Using iPSC Cardiomyocytes to Model Diastolic Dysfunction
in Hypertrophic Cardiomyopathy
By Amanda Chase, PhD
July 8, 2019
Hypertrophic cardiomyopathy (HCM) is a common cardiovascular disease that can affect people of any age, and affects men and women equally. It is characterized by abnormal thickening of the ventricular wall of the heard and increased risk of arrhythmia, sudden death, and heart failure. Many HCM patients display symptoms of diastolic dysfunction (DD), characterized by symptoms and signs of heart failure as a result of the left ventricle being unable to accept an adequate volume of blood. Without treatment, DD can progress to heart failure and significant morbidity and mortality. Despite the prevalence and severity of DD, the underlying cellular mechanisms are not well understood, which greatly hinders the development of specific and more effective treatments.
Further impeding the study of DD, there is significant interspecies differences that make it difficult to extrapolate results from animal models to humans. Human induced pluripotent stem cell (iPSC) technology has enabled patient-specific disease modeling of various cardiovascular disease, but there has not yet been an investigation of DD using this model.
Researchers at the Stanford Cardiovascular Institute, led by first author Haodi Wu, Ph.D., and senior author Joseph Wu, M.D., PhD., generated iPSC-derived cardiomyocytes (iPSC-CM) models of DD to provide a novel patient-specific platform for understanding mechanisms of DD in HCM, recently published in European Heart Journal. Using various imaging techniques, they were able to reveal novel cellular mechanisms or DD. First author Dr. Haodi Wu explains that “this is the first study to show that HCM patient-specific stem cell derived cardiomyocytes are able to recapitulate the DD phenotype at the single cell level. By combined application of multiple functional imaging assays, we are able to identify that both diastolic calcium overload and enhanced myofilament calcium sensitivity contributed to increased diastolic tension and impaired relaxation seen in HCM patient-specific iPSC-CMs. Importantly, this suggests that perturbed calcium homeostasis is a window of potential therapeutic intervention to restore diastolic function.”
The development of iPSC-CMs as a model for impaired diastolic function in HCM is an important contribution to understanding the mechanisms behind DD. “Not only were we able to show that HCM patient-specific iPSC-CMs can be used as a suitable platform for disease modeling of DD, we were also able to apply the platform to better understand the pathological mechanism, and for more efficient drug testing” explains senior author Dr. Joseph Wu. “We confirmed the effect of many first-line drugs on DD in HCM patient-specific cardiomyocytes and identified the transient receptor potential cation channels (TRPCs) as novel therapeutic targets for the treatment of DD in HCM patients.”
Other authors from the Stanford Cardiovascular Institute include Huaxiao Yang, June-Wha Rhee, Joe Z. Zhang, Chi Keung Lam, Karim Sallam, Alex C.Y. Chang, Ning Ma, Jaecheol Lee, Hao Zhang, and Helen M. Blau. Donald M. Bers, a member of the Department of Pharmacology at the University of California, Davis, was also an author. Funding was provided by NIH K99 HL133473, F32 HL134221, R01 HL113006, R01 HL126527, R01 HL130020, R01 HL128170, R01 HL141371, and R01 HL030077; American Heart Association 16POST31150011, 18POST34030106, 18CDA34110411, and 17CSA33590101.