Inhibition of xanthine oxidase ameliorates functional and metabolic impairment in type 2 diabetic hearts under pressure overload

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
Y Igaki ◽  
A Osanami ◽  
M Tanno ◽  
T Sato ◽  
T Ogawa ◽  
...  
Keyword(s):  
Diastolic Dysfunction ◽  
Xanthine Oxidase ◽  
Adenine Nucleotide ◽  
Vascular Dysfunction ◽  
Pressure Overload ◽  
Diabetic Control ◽  
Funding Source ◽  
National Budget ◽  
Adenine Nucleotide Pool

Abstract Background We recently reported that upregulated AMP deaminase (AMPD), via reduction in the tissue adenine nucleotide pool, contributes to exacerbation of diastolic dysfunction under pressure overload in OLETF, a rat model of obese type 2 diabetes (T2DM). Upregulated AMPD also possibly promotes xanthine oxidase (XO)-mediated ROS production, since AMPD deaminases AMP to IMP, which is further converted to inosine, providing substrates of XO, hypoxanthine and xanthine. Here, we examined the hypothesis that inhibition of XO ameliorates the pressure overload-induced diastolic dysfunction by suppression of ROS-mediated mitochondrial dysfunction and/or vascular dysfunction in T2DM rats. Methods and results Metabolomic analyses revealed that levels of xanthine and uric acid in the LV myocardium were significantly higher by 37% and 51%, respectively, in OLETF than in LETO, non-diabetic control rats, under the condition of phenylephrine-induced pressure overloading (200–230 mmHg). Myocardial XO activity in OLETF was 57.9% higher than that in LETO, which may be attributed to 31% higher level of inosine, a positive regulator of XO, in OLETF than in LETO. The activity of XO was significantly attenuated by administration of topiroxostat, an XO inhibitor at 0.5 mg/kg/day for 14 days. Pressure volume loop analyses showed that the pressure overloading resulted in significantly higher LVEDP in OLETF than in LETO (18.3±1.5 vs. 12.2±1.3 mmHg, p<0.05, n=7), though LVEDPs at baseline were comparable in OLETF and LETO (5.6±0.4 vs. 4.7±0.7 mmHg). Treatment with topiroxostat significantly suppressed the pressure overload-induced elevation of LVEDP in OLETF (18.3±1.5 vs. 11.3±1.1 mmHg, p<0.05) but not in LETO. Under the condition of pressure overloading, Ea/Ees, an index for ventricular-arterial coupling, was higher in OLETF than in LETO (2.3±0.3 vs. 1.6±0.3, p<0.05), and it was also improved by topiroxostat in OLETF (1.2±0.2, p<0.05). Myocardial ATP content was lower in OLETF than in LETO (2966±400 vs. 1818±171 nmol/g wet tissue, p<0.05), and treatment with topiroxostat significantly restored the ATP level (2629±307 nmol/g wet tissue). The LV myocardium of OLETF under pressure overload showed significantly higher level of malondialdehyde and 4-hydroxynonenal, an indicator of lipid peroxidation, than that of LETO. Measurement of oxygen consumption rate by Seahorse XFe96 Analyzer in mitochondria isolated from LV tissues revealed that state 3 respiration was significantly suppressed in OLETF by 43% compared to LETO, and it was restored by treatment with topiroxostat. Conclusion Both activity and substrates of XO are increased in T2DM hearts, in which upregulation of AMPD may play a role. Inhibition of XO ameliorates pressure overload-induced diastolic dysfunction and improves ventricular-arterial coupling in diabetic hearts, most likely through protection of mitochondrial function from ROS-mediated injury. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Grant-in-aid for Scientific Research (#26461132, #17K09584) from the Japanese Society for the Promotion of Science

P121 Pressure overload-induced functional and metabolic impairments in type 2 diabetic hearts are ameliorated by inhibition of xanthine oxidase

2020 ◽  
Vol 41 (Supplement_1) ◽  
Author(s):  
Y Igaki ◽  
M Tanno ◽  
H Kouzu ◽  
Y Tatekoshi ◽  
T Yano ◽  
...  
Keyword(s):  
Diastolic Dysfunction ◽  
Xanthine Oxidase ◽  
Pressure Overload ◽  
Ventricular Myocardium ◽  
Left Ventricular ◽  
Left Ventricular Myocardium ◽  
Dependent Manner ◽  
Phenylephrine Infusion ◽  
Type 2 Diabetic

