Development of a novel peptide tracer for detection of cardiac fibrosis and atrial fibrillation using mouse models of cardiomyopathies

Be'eri Niego, Karen Alt, Asif Noor, Ole Jakob How, Xiao-Jun Du, Paul Stephen Donnelly, Julie McMullen, Christoph Hagemeyer

Research output: Contribution to conferenceAbstractOtherpeer-review

Abstract

Background. Atrial fibrillation (AF), the most common cardiac arrhythmia, escalates in aging western societies and predisposes patients to heart failure (HF) and stroke. A solid link has been established between AF and atrial fibrosis, a scarring process leading to distorted atrial architecture and function. Current fibrosis imaging techniques (e.g. MRI) are limited by spatial resolution and image quality. We have developed a targeted peptide tracer (‘T-peptide’) with specific affinity towards MMP-degraded collagen IV, which could improve detection of cardiac fibrosis and AF monitoring.
Aims. We aimed to test whether the T-peptide can specifically bind fibrotic hearts using mouse models of AF and HF.
Methods. Cy5.5-labelled T-peptide (1 mg/kg), or the scrambled control ‘S-peptide’, were intravenously injected to the arrhythmic, double transgenic dominant negative PI3K-Mammalian sterile 20-like kinase 1 (Mst1) mice (AF+HF mice). Perfused hearts were collected 16 h later for histology or homogenisation, and near-infrared signals measured using the Odyssey scanner. Fresh frozen heart sections, also from transgenic mice overexpressing β2 adrenergic receptors (β2-AR) or undergoing experimental myocardial infarction (MI), were incubated with the tracer for microscopic examination.
Results. Interstitial fibrosis was demonstrated in AF+HF hearts by standard histological techniques. T-peptide robustly accumulated in transgenic hearts, with the atria absorbing ~5-fold higher tracer amounts than ventricles per tissue weight. S-peptide uptake was significantly lower than T-peptide. Heart section scans from the β2-AR and MI models detected patchy areas of enhanced staining of yet-to-be identified fibrillary structure.
Conclusions. These results demonstrate that the T-peptide tracer preferentially accumulates in atria, highlighting its potential for AF imaging. Yet, its affinity towards degraded collagen in cardiac pathology has to be examined further. Future in vivo molecular imaging experiments will reveal if the tracer can detect both robust and more subtle cardiac fibrosis as seen in the MI / β2-AR and the AF+HF models, respectively
Original languageEnglish
Publication statusPublished - 9 Jul 2019
EventISTH 2019: The XXVII Congress of International Society on
Thrombosis and Haemostasis and 65th Annual Scientific and
Standardization Committee (SSC) Meeting
- Melbourne, Australia
Duration: 6 Jul 201910 Jul 2019

Conference

ConferenceISTH 2019: The XXVII Congress of International Society on
Thrombosis and Haemostasis and 65th Annual Scientific and
Standardization Committee (SSC) Meeting
CountryAustralia
CityMelbourne
Period6/07/1910/07/19

