scholarly journals The von Hippel-Lindau Chuvash mutation in mice alters cardiac substrate and high-energy phosphate metabolism

2016 ◽  
Vol 311 (3) ◽  
pp. H759-H767 ◽  
Author(s):  
Mary Slingo ◽  
Mark Cole ◽  
Carolyn Carr ◽  
Mary K. Curtis ◽  
Michael Dodd ◽  
...  
Keyword(s):  
Gene Expression ◽  
Magnetic Resonance ◽  
Genetic Disorder ◽  
High Energy ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Resonance Spectroscopy ◽  
Ventricular Ejection Fraction ◽  
Hif Pathway

Hypoxia-inducible factor (HIF) appears to function as a global master regulator of cellular and systemic responses to hypoxia. HIF pathway manipulation is of therapeutic interest; however, global systemic upregulation of HIF may have as yet unknown effects on multiple processes. We used a mouse model of Chuvash polycythemia (CP), a rare genetic disorder that modestly increases expression of HIF target genes in normoxia, to understand what these effects might be within the heart. An integrated in and ex vivo approach was employed. Compared with wild-type controls, CP mice had evidence (using in vivo magnetic resonance imaging) of pulmonary hypertension, right ventricular hypertrophy, and increased left ventricular ejection fraction. Glycolytic flux (measured using [3H]glucose) in the isolated contracting perfused CP heart was 1.8-fold higher. Net lactate efflux was 1.5-fold higher. Furthermore, in vivo 13C-magnetic resonance spectroscopy (MRS) of hyperpolarized [13C1]pyruvate revealed a twofold increase in real-time flux through lactate dehydrogenase in the CP hearts and a 1.6-fold increase through pyruvate dehydrogenase. 31P-MRS of perfused CP hearts under increased workload (isoproterenol infusion) demonstrated increased depletion of phosphocreatine relative to ATP. Intriguingly, no changes in cardiac gene expression were detected. In summary, a modest systemic dysregulation of the HIF pathway resulted in clear alterations in cardiac metabolism and energetics. However, in contrast to studies generating high HIF levels within the heart, the CP mice showed neither the predicted changes in gene expression nor any degree of LV impairment. We conclude that the effects of manipulating HIF on the heart are dose dependent.

scholarly journals Cardiac Energetics Before, During and After Anthracycline-based Chemotherapy in Breast Cancer Patients Using 31P Magnetic Resonance Spectroscopy: A Pilot Study

2020 ◽  
Author(s):  
Gillian Macnaught ◽  
Olga Oikonomidou ◽  
Christopher T. Rodgers ◽  
William Clarke ◽  
Annette Cooper ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Pilot Study ◽  
Magnetic Resonance ◽  
Magnetic Resonance Spectroscopy ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Resonance Spectroscopy ◽  
Ventricular Ejection Fraction ◽  
Time Points ◽  
Change In Mean

Abstract PURPOSETo explore the utility of phosphorus magnetic resonance spectroscopy (31P MRS) in identifying anthracycline-induced cardiac toxicity in patients with breast cancer.METHODS20 patients with newly diagnosed breast cancer receiving anthracycline-based chemotherapy had cardiac magnetic resonance assessment of left ventricular ejection fraction (LVEF) and 31P MRS to determine myocardial Phosphocreatine/Adenosine Triphosphate ratio (PCr/ATP) at three time points: pre, mid and end-chemotherapy. Plasma high sensitivity cardiac troponin-I (cTn-I) tests and electrocardiograms were also performed at these same time points. RESULTS PCr/ATP ratio did not change significantly between pre- and mid-chemo (2.16±0.46 v 2.00±0.56, p=0.80) and pre- and end-chemo (2.16±0.46 v 2.17±0.86, p=0.99). Mean LVEF reduced significantly by 5.1% between pre- and end-chemo (61.4±4.4 vs 56.3±8.1 %, p=0.02). Change in PCr/ATP ratios from pre- to end-chemo correlated inversely with changes in LVEF over the same period (r=-0.65, p=0.006). Plasma cTn-I increased progressively during chemotherapy from pre- to mid-chemo (1.35±0.81 to 4.40±2.64 ng/L; p=0.01) and from mid to end-chemo (4.40±2.64 to 18.33±13.23 ng/L; p=0.001). CONCLUSIONSIn this small cohort pilot study, we did not observe a clear change in mean PCr/ATP values during chemotherapy despite evidence of increased plasma cardiac biomarkers and reduced LVEF. Future similar studies should be adequately powered to take account of patient drop-out and variable changes in PCr/ATP.

