Abstract 1553: Comparative Gene Expression Analysis of Blood and Heart Identifies Genomic Predictors of Myocardial Injury Following Cardiopulmonary Bypass and Cardioplegic Arrest in the Rat

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Mihai V Podgoreanu ◽  
Kenji Yoshitani ◽  
Adrian Dobra ◽  
Qing Ma ◽  
Bin Zhu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cardiac Surgery ◽  
Cardiopulmonary Bypass ◽  
Myocardial Injury ◽  
Expression Profiles ◽  
Left Ventricular ◽  
Male Rats ◽  
Cardioplegic Arrest ◽  
Fatty Acid Binding ◽  
Tissue Specific

Background: Perioperative myocardial injury (PMI) complicating cardiac surgery remains poorly predicted by clinical risk factors. In a novel rat model of cardiopulmonary bypass (CPB) and cardioplegic arrest (CA) we tested the hypothesis that microarray expression profiles in peripheral blood leukocytes (PBL) can accurately predict degree of PMI, and compared genomic signatures in left ventricular myocardium (LVM) and PBL to identify PMI-associated genes that generalize across tissues. Methods: Male rats subjected to CPB only (75 min), CPB with CA (30 min), and sham surgery (n=5 each) had plasma heart fatty acid binding protein (HFABP) and cardiac troponin I (cTnI) measured 1 hour post CPB and microarray profiling of total RNA from LVM and PBL. PMI genomic classification models were constructed using shotgun stochastic search approach and Bayesian model averaging and their accuracy tested by five-fold cross validation. Results: A spectrum of PMI was observed in the experimental groups as well as robust deregulation of gene expression in a stimulus and tissue-specific manner (Figure ). Estimates of PMI classification accuracy from PBL and LVM are presented in Table . Conclusions: Cardiac surgery induces changes in leukocyte gene expression that predict the spectrum of PMI, with potential applications in perioperative risk stratification and selection of cardioprotective strategies. Predictive accuracy of tissue-specific myocardial injury genomic classifiers

scholarly journals Identification of Differentially Expressed Genes and Processes in Myocardial Tissue of Liver-Specific Gck Knockout Mice

2020 ◽  
Author(s):  
Hui Li ◽  
Wei Xu ◽  
Yiqing Mao ◽  
Xi Wang ◽  
Ruoxuan Zhang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Gene Expression ◽  
Enzyme Activity ◽  
Knockout Mice ◽  
Myocardial Injury ◽  
Molecular Mechanisms ◽  
Gene Knockout ◽  
Expression Profiles ◽  
Left Ventricular ◽  
Significant Difference

Abstract Background: Diabetic cardiomyopathy is a ventricular disease caused by diabetes mellitus. Abnormalities in the function of the glucokinase (GCK) play an important role in the development of diabetes. The present study is aimed at exploring changes in gene expression and related molecular mechanisms of diabetic myocardial injury in Gck knockout mice. Methods: Liver-specific glucokinase gene knockout mice( Gck w/- ) and wide type ( Gck w/w )mice generated using the Cre-loxP gene targeting strategy of 30- and 60-weeks of age were used in these studies. Determination of liver glucokinase enzyme activity, liver glycogen content and serum biochemistry parameters reflect the metabolic disorder in these mice. Echocardiography and surface electrocardiographs were used to evaluate cardiac function. Superoxide dismutase activity and malondialdehyde levels reflect oxidative stress in the myocardium. RNAseq, GO enrichment analysis and qPCR wereused to detect differences in the myocardial gene expression profiles of Gck w/- and Gck w/w mice. Results: Hyperglycemia and insulin resistance induced by decreased liver glucokinase expression and enzyme activity throughout the life of heterozygous Gck knockout mice do not yield body weight significant difference. However, prolonged PR interval and QRS duration, decreased left ventricular diameter and increased thickness of the posterior wall of the left ventricle were accompanied by increase of PAS and Masson positive substances in the myocardium of 60-week-old Gck knockout mice. RNAseq analysis showed that genes related tothe myosin heavy and light chains, insulin signaling pathway and oxidative phosphorylation were significantly differentially expressedbetween60-week-old Gck w/- and Gck w/w mice. Phosphorylation of AMPKβ1 and ACC in 60-week-old Gck knockout mice was decreased. Conclusions: Liver-specific Gck knock-out can induce myocardial fibrosis at an early stage and diabetic myocardial injury at alate stage. Through this process, the proportion of myosin heavy chain and light chain falls out of balance, the insulin signal pathway becomes down regulated and mitochondrial oxidative stress is up regulated, leading to myocardial disease.