Abstract Funding Acknowledgements SANWA KAGAKU KENKYUSHO Co., Ltd. Background   We have recently demonstrated that AMP deaminase (AMPD) is upregulated in OLETF, obese type 2 diabetic (T2DM) rats, and that the upregulated AMPD contributes to depletion of myocardial ATP at the time of pressure overload, leading to diastolic dysfunction.  On the other hand, AMPD promotes the formation of IMP from AMP, and IMP is in turn further converted to hypoxanthine and xanthine, substrates of xanthine oxidase (XO), which produces uric acid with ROS as a byproduct.  Based on these findings, we tested the hypothesis that inhibition of XO ameliorates the pressure overload-induced diastolic dysfunction in T2DM rats.  Methods and results Metabolomic analyses of the left ventricular myocardium revealed that levels of myocardial hypoxanthine and xanthine were significantly higher by 30% and 28%, respectively, in OLETF than in LETO, non-diabetic control rats, under the condition of pressure overloading (200-230 mmHg) induced by phenylephrine infusion. Myocardial XO activity in OLETF was 57.9% higher than that in LETO, and the activity was significantly attenuated by oral administration of topiroxostat, an XO inhibitor, at 0.1-0.5 mg/kg/day for 14 days in a dose-dependent manner.  Pressure volume loop analyses showed that the pressure overloading induced by phenylephrine infusion resulted in significantly higher LVEDP in OLETF than in LETO (18.3 ± 1.5 vs. 12.2 ± 1.3 mmHg, p < 0.05, n = 7), though LVEDPs at baseline were comparable in OLETF and LETO (5.6 ± 0.4 vs. 4.7 ± 0.7 mmHg).  Treatment with topiroxostat significantly suppressed the pressure overload-induced elevation of LVEDP in OLETF (18.3 ± 1.5 vs. 11.3 ± 1.1 mmHg, p < 0.05) but not in LETO.  Tau, the time constant of LV pressure decay, was significantly prolonged to 14.7 ± 0.7 ms (p < 0.05) by pressure overloading in OLETF but not in LETO, though baseline Tau values were similar in LETO and OLETF (6.1 ± 0.2 vs. 8.0 ± 0.4 ms).  The prolongation of Tau by pressure overloading in OLETF was significantly attenuated by treatment with topiroxostat.  Ea/Ees, an index for ventricular-arterial coupling, was higher in OLETF than in LETO (2.3 ± 0.3 vs. 1.6 ± 0.3, p < 0.05) under the condition of pressure overloading, and it was also improved by topiroxostat in OLETF (1.2 ± 0.2, p < 0.05).  Myocardial ATP content was lower in OLETF than in LETO under the condition of pressure overloading (2966 ± 400 vs. 1818 ± 171 nmol/g wet tissue, p < 0.05), but treatment with topiroxostat significantly restored the ATP level (2629 ± 307 nmo/g wet tissue). Conclusion:  In T2DM hearts, not only XO activity but also XO substrates are upregulated and upregulated AMPD may be involved in the upregulation.  Inhibition of XO ameliorates pressure overload-induced diastolic dysfunction and improves ventricular-arterial coupling most likely through augmented ATP preservation.

Purine metabolic pathways in rat hindlimb perfusion model during ischemia and reperfusion

1993 ◽  
Vol 265 (4) ◽  
pp. H1074-H1081 ◽  
Author(s):  
B. Soussi ◽  
K. Lagerwall ◽  
J. P. Idstrom ◽  
T. Schersten
Keyword(s):  
Skeletal Muscle ◽  
Blood Cell ◽  
Xanthine Oxidase ◽  
Flow Rate ◽  
Adenine Nucleotide ◽  
Vascular Endothelial Cell ◽  
Nucleotide Metabolism ◽  
Computer Simulation Model ◽  
Tissue Homogenates ◽  
Adenine Nucleotide Pool