MRI/MRS assessment of in vivo murine cardiac metabolism, morphology, and function at physiological heart rates

2000 ◽  
Vol 279 (5) ◽  
pp. H2218-H2224 ◽  
Author(s):  
V. P. Chacko ◽  
Francesca Aresta ◽  
Sonia M. Chacko ◽  
Robert G. Weiss
Keyword(s):  
Magnetic Resonance ◽  
Magnetic Resonance Spectroscopy ◽  
Cardiac Metabolism ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Resonance Spectroscopy ◽  
Heart Rates ◽  
Physiological Conditions ◽  
And Function

Transgenic mice are increasingly used to probe genetic aspects of cardiovascular pathophysiology. However, the small size and rapid rates of murine hearts make noninvasive, physiological in vivo studies of cardiac bioenergetics and contractility difficult. The aim of this report was to develop an integrated, noninvasive means of studying in vivo murine cardiac metabolism, morphology, and function under physiological conditions by adapting and modifying noninvasive cardiac magnetic resonance imaging (MRI) with image-guided 31P magnetic resonance spectroscopy techniques used in humans to mice. Using spatially localized, noninvasive 31P nuclear magnetic resonance spectroscopy and MRI at 4.7 T, we observe mean murine in vivo myocardial phosphocreatine-to-ATP ratios of 2.0 ± 0.2 and left ventricular ejection fractions of 65 ± 7% at physiological heart rates (∼600 beats/min). These values in the smallest species studied to date are similar to those reported in normal humans. Although these observations do not confirm a degree of metabolic scaling with body size proposed by prior predictions, they do suggest that mice can serve, at least at this level, as a model for human cardiovascular physiology. Thus it is now possible to noninvasively study in vivo myocardial bioenergetics, morphology, and contractile function in mice under physiological conditions.

scholarly journals 4D cardiac magnetic resonance imaging, 4D and 2D transthoracic echocardiography: a comparison of in-vivo assessment of ventricular function in rats

2018 ◽  
Vol 53 (2) ◽  
pp. 169-179
Author(s):  
Hedwig Stegmann ◽  
Tobias Bäuerle ◽  
Katharina Kienle ◽  
Sven Dittrich ◽  
Muhannad Alkassar
Keyword(s):  
Cardiac Magnetic Resonance ◽  
Magnetic Resonance ◽  
Ventricular Function ◽  
Heart Function ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Ventricular Ejection Fraction ◽  
Technical Effort ◽  
In Vivo Assessment

Preclinical cardiovascular research is the foundation of our understanding and broad knowledge of heart function and cardiovascular disease. Reliable cardiac imaging modalities are the basis for applicable results. Four-dimensional cardiac magnetic resonance (4D CMR) has been set as the gold standard for in-vivo assessment of ventricular function in rodents. However, technical improvements in echocardiography now allow us to image the whole heart, which makes four-dimensional echocardiography (4DE) a possible alternative to 4D CMR. To date, no study has systematically assessed 4DE in comparison with 4D CMR in rats. In total we studied 26 juvenile Sprague-Dawley rats (Crl: CD (SD) IGS). Twenty rats underwent echocardiographic imaging (2D and 4D) and 4D CMR. Five of those rats underwent a ligation of the superior and inferior vena cava to reduce the cardiac inflow as a disease model. Six additional rats were used to assess reproducibility of echocardiography and underwent three echocardiographic examinations. 4D CMR was performed on a 7T scanner; 2D and 4D echocardiography was conducted using a 40 MHz transducer. Correlation between 4D CMR, 4DE and 2DE for left-ventricular ejection fraction (LVEF) was assessed. An excellent correlation was observed between 4DE and 4D CMR ( r = 0.95, p < 0.001). Correlation of 2DE and 4D CMR was weak ( r = 0.57, p < 0.01). 4DE provides results that are equally precise as 4D CMR and highly reproducible with less technical effort than 4D CMR.

