Quantification of global myocardial oxygenation in humans: initial experience

<p>Abstract</p> <p>Purpose</p> <p>To assess the feasibility of our newly developed cardiovascular magnetic resonance (CMR) methods to quantify global and/or regional myocardial oxygen consumption rate (MVO₂) at rest and during pharmacologically-induced vasodilation in normal volunteers.</p> <p>Methods</p> <p>A breath-hold T₂quantification method is developed to calculate oxygen extraction fraction (OEF) and MVO₂rate at rest and/or during hyperemia, using a two-compartment model. A previously reported T₂quantification method using turbo-spin-echo sequence was also applied for comparison. CMR scans were performed in 6 normal volunteers. Each imaging session consisted of imaging at rest and during adenosine-induced vasodilation. The new T₂quantification method was applied to calculate T₂in the coronary sinus (CS), as well as in myocardial tissue. Resting CS OEF, representing resting global myocardial OEF, and myocardial OEF during adenosine vasodilation were then calculated by the model. Myocardial blood flow (MBF) was also obtained to calculate MVO₂, by using a first-pass perfusion imaging approach.</p> <p>Results</p> <p>The T₂quantification method yielded a hyperemic OEF of 0.37 ± 0.05 and a hyperemic MVO₂of 9.2 ± 2.4 μmol/g/min. The corresponding resting values were 0.73 ± 0.05 and 5.2 ± 1.7 μmol/g/min respectively, which agreed well with published literature values. The MVO₂rose proportionally with rate-pressure product from the rest condition. The T₂sensitivity is approximately 95% higher with the new T₂method than turbo-spin-echo method.</p> <p>Conclusion</p> <p>The CMR oxygenation method demonstrates the potential for non-invasive estimation of myocardial oxygenation, and should be explored in patients with altered myocardial oxygenation.</p

Resting myocardial perfusion quantification with CMR arterial spin labeling at 1.5 T and 3.0 T

<p>Abstract</p> <p>Background</p> <p>The magnetic resonance technique of arterial spin labeling (ASL) allows myocardial perfusion to be quantified without the use of a contrast agent. This study aimed to use a modified ASL technique and <it>T</it>₁regression algorithm, previously validated in canine models, to calculate myocardial blood flow (MBF) in normal human subjects and to compare the accuracy and repeatability of this calculation at 1.5 T and 3.0 T. A computer simulation was performed and compared with experimental findings.</p> <p>Results</p> <p>Eight subjects were imaged, with scans at 3.0 T showing significantly higher <it>T</it>₁values (<it>P </it>< 0.001) and signal-to-noise ratios (SNR) (<it>P </it>< 0.002) than scans at 1.5 T. The average MBF was found to be 0.990 ± 0.302 mL/g/min at 1.5 T and 1.058 ± 0.187 mL/g/min at 3.0 T. The repeatability at 3.0 T was improved 43% over that at 1.5 T, although no statistically significant difference was found between the two field strengths. In the simulation, the accuracy and the repeatability of the MBF calculations were 61% and 38% higher, respectively, at 3.0 T than at 1.5 T, but no statistically significant differences were observed. There were no significant differences between the myocardial perfusion data sets obtained from the two independent observers. Additionally, there was a trend toward less variation in the perfusion data from the two observers at 3.0 T as compared to 1.5 T.</p> <p>Conclusion</p> <p>This suggests that this ASL technique can be used, preferably at 3.0 T, to quantify myocardial perfusion in humans and with further development could be useful in the clinical setting as an alternative method of perfusion analysis.</p

Mitochondrial pyruvate carrier inhibition initiates metabolic crosstalk to stimulate branched chain amino acid catabolism

OBJECTIVE: The mitochondrial pyruvate carrier (MPC) has emerged as a therapeutic target for treating insulin resistance, type 2 diabetes, and nonalcoholic steatohepatitis (NASH). We evaluated whether MPC inhibitors (MPCi) might correct impairments in branched chain amino acid (BCAA) catabolism, which are predictive of developing diabetes and NASH. METHODS: Circulating BCAA concentrations were measured in people with NASH and type 2 diabetes, who participated in a recent randomized, placebo-controlled Phase IIB clinical trial to test the efficacy and safety of the MPCi MSDC-0602K (EMMINENCE; NCT02784444). In this 52-week trial, patients were randomly assigned to placebo (n = 94) or 250 mg MSDC-0602K (n = 101). Human hepatoma cell lines and mouse primary hepatocytes were used to test the direct effects of various MPCi on BCAA catabolism in vitro. Lastly, we investigated how hepatocyte-specific deletion of MPC2 affects BCAA metabolism in the liver of obese mice and MSDC-0602K treatment of Zucker diabetic fatty (ZDF) rats. RESULTS: In patients with NASH, MSDC-0602K treatment, which led to marked improvements in insulin sensitivity and diabetes, had decreased plasma concentrations of BCAAs compared to baseline while placebo had no effect. The rate-limiting enzyme in BCAA catabolism is the mitochondrial branched chain ketoacid dehydrogenase (BCKDH), which is deactivated by phosphorylation. In multiple human hepatoma cell lines, MPCi markedly reduced BCKDH phosphorylation and stimulated branched chain keto acid catabolism; an effect that required the BCKDH phosphatase PPM1K. Mechanistically, the effects of MPCi were linked to activation of the energy sensing AMP-dependent protein kinase (AMPK) and mechanistic target of rapamycin (mTOR) kinase signaling cascades in vitro. BCKDH phosphorylation was reduced in liver of obese, hepatocyte-specific MPC2 knockout (LS-Mpc2-/-) mice compared to wild-type controls concomitant with activation of mTOR signaling in vivo. Finally, while MSDC-0602K treatment improved glucose homeostasis and increased the concentrations of some BCAA metabolites in ZDF rats, it did not lower plasma BCAA concentrations. CONCLUSIONS: These data demonstrate novel cross talk between mitochondrial pyruvate and BCAA metabolism and suggest that MPC inhibition leads to lower plasma BCAA concentrations and BCKDH phosphorylation by activating the mTOR axis. However, the effects of MPCi on glucose homeostasis may be separable from its effects on BCAA concentrations

