Multimodal functional cardiac MRI in creatine kinase-deficient mice reveals subtle abnormalities in myocardial perfusion and mechanics

Nahrendorf, Matthias; Streif, Joerg U; Hiller, K. H.; Hu, Kai; Nordbeck, Peter; Ritter, Oliver; Sosnovik, David E.; Bauer, Laurie; Neubauer, Stefan; Jakob, Peter M.; Ertl, Georg; Spindler, Matthias; Bauer, Wolfgang R.

doi:10.1152/ajpheart.01038.2005

Cited by 53 publications

(47 citation statements)

References 28 publications

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“…6,7,9 In these studies, coronary artery responses to vasodilators were evaluated in vitro with coronary artery rings [5][6][7] or isolated hearts. 8 -10 Other methods to assess coronary flow, such as magnetic resonance imaging 11 and Doppler echocardiogra-phy, 12 have been proposed, but these technically challenging modalities remain unvalidated against a "gold standard" in mice. The ability to noninvasively evaluate MBF in vivo in mice both at rest and after administration of vasodilators would provide an important tool for cardiovascular disease research.…”

Section: Clinical Perspective P 1257mentioning

confidence: 99%

In Vivo Characterization of Murine Myocardial Perfusion With Myocardial Contrast Echocardiography

et al. 2007

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Background-The ability to noninvasively evaluate murine myocardial blood flow (MBF) in vivo would provide an important tool for cardiovascular research. Myocardial contrast echocardiography (MCE) has been used to measure MBF; however, it has not been validated in mice. This study assesses whether MCE can evaluate MBF at rest and after vasodilation and measure the maximal augmentation (coronary reserve) of MBF in mice. Wild-type (WT) and nitric oxide synthase 3 (NOS3)-deficient (NOS3 Ϫ/Ϫ ) mice were studied. Methods and Results-MCE was performed at baseline and after intravenous infusion of acetylcholine or adenosine.Definity contrast agent was infused, and parasternal views were acquired in real-time mode. Replenishment curves of myocardial contrast were obtained, and rates of signal rise (␤) and plateau intensity (A) were calculated. MBF estimated by the product of A and ␤ (A␤) was compared with that measured with fluorescent microspheres. MCE analysis was feasible in 98% (52/53) of mice. MBF measured by microspheres increased with adenosine and correlated closely with A␤. There was no difference in MCE-derived MBF between WT and NOS3 Ϫ/Ϫ mice at rest. Adenosine infusion increased MBF by 3.0Ϯ0.6-fold in NOS3 Ϫ/Ϫ mice and 2.5Ϯ0.3-fold in WT (Pϭ0.58 between genotypes). Acetylcholine induced an increase of 2.4Ϯ0.2-fold in MBF in WT mice but did not increase MBF in NOS3 Ϫ/Ϫ mice (PϽ0.0005 versus WT). Conclusions-MBF, coronary reserve, and vasodilator responses can be evaluated accurately in the intact mouse by MCE.This method demonstrated a preserved coronary response to adenosine but an impaired acetylcholine-induced vasodilation in NOS3 Ϫ/Ϫ mice compared with WT mice.

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Section: Clinical Perspective P 1257mentioning

confidence: 99%

In Vivo Characterization of Murine Myocardial Perfusion With Myocardial Contrast Echocardiography

et al. 2007

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“…However, previous studies on CK(À/À) mice did not show overt LV dysfunction (214). MRI techniques were used to assess maximal myocardial velocity (vmax) and myocardial perfusion to determine whether subclinical abnormalities existed in the myocardial phenotype of CK(À/À) mice, at baseline and 4 weeks after myocardial infarction (211). Myocardial hypertrophy was seen in all CK(À/À) mice, but the ejection fraction remained normal.…”

Section: Heart Diseasementioning

confidence: 96%

“…Multimodal cardiac MRI provides additional information that may reveal early pathological changes, as elegantly demonstrated by Nahrendorf et al (211). A decrease in the supply of ATP from the creatine kinase (CK) system is thought to contribute to the evolution of heart failure (212,213).…”

Section: Heart Diseasementioning

confidence: 99%

“…Thus, myocardial function in transgenic mice may appear normal when gross indices of performance such as ejection fraction are assessed. However, the use of a combination of MRI techniques to measure myocardial perfusion and mechanics allowed abnormalities in the CK(À/À) phenotype to be detected (211). The reduced perfusion and vmax of the myocardium observed in CK-deficient mice suggests that the adaptive myocardial hypertrophy in these mice cannot fully compensate for the absence of the CK system.…”

Section: Heart Diseasementioning

confidence: 99%

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In Vivo mouse imaging and spectroscopy in drug discovery

et al. 2007

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Imaging modalities such as micro-computed tomography (micro-CT), micro-positron emission tomography (micro-PET), high-resolution MRI, optical imaging, and high-resolution ultrasound have become invaluable tools in preclinical pharmaceutical research. They can be used to non-invasively investigate, in vivo, rodent biology and metabolism, disease models, and pharmacokinetics and pharmacodynamics of drugs. The advantages and limitations of each approach usually determine its application, and therefore a small-rodent imaging laboratory in a pharmaceutical environment should ideally provide access to several techniques. In this paper we aim to illustrate how these techniques may be used to obtain meaningful information for the phenotyping of transgenic mice and for the analysis of compounds in murine models of disease.

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“…The use of MRI techniques to measure myocardial perfusion and mechanics allowed these researchers to detect the abnormalities in the CK -/-phenotype. The myocardium in CK -/-mice was characterized by reduced perfusion and a reduced maximum contraction velocity (Nahrendorf et al 2006).…”

Section: Architectural and Functional Remodeling In Cardiac Cellsmentioning

confidence: 99%

Architectural and functional remodeling of cardiac and skeletal muscle cells in mice lacking specific isoenzymes of creatine kinase

Tylková¹

2009

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Abstract. Muscle is the major consumer of fuels and ATP in the body. Mitochondria and glycolytic complexes serve as the main energy production locations, while the highest energy demands are associated with the sarcoplasmic reticulum, myofibrillar compartments and plasma membrane. Creatine kinase (CK) is a dimeric protein, which is deeply involved in the production of high energy storage compounds. This enzyme reversibly phosphorylates creatine (Cr) to phosphocreatine (PCr), and it is also highly adapted to specialized muscle function. To date, four major isoenzymes of CK have been identified, two of which occur in the cytosol and two in mitochondria.Disruption of the phosphotransfer system induced by an absence of either the sarcomeric mitochondrial CK or cytosolic CK or both isoenzymes of CK (CK -/-) in muscle cells leads to morphological and functional adaptations towards preservation of muscle contractile abilities. Remodeling of the cell ultrastructure observed in CK -/-cardiomyocytes and glycolytic fibers was associated with direct transfer of energy from places of energy production to locations of energy utilization. This direct interaction among the organelles can maintain a high ATP/ADP ratio near the cellular ATPases when CK is not functionally active. This review summarizes the function and role of CK across different muscle cells in knockout mice.

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Multimodal functional cardiac MRI in creatine kinase-deficient mice reveals subtle abnormalities in myocardial perfusion and mechanics

Cited by 53 publications

References 28 publications

In Vivo Characterization of Murine Myocardial Perfusion With Myocardial Contrast Echocardiography

In Vivo Characterization of Murine Myocardial Perfusion With Myocardial Contrast Echocardiography

In Vivo mouse imaging and spectroscopy in drug discovery

Architectural and functional remodeling of cardiac and skeletal muscle cells in mice lacking specific isoenzymes of creatine kinase

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