scholarly journals The role of IL-6 receptor trans-signalling in ischemia-reperfusion injury, infarct healing and future adverse events in patients with ST-Elevation Myocardial Infarction

2021 ◽  
Vol 42 (Supplement_1) ◽  
Author(s):  
I Tollefsen ◽  
C Shetelig ◽  
P Hoffmann ◽  
J Eritsland ◽  
I Seljeflot ◽  
...  
Keyword(s):  
Infarct Size ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Myocardial Salvage ◽  
Treatment Target ◽  
Clinical Events ◽  
All Cause Mortality ◽  
St Elevation

Abstract Background Inflammation has emerged as a new treatment target in patients with coronary artery disease, and inflammation seems to play an important role in the ischemia/reperfusion injury in ST-elevation myocardial infarction (STEMI). The pro-inflammatory cytokine interleukin-6 (IL-6) has been shown to be associated with myocardial injury and poor prognosis in patients with STEMI. Purpose The aim of the study was to further elucidate possible associations between the IL-6 trans-signalling system and final infarct size, myocardial function, adverse remodelling, and future cardiovascular events in patients with STEMI. Methods A total of 272 patients with first-time STEMI included in the POSTEMI study on ischaemic postconditioning, with symptom duration <6 hours and treated with percutaneous coronary intervention (PCI), were included. Blood samples for analysis of IL-6 and IL-6 receptor (IL-6R) were collected before PCI, immediately after PCI, at day 1 (median 18.3 hours after PCI), and at 4 months follow-up. Cardiac magnetic resonance imaging (CMR) was performed in the acute phase, median 2 days after admission, and repeated after 4 months. Clinical events and all-cause mortality were registered during 12 months' and 70 months' follow-up, respectively. Results There was a significant increase in IL-6 levels from admission to day 1 with a subsequent decline from day 1 to 4 months (Figure 1A). No significant change in IL-6R levels were found from admission to day 1 (Figure 1B). There was no difference between patients treated by postconditioning compared to routine PCI. High levels of IL-6 (> median) at all sampling points were significantly associated with increased infarct size and reduced left ventricular ejection fraction (LVEF) measured by CMR. Additionally, high levels of IL-6 (> median) at day 1 were associated with lower myocardial salvage, more presence of microvascular obstruction and larger increase in indexed LV end diastolic volume (LVEDVi). IL-6R measured during hospitalisation was significantly associated with change in LVEDVi, but did not associate with infarct size, LVEF or myocardial salvage. High levels of IL-6 (>75th percentile) at all sampling points were associated with an increased risk of having an adverse clinical event during the first year and with long-term all-cause mortality (Figure 2), whereas there was no association between IL-6R and adverse clinical events. Conclusion Patients with high IL-6 levels during the acute phase of STEMI had larger infarct size, reduced myocardial salvage, reduced LV function and worse clinical outcome than patients with lower levels of IL-6. High levels of IL-6 measured after 4 months were associated with larger infarct size, reduced LVEF and increased all-cause mortality. IL-6R was significantly associated with increase in LVEDVi. The results add important information to the role of IL-6 in myocardial injury in acute STEMI and the IL-6 pathway as a potential treatment target. FUNDunding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Stein Erik Hagen Foundation for Clinical Heart Research, Oslo, Norway. Figure 1 Figure 2

P6599Upregulation of protein and gene expression of arginase-1 in patients with ST elevation myocardial infarction

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
J Tengbom ◽  
S Cederstrom ◽  
D Verouhis ◽  
P Sorensson ◽  
F Bohm ◽  
...  
Keyword(s):  
Gene Expression ◽  
Nitric Oxide ◽  
Myocardial Infarction ◽  
Infarct Size ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Arginase 1 ◽  
St Elevation ◽  
Myocardial Ischemia Reperfusion