Impact of cardiopulmonary bypass and cardioplegic arrest on myocardial lymphatic function

1995 ◽  
Vol 268 (1) ◽  
pp. H178-H183 ◽  
Author(s):  
U. Mehlhorn ◽  
K. L. Davis ◽  
E. J. Burke ◽  
D. Adams ◽  
G. A. Laine ◽  
...  
Keyword(s):  
Cardiopulmonary Bypass ◽  
Left Ventricular Function ◽  
Ventricular Function ◽  
Myocardial Edema ◽  
Dry Weight ◽  
Myocardial Contraction ◽  
Left Ventricular ◽  
Lymph Flow ◽  
Cardioplegic Arrest ◽  
Lymphatic Function

Cardioplegic arrest (CPA) is associated with interstitial myocardial edema, which has been shown to impair myocardial function. The accumulation of interstitial myocardial edema may be enhanced by impaired myocardial lymph flow. The purpose of this study was to investigate the effects of CPA on myocardial lymphatic function. In nine anesthetized dogs, we cannulated a prenodal cardiac lymphatic and measured myocardial lymph flow rate (QL), myocardial lymph driving pressure (PL), and myocardial lymph hyaluronan (Hya) concentration. We determined left ventricular function using pressure-volume curves derived by sonomicrometry and micromanometry. The dogs were placed on cardiopulmonary bypass (CPB) (28 degrees C) and subjected to 60 min of hypothermic, crystalloid CPA. With the onset of asystole both QL and PL decreased significantly from 70.7 +/- 31.8 (SD) to 3.3 +/- 4.0 microliters/min and from 19.9 +/- 8.0 to 10.4 +/- 1.8 mmHg, respectively (P < 0.01). Following return of sinus rhythm after separation from CPB, QL and PL increased significantly to 135.4 +/- 28.0 microliters/min and 27.3 +/- 7.5 mmHg, respectively (P < 0.01). Post-CPA myocardial edema was demonstrated by gravimetric wet-to-dry weight determination of 3.67 +/- 0.20 (normal 2.90 +/- 0.20, P < 0.001) and was associated with significantly decreased left ventricular function. Myocardial Hya turnover rate was 1.3 +/- 1.0% per day under baseline conditions and increased significantly to 2.7 +/- 0.9% per day post-CPA (P < 0.01). We conclude that organized myocardial contraction is the major determinant of myocardial lymph flow. Myocardial lymph flow impairment during CPA may contribute to post-CPA myocardial edema and left ventricular dysfunction.

scholarly journals Analyzing cancer gene expression data through the lens of normal tissue-specificity

2021 ◽  
Author(s):  
H. Robert Frost
Keyword(s):  
Gene Expression ◽  
Normal Tissue ◽  
Tissue Specificity ◽  
Cancer Genomics ◽  
Expression Profiles ◽  
Genetic Alterations ◽  
Cancer Type ◽  
Tissue Specific ◽  
Normal Tissues ◽  
Cancer Types

AbstractThe genetic alterations that underlie cancer development are highly tissue-specific with the majority of driving alterations occurring in only a few cancer types and with alterations common to multiple cancer types often showing a tissue-specific functional impact. This tissue-specificity means that the biology of normal tissues carries important information regarding the pathophysiology of the associated cancers, information that can be leveraged to improve the power and accuracy of cancer genomic analyses. Research exploring the use of normal tissue data for the analysis of cancer genomics has primarily focused on the paired analysis of tumor and adjacent normal samples. Efforts to leverage the general characteristics of normal tissue for cancer analysis has received less attention with most investigations focusing on understanding the tissue-specific factors that lead to individual genomic alterations or dysregulated pathways within a single cancer type. To address this gap and support scenarios where adjacent normal tissue samples are not available, we explored the genome-wide association between the transcriptomes of 21 solid human cancers and their associated normal tissues as profiled in healthy individuals. While the average gene expression profiles of normal and cancerous tissue may appear distinct, with normal tissues more similar to other normal tissues than to the associated cancer types, when transformed into relative expression values, i.e., the ratio of expression in one tissue or cancer relative to the mean in other tissues or cancers, the close association between gene activity in normal tissues and related cancers is revealed. As we demonstrate through an analysis of tumor data from The Cancer Genome Atlas and normal tissue data from the Human Protein Atlas, this association between tissue-specific and cancer-specific expression values can be leveraged to improve the prognostic modeling of cancer, the comparative analysis of different cancer types, and the analysis of cancer and normal tissue pairs.

