Selected summaries.

INTRODUCTION

Like in the previous issue, we will present a table [Table 1] that summarizes significant publications in pediatric cardiac sciences that have appeared in the recent months. We have selected two papers for a detailed review. In the forthcoming issues we will seek to improve this section further. We would especially solicit contributions from trainees and fellows who could chose a recent publication in any of the pediatric cardiac specialties — cardiology, cardiac surgery, intensive care, and anesthesiology. Papers selected for journal clubs in their respective institutions can be discussed at length. It is particularly useful if the discussions include a critique as well as an effort to contextualize the paper to the low resource environments.

Table 1

A summary of significant publications in pediatric cardiac sciences in period June 2014-November 2014

Olsson KM, Delcroix M, Ghofrani HA, Tiede H, Huscher D, Speich R, et al. Anticoagulation and survival in Pulmonary Arterial Hypertension: Results from the COMPERA Registry: Circulation 2014;129:57-65.

Pulmonary arterial hypertension (PAH) represents a heterogeneous group of disease entities. A vast number of conditions eventually culminate in increased pulmonary vascular resistance (PVR). The prognosis is, to some extent, influenced by the specific underlying cause of PAH. Wagenvoort and Wagenvoort examined lung biopsy samples of 156 patients with idiopathic (then termed primary) pulmonary hypertension and identified thrombosis of the small pulmonary vessels in a large number of patients.[1] He suggested that chronic thrombosis might contribute to the pathogenesis of this condition. Interest in therapeutic anticoagulation for patients with pulmonary hypertension stepped up after his paper and a number of descriptive studies suggested a survival benefit for patients with pulmonary hypertension on anticoagulants. However, no randomized control trials have been conducted and the ancillary nature of such treatment will make conducting such studies very difficult.

The Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA) is a registry of pulmonary hypertension patients from 41 centers in seven European countries which records data regarding the demographics, severity, functional class (FC), homodynamic, and pharmacological information on newly diagnosed patients with PAH and follows them prospectively for a set of predefined significant clinical events. The study authors analyzed the database for outcome of newly diagnosed PAH patients from 2007 to 2013 with and without anticoagulation as well as subset analysis of idiopathic PAH (IPAH) and PAH due to other causes. The attrition rate on follow-up in the registry was less than 2%.

There were 1,283 newly diagnosed patients with PAH in the registry. Fifty-eight percent of these patients received anticoagulation (90% were on warfarin and the remaining were on heparin or novel oral anticoagulants). The target international normalized ratio (INR) at all participating centers was between 2 and 3. The duration of anticoagulation during the observation period varied among the patients. 16.4% of patients in the anticoagulation group and 18% of patients in the non-anticoagulation group died during the observation period. Subgroup analysis of IPAH and familial PAH revealed that 66% of 800 patients received anticoagulation. Fourteen percent of IPAH patients who received anticoagulation and 21% of patients who did not, died during the observation period. When the baseline hemodynamics was analyzed, it was noticed that the patients on anticoagulation represented a more severe subset of the disease population. Hence, the study group matched 168 patients in each group on the basis of age, sex, function class, and baseline PVR and demonstrated a statistically significant survival advantage for patients on anticoagulation. On multivariate analysis, male patients, older age group, and patients in FC IV were found to have an increased risk for death, while anticoagulation therapy was the only factor noticed to be protective. These patients were however not matched on the basis of treatment and a larger number of patients in the anticoagulation group were on combination therapy. Four of the 75 deaths in the anticoagulation group were directly attributed to a major bleeding event. There were four other admissions during the observation period for a nonfatal bleeding event. No data on minor bleeds were available in the registry. Analysis of the non-IPAH patients in the registry did not demonstrate a similar survival benefit for anticoagulation (21 vs 17% deaths) with a negative survival benefit noticed among the small subset of patients with scleroderma associated PAH.

The strengths of the study include the large number of patients, longer period of observation, and the low attrition rate. However, it is an observational study on the data from the registry and not a randomized controlled trial. The treatment strategy for a particular patient was based on the discretion of the treating physician. A larger number of patients in the anticoagulation group were on combination therapy that would have contributed to an improved control of pulmonary artery pressure. The registry data did not include minor bleeding events in patients on anticoagulation as well as information on the therapeutic range of anticoagulation in individual patients. Patients on anticoagulation were found to have more severe disease at diagnosis and, despite the abovementioned limitations, survived longer than patients without anticoagulation. This data cannot perhaps be ignored. Deaths directly attributable to a clinically significant bleeding event were infrequent during the observation period.

As the authors rightly pointed out in the discussion, most therapeutic trials on PAH (including newer pulmonary vasodilators and combination therapy) have been of shorter durations and have focused on functional endpoints of doubtful clinical significance (such as a small increase in 6-min walk test distance). Given the heterogeneity of the condition and the small number of patients in each subcategory, such registries will continue to be an important source of information for the management patients with PAH. Based on the evidence from this paper, it seems reasonable to consider anticoagulation in patients with IPAH and familial PAH.

