Infarct Size Of Left Ventricle Research Articles

Clinical significance of R-wave amplitude in lead V1 and inferobasal myocardial infarction in patients with inferior wall myocardial infarction.

To assess electrocardiogram (ECG) for risk stratification in inferior ST-elevation myocardial infarction (STEMI) patients within 24 h. Three hundred thirty-four patients were divided into four ECG-based groups: Group A: R V1 <0.3 mV with ST-segment elevation (ST↑) V7-V9, Group B: R V1 <0.3 mV without ST↑ V7-V9, Group C: R V1 ≥0.3 mV with ST↑ V7-V9, and Group D: R V1 ≥0.3 mV without ST↑ V7-V9. Group A demonstrated the longest QRS duration, followed by Groups B, C, and D. ECG signs for right ventricle (RV) infarction were more common in Groups A and B (p < .01). ST elevation in V6, indicative of left ventricle (LV) lateral injury, was more higher in Group C than in Group A, while the ∑ST↑ V3R + V4R + V5R, representing RV infarction, showed the opposite trend (p < .05). The estimated LV infarct size from ECG was similar between Groups A and C, yet Group A had higher creatine kinase MB isoform (CK-MB; p < .05). Cardiac troponin I (cTNI) was higher in Groups A and C than in B and D (p < .05 and p = .16, respectively). NT-proBNP decreased across groups (p = .20), with the highest left ventricular ejection fraction (LVEF) observed in Group D (p < .05). Group A notably demonstrated more cardiac dysfunction within 4 h post-onset. For inferior STEMI patients, concurrent R V1 <0.3 mV with ST↑ V7-V9 suggests prolonged ventricular activation and notable myocardial damage. RV infarction's dominance over LV lateral injury might explain these observations.

Agomir of miRNA-30d – a potential new therapeutic target for prevention of ischemic cardiomyopathy after myocardial infarction?

Abstract Background MicroRNA (miR)-30d is not only a valuable biomarker for assessing the extent of cardiac remodeling after myocardial infarction (MI), but also an important predictor of clinical outcome in heart failure. Overexpression of miRNA-30d appears to have a cardioprotective effect by preventing cardiomyocyte apoptosis as well as averting cardiac fibroblast proliferation via multiple molecular pathways. The aim of the present in vivo and in vitro study was to demonstrate whether an miR-30d can be a potential therapeutic target to reduce the risk of ischemic cardiomyopathy (iCMP) after MI. Methods First of all, miRNA profiling was performed by next generation sequencing (NGS) to assess differences in miRNA expression in ischemic vs. healthy myocardium in a rat model of MI using coronary artery ligation (ischemia/reperfusion injury, IR). MiR-30d was selected as the most promising target as it was significantly downregulated in ischemic myocardium and can be upregulated by cardioprotective agents. Therefore, an agomir of miR-30d was administered in the respective treatment group intraperitoneally, whereas non-functional, scrambled miRNA was administered in the control group. To analyze the ratio between phosphorylated p53 (pp53) and total p53, apoptosis was evaluated in human cardiomyocytes using a p53 and pp53 ELISA kit. To gain indirect insight into infarct healing, scratch assays were used to obtain information on cell migration in human umbilical vein endothelial cells (HUVEC) in vitro. Six weeks after the in vivo induction of acute MI/IR with consequential iCMP in a rat model, the extent of MI was evaluated by planimetry. Results The majority of miRNAs studied here showed significant up-regulation in the MI-induced heart tissue in comparison to the sham operated controls. In contrast, miRNA-30d was highly significantly reduced (p&amp;lt;0.001). Based on these investigations and the already repeatedly documented cardioprotective effect of miR-30d overexpression, an agomir was selected as a potential therapy target. Human cardiomyocytes under the influence of an agomir of miR-30d showed a decreased pp53/total p53 ratio (0.66±0.09 vs. 0.81±0.19) and thus a distinct tendency (p=0.055) for a reduction in apoptotic rate compared to the control group. In HUVECs, gap closure was significantly faster in the agomir treated cells 20h and 26h post-scratching (19.1% more than scrambled control after 20h; p=0.0028 and 18.7% more than scrambled control after 26h; p=0.0081). In the in vivo model, infarct size of left ventricle was significantly reduced by using the agomir (7.43±4.13% vs. 12.76±4.76%; p=0.0172). Conclusion Using an agomir of miR-30d underlines the cardioprotective effects of miR-30d in MIR/IR and could reduce the risk for iCMP development. Further investigations regarding its therapeutic potential in the human should be considered, as microRNA treatments are gaining more and more clinical applicability today. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Paracelsus Medical University, PMU-FFF