Abstract Background The mechanisms underlying rupture of a coronary atherosclerotic plaque and development of myocardial ischemia-reperfusion injury in ST-elevation myocardial infarction (STEMI) remain unknown. Increased arginase-1 activity leads to reduced nitric oxide production and increased formation of reactive oxygen species due to uncoupling of the endothelial nitric oxide synthase (eNOS). These events lead to endothelial dysfunction, plaque instability and increased susceptibility to ischemia-reperfusion injury in acute myocardial infarction. Experimental studies have shown that arginase-1 expression and activity are increased in atherosclerosis and during myocardial ischemia-reperfusion. Accordingly, inhibition of arginase-1 reduces atherosclerotic lesion development and limits the extent of infarct size during ischemia-reperfusion via an eNOS-dependent mechanism. Furthermore, arginase-1 inhibition improves endothelial function in patients with coronary artery disease but the potential role of arginase-1 in patients with STEMI is poorly understood. Purpose The purpose of the current study was to test the hypothesis that arginase-1 is upregulated and correlate to infarct size in STEMI patients. Methods and results Two independent cohorts of STEMI patients were included. In cohort 1, plasma and buffy coat leukocytes were collected from 53 STEMI patients at the time of arterial puncture for percutaneous coronary intervention, at 24–48 hours post STEMI and at 3 months post STEMI. Gene expression in leukocytes was determined in 51 patients with Affymetrix Human Transcriptome Array 2.0. In cohort 2, plasma was collected from 82 STEMI patients at admission and at 6 months for determination of plasma arginase-1. These patients underwent cardiac magnetic resonance imaging performed at day 4–7 and at 6 months post STEMI. Plasma arginase-1 levels were quantified with ELISA. Control blood samples were collected from 56 healthy age matched subjects. In cohort 1, ARG1 gene expression was four-fold higher in STEMI patients at admission compared to controls (Figure A). This expression returned to control levels within 3 months. Plasma arginase-1 levels were two times higher in STEMI patients at admission compared to controls, and remained elevated at 24–48 hours and at 3 months post STEMI (Figure B). The increase in plasma arginase-1 in STEMI patients was confirmed in cohort 2 (Figure C). Arginase-1 levels did not correlate with infarct size. Conclusions STEMI patients demonstrate increased gene expression and plasma levels of arginase-1 in the acute setting. In contrast to gene expression plasma arginase-1 levels remain significantly elevated over time. The markedly increased expression of arginase-1 already at admission may suggest a mechanistic role of arginase-1 in the development of STEMI. Further studies are needed to elucidate whether increased expression, induction and activity of arginase-1 are contributing factors for the development of STEMI.

scholarly journals High levels of interleukin-6 are associated with final infarct size and adverse clinical events in patients with STEMI

Open Heart ◽  
2021 ◽  
Vol 8 (2) ◽  
pp. e001869
Author(s):  
Ingvild Maria Tøllefsen ◽  
Christian Shetelig ◽  
Ingebjørg Seljeflot ◽  
Jan Eritsland ◽  
Pavel Hoffmann ◽  
...  
Keyword(s):  
Infarct Size ◽  
Interleukin 6 ◽  
Left Ventricular ◽  
Clinical Event ◽  
Left Ventricular Ejection ◽  
Clinical Events ◽  
Sampling Points ◽  
All Cause Mortality

ObjectiveInflammation has emerged as a new treatment target in patients with coronary artery disease and inflammation seems to play an important role in ischaemia/reperfusion injury that follows ST-elevation myocardial infarction (STEMI). We aimed to explore the role of acute and sustained interleukin 6 (IL-6) signalling, including soluble IL-6 receptor (IL-6R), with regard to infarct size, adverse remodelling and future cardiovascular events in patients with STEMI.MethodsWe included 269 patients with first-time STEMI, symptom duration <6 hours and treated with percutaneous coronary intervention. Blood sampling and cardiac MRI were performed in the acute phase and after 4 months. Clinical events and all-cause mortality were registered during 12-month and 70-month follow-up, respectively.ResultsIL-6 levels above median at all sampling points were significantly associated with increased infarct size and reduced left ventricular ejection fraction (LVEF). IL-6 levels in the highest quartile were at all sampling points associated with an increased risk of having an adverse clinical event during the first 12 months and with long-term all-cause mortality. IL-6R was not associated with infarct size, LVEF, myocardial salvage or long-term all-cause mortality.ConclusionAcute and sustained elevation of IL-6 measured 4 months after STEMI were associated with larger infarct size, reduced LVEF and adverse clinical events including all-cause mortality. The results add important information to the sustained role of inflammation in patients with STEMI and IL-6 as a potential target for long-term intervention.Trial registration numberNCT00922675.

