Cardiovascular drugs account for only ~3% of new active substances approved globally (2014–2023), with fewer than 1 in 20 novel compounds achieving regulatory approval—a rate far below oncology. This attrition reflects three critical limitations of conventional preclinical models: inter-species divergence in cardiac electrophysiology, failure to recapitulate multicellular tissue architecture and paracrine signalling, and poor fidelity of animal disease models to clinical pathophysiology. An intermediate-complexity platform preserving native three-dimensional architecture, cellular heterogeneity, and intact electromechanical function is therefore urgently required..
OBJECTIVES
Cardiovascular drugs account for only ~3% of new active substances approved globally (2014–2023), with fewer than 1 in 20 novel compounds achieving regulatory approval—a rate far below oncology. This attrition reflects three critical limitations of conventional preclinical models: inter-species divergence in cardiac electrophysiology, failure to recapitulate multicellular tissue architecture and paracrine signalling, and poor fidelity of animal disease models to clinical pathophysiology. An intermediate-complexity platform preserving native three-dimensional architecture, cellular heterogeneity, and intact electromechanical function is therefore urgently required..
MATERIALS AND METHODS
We developed a translational platform based on living myocardial slices (LMS; 100–400 μm) prepared via precision vibratome sectioning under temperature-controlled conditions with excitation–contraction uncoupling. Tissue was sourced from rat, rabbit, guinea pig, pig, and human surgical specimens. A custom multi-channel bioreactor incorporating mechanical loading and electrical field stimulation sustained LMS viability for up to 7 days. Functional assessment employed optical mapping of action potentials (Fluovolt) and calcium transients (Calbryte 520-AM, Rhod-2AM), multi-electrode electrophysiological mapping, and contractile force measurement. Drug validation followed blinded, standardised SOPs.
RESULTS
LMS preserved native multicellular composition, extracellular matrix integrity, transmural electrophysiological heterogeneity, and contractile function. Stable APD90 and CTD90 were maintained across 1–6 Hz stimulation; an optimised recovery protocol markedly reduced inter-sample variability. Platform validation demonstrated: (1) aconitine-induced automaticity recapitulating whole-heart responses; (2) transmural APD/CTD heterogeneity revealing differential repolarisation effects of a candidate compound; (3) dose-dependent isoprenaline contractile responsiveness.
CONCLUSION
LMS constitutes a reproducible, scalable, and clinically relevant ex vivo platform bridging the gap between single-cell models and whole-animal experiments, offering significant promise for accelerating cardiovascular drug translation and reducing preclinical attrition.
Prof Guoliang Hao1,2, Mr. Gongxin Wang1,2, Dr. Gang Wang1, Dr. Xintao Zhou1, Mr. Jiakuan Niu1, Ms. Mengyi Song1, Mr. Shuaihao Yao1, Ms. Mengmeng Han2
Cardiovascular drugs account for only ~3% of new active substances approved globally (2014–2023), with fewer than 1 in 20 novel compounds achieving regulatory approval—a rate far below oncology. This attrition reflects three critical limitations of conventional preclinical models: inter-species divergence in cardiac electrophysiology, failure to recapitulate multicellular tissue architecture and paracrine signalling, and poor fidelity of animal disease models to clinical pathophysiology. An intermediate-complexity platform preserving native three-dimensional architecture, cellular heterogeneity, and intact electromechanical function is therefore urgently required..
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