Abstract
AIMS: Diastolic dysfunction (DD) is common among hypertrophic cardiomyopathy (HCM) patients, causing major morbidity and mortality. 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. METHODS AND RESULTS: 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 β-adrenergic challenge. Combining Ca2+ imaging and traction force microscopy, we observed enhanced myofilament Ca2+ sensitivity (measured as dF/Δ[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. CONCLUSION: 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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 3685-3695 |
| Number of pages | 11 |
| Journal | European heart journal |
| Volume | 40 |
| Issue number | 45 |
| DOIs | |
| State | Published - Dec 1 2019 |
Fingerprint
Keywords
- Calcium homeostasis
- Cardiomyocytes
- Diastolic dysfunction
- Hypertrophic cardiomyopathy
- Induced pluripotent stem cells
- MYBPC3
- MYH7
- TNNT2
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine
Cite this
Modelling diastolic dysfunction in induced pluripotent stem cell-derived cardiomyocytes from hypertrophic cardiomyopathy patients. / Wu, Haodi; Yang, Huaxiao; Rhee, June Wha; Zhang, Joe Z.; Lam, Chi Keung; Sallam, Karim; Chang, Alex C.Y.; Ma, Ning; Lee, Jaecheol; Zhang, Hao; Blau, Helen M.; Bers, Donald M.; Wu, Joseph C.
In: European heart journal, Vol. 40, No. 45, 01.12.2019, p. 3685-3695.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Modelling diastolic dysfunction in induced pluripotent stem cell-derived cardiomyocytes from hypertrophic cardiomyopathy patients
AU - Wu, Haodi
AU - Yang, Huaxiao
AU - Rhee, June Wha
AU - Zhang, Joe Z.
AU - Lam, Chi Keung
AU - Sallam, Karim
AU - Chang, Alex C.Y.
AU - Ma, Ning
AU - Lee, Jaecheol
AU - Zhang, Hao
AU - Blau, Helen M.
AU - Bers, Donald M.
AU - Wu, Joseph C.
PY - 2019/12/1
Y1 - 2019/12/1
N2 - AIMS: Diastolic dysfunction (DD) is common among hypertrophic cardiomyopathy (HCM) patients, causing major morbidity and mortality. 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. METHODS AND RESULTS: 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 β-adrenergic challenge. Combining Ca2+ imaging and traction force microscopy, we observed enhanced myofilament Ca2+ sensitivity (measured as dF/Δ[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. CONCLUSION: 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.
AB - AIMS: Diastolic dysfunction (DD) is common among hypertrophic cardiomyopathy (HCM) patients, causing major morbidity and mortality. 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. METHODS AND RESULTS: 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 β-adrenergic challenge. Combining Ca2+ imaging and traction force microscopy, we observed enhanced myofilament Ca2+ sensitivity (measured as dF/Δ[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. CONCLUSION: 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.
KW - Calcium homeostasis
KW - Cardiomyocytes
KW - Diastolic dysfunction
KW - Hypertrophic cardiomyopathy
KW - Induced pluripotent stem cells
KW - MYBPC3
KW - MYH7
KW - TNNT2
UR - http://www.scopus.com/inward/record.url?scp=85073318541&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85073318541&partnerID=8YFLogxK
U2 - 10.1093/eurheartj/ehz326
DO - 10.1093/eurheartj/ehz326
M3 - Article
C2 - 31219556
AN - SCOPUS:85073318541
VL - 40
SP - 3685
EP - 3695
JO - European Heart Journal
JF - European Heart Journal
SN - 0195-668X
IS - 45
ER -