Acute-Phase Inflammatory Reaction Predicts CMR Myocardial Scar Pattern and 2-Year Mortality in STEMI Patients Undergoing Primary PCI.

(1) Background: The inflammatory response following MI plays an important role in the healing, scar formation, and left ventricle (LV) remodeling. Cardiac magnetic resonance (CMR) imaging can accurately quantify the extent of myocardial scarring. The study aimed to investigate: (a) the relationship between acute inflammatory response and the CMR parameters of the scarring extent, and (b) the predictive power of inflammatory biomarkers and myocardial scarring for 2-year mortality. (2) Methods: The study included 202 STEMI patients, who underwent pPCI. Serum hs-CRP, IL-6, P-selectin, E-selectin, I-CAM, and V-CAM levels were determined at admission, and hs-CRP on the fifth day. Patients underwent LGE-CMR after 1 month, for LV volumes, ejection fraction (EF), infarct size (IS), and transmurality. Subjects were divided into tertiles according to the IS, and 2-year all-cause mortality was determined. (3) Results: IL-6 was associated with IS (r = 0.324, p = 0.01), increased transmurality index (r = 0.3, p = 0.01), and lower LVEF (r = −0.3, p = 0.02). Admission hs-CRP levels were not associated with IS, transmurality, or mortality, while hs-CRP at day 5 was a significant predictor for IS (AUC = 0.635, p = 0.05) as well as IL-6 levels (AUC = 0.685, p < 0.001). Mortality was significantly higher in the upper IS tertiles (6% vs. 8.7% vs. 24.52%, p = 0.005). IS was a significant predictor of 2-year mortality (AUC = 0.673, p = 0.002), with a cut-off value of 28.81 g, as well as high transmurality (AUC = 0.641, p = 0.013), with a cut off value of 18.38 g. (4) Conclusions: The serum levels of IL-6 and day-5 hs-CRP predict IS and transmurality, and day-5 hs-CRP levels are independent predictors of 2-year mortality in STEMI patients treated with pPCI. The CMR pattern of myocardial scarring after 1 month, as expressed by the magnitude of IS and transmurality, is a significant predictor for 2-year mortality after revascularized STEMI.

Relationship of Microvascular Obstruction with Global and Regional Myocardial Function Determined by Cardiac Magnetic Resonance after ST-Segment Elevation Myocardial Infarction

ObjectiveTo investigate the impact of microvascular obstruction (MVO) on the global and regional myocardial function by cardiac magnetic resonance feature-tracking (CMR-FT) in ST-segment-elevation myocardial infarction (STEMI) patients after percutaneous coronary intervention. MethodsConsecutive acute STEMI patients who underwent cardiac magnetic resonance imaging 1 - 7 days after successful reperfusion by percutaneous coronary intervention treatment were included in this retrospective study. Based on the presence or absence of MVO on late gadolinium enhancement images, patients were divided into groups with MVO and without MVO. The infarct zone, adjacent zone, and remote zone were determined based on a myocardial 16-segment model. The radial strain (RS), circumferential strain (CS), and longitudinal strain (LS) of the global left ventricle (LV) and the infarct, adjacent, and remote zones were measured by CMR-FT from cine images and compared between patients with and without MVO using independent-samples t-test. Logistic regression analysis was used to assess the association of MVO with the impaired LV function. ResultsA total of 157 STEMI patients (mean age 56.66 ± 11.38 years) were enrolled. MVO was detected in 37.58% (59/157) of STEMI patients, and the mean size of MVO was 3.00 ±3.76 mL. Compared with patients without MVO (n = 98), the MVO group had significantly reduced LV global RS (t = −4.30, P < 0.001), global CS (t = 4.99, P < 0.001), and global LS (t = 3.51, P = 0.001). The RS and CS of the infarct zone in patients with MVO were significantly reduced (t = −3.38, P = 0.001; t = 2.64, P = 0.01; respectively) and the infarct size was significantly larger (t = 8.37, P < 0.001) than that of patients without MVO. The presence of LV MVO [OR = 4.10, 95%CI: 2.05 – 8.19, P < 0.001) and its size [OR = 1.38, 95% CI: 1.10–1.72, P=0.01], along with the heart rate and LV infarct size were significantly associated with impaired LV global CS in univariable Logistic regression analysis, while only heart rate (OR=1.08, 95%CI: 1.03 – 1.13, P=0.001) and LV infarct size (OR=1.10, 95%CI: 1.03 - 1.16, P=0.003) were independent influencing factors for the impaired LV global CS in multivariable Logistic regression analysis. ConclusionThe infarct size was larger in STEMI patients with MVO, and MVO deteriorates the global and regional LV myocardial function.

