Research led by Muhammad Riaz, PhD, Jinkyu Park, PhD, and Lorenzo Sewanan, MD, PhD, of the Qyang and Campbell Laboratories at Yale, provides a mechanism to identify abnormalities associated with a hereditary heart disease called hypertrophic cardiomyopathy ( HCM), in which walls of the left ventricle become abnormally thick and often stiff. The findings appear in the journal Circulation.
Patients with familial HCM have an increased risk of sudden death, heart failure and arrhythmias. HCM is the most common hereditary heart disease, affecting one in 500 people. The disease is thought to be caused by mutations that regulate the contraction of the heart muscle, compromising the heart’s ability to pump blood. However, the mechanisms behind the disease are poorly understood.
For this multi-model study, the researchers used stem cell approaches to understand the mechanisms driving hereditary HCM. The technology, induced pluripotent stem cells (iPSCs), can accelerate the understanding of the genetic causes of disease and the development of new treatments using the patient’s own cells.
“This is a humbling experience that the phenotypes of a patient’s disease provide researchers with fundamental knowledge that paves the way for innovative new therapies. In addition, our research has provided a great model to help many physicians at Yale School of Medicine and Yale New Haven Hospital unravel mechanistic insights into disease progression using the patient’s own iPSCs and engineered tissues,” said Yibing Qyang. , PhD, associate professor of medicine (cardiology) and pathology.
“We wanted to understand the disease mechanism and find a new therapeutic strategy,” Park said.
The concept originated in an 18-month-old patient who suffered from familial HCM. Through a collaboration with Daniel Jacoby, MD, an adjunct associate professor of cardiovascular medicine and an expert on HCM, who provided medical care to this patient, Park and the team used stem cell technologies to address a fundamental question, the disease mechanisms behind HCM. They collected 10 cc of blood from the patient and introduced stem cell factors into the blood cells to generate self-renewable iPSCs. By applying heart knowledge, they coaxed iPSCs into the patient’s own cardiomyocytes (heart cells) for heart disease studies. “We have discovered a general mechanism that explains the progression of the disease,” says Park.
They then developed heart tissues that resembled the young patient’s early disease scenario. The disease was severe at 18 months of age, indicating that the disease started in the fetal/neonatal stage.
The next phase of the research was to simulate a 3D model used to mimic the progression of the disease, including mechanical properties such as contraction and force production of that muscle, to understand how much force is compromised when the mutation is present. This was conducted in collaboration with Stuart Campbell, PhD, and Sewanan of Yale’s Department of Biomedical Engineering. In combination with computational modeling for muscle contraction, the authors developed robust systems that allowed them to investigate the biomechanical properties of the tissue at three-dimensional levels.
Finally, the research team modified these mutations using advanced gene-editing technologies. They found that after the mutations were corrected, the disease was reversed. These insights about mutations in sarcomere proteins could lead to new therapies for HCM and other diseases. The interaction between mutations could also suggest that the same biomechanical mechanism exists in other conditions such as ischemic heart disease.
“We can apply these findings to heart disease related to hypertension, diabetes or aging,” Riaz said.
“One of the fundamental challenges was that we had to generate iPSCs from the patient’s family,” Riaz added. Using this technology, Park was able to recreate primary cells from the cells of a patient with HCM, a process that takes more than a month. Riaz and Park used stem cells to identify the vital role of pathological tissue remodeling, which is caused by sarcomeric hypertrophic cardiomyopathy mutations.
“We are hopeful that our findings will be replicated in the scientific community,” Riaz said. “This is an example of bed-to-bench research, where scientists take materials from clinics and conduct the experiment in the lab, then discover new methods of treating patients.”
The authors also noted that RNA sequencing can be used as a guide to characterize disease at the molecular level. Scientists may be able to identify more targeted drugs by examining the biomechanical properties of the tissue. “We can now screen multiple drugs to see if any of those drugs can rescue the phenotype,” they said.
Riaz, now an associate research scientist in the Qyang lab, started out as a cancer researcher. He obtained a PhD from the Erasmus University Medical Center, located in Rotterdam, the Netherlands. He later studied genetic disorders in skeletal muscle disease before joining the lab in 2017.
Park, also of the Qyang lab, graduated from Seoul National University, South Korea, in 2013. He completed postdoctoral research at the University of Missouri, where he focused on vascular biology and emerging areas in stem cell technology.
Lorenzo R. Sewanan of Yale, MD, PhD, Yongming Ren, PhD, Jonas Schwan, PhD, Subhash K. Das, PhD, Pawel T. Pomianowski, MD, Yan Huang, PhD, Matthew W. Ellis, BS, Jiesi Luo, PhD, Caihong Qiu, PhD, George Tellides, MD, PhD, John Hwa, MD, PhD, Lawrence H. Young, MD, Daniel L. Jacoby, MD, and Yibing Qyang contributed to this research. Additional co-authors are Juli Liu, PhD from Indiana University and Lei Yang, PhD; Columbia University’s Loujin Song, PhD, Masayuki Yazawa, PhD, and I-Ping Chen, DDS, PhD.
Funding for the research came in part from the National Institutes of Health, the Department of Defense and the American Heart Association.