Abstract 16598: The Role of Paraoxonase 2 in Myocardial Ischemia/Reperfusion Injury

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Jingyuan Li ◽  
Victor R Grijalva ◽  
Srinivasa T Reddy ◽  
Mansoureh Eghbali
Keyword(s):  
Myocardial Ischemia ◽  
Infarct Size ◽  
Er Stress ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Ros Production ◽  
Myocardial Ischemia Reperfusion Injury ◽  
Myocardial Ischemia Reperfusion

Objectives: Paraoxonases (PON) gene family consists of three proteins PON1, PON2, and PON3. PON2 is an intracellular membrane-associated protein that is widely expressed in vascular cells and many tissues. At the subcellular level, PON2 is localized to both the ER and mitochondria, and protects against oxidative stress. Hypothesis: The aim of this study was to investigate the role of PON2 in myocardial ischemia reperfusion injury. Methods: PON2 deficient (PON2-/-) and WT male mice were subjected to in-vivo ischemia/reperfusion injury. The left anterior descending coronary artery was occluded for 30 min followed by 24 hr of reperfusion. The infarct size, mitochondrial calcium retention capacity (CRC) and reactive oxygen species (ROS) generation were measured. The expression of C/EBP homologous protein (CHOP), GSK3b and phosphate GSK3b protein were examined by Western Blot. The number of animals was 5-7/group and data were expressed as mean±SEM. T test were used for statistical analysis. Probability values <0.05 were considered statistically significant. Results: The infarct size was ~2 fold larger in PON2 deficient mice compared to WT mice (p<0.05). The threshold for opening of mitochondrial permeability transition pore (mPTP) in response to calcium overload was much lower in PON2-/- mice compared with WT mice (173±19 in PON2-/-, 250±41 in WT, nmol/mg-mitochondrial protein, p<0.05). The ROS production was ~2 fold higher in isolated cardiac mitochondria from PON2-/- mice compared with WT mice (p<0.05). ER stress protein CHOP increased significantly in PON2-/- mice compared to WT mice (normalized to WT: 1±0.05 in WT, 1.66±0.08 in PON2-/-, p<0.001). Phospho-GSK3b level was significantly downregulated in in PON2-/- mice compared to WT mice (pGSK3b/GSK3b normalized to WT: 1±0.06 in WT 0.67±0.08 in PON2-/-, p<0.05). Conclusions: PON2 regulates myocardial ischemia/reperfusion injury via inhibiting the opening of mPTP, which is associated with reduced mitochondria ROS production, deactivation of ER stress signaling CHOP and GSK3b.

scholarly journals Sex-related resistance to myocardial ischemia-reperfusion injury is associated with high constitutive ARC expression

2010 ◽  
Vol 298 (5) ◽  
pp. H1510-H1517 ◽  
Author(s):  
Wobbe Bouma ◽  
Mio Noma ◽  
Shinya Kanemoto ◽  
Muneaki Matsubara ◽  
Bradley G. Leshnower ◽  
...  
Keyword(s):  
Cell Death ◽  
Infarct Size ◽  
Ischemia Reperfusion Injury ◽  
Apoptotic Cell ◽  
Ischemia Reperfusion ◽  
Apoptotic Cell Death ◽  
Cardiomyocyte Apoptosis ◽  
Myocardial Salvage ◽  
Area At Risk ◽  
Myocardial Area