A Selective TRPC3 Inhibitor Pyr3 Attenuates Myocardial Ischemia/Reperfusion Injury in Mice.

An emerging body of evidence indicates that transient receptor potential TRP channels act as important mediators for a wide variety of physiological functions and are potential targets for drug discovery. Our previous study has identified transient receptor potential channel 3 (TRPC3) and TRPC6 as cation channels through which most of the damaging calcium enters, aggravates pathological changes in vivo and increases ischemia/reperfusion (I/R) injury in mice. This study aimed to verify the effects of TRPC3 inhibitor Pyr3 on myocardial I/R injury in mice. C57BL/6J wild-type male mice (8 to 12 weeks old) were anesthetized with 3.3% chloral hydrate. A murine I (30 min)/R (24 h) injury model was established by temporary occlusion of the left anterior descending (LAD) coronary artery. Pyr3 was administered at concentrations of 0, 2.5, 5, or 10 mg/kg via the right jugular vein 5 min before reperfusion. We observed that the selective TRPC3 inhibitor, 10 mg/kg Pyr3, significantly decreased the infarct size of left ventricle, and reduced the myocardial cell apoptosis rate and inflammatory response in mice. In a conclusion, TRPC3 can function as a candidate target for I/R injury prevention, and Pyr3 may directly bind to TRPC3 channel protein, inhibit TRPC3 channel activity, and improve TRPC3-related myocardial I/R injury. Pyr3 may be used for clarification of TRPC3 functions and for treatments of TRPC3-mediated diseases.

The role of Nrf2 in astragaloside IV-mediated antioxidative protection on heart failure

Context Heart failure is one of the most serious diseases worldwide. Astragaloside IV (ASI) is widely used in the treatment of cardiovascular diseases. Objective To elucidate the antioxidative mechanism of ASI in a rat model of left coronary artery ligation. Materials and methods Left coronary artery of Sprague–Dawley rats was ligated to establish the model of heart failure, and then vehicle (saline) or ASI (1 mg/kg/day) was orally administered to the rats (n = 15) for 6 weeks. Echocardiography was used to evaluate the cardiac function. Myocardial infarct size was measured by triphenyltetrazolium chloride staining. Oxidative stress in the ventricular myocardium was determined. Molecular mechanisms were investigated by Western blot and chromatin immunoprecipitation. Results ASI improved the cardiac function, especially ejection fraction (75.27 ± 5.75% vs. 36.26 ± 4.14%) and fractional shortening (45.39 ± 3.66% vs. 17.88 ± 1.32%), and reduced the infarct size of left ventricle (20.69 ± 2.98% vs. 39.11 ± 3.97%). ASI maintained the levels of glutathione, catalase and superoxide dismutase and prevented the leakage of creatine kinase. In addition, ASI induced the protein expression of Nrf2 (1.97-fold) and HO-1 (2.79-fold), while reduced that of Keap-1 (0.77-fold) in the ventricular myocardium. In H9c2 cells, a rat cardiomyocyte cell line, ASI induced the translocation of Nrf2 from cytoplasm to nucleus, followed by transcriptional activation of NQO-1 (8.27-fold), SOD-2 (3.27-fold) and Txn-1 (9.83-fold) genes. Discussion and conclusions ASI prevented heart failure by counteracting oxidative stress through the Nrf2/HO-1 pathway. Application in clinical practice warrants further investigation.

