Comprehensive cardiac phenotyping in large animals: comparison of pressure–volume analysis and cardiac magnetic resonance imaging in pig post-myocardial infarction systolic heart failure

Raake, Philip; Barthelmes, Jens; Krautz, Birgit; Buss, Sebastian J.; Huditz, Regina; Weber, Christophe; Stangassinger, M.; Haberkorn, Uwe; Katus, Hugo A.; Most, Patrick; Pleger, Sven T.

doi:10.1007/s10554-019-01610-z

Cited by 5 publications

(4 citation statements)

References 18 publications

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“…Our mechanical simulation based on measured fiber elasticity and orientation confirmed the accuracy of the model. By simulating the P-V loop, our results showed that the numerical model demonstrated a progressive increase in volume caused by internal pressure, which was compatible with a measured P-V loop (Raake et al, 2019).…”

Section: Discussionsupporting

confidence: 83%

“…The simulated ventricular pressure was increased from 5.5 mmHg to 11 mmHg, while the ventricular volume was accordingly increased to 112 mL in the CT-based model and 113 mL in the cylindrical model. This pressure-volume change was compared to a known Pressure-Volume loop issued from a healthy pig heart (Raake et al, 2019). The simulation demonstrated a linear change regression between pressure and volume, which was compatible with the detected P-V loop (Figure 7).…”

Section: Mechanical Evaluation Of the Numerical Model Of The Left Ventriclesupporting

confidence: 68%

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Transverse isotropic modelling of left-ventricle passive filling: Mechanical characterization for epicardial biomaterial manufacturing

Jehl

Dan

Voignier

et al. 2021

Journal of the Mechanical Behavior of Biomedical Materials

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Biomaterials applied to the epicardium have been studied intensively in recent years for different therapeutic purposes. Their mechanical influence on the heart, however, has not been clearly identified. Most biomaterials for epicardial applications are manufactured as membranes or cardiac patches that have isotropic geometry, which is not well suited to myocardial wall motion. Myocardial wall motion during systole and diastole produces a complex force in different directions. Membrane or cardiac patches that cannot adapt to these specific directions will exert an inappropriate force on the heart, at the risk of overly restricting or dilating it. Accurately characterizing the mechanical properties of the myocardial wall is thus essential, through analysis of muscle orientation and elasticity. In this study, we investigated the Hertz contact theory for characterizing cardiac tissue, using nanoindentation measurements to distinguish different patterns in the local myocardium. We then evaluated the predictive accuracy of this model using Finite Element Analysis (FEA) to mimic the diastolic phase of the heart. Our results, extracted from instrumented nanoindentation experiments in a liquid environment using five pig hearts, revealed variations in elasticity according to the local orientation of the myocardial tissue. In addition, applying the Finite Element Method (FEM) in our model based on transverse isotropy and local tissue orientation proved able to accurately simulate the passive filling of a left ventricle (LV) in a representative 3D geometry. Our model enables improved understanding of the underlying mechanical properties of the LV wall and can serve as a guide for designing and manufacturing biomedical material better adapted to the local epicardial tissue.

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Section: Discussionsupporting

confidence: 83%

Section: Mechanical Evaluation Of the Numerical Model Of The Left Ventriclesupporting

confidence: 68%

Transverse isotropic modelling of left-ventricle passive filling: Mechanical characterization for epicardial biomaterial manufacturing

Jehl

Dan

Voignier

et al. 2021

Journal of the Mechanical Behavior of Biomedical Materials

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“…17,20,35 Cardiac magnetic resonance and imaging analysis Assessment of left ventricular (LV) ejection fraction (EF) and myocardial infarct (MI) size was performed by published standard cardiac magnetic resonance protocols adopted to porcine anatomy. [36][37][38]…”

