Browsing by Subject "Myocardium"
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Item The aging myocardium (presbycardia): physiological (?) changes and their clinical implications(1979-01-18) Mitchell, Jere H.Item Biochemical and Functional Analysis of Members of the Myocardin Family During Cardiovascular Development(2006-12-20) Oh, Jiyeon; Olson, Eric N.The various stages of muscle development are characterized by distinct patterns of gene expression precisely controlled by combinatorial interaction between a large number of muscle-specific and ubiquitous transcription factors. Myocardin is a cardiac and smooth muscle-specific transcriptional coactivator of serum response factor (SRF) that forms a ternary complex with SRF on DNA and provides its strong transcriptional activation domain (TAD) to SRF. SRF has been shown to stimulate expression of smooth and cardiac muscle genes in association with GATA transcription factors, which play important roles in cardiac and smooth muscle development. I show that GATA transcription factors can either stimulate or suppress the transcriptional activity of myocardin, depending on the target gene. Modulation of myocardin activity by GATA4 is mediated by the physical interaction of myocardin with the DNA binding domain of GATA4 but does not require binding of GATA4 to DNA. The ability of GATA transcription factors to modulate myocardin activity provides a potential mechanism for fine tuning the expression of serum response factor target genes in a gene-specific manner. Two Myocardin Related Transcription Factors, referred to as MRTF-A and B, are expressed in numerous embryonic and adult tissues, implying their potential to modulate SRF target genes in a wide range of tissues. To determine the functions of MRTF-B in vivo, I generated MRTF-B mutant mice by targeted inactivation of the MRTF-B gene. I show that mice homozygous for an MRTF-B loss-of-function mutation die during mid-gestation from a spectrum of cardiovascular defects. These abnormalities are accompanied by a failure in differentiation of smooth muscle cells within the branchial arch arteries, which are derived from the neural crest. The phenotype of MRTF-B mutant mice is distinct from that of mice lacking myocardin and MRTF-A, revealing unique roles for these SRF coactivators in the development of different subsets of smooth muscle cells in vivo.Item Perfusion Solution Optimization by Substrate Alteration and Nanoparticle Delivery for Cardiac Hypothermic Machine Perfusion(2018-04-12) Holmes, Cyonna Theresa; Jessen, Michael; Peltz, Matthias; Nguyen, Kytai T.; Eberhart, Robert C.; Jin, EunsookCurrent heart donor procurement involves a period of cold storage during transport and rarely exceeds 6 hours. While this method reduces myocardial metabolism, it still results in ATP depletion, lactate accumulation, and myocyte damage. Hypothermic machine perfusion (HMP) has emerged as an alternative technique. Previous studies from our laboratory showed HMP maintains myocardial oxygen consumption, preserves ATP, reduces myocardial injury, minimizes lactate accumulation, and improves cardiac function after transplantation for storage intervals of over fourteen hours. Though HMP is more advantageous, myocardial metabolism and adjunctive protective strategies under these conditions are poorly understood. The purpose of this study was to 1) Determine myocardial substrate preferences during HMP 2) Evaluate the effect of metformin and insulin on substrate oxidation in the perfused heart 3) Demonstrate delivery of nanoparticles to the heart during HMP. In Aim 1, I investigated myocardial substrate selection by perfusing isolated rat hearts octanoate, ketones, or acetate with and without an anaplerotic substrate. 