Cite this

Niego, B., Alt, K., Noor, A., How, O. J., Du, X-J., Donnelly, P. S., ... Hagemeyer, C. (2019). Development of a novel peptide tracer for detection of cardiac fibrosis and atrial fibrillation using mouse models of cardiomyopathies. Abstract from ISTH 2019: The XXVII Congress of International Society on
Thrombosis and Haemostasis and 65th Annual Scientific and
Standardization Committee (SSC) Meeting, Melbourne, Australia.
Niego, Be'eri ; Alt, Karen ; Noor, Asif ; How, Ole Jakob ; Du, Xiao-Jun ; Donnelly, Paul Stephen ; McMullen, Julie ; Hagemeyer, Christoph. / Development of a novel peptide tracer for detection of cardiac fibrosis and atrial fibrillation using mouse models of cardiomyopathies. Abstract from ISTH 2019: The XXVII Congress of International Society on
Thrombosis and Haemostasis and 65th Annual Scientific and
Standardization Committee (SSC) Meeting, Melbourne, Australia.
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title = "Development of a novel peptide tracer for detection of cardiac fibrosis and atrial fibrillation using mouse models of cardiomyopathies",
abstract = "Background. Atrial fibrillation (AF), the most common cardiac arrhythmia, escalates in aging western societies and predisposes patients to heart failure (HF) and stroke. A solid link has been established between AF and atrial fibrosis, a scarring process leading to distorted atrial architecture and function. Current fibrosis imaging techniques (e.g. MRI) are limited by spatial resolution and image quality. We have developed a targeted peptide tracer (‘T-peptide’) with specific affinity towards MMP-degraded collagen IV, which could improve detection of cardiac fibrosis and AF monitoring. Aims. We aimed to test whether the T-peptide can specifically bind fibrotic hearts using mouse models of AF and HF.Methods. Cy5.5-labelled T-peptide (1 mg/kg), or the scrambled control ‘S-peptide’, were intravenously injected to the arrhythmic, double transgenic dominant negative PI3K-Mammalian sterile 20-like kinase 1 (Mst1) mice (AF+HF mice). Perfused hearts were collected 16 h later for histology or homogenisation, and near-infrared signals measured using the Odyssey scanner. Fresh frozen heart sections, also from transgenic mice overexpressing β2 adrenergic receptors (β2-AR) or undergoing experimental myocardial infarction (MI), were incubated with the tracer for microscopic examination. Results. Interstitial fibrosis was demonstrated in AF+HF hearts by standard histological techniques. T-peptide robustly accumulated in transgenic hearts, with the atria absorbing ~5-fold higher tracer amounts than ventricles per tissue weight. S-peptide uptake was significantly lower than T-peptide. Heart section scans from the β2-AR and MI models detected patchy areas of enhanced staining of yet-to-be identified fibrillary structure. Conclusions. These results demonstrate that the T-peptide tracer preferentially accumulates in atria, highlighting its potential for AF imaging. Yet, its affinity towards degraded collagen in cardiac pathology has to be examined further. Future in vivo molecular imaging experiments will reveal if the tracer can detect both robust and more subtle cardiac fibrosis as seen in the MI / β2-AR and the AF+HF models, respectively",
author = "Be'eri Niego and Karen Alt and Asif Noor and How, {Ole Jakob} and Xiao-Jun Du and Donnelly, {Paul Stephen} and Julie McMullen and Christoph Hagemeyer",
year = "2019",
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Niego, B, Alt, K, Noor, A, How, OJ, Du, X-J, Donnelly, PS, McMullen, J & Hagemeyer, C 2019, 'Development of a novel peptide tracer for detection of cardiac fibrosis and atrial fibrillation using mouse models of cardiomyopathies' ISTH 2019: The XXVII Congress of International Society on
Thrombosis and Haemostasis and 65th Annual Scientific and
Standardization Committee (SSC) Meeting, Melbourne, Australia, 6/07/19 - 10/07/19, .

Development of a novel peptide tracer for detection of cardiac fibrosis and atrial fibrillation using mouse models of cardiomyopathies. / Niego, Be'eri; Alt, Karen; Noor, Asif; How, Ole Jakob; Du, Xiao-Jun; Donnelly, Paul Stephen; McMullen, Julie; Hagemeyer, Christoph.

2019. Abstract from ISTH 2019: The XXVII Congress of International Society on
Thrombosis and Haemostasis and 65th Annual Scientific and
Standardization Committee (SSC) Meeting, Melbourne, Australia.

Research output: Contribution to conferenceAbstractOtherpeer-review

TY - CONF

T1 - Development of a novel peptide tracer for detection of cardiac fibrosis and atrial fibrillation using mouse models of cardiomyopathies