Long-term exposure to high altitude hypoxia during pregnancy increases fetal heart susceptibility to ischemia/reperfusion injury and cardiac dysfunction

BackgroundHigh altitude hypoxia (HAH) exposure affects fetal development. However, the fetal cardiovascular responses to the HAH are not well understood. We have tested the hypothesis that long-term HAH exposure alters the hypoxia/ischemia-sensitive gene expressions, leading to an increase in fetal heart susceptibility to ischemia/reperfusion (I/R) injury and cardiac dysfunction. MethodsTime-dated pregnant sheep were exposed to high-altitude (3820 m) or were maintained at sea level (~300 m) for 110 days. Fetal hearts were isolated from the near-term ewes and subjected to I/R in a Langendorff preparation. ResultsHAH decreased the fetal body and heart weights in the female but not male fetuses. HAH had no effect on the left ventricle (LV) function at baseline, but increased the LV infarct size and attenuated the post-ischemic recovery of LV function in both male and female fetuses, as compared with the normoxic groups. HAH increased the protein levels of hypoxia-inducible factor (HIF)-1α and DNA methyltransferases type 3b (DNMT3b), but attenuated protein kinase C epsilon (PKCε) levels in the fetal hearts. AHA induced a 4.3 fold increase of miR-210 in the males and a 2.9 fold increase in female hearts. In addition, HAH had no effect on mTOR protein and phosphorylation levels but increased the autophagy biomarker, LC3B-II protein levels and LC3B-II/LC3B-I ratio in the fetal hearts. ConclusionThe results suggest that gestational HAH exposure induces in utero programming of the hypoxia/ischemia-sensitive gene expression pattern in the developing heart and increases cardiac susceptibility to I/R injury.

Propofol Provides Cardiac Protection by Suppressing the Proteasome Degradation of Caveolin-3 in Ischemic/Reperfused Rat Hearts.

The mechanisms underlying propofol's cardioprotective role remain elusive. Caveolin-3 (Cav-3) has been shown to mediate both opioids- and volatile anesthetics-induced cardioprotection against ischemia/reperfusion (I/R) injury. We hypothesize that the cardioprotective role of propofol is mediated through Cav-3 and its regulation of PI3K/Akt/GSK3β signal pathway. Rats or H9c2 cardiomyocytes were exposed to propofol before I/R or simulated ischemia/reperfusion (SI/R). Propofol pretreatment significantly decreased left ventricle infarct size in vivo (P < 0.05) and terminal deoxynucleotidyl transferase nick-end labeling-positive cells both in vivo and in vitro (P < 0.05), along with an increased Cav-3 protein expression and binding of Cav-3 to p85-subunit of PI3K. No significant change in Cav-3 mRNA expression in left ventricle tissues was found in either I/R or propofol-treated groups. Methyl-β-cyclodextrin or Cav-3 siRNA was used to knockdown Cav-3 expression in vitro, which virtually abolished propofol-induced cardiac protection and PI3K/Akt/GSK3β pathway activation. In contrast, MG132, a proteasome inhibitor, could significantly restore SI/R-induced Cav-3 decrease. It is concluded that Cav-3 mediates propofol-induced cardioprotection against I/R injury and the relevant PI3K/Akt/GSK3β activation. The downregulation of Cav-3 under SI/R may be caused by proteasome degradation, and this process can be prevented by propofol.