The female sex has been associated with improved myocardial salvage after ischemia and reperfusion (I/R). Estrogen, specifically 17β-estradiol, has been demonstrated to mediate this phenomenon by limiting cardiomyocyte apoptosis. We sought to quantitatively assess the effect of sex, ovarian hormone loss, and I/R on myocardial Bax, Bcl-2, and apoptosis repressor with caspase recruitment domain (ARC) expression. Male ( n = 48), female ( n = 26), and oophorectomized female ( n = 20) rabbits underwent 30 min of regional ischemia and 3 h of reperfusion. The myocardial area at risk and infarct size were determined using a double-staining technique and planimetry. In situ oligo ligation was used to assess apoptotic cell death. Western blot analysis was used to determine proapoptotic (Bax) and antiapoptotic (Bcl-2 and ARC) protein levels in all three ischemic groups and, additionally, in three nonischemic groups. Infarct size (43.7 ± 3.2%) and apoptotic cell death (0.51 ± 0.10%) were significantly attenuated in females compared with males (56.4 ± 1.6%, P < 0.01, and 4.29 ± 0.95%, P < 0.01) and oophorectomized females (55.7 ± 3.4%, P < 0.05, and 4.36 ± 0.51%, P < 0.01). Females expressed significantly higher baseline ARC levels (3.62 ± 0.29) compared with males (1.78 ± 0.18, P < 0.01) and oophorectomized females (1.08 ± 0.26, P < 0.01). Males expressed a significantly higher baseline Bax-to-Bcl-2 ratio (4.32 ± 0.99) compared with females (0.65 ± 0.13, P < 0.01) and oophorectomized females (0.42 ± 0.10, P < 0.01). I/R significantly reduced Bax-to-Bcl-2 ratios in males. In all other groups, ARC levels and Bax-to-Bcl-2 ratios did not significantly change. These results support the conclusion that in females, endogenous estrogen limits I/R-induced cardiomyocyte apoptosis by producing a baseline antiapoptotic profile, which is associated with estrogen-dependent high constitutive myocardial ARC expression.

Abstract 11928: Cardiospecific Overexpression of Carnosine Synthase Attenuates Myocardial Ischemia Reperfusion Injury

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Shahid Baba ◽  
Deqing zhang ◽  
David Hoetker ◽  
Yiru Guo ◽  
Aruni Bhatnagar
Keyword(s):  
Myocardial Ischemia ◽  
Infarct Size ◽  
Ischemia Reperfusion Injury ◽  
Membrane Lipids ◽  
Ischemia Reperfusion ◽  
Glycolytic Activity ◽  
Myocardial Ischemia Reperfusion Injury ◽  
Myocardial Ischemia Reperfusion ◽  
Underlying Mechanisms

Even though myocardial ischemia/reperfusion (I/R) remains the leading cause of death, the underlying mechanisms remain incompletely understood. Increased formation of reactive carbonyl has been shown to be a common biochemical feature of I/R injury. These carbonyls are generated from the oxidation of proteins and membrane lipids. Reactive carbonyls such as methylglyoxal are generated from increased glycolytic activity during ischemia. Previous work in our lab has shown that the endogenous dipeptide carnosine (β-alanine-histidine) quenches both protein and lipid derived carbonyls. It can also buffer changes in intracellular pH and chelate metals that catalyze ROS production. In the heart, carnosine is synthesized by the ATP grasp enzyme (ATPGD1). Hence, we examined whether overexpression of ATPGD1 could increase carnosine synthesis in the heart and attenuate I/R injury. To overexpress ATPGD1, we generated mice in which the expression of the transgene was driven by cardiospecific α-MHC promoter. Two different ATPGD1Tg mouse lines were generated, which showed 10-15 fold higher abundance of ATPGD1 protein in the heart compared with their wild-type (WT) littermates. Cardiac levels of the histidyl dipeptides anserine and carnosine were approximately 100 fold higher in the ATPGD1Tg than WT mice hearts (WT: anserine 1.8±0.3 pmoles/mg protein, carnosine 6±1 pmoles/mg protein; ATPGD1-Tg: anserine 114±15 pmoles/mg protein, carnosine 615±44 pmoles/mg protein). No changes in the levels of these dipeptides were observed in other tissues of the ATPGD1Tg mice. Echocardiographic analysis showed that ATPGD1 overexpression did not affect cardiac function. When subjected to 30 min of coronary occlusion followed by 24 h of reperfusion, the infarct size was significantly lower in ATPGD1Tg than WT mice. Infarct size as the area of risk of left ventricle was 59±3.02% in WT mice and 38±2.73% in the ATPGD1-Tg mice (p<0.05 vs WT; n=7-8), indicating that increasing carnosine levels attenuates myocardial I/R injury. These findings reveal a novel cardioprotective role of endogenous histidyl dipeptides in decreasing I/R injury and suggest that treatment with such peptides may be a potential therapy for decreasing myocardial I/R injury and its progression of heart failure.