The perfused rat hindlimb preparation was used with a blood cell-free perfusate to investigate alterations in the purine nucleotide metabolism, flow rate, perfusion pressure, and venous excretion in response to ischemia and ischemia followed by reperfusion in skeletal muscle. The development of a physical hindrance during postischemic reperfusion, indicated by an increase in reperfusion pressure and a decrease in flow rate, coincided with a 90% decrease in phosphocreatine and a 50-70% reduction in total adenine nucleotide pool. The reflow impairment could not be explained by blood cell plugging of the capillaries. Washout of several metabolites was demonstrated during reperfusion. Hypoxanthine accumulated intracellularly during ischemia, and a substantial amount of uric acid was excreted into the venous effluent during reperfusion. The experimental data were fitted into a computer simulation model of the purine pathways. The model indicated that AMP deaminase was the predominant enzymatic pathway for the AMP degradation. It was demonstrated that ATP preferably accumulated as inosine-5'-monophosphate during ischemia and that xanthine oxidase was undetectable in skeletal muscle tissue homogenates. However, vascular endothelial cell xanthine oxidase activity responsible for a free radical-induced reperfusion injury could not be excluded.

High HBA1C Level Is Associated With Low Heamoglobin Level

2018 ◽  
Vol 3 (02) ◽  
Author(s):  
Mafooza Rashid ◽  
B. K. Gupta, Vinay Bharat ◽  
Abhishek Gupta ◽  
Zubair Rashid
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Glycosylated Hemoglobin ◽  
Good Control ◽  
Diabetic Control ◽  
Medical College ◽  
High Hba1c ◽  
Normal Controls

Background: The aim of the study was to compare the hemoglobin levels among normal controls (patients) and patients of TypeII diabetes with HbA1c levels below 7 % & above 7 %.and secondly to identify the undetected cases of anemia in TypeII diabetes. Materials & Methods - 50 patients of type 2 diabetes mellitus with their glycosylated hemoglobin levels less than 7 %, 50 patients of type 2 diabetes mellitus with their glycosylated hemoglobin levels more than 7 % attending the Medicine outpatient department of Subharti Medical College and Hospital will be the subjects for the study.50 age and sex matched controls will be selected randomly from Subharti Medical College and Hospital. Informed written consent will be taken from all the subjects. The study will be conducted from January 2016 to January. Result - We studied 50 cases with HbA1C>7(poor control),50 cases with HbA1C 5.6 to7 (good control) and 50 controls with HbA1C ≤5.6, we observed in cases with HbA1C>7 (poorly control) ,the mean HbA1C is 9.9±2 and mean Hb is 9.8±1.3 as compared to cases with HbA1C 5.6 to 7(good control) where mean HbA1C is 6±0.4 and Hb is 13±0.5,this clearly indicates that in cases HbA1C is more Hb levels are low and when HbA1C is less Hb levels are higher. Conclusion - In the present study we found negative correlation between HbA1c & Hb levels. As the value of HbA1c increases, as in cases of HbA1c >7(poor diabetic control), we found low Hb levels as compared to the cases with HbA1c <7(5.6-7) (good control).

Type 1 Diabetes Mellitus - Risk Factor for Cardiovascular Disease Morbidity and Mortality

2020 ◽  
Vol 17 (1) ◽  
pp. 37-54
Author(s):  
Tatyana Chalakova ◽  
Yoto Yotov ◽  
Kaloyan Tzotchev ◽  
Sonya Galcheva ◽  
Boyan Balev ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 1 Diabetes ◽  
Type 1 Diabetes Mellitus ◽  
Diabetic Control ◽  
Macrovascular Complications ◽  
Morbidity And Mortality ◽  
Diabetes Mellitus Risk

: Type 1 diabetes mellitus (T1DM) is a chronic disease that starts early in life and often leads to micro- and macrovascular complications. The incidence of the disease is lower than that of type 2 DM and varies in different countries and ethnic groups, and the etiological and pathogenetic factors are different from T2DM. The aim of this overview is to investigate the effect of T1DM on all-cause mortality and CVD morbidity and mortality. During the last decades, the treatment of T1DM has improved the prognosis of the patients. Still, the mortality rates are higher than those of the age- and sex-matched general population. With the prolonged survival, the macrovascular complications and cardiovascular diseases (CVD) appear as major health problems in the management of patients with T1DM. The studies on the CVD morbidity and mortality in this disease group are sparse, but they reveal that T1DM is associated with at least 30% higher mortality. In comparison to healthy people, CVDs are more common in T1DM patients and they occur earlier in life. : Furthermore, they are a major cause for death and impaired quality of life in T1DM patients. The correlation between diabetic control and the duration of T1DM is not always present or is insignificant. Nevertheless, the early detection of the preclinical stages of the diseases and the risk factors for their development is important; similarly, the efforts to improve glycemic and metabolic control are of paramount importance.