13C magnetic resonance spectroscopy (MRS) was performed on myocardial extracts and substrate contributions to oxidative metabolism were assessed by isotopomer analysis. Additional samples were analyzed by gas chromatography/mass spectroscopy to determine substrate effects on tricarboxylic acid (TCA) cycle intermediates and isotopomer distributions. Aim 2 assessed the ability of metformin and insulin to alter myocardial substrate oxidation during normokalemic, hyperkalemic, and post-ischemic reperfusion using a rat normothermic Langendorff model. Substrate selection and oxidation rates were determined by 13C MRS and isotopomer analysis as in Aim 1. Cardiac function and efficiency were measured. For Aim 3, a nanoparticle delivery system was constructed, and a nanoparticle perfusion model was validated for future addition of nanoparticles to the perfusate to modify cardiac injury. Nanoparticles were characterized and then tested in three and six-hour perfusion models for their ability to localize in cells. Data from Aim 1 demonstrated that octanoate and acetate were preferentially oxidized during HMP. Ketone oxidation remained a minor contributing substrate. TCA cycle intermediates were increased in all substrate containing groups compared to hearts immediately recovered or perfused without oxidizable substrate. An anaplerotic substrate was not required to achieve these results. In Aim 2, during normokalemia, insulin reduced ketone oxidation while the combination of insulin and metformin restored the control profile. Metformin reduced fatty acid oxidation in the cardioplegia model while neither drug influenced substrate selection during post-ischemic reperfusion. Cardiac function and efficiency were not altered in treatment groups. Lastly, Aim 3 results indicated that nanoparticles (diameter=376+/-98nm; polydispersity index=0.16+/-0.06; encapsulation efficiency=65+/-12%) showed successful uptake, reduced lactate, and increased high energy phosphate ratios in the 3-hour model. Outcomes from these experiments demonstrate that myocardial substrate preferences are different during HMP compared to normothermia. Nanoparticle delivery to myocardium during HMP is possible and has the potential to modify myocardial injury by delivering therapeutic agents, miRNA (miRNA-499), or other gene products. This data is critical in designing preservation solutions for the machine perfused heart.Item Propionate Increase Hyperpolarized H13CO3- Signal in Perfused Mouse Hearts(2014-02-04) Purmal, Colin; Malloy, Craig R.; Sherry, A. Dean; Merritt, Matthew E.BACKGROUND: As early as 2008, MR imaging of [1-13C]pyruvate and its metabolites, including bicarbonate, in post-ischemic pig hearts was reported (1). Since the method does not use ionizing radiation, there is widespread interest in applications in other fields including oncology (2). In the heart, pyruvate is oxidized to acetyl-CoA and CO2. Oxidation of hyperpolarized (HP) [1-13C]pyruvate to HP [13C]bicarbonate is reduced in injured myocardium, and the presence of preserved flux through pyruvate dehydrogenase (PDH) may identify viable myocardium (1). However, oxidation of alternative substrates normally present in the blood also reduces the appearance of HP [13C]bicarbonate even in healthy myocardium (3). Propionate, a short-chain three-carbon fatty acid normally present in the blood, is known to activate PDH, and it is under study as a nutritional therapy for heart failure (4). The efficacy of propionate for restoring PDH flux in hearts supplied with high concentrations of glucose and fatty acids was studied using 13C NMR isotopomer analysis paired with experiments using HP [1-13C]pyruvate. 13C NMR is a standard method for measuring fluxes in metabolic pathways. METHODS AND RESULTS: Hearts excised from fed C57/bl6 mice were perfused in Langendorff mode using a mixture of acetate (2 mM), glucose (8.25 mM), and with and without propionate (2 mM). O2 consumption was not changed for the two different perfusion conditions. Isotopomer analysis of extracts of the freeze-clamped hearts indicated that carboxylation of propionate was very active, as expected, and glucose oxidation was minimal. For HP experiments, the perfused heart was located inside a 10 mm cryogenically-cooled probe paired with a 14.1 Tesla nuclear magnetic resonance spectrometer. After addition