Abstract 15948: Inhibition of NF-kB Signaling Attenuates Age-related Aggravation of Myocardial Ischemia/Reperfusion Injury

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Guangming Cheng ◽  
Sheng Ye ◽  
Magdy Girgis ◽  
Lin Zhao ◽  
Xing Chen ◽  
...  
Keyword(s):  
Myocardial Ischemia ◽  
Infarct Size ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
The Elderly ◽  
Age Related ◽  
Redox Responsive ◽  
Myocardial Ischemia Reperfusion Injury ◽  
Myocardial Ischemia Reperfusion

Introduction: Emerging evidence indicates that myocardial ischemia/reperfusion (I/R) injury is more severe in aged hearts. Although nuclear factor-kappaB (NF-kB) activity increases with aging, whether this redox-responsive transcription factor plays any role in age-related worsening of I/R injury remains unknown. Hypothesis: We hypothesized that activation of myocardial NF-kB exerts deleterious effects during I/R injury in young as well as aged hearts; and that NF-kB signaling contributes to age-related worsening of myocardial I/R injury. Methods: We used transgenic mice overexpressing a mutant IkBa that prevents NF-kB activation only in the heart. Age-matched young (10-week-old) and aged (86-week-old) male non-transgenic littermates (NTg) and IkBa transgenic (Tg) mice underwent a 30-min coronary occlusion followed by 24 h of reperfusion. Following sacrifice, infarct size was measured and molecular assays were performed. Results: The infarct size was significantly smaller in young Tg mice compared with young NTg mice (Fig), indicating a deleterious role of NF-kB signaling during myocardial I/R injury even in the young. The infarct size in aged NTg hearts was greater compared with young NTg hearts, consistent with an age-related worsening of I/R injury effects. However, infarct size in aged Tg hearts was significantly smaller than aged NTg hearts, and similar to young Tg hearts, indicating that NF-kB signaling contributes toward age-related aggravation of I/R injury. Interestingly, the levels of molecular markers of senescence, such as p16, were lower in aged Tg hearts (Fig), indicating a deleterious role of NF-kB in cardiac aging and susceptibility to I/R injury. Conclusions: We conclude that inhibition of cardiac NF-kB signaling protects against age-related aggravation of acute myocardial I/R injury. These findings suggest that modulation of NF-kB signaling may be potentially used to achieve therapeutic cardioprotection in the elderly.

scholarly journals Hyperglycemia-Induced Inhibition of DJ-1 Expression Compromised the Effectiveness of Ischemic Postconditioning Cardioprotection in Rats

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Min Liu ◽  
Bin Zhou ◽  
Zhong-Yuan Xia ◽  
Bo Zhao ◽  
Shao-Qing Lei ◽  
...  
Keyword(s):  
Myocardial Ischemia ◽  
Infarct Size ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Diabetic Rats ◽  
Ischemia And Reperfusion Injury ◽  
Correlation Relationship ◽  
Myocardial Ischemia Reperfusion

Ischemia postconditioning (IpostC) is an effective way to alleviate ischemia and reperfusion injury; however, the protective effects seem to be impaired in candidates with diabetes mellitus. To gain deep insight into this phenomenon, we explored the role of DJ-1, a novel oncogene, that may exhibit powerful antioxidant capacity in postconditioning cardioprotection in a rat model of myocardial ischemia reperfusion injury. Compared with normal group, cardiac DJ-1 was downregulated in diabetes. Larger postischemic infarct size as well as exaggeration of oxidative stress was observed, while IpostC reversed the above changes in normal but not in diabetic rats. DJ-1 was increased after ischemia and postconditioning contributed to a further elevation; however, no alteration of DJ-1 was documented in all subgroups of diabetic rats. Alteration of the cardioprotective PI3K/Akt signaling proteins may be responsible for the ineffectiveness of postconditioning in diabetes. There is a positive correlation relationship between p-Akt and DJ-1 but a negative correlation between infarct size and DJ-1, which may partially explain the interaction of DJ-1 and IpostC cardioprotection. Our result indicates a beneficial role of DJ-1 in myocardial ischemia reperfusion. Downregulation of cardiac DJ-1 may be responsible for the compromised diabetic heart responsiveness to IpostC cardioprotection.