scholarly journals Monocyte subsets predict mortality after cardiac arrest

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
K.A Krychtiuk ◽  
M Lenz ◽  
B Richter ◽  
K Huber ◽  
J Wojta ◽  
...  
Keyword(s):  
Cardiac Arrest ◽  
Spontaneous Circulation ◽  
Strong Increase ◽  
Funding Source ◽  
Monocyte Subset ◽  
Male Mortality ◽  
National Budget ◽  
Classical Monocytes ◽  
Intermediate Monocytes ◽  
Subset Distribution

Abstract Background After successful cardiopulmonary resuscitation with return of spontaneous circulation (ROSC), many patients show signs of an overactive immune activation. Monocytes are a heterogenous cell population that can be distinguished into three subsets. Purpose The aim of this prospective, observational study was to analyze whether monocyte subset distribution is associated with mortality at 6 months in patients after cardiac arrest. Methods We included 53 patients admitted to our medical ICU after cardiac arrest. Blood was taken on admission and monocyte subset distribution was analyzed by flow cytometry and distinguished into classical monocytes (CM; CD14++CD16-), intermediate monocytes (IM; CD14++CD16+CCR2+) and non-classical monocytes (NCM; CD14+CD16++CCR2-). Results Median age was 64.5 (IQR 49.8–74.3) years and 75.5% of patients were male. Mortality at 6 months was 50.9% and survival with good neurological outcome was 37.7%. Of interest, monocyte subset distribution upon admission to the ICU did not differ according to survival. However, patients that died within 6 months showed a strong increase in the pro-inflammatory subset of intermediate monocytes (8.3% (3.8–14.6)% vs. 4.1% (1.5–8.2)%; p=0.025), and a decrease of classical monocytes (87.5% (79.9–89.0)% vs. 90.8% (85.9–92.7)%; p=0.036) 72 hours after admission. In addition, intermediate monocytes were predictive of outcome independent of initial rhythm and time to ROSC and correlated with the CPC-score at 6 months (R=0.32; p=0.043). Discussion Monocyte subset distribution is associated with outcome in patients surviving a cardiac arrest. This suggests that activation of the innate immune system may play a significant role in patient outcome after cardiac arrest. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): FWF - Fonds zur Förderung der wissenschaftlichen Forschung

scholarly journals Quantitative 4D Flow CMR analysis of intracardiac blood flow energetics in ischemic cardiomyopathy patients

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
A Riva ◽  
A Camporeale ◽  
F Sturla ◽  
S Pica ◽  
L Tondi ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Ischemic Cardiomyopathy ◽  
Inverse Correlation ◽  
Lv Function ◽  
Funding Source ◽  
4D Flow ◽  
Anterior Myocardial Infarction ◽  
National Budget ◽  
4D Flow Cmr ◽  
Public Grant

Abstract Background Ischemic cardiomyopathy (ICM) is often associated with negative LV remodelling after myocardial infarction, sometimes resulting in impaired LV function and dilation (iDCM). 4D Flow CMR has been recently exploited to assess intracardiac hemodynamic changes in presence of LV remodelling. Purpose To quantify 4D Flow intracardiac kinetic energy (KE) and viscous energy loss (EL) and investigate their relation with LV dysfunction and remodelling. Methods Patients with prior anterior myocardial infarction underwent a CMR study with 4D Flow sequences acquisition; they were divided into ICM (n=10) and iDCM (n=10, EDV&gt;208 ml and EF&lt;40%). 10 controls were used for comparison. LV was semi-automatically segmented using short axis CMR stacks and co-registered with 4D Flow. Global KE and EL were computed over the cardiac cycle. NT-proBNP measurements were correlated with average and peak values, during systole and diastole. Results Both LV volume and EF significantly differ (P&lt;0.0001) between iDCM (EDV=294±56 ml, EF=24±8%), ICM (EDV=181±32 ml, EF=34±6%) and controls (EDV=124±29 ml, EF=72±5%). If compared to controls, both ICM and iDCM showed significantly lower KE (P≤0.0008); though lower than controls, EL was higher in iDCM than ICM. Within the iDCM subgroup, diastolic mean KE and peak EL reported good inverse correlation with NT-proBNP (r=−0.75 and r=−0.69, respectively). EL indexed (ELI) to average KE during systole was higher in the entire ischemic group as compared to controls (ELI(ischemic) = 0.17 vs. ELI(controls) = 0.10, P=0.0054). Conclusions 4D Flow analyses effectively mapped post-ischemic LV energetic changes, highlighting the disproportionate intraventricular EL relative to produced KE; preliminary good correlation between LV energetic changes and NT-proBNP will deserve further investigation in order to contribute to early detection of heart failure. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Italian Ministry of Health

