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However, its cellular mechanisms are not fully understood, and presently there is no effective treatment. Patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) hold great potential for investigating the mechanisms underlying DD in HCM and as a platform for drug discovery.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods and results<\/jats:title>\n                  <jats:p>In the present study, beating iPSC-CMs were generated from healthy controls and HCM patients with DD. Micropatterned iPSC-CMs from HCM patients showed impaired diastolic function, as evidenced by prolonged relaxation time, decreased relaxation rate, and shortened diastolic sarcomere length. Ratiometric Ca2+ imaging indicated elevated diastolic [Ca2+]i and abnormal Ca2+ handling in HCM iPSC-CMs, which were exacerbated by \u03b2-adrenergic challenge. Combining Ca2+ imaging and traction force microscopy, we observed enhanced myofilament Ca2+ sensitivity (measured as dF\/\u0394[Ca2+]i) in HCM iPSC-CMs. These results were confirmed with genome-edited isogenic iPSC lines that carry HCM mutations, indicating that cytosolic diastolic Ca2+ overload, slowed [Ca2+]i recycling, and increased myofilament Ca2+ sensitivity, collectively impairing the relaxation of HCM iPSC-CMs. Treatment with partial blockade of Ca2+ or late Na+ current reset diastolic Ca2+ homeostasis, restored diastolic function, and improved long-term survival, suggesting that disturbed Ca2+ signalling is an important cellular pathological mechanism of DD. Further investigation showed increased expression of L-type Ca2+channel (LTCC) and transient receptor potential cation channels (TRPC) in HCM iPSC-CMs compared with control iPSC-CMs, which likely contributed to diastolic [Ca2+]i overload.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>In summary, this study recapitulated DD in HCM at the single-cell level, and revealed novel cellular mechanisms and potential therapeutic targets of DD using iPSC-CMs.<\/jats:p>\n                  <jats:p\/>\n               <\/jats:sec>","DOI":"10.1093\/eurheartj\/ehz326","type":"journal-article","created":{"date-parts":[[2019,5,14]],"date-time":"2019-05-14T19:40:22Z","timestamp":1557862822000},"page":"3685-3695","source":"Crossref","is-referenced-by-count":133,"title":["Modelling diastolic dysfunction in induced pluripotent stem cell-derived cardiomyocytes from hypertrophic cardiomyopathy patients"],"prefix":"10.1093","volume":"40","author":[{"given":"Haodi","family":"Wu","sequence":"first","affiliation":[{"name":"Stanford Cardiovascular Institute, Stanford University School of Medicine , 265 Campus Drive, Stanford, CA, USA"},{"name":"Division of Cardiology, Department of Medicine, Stanford University School of Medicine , Stanford, CA, USA"},{"name":"Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine , Stanford, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huaxiao","family":"Yang","sequence":"additional","affiliation":[{"name":"Stanford Cardiovascular Institute, Stanford University School of Medicine , 265 Campus Drive, Stanford, CA, USA"},{"name":"Division of Cardiology, Department of Medicine, Stanford University School of Medicine , Stanford, CA, USA"},{"name":"Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine , Stanford, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"June-Wha","family":"Rhee","sequence":"additional","affiliation":[{"name":"Stanford Cardiovascular Institute, Stanford University School of Medicine , 265 Campus Drive, Stanford, CA, USA"},{"name":"Division of Cardiology, Department of Medicine, Stanford University School of Medicine , Stanford, CA, USA"},{"name":"Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine , Stanford, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joe Z","family":"Zhang","sequence":"additional","affiliation":[{"name":"Stanford Cardiovascular Institute, Stanford University School of Medicine , 265 Campus Drive, Stanford, CA, USA"},{"name":"Division of Cardiology, Department of Medicine, Stanford University School of Medicine , Stanford, CA, USA"},{"name":"Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine , Stanford, CA, 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