Section: Pig Myocardial Infarction Modelmentioning

confidence: 99%

“…[46][47][48] Standardized CMR acquisition sequences were adopted to the porcine cardiac anatomy and utilized for the serial measurement of LVEF and LVMI size. [36][37][38] and the CMR analysis was blinded to the treatment type. LVMI size was quantified by late gadolinium enhancement (LGE) and, additionally assessed by global native T1-relaxation 2 weeks after experimental MI before study enrollment.…”

Section: Impact Of Raav5-hs100a1 On Cardiac Performance and Damage In...mentioning

confidence: 99%

Cardiac-targeted rAAV5-S100A1 gene therapy protects against adverse remodeling and contractile dysfunction in post-ischemic hearts

Kehr

Salatzki

Krautz

et al. 2023

Preprint

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SummaryToxicity by recombinant adeno-associated viruses (rAAV) in clinical gene therapy trials (e.g., by rAAV9-mediated fatal liver failure) significantly impairs translation of preclinical rAAV-based cardiac gene therapies employing these vectors. For rAAV5 - a capsid that has shown long-term safety in clinical trials - our translational study demonstrates effective transduction of the left ventricle (LV) of healthy pigs via catheter-based retrograde intravenous delivery (CRID) by means of luciferase reporter gene biodistribution analyses. Combination of rAAV5 with the cardioprotective human geneS100A1(hS100A1) prevents LV myocardial infarct (MI) enlargement and improves LV systolic contractile performance in a porcine model of post-MI chronic cardiac dysfunction. Use of a cardiac-biased promoter ensured the cardiac-directed expression of the therapeutic human transgene without signs of clinical toxicity. The beneficial effects of rAAV5-hS100A1were linked to an attenuated activity of post-MI inflammatory gene networks and this was further validated in a murine model. These novel data together with proven scalable producibility and low pre-existing immunity against rAAV5 in humans may collectively advance clinical translation of rAAV5-hS100A1as a gene therapy medicinal product (GTMP) for a common cardiovascular disease, such as chronic heart failure (CHF).HighlightsRecent fatal adverse events in recombinant adeno-associated virus (AAV)-based clinical gene therapy trials advise the use of rAAV serotypes with proven long-term clinical safety, such as rAAV5, for the pre-clinical development and clinical translation of rAAV-based cardiac gene therapy medicinal products.In a biodistribution and therapeutic proof-of-concept study in farm pigs, rAAV5 was identified as an effective viral vector for cardiac gene transfer and gene therapy for post-ischemic cardiac dysfunction when applied by a standardized cardiac-targeted catheter-based route of administration with the luciferase reporter and cardioprotective human gene S100A1 (hS100A1), respectively.A systems biology analysis linked the novel finding of mitigated inflammatory and activated cardioprotective gene network activities in rAAV5-hS100A1treated postischemic myocardium with improved study left ventricular ejection fraction and prevention of myocardial infarct extension, respectively, which warrants further mechanistic molecular studies.Since rAAV5 has been recently approved for clinical use in a non-cardiac indication and cardiac-targeted S100A1 gene therapy has been effective in numerous pre-clinical animal models of acute and chronic cardiac dysfunction, our translational data support an expedited developmental path for rAAV5-hS100A1throughout investigational new drug-enabling studies towards a first-in-human clinical trial for post-myocardial infarction heart failure.

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Left Ventricular Pressure Volume Assessment Using Carotid Artery Access in the Rat

Mavropoulos

Ishikawa

2022

Methods in Molecular Biology

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Comprehensive cardiac phenotyping in large animals: comparison of pressure–volume analysis and cardiac magnetic resonance imaging in pig post-myocardial infarction systolic heart failure

Cited by 5 publications

References 18 publications

Transverse isotropic modelling of left-ventricle passive filling: Mechanical characterization for epicardial biomaterial manufacturing

Transverse isotropic modelling of left-ventricle passive filling: Mechanical characterization for epicardial biomaterial manufacturing

Cardiac-targeted rAAV5-S100A1 gene therapy protects against adverse remodeling and contractile dysfunction in post-ischemic hearts

Left Ventricular Pressure Volume Assessment Using Carotid Artery Access in the Rat

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