Myocardial energy metabolism and morphology in a canine model of sepsis

1994 ◽  
Vol 266 (2) ◽  
pp. H757-H768 ◽  
Author(s):  
M. A. Solomon ◽  
R. Correa ◽  
H. R. Alexander ◽  
L. A. Koev ◽  
J. P. Cobb ◽  
...  
Keyword(s):  
Free Energy ◽  
Energy Metabolism ◽  
Canine Model ◽  
High Energy ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Resonance Spectroscopy ◽  
Myocardial Depression ◽  
Ventricular Ejection Fraction ◽  
Myocardial Energy Metabolism

The mechanism responsible for sepsis-induced myocardial depression is not known. To determine if sepsis-induced myocardial depression is caused by inadequate free energy available for work, we studied myocardial energy metabolism in a canine model of sepsis. Escherichia coli-infected (n = 18) or sterile (n = 16) fibrin clots were implanted intraperitoneally into beagles. Myocardial function and structure was assessed using radionuclide ventriculograms, echocardiograms, and light and electron microscopy. The adequacy of energy metabolism was evaluated by comparing catecholamine-induced work increases [myocardial O2 consumption (MVO2) and rate pressure product (RPP)] with a simultaneously obtained estimate of intracellular free energy [phosphocreatine-to-adenosine triphosphate ratio (PCr:ATP)] determined by 31P-magnetic resonance spectroscopy. When compared with control animals, septic animals had a decrease in left ventricular ejection fraction (EF, P < 0.0001) on day 1 and fractional shortening (FS, P < 0.0003) on day 2 after clot implantation. On day 2, neither septic nor control animals had statistically significant decreases in PCr:ATP, despite catecholamine-induced increases in MVO2 and RPP (mean maximal increases in septic animals 135 +/- 31 and 51 +/- 10%, respectively). Light and electron microscopic findings showed that hearts of septic animals, compared with control animals, had a greater degree of morphological abnormalities. Thus, in a canine model of sepsis with alterations in myocyte ultrastructure and documented myocardial depression (decreased EF and FS), intracellular free energy levels (PCr:ATP) were maintained despite catecholamine-induced increases in myocardial work (increased MVO2 and RPP), suggesting high-energy synthetic capabilities are not limiting cardiac function.

scholarly journals EpCAM and microvascular obstruction in patients with STEMI: a cardiac magnetic resonance study

2021 ◽  
Vol 22 (Supplement_2) ◽  
Author(s):  
C Rios-Navarro ◽  
J Gavara ◽  
J Nunez ◽  
C Bonanad Lozano ◽  
E Revuelta-Lopez ◽  
...  
Keyword(s):  
Cardiac Magnetic Resonance ◽  
Magnetic Resonance ◽  
Microvascular Obstruction ◽  
Systolic Function ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
P Value ◽  
Ventricular Ejection Fraction ◽  
Systolic Volume

