Paired Pressure–Volume Loop Analysis and Biaxial Mechanical Testing Characterize Differences in Left Ventricular Tissue Stiffness of Volume Overload and Angiotensin-Induced Pressure Overload Hearts

Childers, Rachel C.; Trask, Aaron J.; Li, Jun; Lucchesi, Pamela A.; Gooch, Keith J.

doi:10.1115/1.4050541

Cited by 3 publications

(5 citation statements)

References 38 publications

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“…The data summarized above strongly support the notion that decreasing substrate stiffness can push CFs towards a hypofibrotic phenotype and support our notion that thẽ 50% reduction in stiffness seen in volume hearts [15] contributes to hypofibrotic nature of the CFs isolated from these hearts [14]. A potential objection to this view is that since CFs respond to their current stiffness in culture, any measurements made in vitro will reflect their current substrate stiffness and not what they experienced previously in vivo.…”

Section: Discussionsupporting

confidence: 77%

“…Here we show that normal CFs behave more like hypofibrotic CFs on soft substrates and that CFs from ACF have a dampened response to stiffness. Our observations that ACFs have approximately half the tissue modulus compared to sham [15], that CFs isolated from ACF have a more hypofibrotic phenotype compared to sham CFs [14], and here that a more hypofibrotic phenotype results from exposure to decreased substrate modulus in CFs, suggest the reduced stiffness in ACF hearts may cause CFs to adopt a hypofibrotic phenotype. In addition, our previous observations that ACFs are primed in an environment with decreased tissue modulus [15] yet retain a hypofibrotic phenotype even in culture on stiff plastic [14]), coupled with our observations here that ACF CFs have a dampened response to stiffness compared to sham CFs, is consistent with the notion of mechanical memory.…”

Section: Discussionmentioning

confidence: 51%

“…Why CFs in VO hearts adopt this hypofibrotic phenotype is not known but we reasoned that changes in matrix stiffness might play a role. We recently reported the stiffness of the heart in the ACF model of VO decreases relative to control hearts as evidenced by altered pressure-volume loops in vivo and stress-stress curves from in vitro biaxial mechanical testing [15]. Matrix stiffness is an important regulator of many cellular functions including survival, proliferation, differentiation, and migration [16].…”

Section: Introductionmentioning

confidence: 99%

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Decreased Substrate Stiffness Promotes a Hypofibrotic Phenotype in Cardiac Fibroblasts

Childers

Lucchesi

Gooch

2021

IJMS

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A hypofibrotic phenotype has been observed in cardiac fibroblasts (CFs) isolated from a volume overload heart failure model, aortocaval fistula (ACF). This paradoxical phenotype results in decreased ECM synthesis despite increased TGF-β presence. Since ACF results in decreased tissue stiffness relative to control (sham) hearts, this study investigates whether the effects of substrate stiffness could account for the observed hypofibrotic phenotype in CFs isolated from ACF. CFs isolated from ACF and sham hearts were plated on polyacrylamide gels of a range of stiffness (2 kPa to 50 kPa). Markers related to cytoskeletal and fibrotic proteins were measured. Aspects of the hypofibrotic phenotype observed in ACF CFs were recapitulated by sham CFs on soft substrates. For instance, sham CFs on the softest gels compared to ACF CFs on the stiffest gels results in similar CTGF (0.80 vs. 0.76) and transgelin (0.44 vs. 0.57) mRNA expression. The changes due to stiffness may be explained by the observed decreased nuclear translocation of transcriptional regulators, MRTF-A and YAP. ACF CFs appear to have a mechanical memory of a softer environment, supported by a hypofibrotic phenotype overall compared to sham with less YAP detected in the nucleus, and less CTGF and transgelin on all stiffnesses.

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Section: Discussionsupporting

confidence: 77%

Section: Discussionmentioning

confidence: 51%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Decreased Substrate Stiffness Promotes a Hypofibrotic Phenotype in Cardiac Fibroblasts

Childers

Lucchesi

Gooch

2021

IJMS

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“…Therefore, it is important that the study of myocardial muscle behaviour be carried out along more than a single dimension. Some researchers [8,10] recommended the use of multiaxial analysis of cardiac tissue due to the intrinsic anisotropy and variation of myocyte fiber orientation and mechanical properties of myocardial tissues. It is stated that biaxial cardiac in vitro models can precisely represent the mechanobiological behaviour of cardiac tissue [11].…”

