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4. Heart failure biomarkers: The importance of cardiac specificity

Author

Piek, Arnold and Piek, Arnold

Abstract

In this thesis, three different approaches to study biomarkers (bioinformatics, animal models and clinical cohorts) were combined to improve our knowledge on HF biomarker biology, clinical utility, and HF biomarkers as treatment targets. The results of our unique and elaborate approach shed new light on the biomarker field as a whole. We showed that many novel HF biomarkers lack cardiac specificity and are produced by non-cardiac organs and tissues. Relating the levels of these markers to processes of pathological processes in the heart seems therewith impossible. Nevertheless, non-specific markers might still have clinical value, for example as markers of peripheral effects of HF or as pharmacological treatment targets. Finally, this thesis showed that for future biomarker studies it is indispensable to investigate tissue origin of markers in order to improve their specificity and therewith their clinical utility.

Published
2020

11. A novel method optimizing the normalization of cardiac parameters in small animal models: the importance of dimensional indexing.

Author

Hagdorn QAJ, Bossers GPL, Koop AC, Piek A, Eijgenraam TR, van der Feen DE, Silljé HHW, de Boer RA, and Berger RMF

Subjects
Animals, Disease Models, Animal, Echocardiography, Female, Heart diagnostic imaging, Heart Failure diagnostic imaging, Heart Failure pathology, Heart Ventricles anatomy & histology, Heart Ventricles diagnostic imaging, Male, Mice, Organ Size, Rats, Wistar, Reproducibility of Results, Species Specificity, Body Weight, Heart anatomy & histology, Models, Biological, Tibia anatomy & histology
Abstract

For indexing cardiac measures in small animal models, tibia length (TL) is a recommended surrogate for body weight (BW) that aims to avoid biases because of disease-induced BW changes. However, we question if indexing by TL is mathematically correct. This study aimed to investigate the relation between TL and BW, heart weight, ventricular weights, and left ventricular diameter to optimize the current common practice of indexing cardiac parameters in small animal models. In 29 healthy Wistar rats (age 5-34 wk) and 116 healthy Black 6 mice (age 3-17 wk), BW appeared to scale nonlinearly to TL 1 but linearly to TL 3 . Formulas for indexing cardiac weights were derived. To illustrate the effects of indexing, cardiac weights between the 50% with highest BW and the 50% with lowest BW were compared. The nonindexed cardiac weights differed significantly between groups, as could be expected ( P < 0.001). However, after indexing by TL 1 , indexed cardiac weights remained significantly different between groups ( P < 0.001). With the derived formulas for indexing, indexed cardiac weights were similar between groups. In healthy rats and mice, BW and heart weights scale linearly to TL 3 . This indicates that not TL 1 but TL 3 is the optimal surrogate for BW. New formulas for indexing heart weight and isolated ventricular weights are provided, and we propose a concept in which cardiac parameters should not all be indexed to the same measure but one-dimensional measures to BW 1/3 or TL 1 , two-dimensional measures to BW 2/3 or TL 2 , and three-dimensional measures to BW or TL 3 . NEW & NOTEWORTHY In healthy rats and mice, body weight (BW) scales linearly to tibia length (TL) to the power of three (TL 3 ). This indicates that for indexing cardiac parameters, not TL 1 but TL 3 is the optimal surrogate for BW. New formulas for indexing heart weight and isolated ventricular weights are provided, and we propose a concept of dimensionally consistent indexing. This concept is proposed to be widely applied in small animal experiments.

Published
2019
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