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): This study was funded by “Instituto de Salud Carlos III” and “Fondos Europeos de Desarrollo Regional FEDER” Bachground. Microvascular obstruction (MVO) is negatively associated with cardiac structure and worse prognosis after ST-segment elevation myocardial infarction (STEMI). Epithelial cell adhesion molecule (EpCAM), involved in endothelium adhesion, is an understudied area in the MVO setting. Purpose. We aimed to evaluate whether EpCAM is associated with the appearance of cardiac magnetic resonance (CMR)-derived MVO and long-term systolic function in reperfused STEMI. Methods. We prospectively included 106 patients with a first STEMI treated with primary percutaneous coronary intervention, quantifying serum levels of EpCAM 24 hours post-reperfusion. All patients underwent CMR imaging 1 week and 6 months post-STEMI. The independent correlation of EpCAM with MVO, systolic volume indices, and left ventricular ejection fraction (LVEF) was evaluated. Results. The mean age of the sample was 59 ± 13 years and 76% were male. Patients were dichotomized according to EpCAM median (4.48 pg/mL). At 1-week CMR, lower EpCAM was related to extensive MVO (p-value = 0.02) and greater infarct size (p-value = 0.02). At presentation, only EpCAM values were significantly associated with the presence of MVO in univariate (Odds Ratio [95% confidence interval] (OR [95% CI]): 0.58 [0.38-0.88], p-value = 0.01) and multivariate logistic regression models (OR [95% CI]: 0.54 [0.34-0.85], p-value = 0.007). Although MVO tends to resolve at chronic phases, decreased EpCAM was associated with worse systolic function: depressed LVEF (p-value = 0.009) and higher left ventricular end-systolic volume (p-value = 0.04). Conclusions. EpCAM is associated with occurrence of CMR-derived MVO at acute phases and long-term adverse ventricular remodeling post-STEMI. Future studies are needed to confirm EpCAM as biomarker, and eventually biotarget in STEMI pathophysiology.

scholarly journals The Diagnostic and Prognostic Utility of Contemporary Cardiac Magnetic Resonance in Suspected Acute Myocarditis

Diagnostics ◽  
2022 ◽  
Vol 12 (1) ◽  
pp. 156
Author(s):  
Jakub Lagan ◽  
Christien Fortune ◽  
David Hutchings ◽  
Joshua Bradley ◽  
Josephine H. Naish ◽  
...  
Keyword(s):  
Magnetic Resonance ◽  
Volume Fraction ◽  
Acute Myocarditis ◽  
Multivariable Analysis ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Ventricular Ejection Fraction ◽  
Parametric Mapping ◽  
The Impact

Cardiovascular magnetic resonance (CMR) is used to investigate suspected acute myocarditis, however most supporting data is retrospective and few studies have included parametric mapping. We aimed to investigate the utility of contemporary multiparametric CMR in a large prospective cohort of patients with suspected acute myocarditis, the impact of real-world variations in practice, the relationship between clinical characteristics and CMR findings and factors predicting outcome. 540 consecutive patients we recruited. The 113 patients diagnosed with myocarditis on CMR performed within 40 days of presentation were followed-up for 674 (504–915) days. 39 patients underwent follow-up CMR at 189 (166–209) days. CMR provided a positive diagnosis in 72% of patients, including myocarditis (40%) and myocardial infarction (11%). In multivariable analysis, male sex and shorter presentation-to-scan interval were associated with a diagnosis of myocarditis. Presentation with heart failure (HF) was associated with lower left ventricular ejection fraction (LVEF), higher LGE burden and higher extracellular volume fraction. Lower baseline LVEF predicted follow-up LV dysfunction. Multiparametric CMR has a high diagnostic yield in suspected acute myocarditis. CMR should be performed early and include parametric mapping. Patients presenting with HF and reduced LVEF require closer follow-up while those with normal CMR may not require it.

Electrophysiologic properties and ventricular fibrillation in normal and myopathic hearts

1999 ◽  
Vol 77 (7) ◽  
pp. 510-519 ◽  
Author(s):  
Katherine M Kavanagh ◽  
Patricia A Guerrero ◽  
Bodh I Jugdutt ◽  
Francis X Witkowski ◽  
Jeffrey E Saffitz
Keyword(s):  
Ventricular Fibrillation ◽  
Myocardial Dysfunction ◽  
Myocardial Cell ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Control Group ◽  
Functional Abnormality ◽  
Ventricular Ejection Fraction ◽  
Anisotropic Properties

