Myocardial tissue slices for modeling of the human PLN p.Arg14del associated cardiomyopathy

Abstract

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): NWO - The Dutch Research Council Background Current in vivo preclinical models lack the predictability of the clinical efficacy resulting in a high dropout rate of therapeutic candidates. Advanced human-based models are required to bridge this gap and indicate the potential of novel therapeutic approaches[1]. Myocardial tissue slices are an in vitro model that recapitulates the native multicellular architecture of the heart. This allows for modeling cellular processes in a macroscopic context entailing great promise. The most common cardiomyopathy-related mutation in the Netherlands is the loss of arginine at position 14 (p.Arg14del) in the phospholamban protein (PLN). PLN is a critical regulator of calcium cycling and contractility in the heart. The p.Arg14del mutation results in a super inhibition of SERCA2a and thus aberrant calcium handling and reduced contractile force. Mice models harbouring the PLN p.Arg14del do not completely recapitulate the human manifestation mainly due to the difference between species; heart rate, Calcium-cycling and ion properties, and different myosin heavy chain isoforms, showing the unmet need for a human-based model[2,3]. Methods & Results 300 µm thick viable myocardial tissue were sectioned from a PLN p.Arg14del patient’s left ventricle. Although the myocardial tissue slices were kept alive for eight days in static culture, these conditions initiated cell death and dedifferentiation. The tissue slices show the greatest resemblance to the intact architecture of the in vivo human heart, it is the most relevant model for viral transduction in the human heart, and proof-of-principle of this is performed. Myocardial tissue slices of a PLN p.Arg14del patient retain the structural phenotype shown by the fibrofatty deposition. Similarly, functional patient characteristics, aberrant calcium handling, and reduced contractile force are preserved. Conclusion Myocardial tissue slices recapitulate the (patho)physiology of the heart, as shown here with the PLN p.Arg14del case. However, the static culture conditions induce remodeling of the heart and thus only allow for acute measures in the native heart. To prolong the period that the slices recapitulate the native heart, culture conditions should mimic the environment of the heart. The tissue slices allow for a currently unmet need to modulate the complex architecture of the human heart with e.g. novel delivery tools or therapeutic interventions. All in all, myocardial tissue slices are a promising model that can give novel insights into the physiology of the human heart, and therapeutic intervention on induced or genetic cardiomyopathies.