Publications

@article{Hall2021-eq,

title = {Complex relationship between cardiac fibroblasts and 

 cardiomyocytes in health and disease},

author = {Caitlin Hall and Katja Gehmlich and Chris Denning and Davor Pavlovic},

year  = {2021},

date = {2021-02-01},

journal = {J. Am. Heart Assoc.},

volume = {10},

number = {5},

pages = {e019338},

publisher = {Ovid Technologies (Wolters Kluwer Health)},

abstract = {Cardiac fibroblasts are the primary cell type responsible for 

 deposition of extracellular matrix in the heart, providing 

 support to the contracting myocardium and contributing to a 

 myriad of physiological signaling processes. Despite the 

 importance of fibrosis in processes of wound healing, excessive 

 fibroblast proliferation and activation can lead to pathological 

 remodeling, driving heart failure and the onset of arrhythmias. 

 Our understanding of the mechanisms driving the cardiac 

 fibroblast activation and proliferation is expanding, and 

 evidence for their direct and indirect effects on cardiac 

 myocyte function is accumulating. In this review, we focus on 

 the importance of the fibroblast-to-myofibroblast transition and 

 the cross talk of cardiac fibroblasts with cardiac myocytes. We 

 also consider the current use of models used to explore these 

 questions.},

keywords = {arrhythmias, cardiac fibroblasts, cardiomyocytes, fibrosis, heart failure, myofibroblast},

pubstate = {published},

tppubtype = {article}

}

@article{Saleem2020-kf,

title = {Blinded, multicenter evaluation of drug-induced changes in 

 contractility using human-induced pluripotent stem cell-derived 

 cardiomyocytes},

author = {Umber Saleem and Berend J Meer and Puspita A Katili and Nurul A N Mohd Yusof and Ingra Mannhardt and Ana Krotenberg Garcia and Leon Tertoolen and Tessa Korte and Maria L H Vlaming and Karen McGlynn and Jessica Nebel and Anthony Bahinski and Kate Harris and Eric Rossman and Xiaoping Xu and Francis L Burton and Godfrey L Smith and Peter Clements and Christine L Mummery and Thomas Eschenhagen and Arne Hansen and Chris Denning},

year  = {2020},

date = {2020-07-01},

journal = {Toxicol. Sci.},

volume = {176},

number = {1},

pages = {103\textendash123},

publisher = {Oxford University Press (OUP)},

abstract = {Animal models are 78% accurate in determining whether drugs 

 will alter contractility of the human heart. To evaluate the 

 suitability of human-induced pluripotent stem cell-derived 

 cardiomyocytes (hiPSC-CMs) for predictive safety pharmacology, 

 we quantified changes in contractility, voltage, and/or Ca2+ 

 handling in 2D monolayers or 3D engineered heart tissues (EHTs). 

 Protocols were unified via a drug training set, allowing 

 subsequent blinded multicenter evaluation of drugs with known 

 positive, negative, or neutral inotropic effects. Accuracy 

 ranged from 44% to 85% across the platform-cell 

 configurations, indicating the need to refine test conditions. 

 This was achieved by adopting approaches to reduce 

 signal-to-noise ratio, reduce spontaneous beat rate to $\leq$ 1 

 Hz or enable chronic testing, improving accuracy to 85% for 

 monolayers and 93% for EHTs. Contraction amplitude was a good 

 predictor of negative inotropes across all the platform-cell 

 configurations and of positive inotropes in the 3D EHTs. 

 Although contraction- and relaxation-time provided confirmatory 

 readouts forpositive inotropes in 3D EHTs, these parameters 

 typically served as the primary source of predictivity in 2D. 

 The reliance of these ``secondary'' parameters to inotropy in 

 the 2D systems was not automatically intuitive and may be a 

 quirk of hiPSC-CMs, hence require adaptations in interpreting 

 the data from this model system. Of the platform-cell 

 configurations, responses in EHTs aligned most closely to the 

 free therapeutic plasma concentration. This study adds to the 

 notion that hiPSC-CMs could add value to drug safety evaluation.},

keywords = {alternatives to animal testing, cardiomyocytes, contractility, CRACK-IT project, electrophysiology, human-induced   pluripotent stem cells, inotropy, predictive toxicology, safety   pharmacology},

pubstate = {published},

tppubtype = {article}

}