Towards standardization of echocardiography for the evaluation of left ventricular function in adult rodents: a position paper of the ESC Working Group on Myocardial Function

Zacchigna, Serena; Paldino, Alessia; Falcão-Pires, Inês; Daskalopoulos, Evangelos P.; Ferro, Matteo Dal; Vodret, Simone; Lesizza, Pierluigi; Cannatà, Antonio; Miranda-Silva, Daniela; Lourenço, André P.; Pinamonti, Bruno; Sinagra, Gianfranco; Weinberger, Florian; Eschenhagen, Thomas; Carrier, Lucie; Kehat, Izhak; Tocchetti, Carlo G.; Russo, Michele; Ghigo, Alessandra; Cimino, James J.; Hirsch, Emilio; Dawson, Dana; Ciccarelli, Michele; Oliveti, Marco; Linke, Wolfgang A.; Cuijpers, Ilona; Heymans, Stéphane; Hamdani, Nazha; Boer, Martine de; Duncker, Dirk J.; Kuster, Diederik W.D.; Velden, Jolanda van der; Beauloye, Christophe; Bertrand, Luc; Mayr, Manuel; Giacca, Mauro; Leuschner, Florian; Backs, Johannes; Thum, Thomas

doi:10.1093/cvr/cvaa110

Cited by 96 publications

(84 citation statements)

References 116 publications

(133 reference statements)

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“…In the metoprolol subgroup, mice were also anaesthetised to undergo TTE just before starting drinking water + metoprolol, which corresponds to 10 days before chemotherapy. Two‐dimensional short‐axis M‐mode echocardiography 15 was performed to measure left ventricular (LV) end‐systolic diameter, LV end‐diastolic diameter, LV septal and posterior wall thickness in diastole and systole, and LV end‐systolic and end‐diastolic volumes to calculate LVEF according to Quinones et al 16 . Heart rate was also assessed during TTE.…”

Section: Methodsmentioning

confidence: 99%

Doxorubicin‐induced and trastuzumab‐induced cardiotoxicity in mice is not prevented by metoprolol

et al. 2021

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Aims Our objectives were to validate a murine model of chronic cardiotoxicity induced by Doxorubicin (Dox) and Trastuzumab (Trast) and to test the potential cardio-protective effect of metoprolol. Methods and results Male C57Bl6 mice were intraperitoneally injected during 2 weeks with Dox (24 mg/kg) or saline, and then with Trast (10 mg/kg) or saline for two more weeks. Half of the mice received metoprolol (100 mg/kg). Cardiotoxicity was defined by a decline in left ventricular ejection fraction (LVEF) ≥ 10 points. At Day 42, Dox + Trast-treated mice exhibited a 13-points decline in LVEF (74 ± 2.6% vs. 87 ± 0.8% for control mice, P < 0.001) and a severe cardiac atrophy (heart weight: 105 ± 2.7 mg vs. 119 ± 3.9 mg for control mice, P < 0.01). This cardiac atrophy resulted from an excess of cardiac necrosis (assessed by plasma cardiac troponin I level: 3.2 ± 0.4 ng/L vs. 1.3 ± 0.06 ng/L for control mice, P < 0.01), an increase in apoptosis (caspase 3 activity showing a six-fold increase for Dox + Trast-treated mice vs. controls, P < 0.001), and cardiomyocyte atrophy (myocyte size: 0.67 ± 0.08 μm 2 vs. 1.36 ± 0.10 μm 2 for control mice, P < 0.001). In addition, Dox + Trast-treated mice were shown to have an increased cardiac oxidative stress (164 ± 14 dihydroethidine-marked nuclei per area vs. 56 ± 9.5 for control mice, P < 0.01) and increased cardiac fibrosis (the semi-quantitative fibrosis score was threefold higher for Dox + Trast-treated mice as compared with controls, P < 0.01). Metoprolol was not able to prevent either the decrease in LVEF or the severe cardiac atrophy, the cardiac necrosis, and the cardiac remodelling induced by chemotherapies. Conclusion A murine model of chronic cardiotoxicity induced by Dox and Trast was characterized by a decrease in cardiac function, a cardiac apoptosis and necrosis leading to cardiomyocyte atrophy. Metoprolol did not prevent this cardiotoxicity.