scholarly journals Screening of Differentiation-Specific Molecular Biomarkers for Colon Cancer

2018 ◽  
Vol 46 (6) ◽  
pp. 2543-2550 ◽  
Author(s):  
Lu Qi ◽  
Yanqing Ding
Keyword(s):  
Gene Expression ◽  
Colon Cancer ◽  
Molecular Markers ◽  
Cancer Cells ◽  
Cancer Patients ◽  
Roc Curve ◽  
Expression Profiles ◽  
Tissue Specific ◽  
Specificity And Sensitivity ◽  
Cancer Tissues

Background/Aims: Owing to the lack of effective molecular markers to evaluate colon cancer differentiation grade, screening of effective molecular markers for the diagnosis and treatment of colon cancer is of great significance. This study is a screening study for molecular markers related to the differentiation of colon using the tissue-specific genes of colon. Methods: This study compared the expression profiles of colon cancer at various differentiation grades and screened the down-regulated genes associated with decreased differentiation. IL22RA1 gene was derived from the intersection of obtained gene and colon tissue-specific genes. We used DriverDB and The Human Protein Atlas to analyze the expression level of IL22RA1 in various tissue cells, also used Kaplan-Meier method to analyze the correlation between IL22RA1 and the survival of colon cancer patients, and then used the ROC curve to analyze the specificity and sensitivity of IL22RA1 diagnosis of differentiated colon cancer. Results: We found that IL22RA1 gene expression was progressively down-regulated in high-differentiated, moderate-differentiated, low-differentiated, and undifferentiated colon cancer tissues. Both RNA and protein levels of IL22RA1 were higher in colon tissues and colon cancer tissues than in other normal and cancer tissues. Comparison of IL22RA1 expression in different cancer cells found that IL22RA1 expression was significantly higher in CACO-2 colon cancer cells than in other cancer cells. Survival analysis showed that IL22RA1 gene expression was positively correlated with the overall survival rate of colon cancer patients (P=0.0224). ROC curve analysis revealed that IL22RA1 expression had good specificity and sensitivity to stage II colon cancer. Conclusion: These findings suggest that IL22RA1 serves as a specific molecular marker for the differentiation of colon cancer.

scholarly journals P774 Utility of global longitudinal strain to predict post-operative outcomes in non-cardiac surgery

2020 ◽  
Vol 21 (Supplement_1) ◽  
Author(s):  
C J Park ◽  
L S Tan ◽  
P Huang ◽  
P J Tan ◽  
J H J See
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Surgery ◽  
Risk Stratification ◽  
Longitudinal Strain ◽  
Myocardial Injury ◽  
Global Longitudinal Strain ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Operative Outcomes ◽  
Lv Dysfunction

Abstract Background Pre-operative echocardiography is performed in selected groups of patients for cardiac risk stratification prior to surgery. Many parameters, including Left Ventricular Ejection Fraction (LVEF), are assessed during echocardiography. While many studies have cited association between low LVEF and poor operative outcomes such as perioperative myocardial infarction or cardiogenic pulmonary edema, LVEF has limitations such as left ventricular (LV) cavity border tracing, geometric assumptions and inter-observer variability. LVEF may also appear normal in the presence of LV hypertrophy and a small LV cavity size. Studies have described the routine use of global longitudinal strain (GLS) as an alternative measure of ventricular function, with GLS having been reported to be a reliable marker in detecting subclinical LV dysfunction. This adds incremental value in predicting myocardial function and in risk stratification. In fact, some studies have documented GLS being a useful preoperative parameter in predicting postoperative LV dysfunction after cardiac valve surgery. Purpose The aim of this study is to determine the value of GLS in predicting post-operative outcomes in patients undergoing non-cardiac surgeries. Methods This was a retrospective study of all patients who had echocardiography performed for a pre-operative indication from February 2017 to October 2017. These patients were screened for those who had normal LVEF, had undergone subsequent non-cardiac surgery, and had post-operative troponins measured. Medical records were traced for baseline demographics, past medical history and echocardiographic features. GLS evaluation was prospectively performed using TOMTEC-ARENA (TOMTEC Imaging Systems GmbH) by assessors blinded to patient outcomes. Outcomes for major adverse cardiovascular events and mortality up to 1 year post surgery were collected. Post-op myocardial injury was defined as a peak Troponin T value of &gt;30 ng/L or a &gt;20% increment from baseline. Results A total of 42 patients were included. 61.9% (n = 26) were male and mean age was 72.3 years. Only 75.6% of patients were fully independent with activities of daily living and mean creatinine was 153.4μmol/L. Mortality at 1 year was 16.7% (n = 7) and 28.6% (n = 12) were deemed to have post-operative myocardial injury. 1-year mortality was associated with a lower GLS (-23.8% vs -19.2%, p = 0.001). However, GLS was not correlated with post-operative myocardial injury or hospital readmissions. In our study population, only a history of past myocardial infarction predicted post-op myocardial injury (58.3% vs 16.7%, p = 0.019). Conclusion Our study did not demonstrate the utility of GLS in predicting post-operative events, but this is likely because of the small sample size with low event rates. Nevertheless, GLS values did correlate with 1-year mortality and could be a marker of frailty and an increased mortality risk.