This study tests the hypothesis that moderate myocardial dysfunction is associated with altered myocardial anisotropic properties and structurally altered ventricular fibrillation (VF). Mongrel dogs were randomized to either a control group or a group that was rapidly paced at 250 beats/min until the left ventricular ejection fraction was [Formula: see text] 40%. Changes in anisotropic properties and the electrical characteristics of VF associated with the development of moderate myocardial dysfunction were assessed by microminiature epicardial mapping studies. In vivo conduction, refractory periods, and repolarization times were prolonged in both longitudinal and transverse directions in myopathic animals versus controls. VF was different in myopathic versus control animals. There were significantly more conducted deflections during VF in normal hearts compared with myopathic hearts. Propagated deflection-to-deflection intervals during VF were significantly longer in myopathic hearts compared with controls (125.5 ± 49.06 versus 103.4 ± 32.9 ms, p = 0.009). There were no abnormalities in cell size, cell shape, or the number of intercellular gap junctions and there was no detectable change in the expression of the gap junction proteins Cx43 and Cx45. Moderate myocardial dysfunction is associated with significant electrophysiological abnormalities in the absence of changes in myocardial cell morphology or intercellular connections, suggesting a functional abnormality in cell-to-cell communication.Key words: cardiomyopathy, anisotropy, fibrillation, defibrillation.

Abstract 165: The 18 kDa FGF-2 Prevents the Doxorubicin-induced Cardiac Damage and Amp-activated Kinase Activation, in vitro and in vivo

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Navid Koleini ◽  
Jon Jon Santiago ◽  
Barbara E Nickel ◽  
Robert Fandrich ◽  
Davinder S Jassal ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Cell Death ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Wild Type ◽  
Rat Cardiomyocytes ◽  
Ventricular Ejection Fraction ◽  
Compound C

Introduction: Protection of the heart from chemotherapeutic (Doxorubicin, DOX) drug-induced toxicity is a desirable goal, to limit side effects of cancer treatments. DOX toxicity has been linked to the activation (phosphorylation) of the AMP-activated kinase, AMPK. The 18 kDa low molecular weight isoform of fibroblast growth factor 2 (Lo-FGF-2) is a known cardioprotective and cytoprotective agent. In this study we have tested the ability of Lo-FGF-2 to protect from DOX-induced damage in rat cardiomyocytes in vitro, and in transgenic mouse models in vivo, in relation to AMPK activation. Methods: Rat neonatal cardiomyocytes in culture were exposed to DOX (0.5 μM) in the presence or absence of pre-treatment Lo-FGF-2 (10 ng/ml). Compound C was used to block phosphorylation (activity) of AMPK. Levels of cell viability/death (using Calcein-AM/Propidium iodide assay), phospho -and total AMPK, and apoptotic markers such as active caspase 3 were analyzed. In addition, transgenic mice expressing only Lo-FGF2, and wild type mice, expressing both high molecular weight (Hi-FGF2) as well as Lo-FGF2 were subjected to DOX injection (20 mg/kg, intraperitoneal); echocardiography was used to examine cardiac function at baseline and at 10 days post-DOX. Results: DOX-induced cell death of cardiomyocytes in culture was maximal at 24 hours post-DOX coinciding with significantly increased in activated (phosphorylated) AMPK. Compound C attenuated DOX-induced cardiomyocyte loss. Pre-incubation with Lo-FGF-2 decreased DOX induced cell death, and also attenuated the phosphorylation of AMPK post-DOX. Relative levels of phospho-AMPK were lower in the hearts of Lo-FGF2-expressing male mice compared to wild type. DOX-induced loss of contractile function (left ventricular ejection fraction and endocardial velocity) was negligible in Lo-FGF2-expressing mice but significant in wild type mice. Conclusion: Lo-FGF-2 protects the heart from DOX-induced damage in vitro and in vivo, by a mechanism likely involving an attenuation of AMPK activity.

Sign in / Sign up

Export Citation Format

Share Document