Clifford Chin

Pediatric heart transplant waiting list mortality in the era of ventricular assist devices

BACKGROUNDnEarlier reviews have reported unacceptably high incidence of pediatric heart transplant (PHT) waiting list mortality. An increase in ventricular assist devices (VAD) suggests a potential positive effect. This study evaluated PHT waiting list mortality in the era of pediatric VADs.nnnMETHODSnUnited Network of Organ Sharing (UNOS) database from 1999 to 2012 showed 5,532 pediatric candidates (aged ≤ 18 years) actively listed for PHT: 2,191 were listed in 1999 to 2004 (Era 1) and 3,341 were listed in 2005 to 2012 (Era 2).nnnRESULTSnWaiting list mortality was lower in Era 2 (8%) vs Era 1 (16%; p < 0.001). VAD therapy was used more frequently in Era 2 (16%) than in Era 1 (6%; p < 0.001) and was associated with better waiting list survival (p < 0.001). There were more UNOS Status 1A patients in Era 2 (80%) vs Era 1 (68%; p < 0.001). Independent predictors of waiting list mortality included weight < 10 kg (odds ratio [OR], 2.7 95% confidence interval [CI], 1.1-6.9), congenital heart disease diagnosis (OR, 2.4; 95% CI, 1.9-3.0), blood type O (OR, 2.2; 95% CI, 1.8-2.8)], extracorporeal membrane oxygenation (OR, 1.5; 95% CI, 1.1-2.2), mechanical ventilation (OR, 1.8; 95% CI, 1.4-2.3), and renal dysfunction (OR 1.6; 95% CI, 1.2-2.0). Independent predictors of survival on the waiting list included VAD therapy (OR 4.2; 95% CI, 2.4-7.6), cardiomyopathy diagnosis (OR 3.3; 95% CI, 2.4-4.6), blood type A (OR, 2.2; 95% CI, 1.8-2.8), UNOS list Status 1B (OR, 1.9; 95% CI, 1.2-3.0), listed in Era 2 (OR 1.8; 95% CI, 1.4-2.2), and white race (OR 1.3; 95% CI, 1.1-1.6).nnnCONCLUSIONSnDespite an increase in the number of children listed as Status 1A, there was more than a 50% reduction in waiting list mortality in the new era. Irrespective of other factors, patients supported with a VAD were 4 times more likely to survive to transplant.

Early Predictors of Survival to and After Heart Transplantation in Children With Dilated Cardiomyopathy

Background— The importance of clinical presentation and pretransplantation course on outcome in children with dilated cardiomyopathy listed for heart transplantation is not well defined. Methods and Results— The impact of age, duration of illness, sex, race, ventricular geometry, and diagnosis of myocarditis on outcome in 261 children with dilated cardiomyopathy enrolled in the Pediatric Cardiomyopathy Registry and Pediatric Heart Transplant Study was studied. End points included listing as United Network for Organ Sharing status 1, death while waiting, and death after transplantation. The median age at the time of diagnosis was 3.4 years, and the mean time from diagnosis to listing was 0.62±1.3 years. Risk factors associated with death while waiting were ventilator use and older age at listing in patients not mechanically ventilated (P=0.0006 and P=0.03, respectively). Shorter duration of illness (P=0.04) was associated with listing as United Network for Organ Sharing status 1. Death after transplantation was associated with myocarditis at presentation (P=0.009), nonwhite race (P<0.0001), and a lower left ventricular end-diastolic dimension z score at presentation (P=0.04). In the myocarditis group, 17% (4 of 23) died of acute rejection after transplantation. Conclusions— Mechanical ventilator use and older age at listing predicted death while waiting, whereas nonwhite race, smaller left ventricular dimension, and myocarditis were associated with death after transplantation. Although 97% of children with clinically or biopsy-diagnosed myocarditis at presentation survived to transplantation, they had significantly higher posttransplantation mortality compared with children without myocarditis, raising the possibility that preexisting viral infection or inflammation adversely affects graft survival.

Donors' characteristics and impact on outcomes in pediatric heart transplant recipients.

