Alternative strategies in cardiac preclinical research and new clinical trial formats

Kreutzer, Fabian Philipp; Meinecke, Anna‐Katharina; Schmidt, Kevin; Fiedler, Jan; Thum, Thomas

doi:10.1093/cvr/cvab075

Cited by 19 publications

(21 citation statements)

References 240 publications

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“…Modeling of these cardiomyopathies is also challenging because of variability in the clinical expression, incomplete penetrance of diseases in carriers of pathogenic variants, and phenotypic overlap between different cardiomyopathies. The understanding of the underlying pathophysiological mechanisms is incomplete [ 30 ], thus urging for better models [ 15 ]. In addition, the pharmacological research for more common causes of heart failure is supported by the description of mechanisms leading to cardiomyopathies, as exemplified by the recent development of actin-myosin regulators.…”

Section: Existing Models Of Cardiomyopathiesmentioning

confidence: 99%

“…There is thus a need for models that can recapitulate key features observed in human cardiomyopathies and can be used for disease modeling and therapeutic testing. Animal models are the most common models for cardiomyopathies [ 13 ] but have inherent limitations to recapitulate complex human physiopathology as well as inter-patient genetic variability [ 14 , 15 ]. For these reasons, the translation of targeted therapies for cardiomyopathies from animal trials to human subjects has been limited so far.…”

Section: Introductionmentioning

confidence: 99%

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Cardiac Organoids to Model and Heal Heart Failure and Cardiomyopathies

et al. 2021

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Cardiac tissue engineering aims at creating contractile structures that can optimally reproduce the features of human cardiac tissue. These constructs are becoming valuable tools to model some of the cardiac functions, to set preclinical platforms for drug testing, or to alternatively be used as therapies for cardiac repair approaches. Most of the recent developments in cardiac tissue engineering have been made possible by important advances regarding the efficient generation of cardiac cells from pluripotent stem cells and the use of novel biomaterials and microfabrication methods. Different combinations of cells, biomaterials, scaffolds, and geometries are however possible, which results in different types of structures with gradual complexities and abilities to mimic the native cardiac tissue. Here, we intend to cover key aspects of tissue engineering applied to cardiology and the consequent development of cardiac organoids. This review presents various facets of the construction of human cardiac 3D constructs, from the choice of the components to their patterning, the final geometry of generated tissues, and the subsequent readouts and applications to model and treat cardiac diseases.

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Section: Existing Models Of Cardiomyopathiesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cardiac Organoids to Model and Heal Heart Failure and Cardiomyopathies

et al. 2021

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“…2b, c). Furthermore, we employed human living myocardial slices, an ex vivo model of human left ventricular heart tissue under constant electrical stimulation ([ 23 , 51 ], details see methods section). qPCR analysis revealed significant down-regulation of FAP (supplemental Fig.…”

Section: Resultsmentioning

confidence: 99%

Development and characterization of anti-fibrotic natural compound similars with improved effectivity

et al. 2022

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Cardiac fibroblasts constitute the major cell type of the murine and human heart. Once activated, they contribute to an excessive deposition of extracellular matrix (ECM) leading to cardiac fibrosis and subsequently organ dysfunction. With the exception of the pulmonary drugs, nintedanib and pirfenidone, drugs specifically targeting anti-fibrotic pathways are scarce. We recently performed large library screenings of natural occurring compounds and identified first lead structures with anti-fibrotic properties in vitro and in vivo. In line, we now aimed to improve efficacy of these anti-fibrotic lead structures by combining in vitro validation studies and in silico prediction. Next to this combined approach, we performed large OMICs-multi-panel-based mechanistic studies. Applying human cardiac fibroblasts (HCF), we analysed 26 similars of the initially identified anti-fibrotic lead molecules bufalin and lycorine and determined anti-proliferative activity and potential toxicity in an array of in vitro and ex vivo studies. Of note, even at lower concentrations, certain similars were more effective at inhibiting HCF proliferation than nintedanib and pirfenidone. Additionally, selected similars showed low cytotoxicity on human iPS-derived cardiomyocytes and anti-fibrotic gene regulation in human ex vivo living myocardial slices. Further, array and RNA sequencing studies of coding and non-coding RNAs in treated HCFs revealed strong anti-fibrotic properties, especially with the lycorine similar lyco-s (also known as homoharringtonine), that led to a nearly complete shutdown of ECM production at concentrations 100-fold lower than the previously identified anti-fibrotic compound lycorine without inducing cellular toxicity. We thus identified a new natural compound similar with strong anti-fibrotic properties in human cardiac fibroblasts and human living heart tissue potentially opening new anti-fibrotic treatment strategies.

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“…contribute to an ECM-like surrounding which can be adjusted depending on the cell types. 35 Scaffold-free approaches use gravity, magnetic levitation or microwells to facilitate the formation of spherical cell aggregates. 13,34…”

Section: Three-dimensional Cell Culturementioning

confidence: 99%

Accelerating cardiovascular research: recent advances in translational 2D and 3D heart models

Mohr

Thum

Bär

2022

European J of Heart Fail

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In vitro modelling the complex (patho‐) physiological conditions of the heart is a major challenge in cardiovascular research. In recent years, methods based on three‐dimensional (3D) cultivation approaches have steadily evolved to overcome the major limitations of conventional adherent two‐dimensional (2D) monolayer cultivation. These 3D approaches aim to study, reproduce or modify fundamental native features of the heart such as tissue organization and cardiovascular microenvironment. Therefore, these systems have great potential for (patient‐specific) disease research, for the development of new drug screening platforms, and for the use in regenerative and replacement therapy applications. Consequently, continuous improvement and adaptation is required with respect to fundamental limitations such as cardiomyocyte maturation, scalability, heterogeneity, vascularization, and reproduction of native properties. In this review, 2D monolayer culturing and the 3D in vitro systems of cardiac spheroids, organoids, engineered cardiac microtissue and bioprinting as well as the ex vivo technique of myocardial slicing are introduced with their basic concepts, advantages, and limitations. Furthermore, recent advances of various new approaches aiming to extend as well as to optimize these in vitro and ex vivo systems are presented.

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Alternative strategies in cardiac preclinical research and new clinical trial formats

Cited by 19 publications

References 240 publications

Cardiac Organoids to Model and Heal Heart Failure and Cardiomyopathies

Cardiac Organoids to Model and Heal Heart Failure and Cardiomyopathies

Development and characterization of anti-fibrotic natural compound similars with improved effectivity

Accelerating cardiovascular research: recent advances in translational 2D and 3D heart models

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