Chitosan hydrogels significantly limit left ventricular infarction and remodeling and preserve myocardial contractility

BackgroundLeft ventricular myocardial infarctions (MIs) consist of a central area of myocardial necrosis that is surrounded by areas of myocardial injury and ischemia. We hypothesized that chitosan hydrogels, when injected around the perimeter of MIs in rats, could decrease left ventricle (LV) wall stress by the Law of LaPlace, and therefore myocardial oxygen requirements, and prevent the ischemic and injured myocardium from becoming necrotic. In this manner, chitosan gels could limit LV infraction size and LV remodeling. Chitosan hydrogels are liquid at 25°C but gel at 37°C. MethodsSeventy Sprague–Dawley rats with ligation of the left coronary artery were treated with either Dulbecco's Modified Eagle Medium (DMEM) or chitosan hydrogel in DMEM, which was injected around the infarct perimeter. Echocardiograms were obtained before MI and at 2, 4, 8, 12, and 16 wk after MI. Hearts from randomly selected rats were harvested at baseline and at the time of echocardiography for determinations of LV infarct size, remodeling, and histopathology. ResultsInfarct sizes as a percentage of the total ventricular myocardium in the DMEM group averaged 17% versus 14% in the chitosan group at 4 wk (P < 0.05), 18% versus 14% at 8 wk (P < 0.01), 19% versus 14% at 12 wk (P < 0.001), and 20% versus 14% at 16 wk (P < 0.001). Injection of chitosan into the infarctions produced LV wall thicknesses in the MI border zones that averaged 0.66 cm at 4 wk, which were greater than the LV wall thicknesses in the border zones of rats treated with DMEM, which averaged 0.33 cm (P < 0.01). Arteriole densities in the MI border zones were 160/mm2 in the chitosan group but only 92/mm2 in the DMEM rats (P < 0.01). The left ventricular end-diastolic diameters (LVEDs) in the rats averaged 0.73 cm before MI. After MI, LVED increased in the DMEM rats to 0.84 cm at 2 wk, then 0.89 cm at 4 wk, 0.89 cm at 8 wk, 0.89 m at 12 wk, and 0.87 cm at 16 wk. In contrast, LVED in the chitosan rats were on average 19% smaller in comparison with the DMEM rats (P < 0.05) and did not significantly change in comparison with their baseline LVEDs. Left ventricular ejection fraction (LVEF) in the rats averaged 83% before infarctions. In the infarction + DMEM group, the LVEFs significantly decreased after MI and averaged 59.7% at 2 wk, 52.5% at 4 wk, 46.1% at 8 wk, 52.4% at 12 wk, and 53.6% at 16 wk (P < 0.05). In the infarction + chitosan-treated rats, the LVEFs were greater and averaged 67.8% at 2 wk (P < 0.02), 68.9% (P < 0.02) at 4 wk, 69% (P < 0.003) at 8 wk, 65.2% at 12 wk (P < 0.05), and 67% at 16 wk (P < 0.05). ConclusionsChitosan gel can increase LV myocardial wall thickness, decrease infarct size and LV remodeling, and preserve LV contractility.

Abstract 12: EMMPRIN-Targeted Magnetic Nanoparticles for in vivo Visualization and Regression of Acute Myocardial Infarction in a Model of Acute Coronary Artery Occlusion

Extracellular matrix metalloproteinase inducer EMMPRIN, is highly expressed in patients with acute myocardial infarction (AMI), and induces activation of several matrix metalloproteinases (MMPs), including MMP-9 and MMP-13. To prevent Extracellular matrix degradation and cardiac cell death we targeted EMMPRIN with paramagnetic/fluorescent micellar nanoparticles with an EMMPRIN binding peptide AP9 conjugated (NAP9), or an AP9 scramble peptide as a negative control (NAPSC). NAP9 binds to endogenous EMMPRIN as detected by confocal microscopy of cardiac myocytes and macrophages incubated with NAP and NAPSC in vitro, and in vivo in mouse hearts subjected to left anterior descending coronary artery occlusion (IV injection 50mγ/Kg NAP9 or NAP9SC). Administration of NAP9 at the same time or 1 hour after AMI reduced infarct size over a 20% respect to untreated and NAPSC injected mice, recovered left ventricle ejection fraction (LVEF) similar to healthy controls, and reduced EMMPRIN downstream MMP9 expression. In magnetic resonance scans of mouse hearts 2 days after AMI and injected with NAP9, we detected a significant gadolinium enhancement in the left ventricle respect to non-injected mice and to mice injected with NAPSC. Late gadolinium enhancement assays exhibited NAP9-mediated left ventricle signal enhancement as early as 30 minutes after nanoprobe injection, in which a close correlation between the MRI signal enhancement and left ventricle infarct size was detected. Taken together, these results point EMMPRIN targeted nanoprobes as a new tool for the treatment of AMI.