Organ availability and acceptability limit pediatric HTx. What characteristics define an unacceptable or high‐risk pediatric donor remains unclear. The purpose of this study was to characterize a large cohort of pediatric donors and determine the donor risk factors, including cumulative risk, that affect recipient survival. Data from the PHTS, a prospective multicenter study, were used to examine the impact of donor factors on the outcomes of patients listed <18 yr of age who received a HTx between 1993 and 2009. Donor data were available for 3149 of 3156 HTx (99.8%). Donor cause of death, need for inotropes, or CPR did not affect survival outcomes (p = 0.05). Ischemic time also did not have an impact on overall recipient survival; however, longer ischemic times negatively impacted one‐yr post‐transplant survival (p < 0.0001). There was no impact of cumulative risk factors on survival (p = 0.8). Although used in a minority of cases, hormonal therapy in the donor positively impacted survival (p = 0.03). In multivariate analysis, the only donor factor associated with decreased survival was smaller donor BSA, the other factors being related to the recipient characteristics. When analyzed by recipient age, there were no donor‐related factors that affected survival for those who received a transplant at <6 months of age. Longer ischemic time (p < 0.0001) and greater age difference between the recipient and donor (p = 0.0098) were donor‐related factors impacting early‐phase survival for recipients who received a graft at ≥10 yr of age. Factors perceived to define a marginal or high‐risk pediatric heart donor including inotrope use, CPR and donor cause of death may have less impact on outcomes than previously thought. Longer ischemic times did impact one yr, but not overall survival, and this impact was much greater with older donors. Parameters for accepting a donor heart can potentially be expanded, especially in the infant age group, but strong consideration should always be given to the interaction between ischemic time and donor age.

Transplantation in the Highly Sensitized Pediatric Patient

Sensitization against HLA antigens is a growing problem in the field of pediatric cardiac transplantation. Although surgical outcomes for congenital heart disease have improved over the decades, these successes have added to the growing list of sensitized patients who eventually may require transplantation.Cardiac transplantation survival has improved, but morbidity and mortality secondary to HLA antibodies hinder outcome. Aside from acute hemodynamic compromise, there is compelling evidence linking sensitization and AMR with the development of CAV, a major limiting factor affecting long-term graft survival. Clinical advances have improved our understanding of the roles of antibody type, CFAs and non-CFAs, and DSAs and non-DSAs. Therapeutic strategies target both the T- and B-cell lines. Combinations that include plasmapheresis, IVIG, cyclophosphamide, and rituximab have been used in clinical studies with variable success.Two newer agents show promise, targeting both ends of the antibody-mediated spectrum: Bortezomib depletes plasma cell populations, and eculizumab blocks the terminal effects of antibody action, thus preventing myocardial cell dysfunction and death. Despite numerous diagnostic and therapeutic advances, many questions remain about the best approaches.The role of HLA antibodies remains the central target of investigation.

Improved detection of cardiac allograft vasculopathy: A multi-institutional analysis of functional parameters in pediatric heart transplant recipients

BACKGROUNDnRecent guidelines recommend assessment of systolic function and filling pressures to augment angiographic grading of cardiac allograft vasculopathy (CAV); however, no data exist on the utility of these guidelines.nnnOBJECTIVESnThe aims of this study were to evaluate whether the assessment of systolic and diastolic graft function, in addition to angiography, improves recognition of patients at high risk of graft loss and to assess the ability of adult filling-pressure thresholds to discriminate graft dysfunction in pediatric patients.nnnMETHODSnThis study reviewed Pediatric Heart Transplant Study data from 1993 to 2009. Graft dysfunction was defined as significant systolic dysfunction (ejection fraction [EF]xa0<45%) or the presence of restrictive hemodynamic features. Additional pediatric hemodynamic cutpoints of right atrial pressure (RAP) >12 mmxa0Hg or pulmonary capillary wedge pressure (PCWP) >15 mmxa0Hg were analyzed.nnnRESULTSnIn the study, 8,122 angiograms were performed in 3,120 patients, and 70% of patients had at least 1 angiogram. Angiographic incidence of CAV was 5%, 15%, and 28% at 2, 5, and 10 years, respectively, and most disease was mild. The presence of graft dysfunction identified patients at greater risk for graft loss even in children with mild angiographic vasculopathy (pxa0< 0.0001). An RAP >12 mmxa0Hg or a PCWP >15 mmxa0Hg was sufficient to detect patients at high risk of graft loss even with mild angiographic disease.nnnCONCLUSIONSnPatients with only mild angiographic CAV have significantly better outcomes than do patients with moderate or severe disease. The presence of an EFxa0<45%, an RAP >12 mmxa0Hg, or a PCWP >15 mmxa0Hg identifies children at increased risk of graft loss even in the presence of only mild angiographic vasculopathy.

