Melanie D. Everitt

Cardiovascular Mortality Among Heart Transplant Recipients With Asymptomatic Antibody-Mediated or Stable Mixed Cellular and Antibody-Mediated Rejection

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.

Incidence of and Risk Factors for Sudden Cardiac Death in Children with Dilated Cardiomyopathy: A Report from the Pediatric Cardiomyopathy Registry

OBJECTIVES The purpose of this study was to establish the incidence of and risk factors for sudden cardiac death (SCD) in pediatric dilated cardiomyopathy (DCM). BACKGROUND The incidence of SCD in children with DCM is unknown. The ability to predict patients at high risk of SCD will help to define who may benefit most from implantable cardioverter-defibrillators. METHODS The cohort was 1,803 children in the PCMR (Pediatric Cardiomyopathy Registry) with a diagnosis of DCM from 1990 to 2009. Cumulative incidence competing-risks event rates were estimated. We achieved risk stratification using Classification and Regression Tree methodology. RESULTS The 5-year incidence rates were 29% for heart transplantation, 12.1% non-SCD, 4.0% death from unknown cause, and 2.4% for SCD. Of 280 deaths, 35 were SCD, and the cause was unknown for 56. The 5-year incidence rate for SCD incorporating a subset of the unknown deaths is 3%. Patients receiving antiarrhythmic medication were at higher risk of SCD (hazard ratio: 3.0, 95% confidence interval: 1.1 to 8.3, p = 0.025). A risk stratification model based on most recent echocardiographic values had 86% sensitivity and 57% specificity. Thirty of 35 SCDs occurred in patients who met all these criteria: left ventricular (LV) end-systolic dimension z-score >2.6, age at diagnosis younger than 14.3 years, and the LV posterior wall thickness to end-diastolic dimension ratio <0.14. Sex, ethnicity, cause of DCM, and family history were not associated with SCD. CONCLUSIONS The 5-year incidence rate of SCD in children with DCM is 3%. A risk stratification rule (86% sensitivity) included age at diagnosis younger than 14.3 years, LV dilation, and LV posterior wall thinning. Patients who consistently meet these criteria should be considered for implantable cardioverter-defibrillator placement.

Morbidity and mortality in heart transplant candidates supported with mechanical circulatory support: is reappraisal of the current United network for organ sharing thoracic organ allocation policy justified?

Background— Survival of patients on left ventricular assist devices (LVADs) has improved. We examined the differences in risk of adverse outcomes between LVAD-supported and medically managed candidates on the heart transplant waiting list. Methods and Results— We analyzed mortality and morbidity in 33 073 heart transplant candidates registered on the United Network for Organ Sharing (UNOS) waiting list between 1999 and 2011. Five groups were selected: patients without LVADs in urgency status 1A, 1B, and 2; patients with pulsatile-flow LVADs; and patients with continuous-flow LVADs. Outcomes in patients requiring biventricular assist devices, total artificial heart, and temporary VADs were also analyzed. Two eras were defined on the basis of the approval date of the first continuous-flow LVAD for bridge to transplantation in the United States (2008). Mortality was lower in the current compared with the first era (2.1%/mo versus 2.9%/mo; P <0.0001). In the first era, mortality of pulsatile-flow LVAD patients was higher than in status 2 (hazard ratio [HR], 2.15; P <0.0001) and similar to that in status 1B patients (HR, 1.04; P =0.61). In the current era, patients with continuous-flow LVADs had mortality similar to that of status 2 (HR, 0.80; P =0.12) and lower mortality compared with status 1A and 1B patients (HR, 0.24 and 0.47; P <0.0001 for both comparisons). However, status upgrade for LVAD-related complications occurred frequently (28%) and increased the mortality risk (HR, 1.75; P =0.001). Mortality was highest in patients with biventricular assist devices (HR, 5.00; P <0.0001) and temporary VADs (HR, 7.72; P <0.0001). Conclusions— Mortality and morbidity on the heart transplant waiting list have decreased. Candidates supported with contemporary continuous-flow LVADs have favorable waiting list outcomes; however, they worsen significantly once a serious LVAD-related complication occurs. Transplant candidates requiring temporary and biventricular support have the highest risk of adverse outcomes. These results may help to guide optimal allocation of donor hearts. # Clinical Perspective {#article-title-31}Background— Survival of patients on left ventricular assist devices (LVADs) has improved. We examined the differences in risk of adverse outcomes between LVAD-supported and medically managed candidates on the heart transplant waiting list. Methods and Results— We analyzed mortality and morbidity in 33 073 heart transplant candidates registered on the United Network for Organ Sharing (UNOS) waiting list between 1999 and 2011. Five groups were selected: patients without LVADs in urgency status 1A, 1B, and 2; patients with pulsatile-flow LVADs; and patients with continuous-flow LVADs. Outcomes in patients requiring biventricular assist devices, total artificial heart, and temporary VADs were also analyzed. Two eras were defined on the basis of the approval date of the first continuous-flow LVAD for bridge to transplantation in the United States (2008). Mortality was lower in the current compared with the first era (2.1%/mo versus 2.9%/mo; P<0.0001). In the first era, mortality of pulsatile-flow LVAD patients was higher than in status 2 (hazard ratio [HR], 2.15; P<0.0001) and similar to that in status 1B patients (HR, 1.04; P=0.61). In the current era, patients with continuous-flow LVADs had mortality similar to that of status 2 (HR, 0.80; P=0.12) and lower mortality compared with status 1A and 1B patients (HR, 0.24 and 0.47; P<0.0001 for both comparisons). However, status upgrade for LVAD-related complications occurred frequently (28%) and increased the mortality risk (HR, 1.75; P=0.001). Mortality was highest in patients with biventricular assist devices (HR, 5.00; P<0.0001) and temporary VADs (HR, 7.72; P<0.0001). Conclusions— Mortality and morbidity on the heart transplant waiting list have decreased. Candidates supported with contemporary continuous-flow LVADs have favorable waiting list outcomes; however, they worsen significantly once a serious LVAD-related complication occurs. Transplant candidates requiring temporary and biventricular support have the highest risk of adverse outcomes. These results may help to guide optimal allocation of donor hearts.

