In the absence of specific high-affinity agonists and antagonists, it has been difficult to define the target genes and biological responses attributable to many of the orphan nuclear receptors (ONRs). Indeed, it appears that many members of this receptor superfamily are not regulated by classical small molecules but rather their activity is controlled by interacting cofactors. Motivated by this finding, we have developed an approach to genetically isolate specific receptor-cofactor pairs in cells, allowing us to define the biological responses attributable to each complex. This is accomplished by using combinatorial peptide phage display to engineer the receptor interacting domain of each cofactor such that it interacts selectively with one nuclear receptor. In this study, we describe the customization of PGC-1alpha and its use to study the biology of the estrogen-related receptor alpha (ERRalpha) in cultured liver cells.

The adult with congenital heart disease (CHD) is at risk of developing atherosclerotic cardiovascular disease (ASCVD). We performed a cross-sectional study to describe established ASCVD risk factors and estimate 10-year and lifetime risk of ASCVD in adults over age 18 with CHD of moderate or great complexity using three validated risk assessment tools—the Framingham Study Cardiovascular Disease Risk Assessment, the Reynolds Risk Score, and the Atherosclerotic Cardiovascular Disease (ASCVD) Risk Estimator. We obtained extensive clinical and survey data on 178 enrolled patients, with average age 37.1±12.6 years, 51% men. At least one modifiable ASCVD risk factor was present in 70%; the two most common were overweight/obesity (53%) and systemic hypertension (24%). Laboratory data was available in 103 of the 178 patients. Abnormal levels of glycated hemoglobin, high-sensitivity C-reactive protein, and high-density lipoprotein (HDL) were each found in around 30% of patients. The 10-year ASCVD predicted risk using all three tools was relatively low (i.e., at least 90% of patients <10% risk), yet the median estimated lifetime risk was 36%. In conclusion, ASCVD risk factors are prevalent in adults with CHD. The risk estimation tools suggest that this population is particularly vulnerable to ASCVD with aging and should undergo guideline-based screening and management of modifiable risk factors.

Fontan-associated liver disease (FALD) encompasses abnormalities in liver structure and function that result from Fontan circulation unrelated to other disease processes. 1 FALD induces liver fibrosis, which is universal in all Fontan patients. 2,3 Fibrosis does not start just with Fontan circulation but begins at some point before Fontan along the patient's single ventricle palliation pathway. 4 FALD can lead to cirrhosis and portal hypertension and complicate the management of patients with "Fontan failure." 5 In some centers, heart transplantation is not offered to patients with Fontan failure and liver fibrosis due to the high morbidity and mortality risk. 6 Combined heart and liver transplantation (CHLT) may be appropriate in certain cases. Liver biopsy in FALD may help to characterize and stage liver fibrosis as part of a comprehensive evaluation of patients considered for heart and/or CHLT. 7-9 However, liver biopsy may not accurately

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Arrhythmia and sudden cardiac death remain common in repaired tetralogy of Fallot and affect even those with excellent anatomic repairs. Atrial arrhythmia often has mechanisms different from those in acquired heart disease. Ventricular arrhythmia remains a major source of mortality in repaired tetralogy of Fallot. Noninvasive risk stratification is important to identify patients who may benefit from ablation or primary prevention implantable cardioverter defibrillators. Multiple noninvasive risk factors are associated with ventricular arrhythmia, but no universally accepted risk stratification algorithm exists. The mechanism of ventricular arrhythmia is usually attributable to a consistent and discrete set of slowly conducting anatomic isthmuses related to both the native anatomy and the consequences of the surgical repair, which interact with ventricular remodeling to provide arrhythmic substrate. This substrate can be identified during electroanatomic mapping and prophylactically ablated in appropriate patients. This scientific statement discusses the mechanisms and treatment of arrhythmia in repaired tetralogy of Fallot.

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