Abdominal complaints as a common first presentation of heart failure in adolescents with dilated cardiomyopathy

OBJECTIVEnWe hypothesized that isolated gastrointestinal complaints (abdominal pain, nausea, anorexia, weight loss), in the absence of other symptoms, were a common mode of initial presentation in children with congestive heart failure (CHF).nnnSTUDY DESIGNnNinety-eight patients younger than 18 years hospitalized with dilated cardiomyopathy at a single institution between January 1, 2000, and December 31, 2009, were included. Retrospective review of their presenting complaints was recorded and analyzed according to 3 age groups: 0 to 1 year (infants), 1 to 10 years (children), and 11 to 18 years (adolescents) of age.nnnRESULTSnRespiratory symptoms were common in all age groups (range, 56%-63%). Gastrointestinal complaints were also common in all age groups (42%, 28%, and 65%, respectively) and were more frequent than respiratory complaints in adolescents. Adolescents were likely to present with abdominal pain as their only complaint (10/43, 23%). Chest pain, syncope, or cardiac arrest occurred rarely.nnnCONCLUSIONSnAbdominal complaints are a common component of the presenting symptom complex of CHF in pediatric dilated cardiomyopathy in all age groups. In adolescents, abdominal complaints occur more frequently than respiratory complaints and often in the absence of any other symptoms. Unlike CHF in adults, chest pain, arrhythmia, or cardiac arrest occurs rarely at presentation in pediatric patients. Recognition of the different presenting symptoms of heart failure in children by primary providers is crucial to ensuring prompt diagnosis and timely initiation of therapy.

Supine Exercise Echocardiographic Measures of Systolic and Diastolic Function in Children

BACKGROUNDnEchocardiography has been used to determine ventricular function, segmental wall motion abnormality, and pulmonary artery pressure before and after peak exercise. No prior study has investigated systolic and diastolic function using echocardiography at various phases of exercise in children. The aim of this study was to determine the fractional shortening (FS), systolic-to-diastolic (S/D) ratio, heart rate-corrected velocity of circumferential fiber shortening (VCFc), circumferential wall stress (WS), ratio of mitral passive inflow to active inflow (E/A), ratio of passive inflow by pulsed-wave to tissue Doppler (E/E), and right ventricular-to-right atrial pressure gradient from tricuspid valve regurgitation jet velocity (RVP) and time duration at various phases of exercise in children.nnnMETHODSnIn an 8-month period (December 2007 to July 2008), 100 healthy children were evaluated, and 97 participants aged 8 to 17 years who performed complete cardiopulmonary exercise stress tests using supine cycle ergometry were prospectively enrolled. The participants consisted of 48 female and 49 male subjects with various body sizes, levels of exercise experience, and physical capacities. The cardiopulmonary exercise stress test consisted of baseline pulmonary function testing, continuous gas analysis and monitoring of blood pressure and heart rate responses, electrocardiographic recordings, and oxygen saturation measurement among participants who pedaled against a ramp protocol based on body weight. All participants exercised to exhaustion. Echocardiography was performed during exercise at baseline, at a heart rate of 130 beats/min, at a heart rate of 160 beats/min, at 5 min after exercise, and at 10 min after exercise. FS, S/D ratio, VCFc, WS, E/A, E, E/E, and RVP at these five phases were compared in all subjects.nnnRESULTSnAll echocardiographic parameters differed at baseline from 160 beats/min (P < .0001) except E/E, which remained at 5.4 to 5.8. Specifically, FS (from 37% to 46%), S/D ratio, VCFc (from 1.1 to 1.6), WS (from 200 to 258 g/cm(2)), E (from 0.2 to 0.3), and RVP (from 18 to 35 mm Hg) increased from baseline to 160 beats/min and then subsequently decreased to at or near baseline, while tricuspid valve regurgitation duration decreased (from 370 to 178 msec).nnnCONCLUSIONSnNormal values for systolic and diastolic echocardiographic measurements of function are now available. FS, VCFc, WS, and RVP increase with exercise and then return to near baseline levels. The E/E ratio is unaltered with exercise in normal subjects.

