New Insights into Mechanisms Underlying Congenital Heart Disease

By Adrienne Mueller, PhD

March 20, 2020

Congenital heart disease (CHD) is characterized by problems with the heart or local vasculature that are present at birth. Abnormalities in the structure of the heart or its proximal veins and arteries can reduce or misdirect blood flow and therefore disrupt circulation. Approximately 25% of children with congenital heart disease need surgery or other invasive procedures before the age of one. Furthermore, many individuals with congenital heart disease must manage their condition well into adulthood. Because these problems arise so early during development, before an individual is even born, they are extremely hard to study.

Recently, a team of researchers at the Stanford Cardiovascular Institute have gained important insights into the mechanisms underlying this challenging disease. Led by co-first authors Tomoya Kitani, MD, PhD, Lei Tian, PhD, and Tiejun Zhang, PhD, as well as senior author Joseph C. Wu, MD, PhD, they investigated congenital heart disease by studying gene expression in human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) generated from 5 patients with single ventricle disease (SVD), 5 patients with tetralogy of Fallot (TOF), and 5 healthy individuals (non-CHD). Using RNA-seq, a method of measuring gene expression through RNA levels, they discovered which genes were abnormally expressed in the cardiomyocytes of two different congenital heart disease patient populations.

Their findings, recently published in Circulation Research, determined that over 900 genes were differentially expressed in iPSC-CMs derived from patients with CHD compared to iPSC-CMs derived from healthy patients. “On one hand, our results suggest the existence of the intrinsic abnormalities of cardiomyocytes in CHD patients. On the other hand, we found the transcriptomic changes in single ventricle disease patients are much larger than those in tetralogy of Fallot patients. This reflects a difference in the magnitude of abnormal cardiomyocytes involved in the disease pathogenesis in each CHD subtype.” Dr. Lei Tian added. One insight into the underlying mechanisms of this dysregulation is that many of the abnormally expressed genes, in both groups of patient-derived cells, are involved with cardiac development. Future work will focus on finding which of the specific pathways and mechanisms implicated by this study may be most relevant for congenital heart disease therapies.

Other authors affiliated with the Circulation Research study include Ilanit Itzhaki, Joe Zhang, Ning Ma, Chun Liu, and June-Wha Rhee. Drs Anitra Romfh and George Lui are affiliated with the Stanford Adult Congenital Heart Disease. Funding was provided by NIH HL141371, R01 HL145676, R01 HL146690, R01 HL130020, and P01 HL141084.

Tomoya Kitani, MD, PhD

Lei Tian, PhD

Joseph Wu, MD, PhD