scholarly journals Cinaciguat, a novel activator of soluble guanylate cyclase, protects against ischemia/reperfusion injury: role of hydrogen sulfide

2012 ◽  
Vol 302 (6) ◽  
pp. H1347-H1354 ◽  
Author(s):  
Fadi N. Salloum ◽  
Anindita Das ◽  
Arun Samidurai ◽  
Nicholas N. Hoke ◽  
Vinh Q. Chau ◽  
...  
Keyword(s):  
Hydrogen Sulfide ◽  
Cardiac Function ◽  
Infarct Size ◽  
Guanylate Cyclase ◽  
Soluble Guanylate Cyclase ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
New Zealand White Rabbits ◽  
Tetrazolium Staining

Cinaciguat (BAY 58–2667) is a novel nitric oxide (NO)-independent activator of soluble guanylate cyclase (sGC), which induces cGMP-generation and vasodilation in diseased vessels. We tested the hypothesis that cinaciguat might trigger protection against ischemia/reperfusion (I/R) in the heart and adult cardiomyocytes through cGMP/protein kinase G (PKG)-dependent generation of hydrogen sulfide (H2S). Adult New Zealand White rabbits were pretreated with 1 or 10 μg/kg cinaciguat (iv) or 10% DMSO (vehicle) 15 min before I/R or with 10 μg/kg cinaciguat (iv) at reperfusion. Additionally, adult male ICR mice were treated with either cinaciguat (10 μg/kg ip) or vehicle 30 min before I/R or at the onset of reperfusion (10 μg/kg iv). The PKG inhibitor KT5283 (KT; 1 mg/kg ip) or dl-propargylglycine (PAG; 50 mg/kg ip) the inhibitor of the H2S-producing enzyme cystathionine-γ-lyase (CSE) were given 10 and 30 min before cinaciguat. Cardiac function and infarct size were assessed by echocardiography and tetrazolium staining, respectively. Primary adult mouse cardiomyocytes were isolated and treated with cinaciguat before simulated ischemia/reoxygenation. Cinaciguat caused 63 and 41% reduction of infarct size when given before I/R and at reperfusion in rabbits, respectively. In mice, cinaciguat pretreatment caused a more robust 80% reduction in infarct size vs. 63% reduction when given at reperfusion and preserved cardiac function following I/R, which were blocked by KT and PAG. Cinaciguat also caused an increase in myocardial PKG activity and CSE expression. In cardiomyocytes, cinaciguat (50 nM) reduced necrosis and apoptosis and increased H2S levels, which was abrogated by KT. Cinaciguat is a novel molecule to induce H2S generation and a powerful protection against I/R injury in heart.

scholarly journals Myocardial salvage by succinate dehydrogenase inhibition in ischemia–reperfusion injury depends on diabetes stage in rats

2021 ◽  
Author(s):  
Pernille Tilma Tonnesen ◽  
Marie Vognstoft Hjortbak ◽  
Thomas Ravn Lassen ◽  
Jacob Marthinsen Seefeldt ◽  
Hans Erik Bøtker ◽  
...  
Keyword(s):  
Infarct Size ◽  
Succinate Dehydrogenase ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Respiratory Control ◽  
Diabetic Control ◽  
Diabetic Rats ◽  
Myocardial Salvage ◽  
Dimethyl Malonate ◽  
Zucker Diabetic Fatty Rats

