Research led by Muhammad Riaz, PhD, Jinkyu Park, PhD, and Lorenzo Sewanan, MD, PhD, of Qyang and Campbell Laboratories at Yale, provides a mechanism to identify abnormalities linked to an inherited heart disease, hypertrophic cardiomyopathy (HCM) , in which the walls of the left ventricle become abnormally thick and often stiff. The results are published in the journal Circulation.
Patients with familial HCM have an increased risk of sudden death, heart failure, and arrhythmias. HCM is the most common inherited heart disease, affecting one in 500 people. The disease is thought to be caused by mutations that regulate heart muscle contraction, compromising the heart’s ability to pump blood. However, the mechanisms underlying the disease are poorly understood.
For this multi-model study, researchers used stem cell approaches to understand the mechanisms behind inherited HCM. The technology, induced pluripotent stem cells (iPSC), can accelerate the understanding of the genetic causes of disease and the development of new treatments using the patient’s own cells.
“It is humbling that a patient’s disease phenotypes teach researchers fundamental background knowledge that sets the stage for innovative new therapies. Additionally, our research has established an excellent model to help many physicians at Yale School of Medicine and Yale New Haven Hospital unravel mechanistic insights into disease progression using own iPSCs and engineered tissues. of patients,” 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.
Probing the mechanism of cardiac disorder
The concept was born with an 18-month-old patient who suffered from familial HCM. Through collaboration with Daniel Jacoby, MD, adjunct associate professor of cardiovascular medicine and HCM expert, who provided medical care for this patient, Park and the team used stem cell technologies to answer a fundamental question, the disease mechanisms behind HCM. They took 10 cc of blood from the patient and introduced stem cell factors into the blood cells to generate self-renewing iPSCs. Applying cardiac knowledge, they integrated iPSCs into the patient’s own cardiomyocytes (heart cells) for heart disease studies. “We discovered a general mechanism that explains disease progression,” Park said.
Next, they engineered heart tissue that resembled the young patient’s early-onset disease scenario. The disease was a severe presentation at 18 months of age, suggesting that the disease started in the fetal/neonatal stage.
The next phase of the study involved recreating a 3D model which was used to mimic disease progression, including mechanical properties such as contraction and force production of this muscle, to understand how much force is compromised. if the mutation is present. . This was done in collaboration with Stuart Campbell, PhD, and Sewanan of Yale’s Department of Biomedical Engineering. Coupled with computer modeling of muscle contraction, the authors developed robust systems that allowed them to examine the biomechanical properties of tissue at three-dimensional levels.
Finally, using advanced gene-editing technologies, the research team modified these mutations. They discovered that once the mutations were corrected, the disease was reversed. This knowledge of sarcomeric protein mutations could lead to new therapies for HCM and other diseases. The interaction between the mutations could also suggest that the same biomechanical mechanism exists in other conditions such as ischemic heart disease.
Our research has established an excellent model to help many physicians at Yale School of Medicine and Yale New Haven Hospital unravel mechanistic insights into disease progression using patients’ own iPSCs and modified tissues.
Yibing Qyang, PhD
“We can apply these findings to heart conditions associated with hypertension, diabetes, or aging,” Riaz said.
Applying the results to heart disease
“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 mutations in sarcomeric hypertrophic cardiomyopathy.
“We hope our findings will be replicated in the scientific community,” Riaz said. “This is an example of in situ research, where scientists extract materials from clinics and conduct the experiment in the lab, and then discover new ways to treat patients.”
The authors also noted that RNA sequencing could be used as a guide to characterizing the disease at the molecular level. Scientists may be able to identify more targeted drugs by examining the biomechanical properties of tissue. “We can now screen multiple drugs to see if any of these drugs are able to rescue the phenotype,” they said.
Riaz, now a research associate at the Qyang lab, started out as a cancer researcher. He obtained a doctorate from the Erasmus University Medical Center, based in Rotterdam, the Netherlands. He then studied genetic disorders of skeletal muscle diseases before joining the lab in 2017.
Park, also from the Qyang lab, graduated from Seoul National University, South Korea, in 2013. He did postdoctoral research at the University of Missouri, where he focused on vascular biology and emerging areas of stem cell technology.