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Three-dimensional molecular reconstruction of rat heart with mass spectrometry imaging

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Abstract

Cardiovascular diseases are the world’s number one cause of death, accounting for 17.1 million deaths a year. New high-resolution molecular and structural imaging strategies are needed to understand underlying pathophysiological mechanism. The aim of our study is (1) to provide a molecular basis of the heart animal model through the local identification of biomolecules by mass spectrometry imaging (MSI) (three-dimensional (3D) molecular reconstruction), (2) to perform a cross-species validation of secondary ion mass spectrometry (SIMS)-based cardiovascular molecular imaging, and (3) to demonstrate potential clinical relevance by the application of this innovative methodology to human heart specimens. We investigated a MSI approach using SIMS on the major areas of a rat and mouse heart: the pericardium, the myocardium, the endocardium, valves, and the great vessels. While several structures of the heart can be observed in individual two-dimensional sections analyzed by metal-assisted SIMS imaging, a full view of these structures in the total heart volume can be achieved only through the construction of the 3D heart model. The images of 3D reconstruction of the rat heart show a highly complementary localization between Na+, K+, and two ions at m/z 145 and 667. Principal component analysis of the MSI data clearly identified different morphology of the heart by their distinct correlated molecular signatures. The results reported here represent the first 3D molecular reconstruction of rat heart by SIMS imaging.

Workflow of the 3D reconstruction. A Tissue section, B gold deposition is done by sputter coating, C, C1 SIMS-ToF mass analyzer, C, C2 mass spectral peaks, C, C3 datacube images; D, E Reconstruction of the heart showing 3D-spatial distributions of three different ions 145 m/z (red), 23 m/z (green), and 39 m/z (blue); F coregistration of 40 individual MS imaging

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Abbreviations

DAG:

Diacylglycerols

FFA:

Free fatty acids

MALDI-MSI:

Matrix-assisted laser desorption/ionization-mass spectrometry imaging

MetA-SIMS:

Metal-assisted-secondary ion mass spectrometry

MS:

Mass spectrometry

MSI:

Mass spectrometry imaging

PCA:

Principal component analysis

SIMS:

Secondary ion mass spectrometry

TAG:

Triacylglycerols

ToF:

Time-of-flight

VARIMAX:

VARIance MAXimization

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Acknowledgments

We gratefully acknowledge the assistance and Informatics (CWI) in the generation of the full-resolution SIMS images.

Sources of funding

This work is supported by the Cardiovascular Pathology, Department of Cardiac, Thoracic, and Vascular Sciences, University of Padua Medical School, and by a grant from the Italian Society of Cardiology. This work is also part of the research program of the Stichting voor Fundamenteel Onderzoek der Materie (FOM) and is financially supported by the Nederlandse organisatie voor Wetenschappelijk Onderzoek (NWO).

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Correspondence to Lara Fornai.

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Please address reprint requests to: Prof. Dr. R.M.A. Heeren, FOM-AMOLF, Science Park 104, 1098 XG Amsterdam, The Netherlands

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Fornai, L., Angelini, A., Klinkert, I. et al. Three-dimensional molecular reconstruction of rat heart with mass spectrometry imaging. Anal Bioanal Chem 404, 2927–2938 (2012). https://doi.org/10.1007/s00216-012-6451-3

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