant individual. Retransplantation should be considered among these subjects with recurrent rejection.

Quantification of myocardial blood flow and flow reserve in children with a history of kawasaki disease and normal coronary arteries using positron emission tomography

OBJECTIVES The purpose of this investigation was to determine whether myocardial blood flow and flow reserve, based on quantitative measurements derived from positron emission tomographic (PET) imaging, would be globally impaired in children with a previous history of Kawasaki disease and normal epicardial coronary arteries. BACKGROUND Kawasaki disease is an acute inflammatory process of the arterial walls that results in panvasculitis in early childhood. Children with a history of Kawasaki disease and normal epicardial coronary arteries were previously considered to have normal coronary flow reserve. However, recent studies have reported exercise-induced regional perfusion abnormalities on single-photon positron emission tomographic (SPECT) imaging. METHODS We assessed myocardial blood flow and flow reserve at rest and during adenosine stress with nitrogen-13 ammonia and PET in 10 children with a history of Kawasaki disease and in 10 healthy young adult volunteers. All children had acute Kawasaki disease 4 to 15 years before the PET study. None of the children had epicardial coronary artery abnormalities at the acute stage of the disease or during follow-up, as assessed by echocardiography. RESULTS Rest blood flows normalized to the rate-pressure product, an index of cardiac work, were similar in both the patients with Kawasaki disease and healthy adult volunteers (82 +/- 14 vs. 77 +/- 16 ml/100 g per min [mean +/- SD], p = NS). However, hyperemic blood flows were significantly lower in the patients with Kawasaki disease than in the control subjects (263 +/- 64 vs. 340 +/- 57 ml/100 g per min, p = 0.01). As a result, estimates of myocardial flow reserve were lower in the patients with Kawasaki disease than in the healthy young adult volunteers (3.2 +/- 0.7 vs. 4.6 +/- 0.9, p = 0.003). In addition, total coronary resistance was higher in the patients with Kawasaki disease than in the healthy adult volunteers (33 +/- 11 vs. 24 +/- 5 mm Hg/ml per g per min, p = 0.04). Quantitative analysis of perfusion images demonstrated no evidence of regional perfusion abnormalities. CONCLUSIONS Children with a previous history of Kawasaki disease and normal epicardial coronary arteries exhibit normal rest myocardial blood flows but reduced hyperemic flows and flow reserve. The abnormal hyperemic blood flows and flow reserve suggest an impaired vasodilatory capacity, possibly due to residual damage of the coronary microcirculation.

Decline in Heart Transplant Wait List Mortality in the United States Following Broader Regional Sharing of Donor Hearts

Background—A change in allocation algorithm in July 2006 allowed broader regional sharing of donor hearts in the United States (US). We assessed if the allocation change has been associated with a decline in wait list mortality in the US. Methods and Results—We compared baseline characteristics and outcomes in patients ≥18 years old listed for a primary heart transplant in the US before (July 1, 2004–July 11, 2006, Era1) and after (July 12, 2006–June 30, 2009, Era 2) the change in allocation algorithm. Of 11 864 patients in the study, 4503 were listed during Era 1 and 7361 during Era 2. Patients listed during Era 2 were more likely to be listed status 1A, have an implantable cardioverter-defibrillator, and supported on a continuous flow assist device (P<0.001 for distribution. Patients listed in Era 2 were at a 17% lower risk of dying on the wait list or becoming too sick to transplant (adjusted hazard ratio, 0.83, 95% CI 0.75, 0.93). Transplant recipients in Era 2 were more likely to be transplanted as status 1A (37% versus 48%, respectively, P<0.001). Post-transplant in-hospital mortality (6.3% versus 5.4%; adjusted odds ratio, 0.86 for Era 2, 95% CI 0.79, 1.06) and 1-year survival were similar. Conclusions—The risk of death on the wait list or becoming too sick to transplant has decreased by 17% in the US since the allocation algorithm allowing broader regional sharing was implemented in 2006. The shift in hearts to sicker candidates has not resulted in higher in-hospital or first year post-transplant mortality.