AU - Niego, Be'eri

AU - Alt, Karen

AU - Noor, Asif

AU - How, Ole Jakob

AU - Du, Xiao-Jun

AU - Donnelly, Paul Stephen

AU - McMullen, Julie

AU - Hagemeyer, Christoph

PY - 2019/7/9

Y1 - 2019/7/9

N2 - Background. Atrial fibrillation (AF), the most common cardiac arrhythmia, escalates in aging western societies and predisposes patients to heart failure (HF) and stroke. A solid link has been established between AF and atrial fibrosis, a scarring process leading to distorted atrial architecture and function. Current fibrosis imaging techniques (e.g. MRI) are limited by spatial resolution and image quality. We have developed a targeted peptide tracer (‘T-peptide’) with specific affinity towards MMP-degraded collagen IV, which could improve detection of cardiac fibrosis and AF monitoring. Aims. We aimed to test whether the T-peptide can specifically bind fibrotic hearts using mouse models of AF and HF.Methods. Cy5.5-labelled T-peptide (1 mg/kg), or the scrambled control ‘S-peptide’, were intravenously injected to the arrhythmic, double transgenic dominant negative PI3K-Mammalian sterile 20-like kinase 1 (Mst1) mice (AF+HF mice). Perfused hearts were collected 16 h later for histology or homogenisation, and near-infrared signals measured using the Odyssey scanner. Fresh frozen heart sections, also from transgenic mice overexpressing β2 adrenergic receptors (β2-AR) or undergoing experimental myocardial infarction (MI), were incubated with the tracer for microscopic examination. Results. Interstitial fibrosis was demonstrated in AF+HF hearts by standard histological techniques. T-peptide robustly accumulated in transgenic hearts, with the atria absorbing ~5-fold higher tracer amounts than ventricles per tissue weight. S-peptide uptake was significantly lower than T-peptide. Heart section scans from the β2-AR and MI models detected patchy areas of enhanced staining of yet-to-be identified fibrillary structure. Conclusions. These results demonstrate that the T-peptide tracer preferentially accumulates in atria, highlighting its potential for AF imaging. Yet, its affinity towards degraded collagen in cardiac pathology has to be examined further. Future in vivo molecular imaging experiments will reveal if the tracer can detect both robust and more subtle cardiac fibrosis as seen in the MI / β2-AR and the AF+HF models, respectively

AB - Background. Atrial fibrillation (AF), the most common cardiac arrhythmia, escalates in aging western societies and predisposes patients to heart failure (HF) and stroke. A solid link has been established between AF and atrial fibrosis, a scarring process leading to distorted atrial architecture and function. Current fibrosis imaging techniques (e.g. MRI) are limited by spatial resolution and image quality. We have developed a targeted peptide tracer (‘T-peptide’) with specific affinity towards MMP-degraded collagen IV, which could improve detection of cardiac fibrosis and AF monitoring. Aims. We aimed to test whether the T-peptide can specifically bind fibrotic hearts using mouse models of AF and HF.Methods. Cy5.5-labelled T-peptide (1 mg/kg), or the scrambled control ‘S-peptide’, were intravenously injected to the arrhythmic, double transgenic dominant negative PI3K-Mammalian sterile 20-like kinase 1 (Mst1) mice (AF+HF mice). Perfused hearts were collected 16 h later for histology or homogenisation, and near-infrared signals measured using the Odyssey scanner. Fresh frozen heart sections, also from transgenic mice overexpressing β2 adrenergic receptors (β2-AR) or undergoing experimental myocardial infarction (MI), were incubated with the tracer for microscopic examination. Results. Interstitial fibrosis was demonstrated in AF+HF hearts by standard histological techniques. T-peptide robustly accumulated in transgenic hearts, with the atria absorbing ~5-fold higher tracer amounts than ventricles per tissue weight. S-peptide uptake was significantly lower than T-peptide. Heart section scans from the β2-AR and MI models detected patchy areas of enhanced staining of yet-to-be identified fibrillary structure. Conclusions. These results demonstrate that the T-peptide tracer preferentially accumulates in atria, highlighting its potential for AF imaging. Yet, its affinity towards degraded collagen in cardiac pathology has to be examined further. Future in vivo molecular imaging experiments will reveal if the tracer can detect both robust and more subtle cardiac fibrosis as seen in the MI / β2-AR and the AF+HF models, respectively

M3 - Abstract

ER -

Niego B, Alt K, Noor A, How OJ, Du X-J, Donnelly PS et al. Development of a novel peptide tracer for detection of cardiac fibrosis and atrial fibrillation using mouse models of cardiomyopathies. 2019. Abstract from ISTH 2019: The XXVII Congress of International Society on
Thrombosis and Haemostasis and 65th Annual Scientific and
Standardization Committee (SSC) Meeting, Melbourne, Australia.