Cheung EW, Richmond ME, Turner ME, Bacha EA and Torres AJ. Pulmonary Atresia/Intact Ventricular Septum: Influence of Coronary Anatomy on Single-Ventricle Outcome Annals of Thoracic Surgery 2014;98:1371-7.

Pulmonary atresia with intact ventricular septum (PA-IVS) represents approximately 1% of all congenital heart diseases and is iconic of the heterogeneity that exists within most congenital cardiac defects. The morphological spectrum varies from a normal sized or dilated right ventricle (RV) to an extremely hypoplastic and hypertensive RV (the so called uniparitate RV) and diminutive tricuspid valve. The low incidence combined with the numerous morphological possibilities means that evidence-based guidelines for management does not exist and the treatment has to be individualized to the particular patient's anatomy. RV to coronary artery fistulae have been reported in 30-68% of patients with PA-IVS and there is speculation that persistence of these fistulous communications may be the primary abnormality leading to the development of pulmonary atresia.[2] The extreme scenario is a RV-dependent coronary circulation (RVDCC) with little or no connection between the proximal coronaries and the aortic root.

Literature on the impact of a RVDCC on outcome of patients with PA-IVS is inconsistent. Early single institutional data suggested that RVDCC was significantly associated with poor outcomes.[3] The same conclusions were not replicated in the multi-institutional Congenital Heart Surgeons Society (CHSS) study in 2004 and a subsequent multicenter study in the United Kingdom.[45] However such multicenter studies, while providing data on a large number of patients, are challenged by inconsistencies in the definition of RVDCC between participating centers. The coronary vessels are frequently very small making delineation difficult even by angiography.

The paper that is being discussed here is a single institution study that retrospectively analyzed all patients with PA-IVS from 2000 to 2012. Thirty percent (17 of 58 children) of PA-IVS patients were considered for single ventricle palliation. All these patients had significant right ventricular hypoplasia. Eighty-eight percent of such patients had fistulous coronary communications of which 10 represented a RVDCC. In contrast, only 20% of biventricular repair patients had fistulous coronary connections. There were a total of five deaths and a single cardiac transplantation in the RVDCC group (60%). All deaths occurred within 6 months of age and all patients who had coronary ostial atresia died. Three of the deaths occurred after cardiac catheterization while awaiting a systemic to pulmonary artery shunt, while two events (one death and one transplant) occurred in the postoperative period. The last patient died suddenly at home at 6 months of age while awaiting superior cavopulmonary anastomosis. All patients had evidence of significant coronary insufficiency (electrocardiogram (ECG) changes, elevated troponin levels or autopsy evidence of coronary stenosis, and significant myocardial ischemia). The patients, who survived, underwent superior cavopulmonary anastomosis and three of them proceeded for Fontan completion successfully. Two of the three patients who underwent Fontan completion had evidence of myocardial ischemia on myocardial viability studies during follow-up. There were no deaths in the non-RVDCC group with one patient lost to follow-up. Repeat angiograms were available in seven patients. There were no changes in coronary artery lesions in the RVDCC group, while three of the four patients in the non-RVDCC group demonstrated significant reduction in the number and size of coronary artery fistulae.

The study impresses upon us the importance of defining the coronary anatomy comprehensively in all patients with PA-IVS before planning surgical repair. A combination of RV, aortic root, and selective coronary angiograms may be required to obtain good anatomic detail. Three of the deaths had a temporal association with cardiac catheterization and these patients require careful intra- and post-procedure monitoring preferably in an intensive care setting. There is a high interstage mortality in patients palliated along the single ventricle pathway and most of them may be related to coronary insufficiency. Some centers currently recommend primary cardiac transplantation for patients with very high-risk coronary anatomy (double coronary atresia).

Of greater interest, most of the patients had evidence of myocardial ischemia even after Fontan completion. PA-IVS probably represents a high-risk subset among patients with a Fontan circulation and requires closer monitoring for subclinical coronary insufficiency on follow-up. No management guidelines currently exist on management of such complications on follow-up. The fate of the fistulous ventricle to coronary artery communications is also gaining greater focus. While no changes were noticed in the RVDCC group, there was significant decrease in the burden of lesions in the non-RVDCC group. This is similar to data from other centers. Long-term follow up has shown two ventricle repair to be superior to Fontan palliation in PA-IVS and combined with promising results of ligation of the larger fistulae and growth of the RV after decompression, it would be worthwhile to aggressively pursue RV decompression in patients who have minor degrees of RV-coronary fistula and a reasonably favorable RV anatomy.

The obvious limitations of this retrospective study are the small number of patients and the complexity of cardiac morphology that greatly reduces the power of the study to identify risk factors. In limited resource environments, few centers currently operate on infants with complex cyanotic congenital heart diseases. It may be possible to define uniform case selection criteria for single versus two-ventricle repair and maintain a disease registry to evaluate outcomes. Such an exercise may prove worthwhile in improving our understanding of the disease and we may all be enriched by the experience.