scholarly journals Cardiac surgery in acute myocardial infarction: crystalloid versus blood cardioplegia – an experimental study

2020 ◽  
Vol 15 (1) ◽  
Author(s):  
Andreas Boening ◽  
Maximilian Hinke ◽  
Martina Heep ◽  
Kerstin Boengler ◽  
Bernd Niemann ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Cardiac Surgery ◽  
Cardiac Function ◽  
Infarct Size ◽  
Left Ventricular ◽  
Coronary Artery Ligation ◽  
Cardioplegic Arrest ◽  
Blood Cardioplegia ◽  
Cardioplegia Solution

Abstract Background Because hearts in acute myocardial infarction are often prone to ischemia-reperfusion damage during cardiac surgery, we investigated the influence of intracellular crystalloid cardioplegia solution (CCP) and extracellular blood cardioplegia solution (BCP) on cardiac function, metabolism, and infarct size in a rat heart model of myocardial infarction. Methods Following euthanasia, the hearts of 50 rats were quickly excised, cannulated, and inserted into a blood-perfused isolated heart apparatus. A regional myocardial infarction was created in the infarction group (18 hearts) for 120 min; the control group (32 hearts) was not subjected to infarction. In each group, either Buckberg BCP or Bretschneider CCP was administered for an aortic clamping time of 90 min. Functional parameters were recorded during reperfusion: coronary blood flow, left ventricular developed pressure (LVDP) and contractility (dp/dt max). Infarct size was determined by planimetry. The results were compared between the groups using analysis of variance or parametric tests, as appropriate. Results Cardiac function after acute myocardial infarction, 90 min of cardioplegic arrest, and 90 min of reperfusion was better preserved with Buckberg BCP than with Bretschneider CCP relative to baseline (BL) values (LVDP 54 ± 11% vs. 9 ± 2.9% [p = 0.0062]; dp/dt max. 73 ± 11% vs. 23 ± 2.7% [p = 0.0001]), whereas coronary flow was similarly impaired (BCP 55 ± 15%, CCP 63 ± 17% [p = 0.99]). The infarct in BCP-treated hearts was smaller (25% of myocardium) and limited to the area of coronary artery ligation, whereas in CCP hearts the infarct was larger (48% of myocardium; p = 0.029) and myocardial necrosis was distributed unevenly to the left ventricular wall. Conclusions In a rat model of acute myocardial infarction followed by cardioplegic arrest, application of BCP leads to better myocardial recovery than CCP.

Improved myocardial performance induced by dofibrate during reperfusion after acute myocardial infarction

1988 ◽  
Vol 66 (12) ◽  
pp. 1518-1523 ◽  
Author(s):  
M. Renuka Prasad ◽  
Ronald Clement ◽  
Hajime Otani ◽  
Randall Jones ◽  
Dipak K. Das ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Myocardial Injury ◽  
Left Ventricular ◽  
Ischemia And Reperfusion ◽  
Cardioplegic Arrest ◽  
Beneficial Effects ◽  
Hypolipidemic Drug ◽  
And Control ◽  
Experimental Pigs