Myocardial flow reserve in patients with a systemic right ventricle after atrial switch repair

OBJECTIVES The purpose of this study was to assess myocardial blood flow (MBF) and flow reserve in systemic right ventricles (RV) in long-term survivors of the Mustard operation. BACKGROUND There is a high prevalence of systemic RV dysfunction and impaired exercise performance in long-term survivors of the Mustard operation. A mismatch between myocardial blood supply and systemic ventricular work demand has been proposed as a potential mechanism. METHODS We assessed MBF at rest and during intravenous adenosine hyperemia in 11 long-term survivors of a Mustard repair (age 18+/-5 years, median age at repair 0.7 years, follow-up after repair 17+/-5 years) and 13 healthy control subjects (age 23+/-7 years), using N-13 ammonia and positron emission tomography imaging. RESULTS There was no difference in basal MBF between the systemic RV of survivors of the Mustard operation and the systemic left ventricle (LV) of healthy control subjects (0.80+/-0.19 vs. 0.74+/-0.15 ml/g/min, respectively, p = NS). However, the hyperemic flows were significantly lower in systemic RVs than they were in systemic LVs (2.34+/-0.0.69 vs. 3.44+/-0.62 ml/g/min respectively, p < 0.01). As a result, myocardial flow reserve was lower in systemic RVs than it was in systemic LVs (2.93+/-0.63 vs. 4.74+/-1.09, respectively, p < 0.01). CONCLUSIONS Myocardial flow reserve is impaired in systemic RVs in survivors of the Mustard operation. This may contribute to systemic ventricular dysfunction in these patients.

Incidence and Risk Factors for Mortality in Infants Awaiting Heart Transplantation in the USA

BACKGROUND Infants awaiting heart transplantation (HT) face the highest wait-list mortality among all children and adults listed for HT in the USA. We sought to determine the risk of death for infants <12 months old while awaiting HT in the current era, and to identify the principle risk factors associated with wait-list mortality. METHODS We analyzed outcomes for all infants listed for HT in the USA from January 1999 to July 2006, using data reported to the U.S. Scientific Registry of Transplant Recipients. RESULTS Of the 1,133 listed infants, 61% were <3 months of age, 80% were listed as Status 1A, 64% had a congenital heart disease (CHD) and 31% had cardiomyopathy. Of 724 infants with CHD, 25% were on prostaglandin (PG) and 27% had a history of prior surgery. By 6 months after listing, 23% died on the wait-list and 54% were transplanted. Multivariate factors associated with wait-list mortality were weight <3 kg (hazard ratio [HR] 1.4, 95% confidence interval [CI] 1.0 to 1.9), extracorporeal membrane oxygenation (ECMO) support (HR 5.6, CI 4.0 to 7.9), ventilator support (HR 2.1, 95% CI 1.6 to 2.8), CHD with PG support (HR 2.8, 95% CI 1.8 to 4.3), CHD without prior surgery (HR 2.8, 95% CI 1.9 to 3.9) and non-white race/ethnicity (HR 1.8, 95% CI 1.4 to 2.3). CONCLUSIONS One in four infants listed for HT in the USA die before a donor heart can be identified. Wait-list mortality is associated with weight <3 kg, level of invasive support and CHD, but not listing status, which captures medical urgency poorly. Measures to expand infant organ donation, especially among neonates, are urgently needed.

Determinants of heart rate recovery following exercise in children.

PURPOSE Heart rate (HR) recovery during the first minute after cessation of exercise is predominantly modulated by reactivation of vagal tone. Attenuated 1-min HR recovery is a cardiovascular risk factor in adults. The purpose of this study was to determine predictors of 1-min HR recovery after a maximum-effort exercise test in healthy children. METHODS HR recovery after cessation of a maximal treadmill exercise test (Bruce protocol) was assessed in 485 children (197 girls, 288 boys) who underwent an exercise test during their clinical evaluation to exclude cardiac disease and who were discharged as normal. The first-minute cool-down period (1.5 mph, 0% inclination on treadmill) was consistent for all subjects. Age- and gender-specific 25th, 50th, and 75th percentile values of 1-min HR recovery were generated. Multivariable linear regression analyses were performed to determine predictors of 1-min HR recovery. RESULTS One-minute HR recovery was higher in boys and correlated inversely with age and with age-adjusted BMI in both boys and girls. In a multivariable linear regression model, age, gender, BMI, and baseline HR were significant predictors of 1-min HR recovery and explained 39% of variance. Exercise duration and peak HR were also significant predictors when added to the model, but they improved the explained variance by only 2%. CONCLUSION One-minute HR recovery after exercise is attenuated with age in children. Children with higher BMI, particularly those who are overweight, and those with lower exercise endurance, have slower 1-min HR recovery.