Silencing alanine transaminase 2 in diabetic liver attenuates hyperglycemia by reducing gluconeogenesis from amino acids

Hepatic gluconeogenesis from amino acids contributes significantly to diabetic hyperglycemia, but the molecular mechanisms involved are incompletely understood. Alanine transaminases (ALT1 and ALT2) catalyze the interconversion of alanine and pyruvate, which is required for gluconeogenesis from alanine. We find that ALT2 is overexpressed in the liver of diet-induced obese and db/db mice and that the expression of the gene encoding ALT2 (GPT2) is downregulated following bariatric surgery in people with obesity. The increased hepatic expression of Gpt2 in db/db liver is mediated by activating transcription factor 4, an endoplasmic reticulum stress-activated transcription factor. Hepatocyte-specific knockout of Gpt2 attenuates incorporation o

Evaluation of urinary hydrogen peroxide as an oxidative stress biomarker in a healthy Japanese population

The usefulness of urinary hydrogen peroxide (H2O2) as an oxidative stress biomarker was evaluated in 766 healthy Japanese. The mean level of urinary concentrations of H2O2 was 5.66 +/- 8.27 mu mol/g creatinine, and was significantly higher in females than in males. Significant correlations of H2O2 were observed with age, aspartate aminotransferase (AST), alanine aminotransferase (ALT), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-c), insulin, 8-hydroxy-2'-deoxyguanosine (8-OHdG), and exercise habit in females. In both sexes, H2O2 showed a significant correlation with 8-OHdG. By a multiple logistic regression analysis, urinary H2O2 was positively associated with urinary 8-OHdG and TC and was inversely associated with insulin. By stratification of sex and age, the association of urinary H2O2 with TC was positive in both sexes under 50 years old and was inverse in males over 50 years old, and that with insulin was inverse in males over 50 years old and in females under 50 years old. Moreover, by stratification of sex and age, a positive association of H2O2 with exercise and an inverse association of H2O2 with alcohol consumption became clear in males under 50 years old, although there were no significant odds for H2O2 after adjustment for covariates. In conclusion, the present results suggest that urinary H2O2 is a useful biomarker for oxidative stress, showing an association with 8-OHdG, TC, and insulin independently

The tuberculosis necrotizing toxin kills macrophages by hydrolyzing NAD.

Mycobacterium tuberculosis (Mtb) induces necrosis of infected cells to evade immune responses. Recently, we found that Mtb uses the protein CpnT to kill human macrophages by secreting its C-terminal domain, named tuberculosis necrotizing toxin (TNT), which induces necrosis by an unknown mechanism. Here we show that TNT gains access to the cytosol of Mtb-infected macrophages, where it hydrolyzes the essential coenzyme NAD(+). Expression or injection of a noncatalytic TNT mutant showed no cytotoxicity in macrophages or in zebrafish zygotes, respectively, thus demonstrating that the NAD(+) glycohydrolase activity is required for TNT-induced cell death. To prevent self-poisoning, Mtb produces an immunity factor for TNT (IFT) that binds TNT and inhibits its activity. The crystal structure of the TNT-IFT complex revealed a new NAD(+) glycohydrolase fold of TNT, the founding member of a toxin family widespread in pathogenic microorganisms

Review of journal of cardiovascular magnetic resonance 2010

There were 75 articles published in the Journal of Cardiovascular Magnetic Resonance (JCMR) in 2010, which is a 34% increase in the number of articles since 2009. The quality of the submissions continues to increase, and the editors were delighted with the recent announcement of the JCMR Impact Factor of 4.33 which showed a 90% increase since last year. Our acceptance rate is approximately 30%, but has been falling as the number of articles being submitted has been increasing. In accordance with Open-Access publishing, the JCMR articles go on-line as they are accepted with no collating of the articles into sections or special thematic issues. Last year for the first time, the Editors summarized the papers for the readership into broad areas of interest or theme, which we felt would be useful to practitioners of cardiovascular magnetic resonance (CMR) so that you could review areas of interest from the previous year in a single article in relation to each other and other recent JCMR articles [1]. This experiment proved very popular with a very high rate of downloading, and therefore we intend to continue this review annually. The papers are presented in themes and comparison is drawn with previously published JCMR papers to identify the continuity of thought and publication in the journal. We hope that you find the open-access system increases wider reading and citation of your papers, and that you will continue to send your quality manuscripts to JCMR for publication