of hyperpolarized pyruvate, NMR signals from lactate, alanine, bicarbonate, CO2, aspartate, malate, acetyl-carnitine, and glutamate were detected in real time and in a highly reproducible manner. The presence of propionate increased appearance of HP [13C]bicarbonate 37-fold. This is the first application of hyperpolarization with detection using a cryogenically-cooled probe. CONCLUSION: In the presence of a high concentration of a competing substrate, propionate stimulates PDH flux in perfused mouse hearts as measured by the appearance of hyperpolarized [13C]bicarbonate from metabolism of hyperpolarized [1-13C]pyruvate. REFERENCES 1. Golman K, Petersson JS, Magnusson P, Johansson E, Akeson P, Chai CM, Hansson G, Månsson S. Cardiac metabolism measured noninvasively by hyperpolarized 13C MRI. Magn Reson Med. 2008; 59: 1005-13. PMID: 18429038 2. Harrison CE, DeBerardinis RJ, Jindal AK, Yang C, Sherry AD, Malloy CR. Analysis of mitochondrial metabolism in cancer cells by combining hyperpolarization and isotopomer analysis. Proc Int Soc Magn Reson Med 2010;18:569. 3. Moreno KX, Sabelhaus SM, Merritt ME, Sherry AD, Malloy CR. Competition of Pyruvate with Physiological Substrates for Oxidation by the Heart: Implications for Studies with Hyperpolarized [1-13C]Pyruvate. Am J Physiol Heart Circ Physiol. 2010; 298: H1556 - 64. PMID: 20207817 4. Lango R, Smoleski RT, Rogowski J, Siebert J, Wujtewicz M, S?omi?ska EM, Lysiak-Szyd?owska W, Yacoub MH. Propionyl-L-carnitine improves hemodynamics and metabolic markers of cardiac perfusion during coronary surgery in diabetic patients. Cardiovasc Drugs Ther. 2005; 19: 267-75. PMID: 16187006Item [Southwestern News](2005-06-12) Siegfried, Amanda; Watson, JohnItem Validation of Feature Tracking Cardiac MRI for Myocardial Strain: The Dallas Heart Study(2017-01-17) Agusala, Vijay; Berry, Jarett; Martens, Spencer; Pandey, Ambarish; Khera, Rohan; Ayers, ColbyBACKGROUND: Prior studies using speckle tracking echocardiography or cardiac magnetic resonance imaging (CMR) with myocardial tissue tagging show several factors to be associated with higher (worse) left ventricular (LV) strain (e.g. African-American race and male gender). The study aims to assess the validity of a new technique, Feature-tracking (FT) CMR, by evaluating the associations between strain measured by FT CMR and demographics and cardiovascular risk factors previously shown to be associated with strain by more established techniques. METHODS: Left ventricular longitudinal (GLS) and circumferential (GCS) strain values were measured in participants from the Dallas Heart Study (DHS), a multi-ethnic, population-based probability sample of adults in Dallas County. Linear regression models were constructed with GCS and GLS as the outcome variables in separate models adjusted for cardiovascular risk factors and left ventricular MRI characteristics (stroke volume (SV), LV mass, end diastolic volume (EDV), and LV ejection fraction(LVEF)). RESULTS: An interim analysis was conducted on 1,134 MRI studies. Greater LV mass was associated with increased (worse) GCS and GLS (ß=0.21, p<0.0001; ß=0.14, p<0.0001, respectively), while higher SV (ß=-0.15, p<0.0001; ß=-0.24, p<0.0001, respectively) and higher LVEF (ß=-0.-0.50, p<0.0001; ß=-0.22, p<0.0001, respectively) were found to be associated with decreased (better) strain values of both types. Higher EDV was associated with increased (worse) GCS strain values (ß=0.18, p<0.0001) but decreased (better) GLS strain values (ß= -0.07, p=0.0279). Male gender was associated with increased (worse) GCS and GLS strain values (ß=0.23, p<0.0001; ß=0.28, p<0.0001, respectively), and African-American race was also similarly associated with increased strain values (ß=0.12, p=0.0004; ß=0.11, p=0.0011, respectively). CONCLUSION: FT CMR is a reliable method of measuring GCS and GLS. Known factors associated with higher (worse) strain in prior studies were reflected in the FT CMR data, as conversely were factors that associated with decreased (better) strain, such as higher LVEF and SV.