Section: Introductionmentioning

confidence: 99%

Determination of Cross-Directional and Cross-Wall Variations of Passive Biaxial Mechanical Properties of Rat Myocardia

et al. 2022

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Heart myocardia are critical to the facilitation of heart pumping and blood circulating around the body. The biaxial mechanical testing of the left ventricle (LV) has been extensively utilised to build the computational model of the whole heart with little importance given to the unique mechanical properties of the right ventricle (RV) and cardiac septum (SPW). Most of those studies focussed on the LV of the heart and then applied the obtained characteristics with a few modifications to the right side of the heart. However, the assumption that the LV characteristics applies to the RV has been contested over time with the realisation that the right side of the heart possesses its own unique mechanical properties that are widely distinct from that of the left side of the heart. This paper evaluates the passive mechanical property differences in the three main walls of the rat heart based on biaxial tensile test data. Fifteen mature Wistar rats weighing 225 ± 25 g were euthanised by inhalation of 5% halothane. The hearts were excised after which all the top chambers comprising the two atria, pulmonary and vena cava trunks, aorta, and valves were all dissected out. Then, 5 × 5 mm sections from the middle of each wall were carefully dissected with a surgical knife to avoid overly pre-straining the specimens. The specimens were subjected to tensile testing. The elastic moduli, peak stresses in the toe region and stresses at 40% strain, anisotropy indices, as well as the stored strain energy in the toe and linear region of up to 40% strain were used for statistical significance tests. The main findings of this study are: (1) LV and SPW tissues have relatively shorter toe regions of 10–15% strain as compared to RV tissue, whose toe region extends up to twice as much as that; (2) LV tissues have a higher strain energy storage in the linear region despite being lower in stiffness than the RV; and (3) the SPW has the highest strain energy storage along both directions, which might be directly related to its high level of anisotropy. These findings, though for a specific animal species at similar age and around the same body mass, emphasise the importance of the application of wall-specific material parameters to obtain accurate ventricular hyperelastic models. The findings further enhance our understanding of the desired mechanical behaviour of the different ventricle walls.

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“…Therefore, it is important that the study of myocardial muscle behaviour be carried out along more than a single dimension. Some researchers [8,10] recommended use of multiaxial analysis of cardiac tissue due to the intrinsic anisotropy and variation of myocyte fiber orientation and mechanical properties of myocardial tissues. It is stated that biaxial cardiac in vitro models can precisely represent the mechanobiological behaviour of cardiac tissue [11].…”

Section: Introductionmentioning

confidence: 99%

Determination of Cross-directional and Cross-Wall Variations of Passive Biaxial Mechanical Properties of Rat Myocardium

Ngwangwa¹,

Ṋemavhola²,

Pandelani³

et al. 2021

Preprint

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Heart myocardia are critical to the facilitation of heart pumping and blood circulating around the body. The biaxial mechanical testing of the Left Ventricle (RV) is utilised to build the computa-tional model of the whole heart with little importance given to the unique mechanical properties of Right Ventricle (RV) and Mid-wall (MDW). Most of those studies focussed on the LV of the heart, and then apply the obtained characteristics with a few modifications to the right side of the heart. However, that view has been contested over time with the realisation that the right side of the heart possesses its own unique mechanical properties that are widely distinct from that of the left side of the heart. This paper is aimed at reporting and evaluating the passive mechanical property dif-ferences in the three main walls of the rat heart based on biaxial tensile test data. Fifteen mature Wistar rats weighing 225 ± 25 g were euthanised by inhalation of 5 % halothane. The hearts were excised after which all the top chambers comprising the two atria, pulmonary and vena cava trunks, aorta and valves are all dissected out. Then 5 x 5 mm sections from the middle of each wall were carefully dissected with a surgical knife to avoid over-prestraining the specimens. The specimens were subjected tensile test. The elastic moduli, peak stresses in the toe region and stresses at 40 % strain, anisotropy indices as well as the stored strain energy in the toe and linear region up to 40 % strain are used for statistical significance tests. The following are the main findings of this study: (1) LV and MDW tissues have relatively shorter toe regions of 10 - 15 % strain as compared to RV tissue whose toe region extends up to twice as much as that (2) LV tissues have higher strain energy storage in the linear region despite being lower in stiffness than the RV (3) the MDW has the highest strain energy storage along both directions which might be directly related to its high level of anisotropy. These findings, though for a specific animal species at similar age and around the same body mass, emphasize the importance of application of wall specific material parameters to obtain accurate ventricular hyperelastic models. The findings further enhance our understanding of the desired mechanical behaviour of the different ventricle walls.

show abstract

Paired Pressure–Volume Loop Analysis and Biaxial Mechanical Testing Characterize Differences in Left Ventricular Tissue Stiffness of Volume Overload and Angiotensin-Induced Pressure Overload Hearts

Cited by 3 publications

References 38 publications

Decreased Substrate Stiffness Promotes a Hypofibrotic Phenotype in Cardiac Fibroblasts

Decreased Substrate Stiffness Promotes a Hypofibrotic Phenotype in Cardiac Fibroblasts

Determination of Cross-Directional and Cross-Wall Variations of Passive Biaxial Mechanical Properties of Rat Myocardia

Determination of Cross-directional and Cross-Wall Variations of Passive Biaxial Mechanical Properties of Rat Myocardium

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