MRI and CT in the diagnosis of coronary artery disease: indications and applications

In recent years, technical advances and improvements in cardiac computed tomography (CT) and cardiac magnetic resonance imaging (MRI) have provoked increasing interest in the potential clinical role of these techniques in the non-invasive work-up of patients with suspected coronary artery disease (CAD) and correct patient selection for these emerging imaging techniques. In the primary detection or exclusion of significant CAD, e.g. in the patient with unspecific thoracic complaints, and also in patients with known CAD or advanced stages of CAD, both CT and MRI yield specific advantages. In this review, the major aspects of non-invasive MR and CT imaging in the diagnosis of CAD will be discussed. The first part describes the clinical value of contrast-enhanced non-invasive CT coronary angiography (CTCA), including the diagnostic accuracy of CTCA for the exclusion or detection of significant CAD with coronary artery stenoses that may require angioplastic intervention, as well as potentially valuable information on the coronary artery vessel wall. In the second section, the potential of CT for the imaging of myocardial viability and perfusion will be highlighted. In the third and final part, the range of applications of cardiac MRI in CAD patients will be outlined

Adenosine stress CMR T1-mapping detects early microvascular dysfunction in patients with type 2 diabetes mellitus without obstructive coronary artery disease

Background Type 2 diabetes mellitus (T2DM) is associated with coronary microvascular dysfunction in the absence of obstructive coronary artery disease (CAD). Cardiovascular magnetic resonance (CMR) T1-mapping at rest and during adenosine stress can assess coronary vascular reactivity. We hypothesised that the non-contrast T1 response to vasodilator stress will be altered in patients with T2DM without CAD compared to controls due to coronary microvascular dysfunction. Methods Thirty-one patients with T2DM and sixteen matched healthy controls underwent CMR (3 T) for cine, rest and adenosine stress non-contrast T1-mapping (ShMOLLI), first-pass perfusion and late gadolinium enhancement (LGE) imaging. Significant CAD (>50% coronary luminal stenosis) was excluded in all patients by coronary computed tomographic angiography. Results All subjects had normal left ventricular (LV) ejection and LV mass index, with no LGE. Myocardial perfusion reserve index (MPRI) was lower in T2DM than in controls (1.60 ± 0.44 vs 2.01 ± 0.42; p = 0.008). There was no difference in rest native T1 values (p = 0.59). During adenosine stress, T1 values increased significantly in both T2DM patients (from 1196 ± 32 ms to 1244 ± 44 ms, p < 0.001) and controls (from 1194 ± 26 ms to 1273 ± 44 ms, p < 0.001). T2DM patients showed blunted relative stress non-contrast T1 response (T2DM: ΔT1 = 4.1 ± 2.9% vs. controls: ΔT1 = 6.6 ± 2.6%, p = 0.007) due to a blunted maximal T1 during adenosine stress (T2DM 1244 ± 44 ms vs. controls 1273 ± 44 ms, p = 0.045). Conclusions Patients with well controlled T2DM, even in the absence of arterial hypertension and significant CAD, exhibit blunted maximal non-contrast T1 response during adenosine vasodilatory stress, likely reflecting coronary microvascular dysfunction. Adenosine stress and rest T1 mapping can detect subclinical abnormalities of the coronary microvasculature, without the need for gadolinium contrast agents. CMR may identify early features of the diabetic heart phenotype and subclinical cardiac risk markers in patients with T2DM, providing an opportunity for early therapeutic intervention

A high resolution atlas of gene expression in the domestic sheep (Ovis aries)

Sheep are a key source of meat, milk and fibre for the global livestock sector, and an important biomedical model. Global analysis of gene expression across multiple tissues has aided genome annotation and supported functional annotation of mammalian genes. We present a large-scale RNA-Seq dataset representing all the major organ systems from adult sheep and from several juvenile, neonatal and prenatal developmental time points. The Ovis aries reference genome (Oar v3.1) includes 27,504 genes (20,921 protein coding), of which 25,350 (19,921 protein coding) had detectable expression in at least one tissue in the sheep gene expression atlas dataset. Network-based cluster analysis of this dataset grouped genes according to their expression pattern. The principle of 'guilt by association' was used to infer the function of uncharacterised genes from their co-expression with genes of known function. We describe the overall transcriptional signatures present in the sheep gene expression atlas and assign those signatures, where possible, to specific cell populations or pathways. The findings are related to innate immunity by focusing on clusters with an immune signature, and to the advantages of cross-breeding by examining the patterns of genes exhibiting the greatest expression differences between purebred and crossbred animals. This high-resolution gene expression atlas for sheep is, to our knowledge, the largest transcriptomic dataset from any livestock species to date. It provides a resource to improve the annotation of the current reference genome for sheep, presenting a model transcriptome for ruminants and insight into gene, cell and tissue function at multiple developmental stages