Chronic Heart Failure in Congenital Heart Disease: A Scientific Statement from the American Heart Association

### Introduction The past 60 years have brought remarkable advancements in the diagnosis and treatment of congenital heart disease (CHD). Early diagnosis and improvements in cardiac surgery and interventional cardiology have resulted in unprecedented survival of patients with CHD, even those with the most complex lesions. Despite remarkable success in treatments, many interventions are palliative rather than curative, and patients often develop cardiac complications, including heart failure (HF). HF management in the setting of CHD is challenged by the wide range of ages at which HF occurs, the heterogeneity of the underlying anatomy and surgical repairs, the wide spectrum of HF causes, the lack of validated biomarkers for disease progression, the lack of reliable risk predictors or surrogate end points, and the paucity of evidence demonstrating treatment efficacy. The purposes of this statement are to review the literature pertaining to chronic HF in CHD and to elucidate important gaps in our knowledge, emphasizing the need for specific studies of HF mechanisms and improving outcomes for those with HF. In this document, the definition of CHD severity is the definition common in CHD documents, including the American College of Cardiology (ACC)/American Heart Association (AHA) guidelines1 for the management of adults with CHD (Table 11–3). The definition of HF corresponds to that found in the multiple guidelines on diagnosis and management of HF. Although nuances and specific details may be controversial,4 the broad definition from the Heart Failure Society of America guidelines states the following: “In physiologic terms, HF is a syndrome characterized by either or both pulmonary and systemic venous congestion and/or inadequate peripheral oxygen delivery, at rest or during stress, caused by cardiac dysfunction.”5 The definition of chronic HF in this document concurs with that of the European Society of Cardiology guidelines, which emphasize chronic HF …

The International Society for Heart and Lung Transplantation Guidelines for the management of pediatric heart failure: Executive summary

From the Freeman Hospital, Newcastle upon Tyne, United Kingdom; Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada; Stanford University, Stanford, California; Columbia University Medical Center, New York, New York; Great Ormond Street Hospital, London, United Kingdom; Joe DiMaggio Children’s Hospital, Hollywood, Florida; Primary Children’s Medical Center, Salt Lake City, Utah; C.S. Mott Children’s Hospital, Ann Arbor, Michigan; Children’s Hospital, Denver, Colorado; Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio; Ann & Robert H Lurie Children’s Hospital, Chicago, Illinois; Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania; and the Royal Melbourne Children’s Hospital, Melbourne, Victoria, Australia.

