The focus of my research from 1994 through 2007 was developmental biology of the cardiovascular system using the zebrafish model, with the overall goal of understanding the molecular basis of congenital heart disease.
MRI of a heterotaxy case with polysplenia.
My lab's main project was understanding how the left-right body axis was specified during embryonic development, in order to gain insight into a syndrome called heterotaxy, occurring at a frequency of 1.00 to 1.44 per 10,000 human live births. Disorders of organ lateralization, such as heterotaxy syndrome and situs inversus totalis, are frequently associated with complex anomalies of the heart and major veins. Despite elaborate staged surgical reconstructive strategies (usually culminating in the Fontan operation), 20-year survival remains <50%.
Since 2008, I have transitioned to part-time status and have resumed two clinical research projects: (1) Identification of informative biomarkers to be used as surveillance tools in the monitoring of late survivors of the Fontan operation for "functional single ventricle"; and (2) computer modeling of the Fontan circulation. My collaborators for Project 1 are at the eleven institutions which form the Consortium of Clinical Investigations for Complex Congenital Heart Diseases (CCI-CCHD). My collaborators for Project 2 are Ray Watrous PhD and Kevin Whitehead MD PhD.
Currently, the two active projects are:
Identification of biomarkers to be used as surveillance tools after the Fontan operation
Fontan's visionary operation and its modifications (collectively termed "cavopulmonary connection") over the ensuing four decades re-established nonturbulent flow and substantially reduced cyanosis for children born with severe hypoplasia of one ventricle. However, a long list of largely unexpected sequelae has emerged over the last 40 years. Thromboembolic deaths are relatively common, with both an early and late hazard phase. Unheard of in single-ventricle patients in the pre-Fontan era, protein-losing enteropathy (PLE) occurs in roughly 10% of Fontan survivors and in 50% of 1-lung Fontan patients. In addition, despite the ongoing assertion that an advantage of the Fontan over long-term systemic-to-pulmonary artery shunt palliation is the avoidance of volume overload on the ventricle, ventricular dysfunction has remained a common cause of death. One complication of all types of cavopulmonary connection, even "total cavopulmonary connection without fenestration," is the development of multiple systemic-to-pulmonary collateral arteries. This phenomenon negates one of the hoped-for advantages of the Fontan operation because the combined flow through all these collaterals usually approaches that imposed by surgically placed systemic artery–to–pulmonary artery shunts in the pre-Fontan era.
In addition to these causes of death, the morbidity of the Fontan circulatory arrangement was also unexpected. Short stature and osteopenia are more common than for survivors of other commonly performed heart operations. Plastic bronchitis and liver cirrhosis, both unheard of in the pre-Fontan era, have emerged with increasing frequency. Although the reasons for these sequelae are still unclear, one clue may be the fact that the average resting cardiac index in Fontan survivors is low, roughly two-thirds of normal and far below the norm for survivors of other forms of congenital heart reconstruction. Although modern variations of the cavopulmonary connection have been designed to minimize power loss, the cardiac index remains well below normal for age, arguing that this is an inherent property of the Fontan circulatory arrangement.
We and others have noted distinctive biochemical signatures of multi-organ system dysfunction which can be detected long before symptoms or grossly observable changes in cardiac imaging can be recognized. Identifying a suite of biomarkers which are particularly informative and which can be serially assayed in a minimally invasive fashion would allow us to markedly reduce, or at least postpone, the need for heart (or heart-liver) transplantation in patients who have undergone a Fontan operation in childhood.
Computer modeling of the Fontan circulation
Our understanding of the physiological effects of a Fontan circulatory arrangement would be greatly aided by having a chronic animal model. Because the costs of developing one appear to be prohibitive, the advent of inexpensive microprocessors has facilitated the design and testing of progressively more comprehensive computational models of Fontan circulatory arrangements. We have revised Clark's lumped parameter model by adding separate inferior and superior systemic circulations and separate right and left pulmonary circulations. Our model, characterized by 35 state variables, features electrical analog components corresponding to flow resistance, inertance of blood volume, and compliance of blood vessels. Nonlinear pressure-volume relationships are used to define venous, vena caval, and arterial compliance. The arteriolar elastance (reciprocal of compliance) functions are scaled by a vasoconstriction parameter, which is adjusted externally. Time-varying elastance functions simulate active atria and ventricles, and this model drives pulsatile flow. The heart is enclosed in a pericardial volume with elastance properties, which impact cardiac pressure as cardiac volume changes. The heart and central circulatory elements are enclosed in a thorax, which is subject to a baseline transthoracic pressure on which respiration is modeled as a time-varying pressure.
The maximum cardiac index we have been able to generate so far is only 86% of that seen in a two-ventricle circulation; however, this is significantly higher than the 60-70% typically observed in Fontan survivors. We hope that our computer modeling efforts will suggest targeted therapies to optimize hemodynamics in this challenging population.
Coronal MRI of patient with heterotaxy after an extracardiac conduit type of Fontan operation.
The Chin Lab of the Penn Cardiovascular Institute publishes the findings of its clinical research in the nation's leading clinical journals.
Peer-reviewed Original Articles
- Chin AJ, Stephens P, Goldmuntz E, Leonard MB.Serum alkaline phosphatase reflects post-Fontan hemodynamics in children.. Pediatr Cardiol. 2009; 30:138-45.
- Chatterjee B*, Chin AJ*, Valdimarsson G*, Finis C, Sonntag JM, Choi L, Tao L, Balasubramanian K, Bell C, Krufka A, Kozlowski DJ, Johnson RG and Lo CW. Developmental regulation and expression of the zebrafish connexin43 gene.. Dev Dyn. 2005;233:890-906.
- Silber JH, Cnaan A, Clark BJ, Paridon SM, Chin AJ, Rychik J, Hogarty AN, Cohen MI, Barber G, Rutkowski MM, Kimball TR, Delaat C, Steinberg LJ, Zhao H.Enalapril to prevent cardiac function decline in long-term survivors of pediatric cancer exposed to anthracyclines.. J Clin Oncol. 2004; 22:820-829.
- Liang D, Chang JR, Chin AJ, Smith A, Kelly C, Weinberg ES, Ge R. The role of vascular endothelial growth factor in vasculogenesis, angiogenesis, and hematopoiesis in zebrafish development.. Mech Dev. 2001;108:29-43.
- Wallace KN, Yussof S, Sonntag JM, Chin AJ, Pack M.Zebrafish hhex regulates liver development and digestive organ chirality.. Genesis (formerly Developmental Genetics). 2001;30:141-143.
- Chin AJ, Tsang M, Weinberg ES. Heart and gut chiralities are controlled independently of initial heart position in the zebrafish. Developmental Biology 2000; 227: 403-421.
- Kochilas L, Potluri V, Gitler A, Balasubramanian K, Chin AJ. Cloning and characterization of zebrafish tbx1. Gene Expr Patterns. 2003; 3:645-651.
- Kelly CS*, Chin AJ*, Leatherman J, Kozlowski DJ, Weinberg ES. Maternally controlled Β-catenin signaling is required for formation of the zebrafish organizer. Development. 2000;127:3899-3911.
*These authors contributed equally to this work.
Peer-reviewed Review Articles