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Section: Methodsmentioning

confidence: 99%

Doxorubicin‐induced and trastuzumab‐induced cardiotoxicity in mice is not prevented by metoprolol

et al. 2021

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“…Despite the small size of the rat heart and the fast heart rate, echocardiography is systematically used in the evaluation of rat heart function (12). Data for 2 main indices of LV contractility were extracted from the list of studies.…”

Section: Methodsmentioning

confidence: 99%

“…x 100 (13) or from the equation: EF (%) = (LVEDV-LVESV)/LVEDV x 100, where LVEDV is the LV end-diastolic volume and LVESV is LV end-systolic volume (12).…”

Section: Methodsmentioning

confidence: 99%

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What is considered cardiotoxicity of anthracyclines in animal studies Corrigendum in /10.3892/or.2020.7717

et al. 2020

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Anthracyclines are commonly used anticancer drugs with well-known and extensively studied cardiotoxic effects in humans. In the clinical setting guidelines for assessing cardiotoxicity are well-established with important therapeutic implications. Cardiotoxicity in terms of impairment of cardiac function is largely diagnosed by echocardiography and based on objective metrics of cardiac function. Until this day, cardiotoxicity is not an endpoint in the current general toxicology and safety pharmacology preclinical studies, although other classes of drugs apart from anthracyclines, along with everyday chemicals have been shown to manifest cardiotoxic properties. Also, in the relevant literature there are not well-established objective criteria or reference values in order to uniformly characterize cardiotoxic adverse effects in animal models. This in depth review focuses on the evaluation of two important echocardiographic indices, namely ejection fraction and fractional shortening, in the literature concerning anthracycline administration to rats as the reference laboratory animal model. The analysis of the gathered data gives promising results and solid prospects for both, defining anthracycline cardiotoxicity objective values and delineating the guidelines for assessing cardiotoxicity as a separate hazard class in animal preclinical studies for regulatory purposes.

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“…Our study’s main goal was to describe the diastolic function alterations occurring before and after pressure overload relief. For this reason, we used the E/é ratio as one of the main outputsof the present study since it is a well known surrogate marker of diastolic dysfunction and elevated filling pressures in clinical [ 25 , 26 ] and in pre-clinical [ 27 ] setting. However, compared to the existing literature, similar mouse studies have shown systolic dysfunction and LV dilation at earlier time points after aorta constriction [ 28 , 29 ], which might be explained by the differences between strains and mainly by the degree of aortic constriction [ 29 , 30 ].…”

Section: Discussionmentioning

confidence: 99%

The Degree of Cardiac Remodelling before Overload Relief Triggers Different Transcriptome and miRome Signatures during Reverse Remodelling (RR)—Molecular Signature Differ with the Extent of RR

Gonçalves-Rodrigues

Miranda-Silva

et al. 2020

IJMS

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This study aims to provide new insights into transcriptome and miRome modifications occurring in cardiac reverse remodelling (RR) upon left ventricle pressure-overload relief in mice. Pressure-overload was established in seven-week-old C57BL/6J-mice by ascending aortic constriction. A debanding (DEB) surgery was performed seven weeks later in half of the banding group (BA). Two weeks later, cardiac function was evaluated through hemodynamics and echocardiography, and the hearts were collected for histology and small/bulk-RNA-sequencing. Pressure-overload relief was confirmed by the normalization of left-ventricle-end-systolic-pressure. DEB animals were separated into two subgroups according to the extent of cardiac remodelling at seven weeks and RR: DEB1 showed an incomplete RR phenotype confirmed by diastolic dysfunction persistence (E/e’ ≥ 16 ms) and increased myocardial fibrosis. At the same time, DEB2 exhibited normal diastolic function and fibrosis, presenting a phenotype closer to myocardial recovery. Nevertheless, both subgroups showed the persistence of cardiomyocytes hypertrophy. Notably, the DEB1 subgroup presented a more severe diastolic dysfunction at the moment of debanding than the DEB2, suggesting a different degree of cardiac remodelling. Transcriptomic and miRomic data, as well as their integrated analysis, revealed significant downregulation in metabolic and hypertrophic related pathways in DEB1 when compared to DEB2 group, including fatty acid β-oxidation, mitochondria L-carnitine shuttle, and nuclear factor of activated T-cells pathways. Moreover, extracellular matrix remodelling, glycan metabolism and inflammation-related pathways were up-regulated in DEB1. The presence of a more severe diastolic dysfunction at the moment of pressure overload-relief on top of cardiac hypertrophy was associated with an incomplete RR. Our transcriptomic approach suggests that a cardiac inflammation, fibrosis, and metabolic-related gene expression dysregulation underlies diastolic dysfunction persistence after pressure-overload relief, despite left ventricular mass regression, as echocardiographically confirmed.

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Towards standardization of echocardiography for the evaluation of left ventricular function in adult rodents: a position paper of the ESC Working Group on Myocardial Function

Cited by 96 publications

References 116 publications

Doxorubicin‐induced and trastuzumab‐induced cardiotoxicity in mice is not prevented by metoprolol

Doxorubicin‐induced and trastuzumab‐induced cardiotoxicity in mice is not prevented by metoprolol

What is considered cardiotoxicity of anthracyclines in animal studies Corrigendum in /10.3892/or.2020.7717

The Degree of Cardiac Remodelling before Overload Relief Triggers Different Transcriptome and miRome Signatures during Reverse Remodelling (RR)—Molecular Signature Differ with the Extent of RR

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