Integration of background genome variation to dissect complex cardiovascular phenotypes (697.5)

The genetic underpinnings of cardiovascular (CV) disease are far more complex than originally imagined. Human genome wide association studies (GWAS) have identified candidate genes, but to date have predicted only a small fraction of the genetic basis. Some of the “missing heritability” is likely due to the interaction of multiple genes and alleles contributing to the disease. Phenotypic and genotypic characterization of two complete comsomic rat panels provides the foundation to analyze the influence of genetic background on CV traits. Phenotyping of PhysGen consomic strains, developed by introgressing Brown Norway (BN) chromosomes onto the Salt‐Sensitive (SS) or Fawn Hooded Hypertensive (FHH) backgrounds, identified consomic strains in introgressed BN chromosomes alter phenotypes on only one genomic background or under only one environmental condition. Introgression of BN chromosome 1 differentially regulates left ventricle infarct size following ischemia on SS and FHH backgrounds. HIF pathway genes on chromosome 1 are nearly identical between SS and FHH, although 12 genes on background chromosomes contain non‐synonymous SNPs (2 in SS only, 6 in FHH only, and 4 in both compared to BN), potentially altering the HIF pathway and CV phenotypes in response to chronic hypoxia. Additional in silico analysis, using gene, QTL and phenotype annotations, in conjunction with strain‐specific sequence variation, enables virtual variant profiles for complex phenotypes or disease pathways to be created for each consomic strain.Grant Funding Source: Supported by R01HL094271 and R01HL064541

Abstract 148: Mst1 Mediates Cell-protective Mechanisms In The Heart Through Phosphorylation Of FoxO1 And C/EBP-beta

Forkhead box O1 (FoxO1) regulates both cell survival and death in the heart. The function of FoxO1 is modulated by posttranslational modifications, including phosphorylation. Mst1 (mammalian sterile 20-like kinase 1), a stress-activated pro-apoptotic kinase, phosphorylates FoxO1 at Ser209/216/231/232. We investigated the molecular mechanism by which FoxO1 regulates both cell survival and death in the heart. Overexpression of FoxO1 significantly suppressed, whereas downregulation of endogenous FoxO1 exacerbated, Mst1 activity and Mst1-induced apoptosis. In the presence of Mst1, FoxO1 downregulated pro-apoptotic genes, including FasL, but upregulated antioxidant genes, including catalase. Chromatin immunoprecipitation assays revealed that Mst1 attenuated FoxO1 binding to the FasL promoter, but it enhanced binding to the catalase promoter. Reporter gene assays showed that C/EBP-β binding elements, but not the FoxO binding ones, in the catalase promoter, are critical for Mst1-mediated upregulation of the catalase gene. FoxO1 interacted with C/EBP-β and their interaction was enhanced in the presence of Mst1. Mass spectrometry analyses revealed that Mst1 phosphorylates C/EBP-β at Thr 299 in its leucine zipper domain. Downregulation of endogenous C/EBP-β reversed the cell-protective effects of FoxO1 expression against Mst1-induced apoptosis. We evaluated the role of Mst1-mediated phosphorylation of FoxO1 and C/EBP-β in mediating survival and death of cardiomyocytes in response to ischemia/reperfusion (I/R). The size of myocardial infarction (MI) in left ventricle (LV) after I/R was significantly greater in cardiac-specific FoxO1 knockout ( c-FoxO1 -/- ) mice than in wild-type mice (MI/area at risk: 59±2, 41±1%, p &lt;0.05, n=6). Injection of a C/EBP-β phospho-mimetic mutant adenovirus into the LV of c-FoxO1 -/- significantly reduced the I/R-induced LV infarct size observed in c-FoxO1 -/- (50±2%, p &lt;0.05, n=6). In summary, Mst1-mediated phosphorylation of FoxO1 inhibits the DNA binding of FoxO1 to the cell death promoting genes whereas it enhances FoxO1-C/EBP-β interaction, Mst1-mediated phosphorylation of C/EBP-β, and C/EBP-β-mediated transcription, which activates cell-protective mechanisms in the heart.