Outcomes of Restrictive Cardiomyopathy in Childhood and the Influence of Phenotype: A Report from the Pediatric Cardiomyopathy Registry

Background— Restrictive cardiomyopathy (RCM) has been associated with poor prognosis in childhood. The goal of the present analysis was to use the Pediatric Cardiomyopathy Registry to analyze outcomes of childhood RCM, with a focus on the impact of phenotype comparing pure RCM with cases that have additional features of hypertrophic cardiomyopathy (HCM). Methods and Results— We analyzed the Pediatric Cardiomyopathy Registry database (1990–2008; N=3375) for cases of RCM. Cases were defined as pure when RCM was the only assigned diagnosis. Additional documentation of HCM at any time was used as the criterion for RCM/HCM phenotype. RCM accounted for 4.5% of cases of cardiomyopathy. In 101 (66%), pure RCM was diagnosed; in 51 (34%), there was a mixed phenotype. Age at diagnosis was not different between groups, but 10% of the pure RCM group was diagnosed in infancy versus 24% of the RCM/HCM group. Freedom from death was comparable between groups with 1-, 2-, and 5-year survival of RCM 82%, 80%, and 68% versus RCM/HCM 77%, 74%, and 68%. Transplant-free survival was 48%, 34%, and 22% and 65%, 53%, and 43%, respectively ( P =0.011). Independent risk factors at diagnosis for lower transplant-free survival were heart failure (hazard ratio 2.20, P =0.005), lower fractional shortening z score (hazard ratio 1.12 per 1 SD decrease in z score, P =0.014), and higher posterior wall thickness in the RCM/HCM group only (hazard ratio 1.32, P <0.001). Overall, outcomes were worse than for all other forms of cardiomyopathy. Conclusions— Transplant-free survival is poor for RCM in childhood. Survival is independent of phenotype; however, the RCM/HCM phenotype has significantly better transplant-free survival. Clinical Trials Registration— URL: . Unique Identifier: [NCT00005391][1]. # Clinical Perspective {#article-title-28} [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00005391&atom=%2Fcirculationaha%2F126%2F10%2F1237.atomBackground— Restrictive cardiomyopathy (RCM) has been associated with poor prognosis in childhood. The goal of the present analysis was to use the Pediatric Cardiomyopathy Registry to analyze outcomes of childhood RCM, with a focus on the impact of phenotype comparing pure RCM with cases that have additional features of hypertrophic cardiomyopathy (HCM). Methods and Results— We analyzed the Pediatric Cardiomyopathy Registry database (1990–2008; N=3375) for cases of RCM. Cases were defined as pure when RCM was the only assigned diagnosis. Additional documentation of HCM at any time was used as the criterion for RCM/HCM phenotype. RCM accounted for 4.5% of cases of cardiomyopathy. In 101 (66%), pure RCM was diagnosed; in 51 (34%), there was a mixed phenotype. Age at diagnosis was not different between groups, but 10% of the pure RCM group was diagnosed in infancy versus 24% of the RCM/HCM group. Freedom from death was comparable between groups with 1-, 2-, and 5-year survival of RCM 82%, 80%, and 68% versus RCM/HCM 77%, 74%, and 68%. Transplant-free survival was 48%, 34%, and 22% and 65%, 53%, and 43%, respectively (P=0.011). Independent risk factors at diagnosis for lower transplant-free survival were heart failure (hazard ratio 2.20, P=0.005), lower fractional shortening z score (hazard ratio 1.12 per 1 SD decrease in z score, P=0.014), and higher posterior wall thickness in the RCM/HCM group only (hazard ratio 1.32, P<0.001). Overall, outcomes were worse than for all other forms of cardiomyopathy. Conclusions— Transplant-free survival is poor for RCM in childhood. Survival is independent of phenotype; however, the RCM/HCM phenotype has significantly better transplant-free survival. Clinical Trials Registration— URL: http://www.clinicaltrials.gov. Unique Identifier: NCT00005391.

Recovery of Echocardiographic Function in Children with Idiopathic Dilated Cardiomyopathy: Results from the Pediatric Cardiomyopathy Registry