AbstractInhibition of succinate dehydrogenase (SDH) by Dimethyl Malonate (DiMal) reduces cardiac ischemia–reperfusion (IR) injury. We investigated the cardioprotective effect of DiMal in a rat model during advancing type 2 diabetes. Zucker Diabetic Fatty rats and lean controls were investigated corresponding to prediabetes, onset and mature diabetes. Hearts were mounted in an isolated perfused model, and subjected to IR for investigation of infarct size (IS) and mitochondrial respiratory control ratio (RCR). DiMal was administered for 10 min before ischemia. Compared with age-matched non-diabetic rats, prediabetic rats had larger IS (49 ± 4% vs. 36 ± 2%, p = 0.007), rats with onset diabetes smaller IS (51 ± 3% vs. 62 ± 3%, p = 0.05) and rats with mature diabetes had larger IS (79 ± 3% vs. 69 ± 2%, p = 0.06). At the prediabetic stage DiMal did not alter IS. At onset of diabetes DiMal 0.6 mM increased IS in diabetic but not in non-diabetic control rats (72 ± 4% vs. 51 ± 3%, p = 0.003). At mature diabetes DiMal 0.1 and 0.6 mM reduced IS (68 ± 3% vs. 79 ± 3% and 64 ± 5% vs. 79 ± 3%, p  = 0.1 and p = 0.01), respectively. DiMal 0.1 mM alone reduced IS in age-matched non-diabetic animals (55 ± 3% vs. 69 ± 2% p = 0.01). RCR was reduced at mature diabetes but not modulated by DiMal. Modulation of SDH activity results in variable infarct size reduction depending on presence and the stage of diabetes. Modulation of SDH activity may be an unpredictable cardioprotective approach.

2232Circulating levels of ST2 are associated with myocardial injury, left ventricular function and future adverse clinical events in patients with ST-elevation myocardial infarction

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
C Shetelig ◽  
T Ueland ◽  
S Limalanathan ◽  
P Hoffmann ◽  
P Aukrust ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Clinical Outcome ◽  
Infarct Size ◽  
Left Ventricular ◽  
St Elevation Myocardial Infarction ◽  
Lv Function ◽  
Clinical Events ◽  
Increased Risk ◽  
All Cause Mortality ◽  
St Elevation

Abstract Background Soluble ST2, a member of the IL-1 receptor family, seems to be associated with adverse outcome in acute myocardial infarction and heart failure (HF), and is suggested to be involved in left ventricular (LV) remodelling. Purpose To elucidate a possible role of ST2 in LV injury, remodelling and prognosis in ST-elevation myocardial infarction (STEMI) patients. The main objectives of the study were to investigate whether circulating ST2 levels were associated with infarct size, LV function, adverse remodeling and clinical outcome in a cohort of patients with STEMI. Methods 270 patients with clinically stable first-time STEMI treated with primary percutaneous coronary intervention (PCI) were included. Blood samples were drawn before and immediately after the PCI procedure, at day 1 (median 18.3 hours after PCI) and after 4 months. Cardiac magnetic resonance (CMR) was performed in the acute phase and after 4 months. Clinical events and all-cause mortality were registered during 12 months' and 70 months' follow-up, respectively. A composite endpoint was defined as death, MI, unscheduled revascularisation >3 months after the index infarction, rehospitalisation for HF or stroke. Associations between ST2 and CMR parameters and clinical events were evaluated with linear regression and logistic regression, respectively. Results There was a significant increase in ST2 levels from the PCI procedure to day 1 with a subsequent decline from day 1 to 4 months in the POSTEMI cohort. Patients with high ST2 levels (>median) at all sampling points during hospitalisation had significantly larger infarct size, lower myocardial salvage, lower LVEF, larger increase in EDV and higher frequency of MVO. After adjustment for relevant clinical variables, peak CRP and peak troponin T, ST2 measured at day 1 remained associated with infarct size (β 2.0 per SD of ST2, p<0.001) and LVEF (β −1.8 per SD of ST2, p=0.02) at 4 months. High levels of ST2 measured at day 1 (>75th percentile) were associated with increased risk of having an adverse clinical event during the first year and with long-term all-cause mortality (Figure). High levels of ST2 measured in a stable phase 4 months after STEMI were also associated with an increased risk of all-cause mortality (Figure). Figure 1 Conclusions High levels of ST2 in STEMI patients were associated with large infarct size, impaired recovery of LV function, and adverse clinical outcome in patients with STEMI. ST2 measured 4 months after STEMI remained associated with all-cause mortality.

Sign in / Sign up

Export Citation Format

Share Document