Cardiac antibody-mediated rejection.

Chin C. Cardiac antibody–mediated rejection.

Allosensitization does not alter post-transplant outcomes in pediatric patients bridged to transplant with a ventricular assist device.

Patients supported with a VAD are at increased risk for sensitization. We aimed to determine risk factors for sensitization as well as the impact of sensitization on post‐transplant outcomes. The UNOS database (January 2004–June 2014) was used to identify patients (≤18 yrs) supported with a durable VAD. Rates and degree of sensitization in the VAD cohort were calculated. Post‐transplant survival was determined comparing outcomes of sensitized vs. non‐sensitized patients. There were 3097 patients included in the study; 19% (n = 579) were bridged with a VAD. Of these, 41.8% were sensitized vs. 29.9% of the patients who were not bridged with a VAD (p < 0.001). VAD was an independent predictor of sensitization (OR 2.05 [1.63–2.57]; p < 0.001). There was no difference in sensitization based on device type (continuous vs. pulsatile flow, p = 0.990). Post‐transplant survival rates between the sensitized and non‐sensitized VAD patients were not different, including patients with a PRA >50% and VAD patients with a positive DSC (p = 0.280 and 0.160, respectively). In conclusion, pediatric VAD patients are more likely to be sensitized, but there was no difference in sensitization based on device type. In addition, sensitization does not appear to impact outcomes.

Outcomes after percutaneous coronary artery revascularization procedures for cardiac allograft vasculopathy in pediatric heart transplant recipients: A multi-institutional study

BACKGROUNDnCardiac allograft vasculopathy is an important cause of long-term graft loss. In adults, percutaneous revascularization procedures (PRPs) have variable success with high restenosis rates and little impact on graft survival. Limited data exist in pediatric recipients of transplants.nnnMETHODSnData from the Pediatric Heart Transplant Study (PHTS) were used to explore associations between PRPs and outcomes after heart transplant in patients listed ≤18 years old who received a first heart transplant between 1993 and 2009.nnnRESULTSnRevascularization procedures were done in 28 of 3,156 (0.9%) patients; 13 patients had multiple PRPs giving a total of 51 PRPs performed across 15 centers. Mean recipient age at time of transplant was 7.7 ± 6.7 years; mean donor age was 15.9 ± 15.4 years. The mean time to first PRP was 5.7 ± 3.2 years. Vessels involved were left anterior descending artery (41%), right coronary artery (25%), circumflex artery (18%), other coronary branches/unknown (16%). PRPs consisted of 38 (75%) stent implantations and 13 (25%) balloon angioplasties with an overall procedural success rate of 73%. Freedom from graft loss after PRPs was 89%, 75%, and 61% at 1, 3, and 12 months. In addition, patients with transplants from donors >30 years old were found to have less freedom from the need for a revascularization procedure than patients with transplants from younger donors (p < 0.0001).nnnCONCLUSIONSnIn this large pediatric heart transplant cohort, use of PRPs for cardiac allograft vasculopathy was rare, likely related to procedural feasibility of the interventions. Despite technically successful interventions, graft loss occurred in 39% within 1 year post-procedure; relisting for heart transplant should be considered.