OBJECTIVES This study sought to determine the incidence and predictors of recovery of normal echocardiographic function among children with idiopathic dilated cardiomyopathy (DCM). BACKGROUND Most children with idiopathic DCM have poor outcomes; however, some improve. METHODS We studied children <18 years of age from the Pediatric Cardiomyopathy Registry who had both depressed left ventricular (LV) function (fractional shortening or ejection fraction z-score <-2) and LV dilation (end-diastolic dimension [LVEDD] z-score >2) at diagnosis and who had at least 1 follow-up echocardiogram 30 days to 2 years from the initial echocardiogram. We estimated the cumulative incidence and predictors of normalization. RESULTS Among 868 children who met the inclusion criteria, 741 (85%) had both echocardiograms. At 2 years, 22% had recovered normal LV function and size; 51% had died or undergone heart transplantation (median, 3.2 months), and 27% had persistently abnormal echocardiograms. Younger age (hazard ratio [HR]: 0.92; 95% confidence interval [CI]: 0.88 to 0.97) and lower LVEDD z-score (HR: 0.78; 95% CI: 0.70 to 0.87) independently predicted normalization. Nine children (9%) with normal LV function and size within 2 years of diagnosis later underwent heart transplantation or died. CONCLUSIONS Despite marked LV dilation and depressed function initially, children with idiopathic DCM can recover normal LV size and function, particularly those younger and with less LV dilation at diagnosis. Investigations related to predictors of recovery, such as genetic associations, serum markers, and the impact of medical therapy or ventricular unloading with assist devices are important next steps. Longer follow-up after normalization is warranted as cardiac failure can recur. (Pediatric Cardiomyopathy Registry; NCT00005391).

Would access to device therapies improve transplant outcomes for adults with congenital heart disease? Analysis of the United Network for Organ Sharing (UNOS)

BACKGROUND Patients with congenital heart disease (CHD) now survive into adulthood and often present with end-stage heart failure (HF). HF management and approach to orthotopic heart transplant (OHT) may differ from adults without CHD. We sought to compare OHT waitlist characteristics and outcomes for these 2 groups. METHODS The Organ Procurement and Transplantation Network (OPTN)/United Network for Organ Sharing (UNOS) database was used to identify adults (≥18 years) listed for OHT from 2005 to 2009. The cohort was divided into those with or without CHD. RESULTS Of 9,722 adults included, 314 (3%) had CHD. Adults with CHD were younger (35 ± 13 vs 52 ± 12 years, p < 0.01) and more often had undergone prior cardiac surgery (85% vs. 34%, p < 0.01). Patients with CHD were less likely to have a defibrillator (44% vs 75%, p < 0.01) or ventricular assist device (5% vs 14%, p < 0.01) and were more likely to be listed at the lowest urgency status than patients without CHD (64% vs 44%, p < 0.01). Fewer CHD patients achieved OHT (53% vs 65%, p < 0.001). Although overall waitlist mortality did not differ between groups (10% vs 8%, p = 0.15), patients with CHD were more likely to experience cardiovascular death (60% vs 40%, p = 0.03), including sudden in 44% and due to HF in 16%. CONCLUSIONS Despite lower urgency status, patients with CHD have greater cardiovascular mortality awaiting OHT than those without. Increased defibrillator use could improve survival to OHT, because sudden death is common. VAD support may benefit select patients, but experience in CHD is limited. Referral to specialized adult congenital heart centers can enhance utilization of device therapies and potentially improve waitlist outcomes.

Early survival after heart transplant in young infants is lowest after failed single-ventricle palliation: A multi-institutional study

BACKGROUND Infant heart transplant (HT) recipients have the best long-term survival of any age group, but the small donor pool and high early mortality limit the therapeutic effectiveness. We sought to determine the relationship between pre-HT diagnosis and early HT outcome to better define the mortality risk associated with a diagnosis of congenital heart disease (CHD) and to examine differences between early and current HT eras. METHODS The Pediatric Heart Transplant Study (PHTS) database was used to identify 739 infant HT recipients at age ≤ 6 months between 1993 and 2008 divided into the following etiologic groups: cardiomyopathy (CM), 18%; hypoplastic left heart syndrome (HLHS) without surgery, 41%; HLHS with surgery, 9%; other CHD without surgery, 16%; and other CHD with surgery, 15%. Severity of illness at HT, post-HT survival, and era effects were compared. RESULTS At 1 year after HT, survival was 89% for the CM group, which was the best, 79% for CHD without surgery, 82% for CHD with surgery, 79% for HLHS without surgery, and 70% for HLHS with surgery, which was the worst outcome. Hazard function analysis demonstrated the difference occurred within the first 3 months after HT. After adjusting for illness severity, differences in mortality risk persisted across etiologic groups. HT survival was similar in the current surgical era for HLHS with surgery, 71% (1993-1998) vs 70% (1999-2008). CONCLUSIONS Infant HT recipients with different pre-HT diagnoses have significantly different post-HT outcomes. HLHS infants with surgery have the lowest survival and their outcome is unchanged in the current era.

A Clinical Correlation Study of Severity of Antibody-mediated Rejection and Cardiovascular Mortality in Heart Transplantation

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.