GDF-15 and neutrophils in patients with heart failure and type 2 diabetes mellitus

2021 ◽  
Vol 28 (Supplement_1) ◽  
Author(s):  
AA Garganeeva ◽  
EA Kuzheleva ◽  
VA Fedyunina ◽  
VA Aleksandrenko
Keyword(s):  
Diabetes Mellitus ◽  
Heart Failure ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Inflammatory Marker ◽  
Study Groups ◽  
Significant Negative Correlation ◽  
Enzyme Linked Immunosorbent Assay ◽  
National Budget

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): This study was funded by (subject of fundamental scientific research on a state assignment № АААА-А17-117052310073-6 от 23.05.2017 Introduction. Growth differentiation factor-15 (GDF-15) is a biomarker associated with inflammatory processes in the pathogenesis of chronic heart failure (CHF) which expresses in cardiomyocytes under pathological conditions. The relationship between the level of GDF-15 and type 2 diabetes mellitus (T2DM) has also been proven. It is necessary to study GDF-15 in patients with CHF and T2DM. Aim To investigate the association between serum GDF-15 levels in patients with CHF of ischemic etiology and the concentration of the main leukocyte fractions depending on presence or absence of T2DM. Material and methods. The study included 42 patients. The patients were divided into 2 groups. The first group consisted of patients with CHF and T2DM (n = 14). The second group  consisted of patients with CHF without T2DM (n = 28). Determination of GDF-15 concentration was carried out by enzyme-linked immunosorbent assay (BioVendor, Czech Republic). The absolute concentration of lymphocytes, neutrophils, as well as the ratio of neutrophils to lymphocytes in the blood were analyzed. Statistical analysis was performed using the Statistica software (v.10.0). The data were described as a median and interquartile range, the Mann-Whitney test was used to compare them. The correlation analysis was tested using the Spearman"s correlation coefficient. Results and discussion. The average level of the GDF-15 in the study groups was comparable: 2389 (2104; 3375) pg/ml and 2309 (2047; 3014) pg/ml in the first and second groups, respectively (p = 0.6). In the general cohort of CHF patients, the GDF-15 concentration was not correlate with the lymphocytes concentration (r = -0.001, p = 0.95), neutrophils (r = -0.14, p = 0.4) and the ratio of neutrophils to lymphocytes (r = -0.12, p = 0.25). At the same time, in the group of patients with T2DM, a significant negative correlation was revealed between the concentration of GDF-15 in the serum and the concentration of neutrophils (r = -0.6, p = 0.022). While both other analyzed parameters did not demonstrate significant correlations with GDF-15 (p &gt; 0.05). In the group of CHF patients without T2DM, no correlations were found between GDF-15 and the studied parameters, including neutrophils (r = 0.02, p = 0.3). Along with this the median of the neutrophils concentration did not vary among groups (3.5 (2.3; 5.3) vs 3.2 (2.7; 4.1) * 109 / l; p = 0.8). Conclusion The concentration of the inflammatory marker GDF-15 in the blood of patients with CHF in combination with T2DM correlates with the concentration of neutrophils. In the absence of T2DM, no significant correlations were found between GDF-15 and the main leukocyte fractions. The results obtained indicate the possible prospect of using the GDF-15 biomarker in a cohort of patients with CHF in combination with T2DM.

scholarly journals FoxO1 inhibition alleviates type 2 diabetes-related diastolic dysfunction by increasing myocardial pyruvate dehydrogenase activity

Cell Reports ◽  
2021 ◽  
Vol 35 (1) ◽  
pp. 108935
Author(s):  
Keshav Gopal ◽  
Rami Al Batran ◽  
Tariq R. Altamimi ◽  
Amanda A. Greenwell ◽  
Christina T. Saed ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Diastolic Dysfunction ◽  
Dehydrogenase Activity ◽  
Pyruvate Dehydrogenase
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