The increase of cellular fatty acids appears to be one of the causes of the myocardial injury during ischemia and reperfusion. This study was designed to examine whether a hypolipidemic drug such as clofibrate can reduce the myocardial injury during ischemia and reperfusion. Clofibrate was fed to experimental pigs for 9 days. Isolated in situ hearts from both experimental and control pigs were subjected to 60 min of regional ischemia induced by occluding the left anterior descending coronary artery, followed by 60 min of global ischemia by hypothermic cardioplegic arrest and 60 min of reperfusion. The clofibrate feeding resulted in the better cardiac performance as judged by increased coronary blood flow, improved left ventricular function, and reduced myocardial injury as judged by creatine kinase release. Although the clofibrate-fed animals contained higher levels of thiobarbituric reactive materials, the free fatty acid levels of plasma and myocardium were much lower compared with control animals. The clofibrate feeding was also associated with increased peroxisomal catalase and (β-oxidation of fatty acids. These results suggest that decreased levels of free fatty acids in the plasma and the myocardium and increased catalase activity induced by antilipolytic therapy appear to provide beneficial effects to the myocardium during ischemia and reperfusion.

scholarly journals p38 MAPK-dependent small HSP27 and αB-crystallin phosphorylation in regulation of myocardial function following cardioplegic arrest

2011 ◽  
Vol 300 (5) ◽  
pp. H1669-H1677 ◽  
Author(s):  
Richard T. Clements ◽  
Jun Feng ◽  
Brenda Cordeiro ◽  
Cesario Bianchi ◽  
Frank W. Sellke
Keyword(s):  
Cardiac Surgery ◽  
Cardiac Function ◽  
P38 Mapk ◽  
Left Ventricular ◽  
Mitogen Activated Protein Kinase ◽  
Cardioplegic Arrest ◽  
Αb Crystallin ◽  
Length Changes ◽  
Sb 203580 ◽  
Isolated Rat

We previously demonstrated that myocardial p38 mitogen-activated protein kinase (MAPK) and heat shock protein 27 (HSP27) are phosphorylated following cardioplegic arrest in patients undergoing cardiac surgery and correlate with reduced cardiac function. The following studies were performed to determine whether inhibition of p38 MAPK and/or overexpression of nonphosphorylatable HSP27 improves cardiac function following cardioplegic arrest. Langendorff-perfused isolated rat hearts were subjected to 2 h of intermittent cold cardioplegia followed by 30 min of reperfusion. Hearts were treated with (CP+SB) or without (CP) the p38 MAPK inhibitor SB-203580 (5 μM) supplied in the cardioplegia. Sham-treated hearts served as controls. In separate experiments, isolated rat ventricular myocytes infected with either green fluorescent protein (GFP) or a nonphosphorylatable HSP27 mutant (3A-HSP27) were subjected to 3 h of cold hypoxic cardioplegia and simulated reperfusion (CP) followed by video microscopy and length change measurements. Baseline parameters of cardiac function were similar between groups [left ventricular developed pressure (LVDP), 119 ± 4.9 mmHg; positive and negative first derivatives of LV pressure (± dP/d t), 3,139 ± 245 and 2, 314 ± 110 mmHg/s]. CP resulted in reduced cardiac function (LVDP, 72.2 ± 5.8 mmHg; ± dP/d t, 2,076 ± 231 and −1,317 ± 156 mmHg/s) compared with baseline. Treatment with 5 μM SB-203580 significantly improved CP-induced cardiac function (LVDP, 101.9 ± 0 mmHg; ±dP/d t, 2,836 ± 163 and −2,108 ± 120 mmHg/s; P = 0.03, 0.01, and 0.04, CP+SB vs. CP). Inhibition of p38 MAPK significantly lowered CP-induced p38 MAPK, HSP27, and αB-crystallin (cryAB) phosphorylation. In vitro CP decreased myocyte length changes from 10.3 ± 1.5% (GFP) to 5.7 ± 0.8% (GFP+CP). Infection with 3A-HSP27 completely rescued CP-induced decreased myocyte contraction (11.1 ± 1.0%). However, infection with 3A-HSP27 did not block the endogenous HSP27 response. We conclude that inhibition of p38 MAPK and subsequent HSP27 and cryAB phosphorylation and/or overexpression of nonphosphorylatable HSP27 significantly improves cardiac performance following cardioplegic arrest. Modulation of HSP27 phosphorylation may improve myocardial stunning following cardiac surgery.

Sign in / Sign up

Export Citation Format

Share Document