Early statin treatment prior to primary PCI for acute myocardial infarction: REPERATOR, a randomized placebo‐controlled pilot trial

The aim of this pilot study was to determine whether early atorvastatin treatment will reduce left ventricle (LV) remodeling, infarct size, and improve microvascular perfusion. In animal studies, early statin therapy reduces reperfusion injury after a percutaneous coronary intervention (PCI) for acute myocardial infarction (AMI). Forty-two consecutive patients (82% male, mean age 61.2 ± 9.8) who underwent a primary PCI for a first ST-elevated AMI were randomized for pretreatment with atorvastatin 80 mg (n = 20) or placebo (n = 22) and continued with the same dosage daily for 1 week. All patients received atorvastatin 80 mg once daily 7 days after primary PCI. The LV function and infarct size were measured by magnetic resonance imaging within 1 day, at 1 week, and 3 months follow up. The primary endpoint was the end-systolic volume index (ESVI) at 3 months. Secondary endpoints were global LV function measurements, myocardial infarct size, biochemical cardiac markers, TIMI flow, and ST-T elevation resolution. ESVI 3 months after AMI was 25.1 mL/m(2) in the atorvastatin arm and 25.0 mL/m(2) in the placebo arm (P = 0.74). The differences in change from baseline to 3 months follow up in global LV function and myocardial infarct size did not differ between both treatment arms. Furthermore, biochemical markers, TIMI flow, and ST-T elevation resolution did not differ between atorvastatin and placebo arm. In this pilot study, pretreatment with atorvastatin in an acute myocardial infarction does not result in an improved cardiac function, microvascular perfusion, or decreased myocardial infarct size.

Effects of exercise of different intensities on the angiogenesis, infarct healing, and function of the left ventricle in postmyocardial infarction rats

Lifestyle interventions, including physical exercise, are feasible options for the prevention and treatment of cardiovascular diseases. In this study, the effects of exercise of different intensities on the infarct region, function, and angiogenesis of the left ventricle (LV) in postmyocardial infarction (MI) rats were investigated and the levels of vascular endothelial growth factor (VEGF) proteins in the LV and plasma were examined. Male Sprague-Dawley rats were randomly assigned to six groups. The exercise-trained rats observed a daily 60-min treadmill routine 5 days/weeks for 6 weeks. Different treadmill speeds were used in the high-intensity exercise (HIE), moderate-intensity exercise (MIE), and low-intensity exercise (LIE) groups, whereas the untrained rats remained sedentary (Sed). At 6 weeks, all rats underwent either an acute MI operation or a sham (Sh) MI operation 24 h after their last treadmill exercise or the corresponding Sed protocol. They were then killed 7 days after recovery. Echocardiographic and hemodynamic measurements were taken at the end of the experimental protocol. The infarct regions were analyzed using Masson's trichrome staining, whereas intramyocardial microvessels were detected using Factor VIII-related antigen staining. The cardiac VEGF protein levels were determined by western blotting analysis, and plasma VEGF concentrations were examined by enzyme-linked immunosorbent assay. Compared with the corresponding parameters in the Sed-Sh group, LV function did not significantly ameliorate and microvessel density did not increase in the MIE-Sh group. Compared with the Sed-MI group, the MIE-MI and HIE-MI groups had significantly reduced LV infarct size, improved hemodynamic parameters, and increased fractional shortening, scar thickness, and microvessel density, these parameters did not significantly change in the LIE-MI group. In addition, the MIE-MI and HIE-MI rats had significant differences in hemodynamic parameters and microvessel density. Compared with those of the Sed-MI group, the heart and plasma of the exercise-trained rats in the MIE-MI and HIE-MI groups displayed higher levels of VEGF protein, but the difference between the MIE-MI and HIE-MI groups was not significant. Moderate-intensity running before acute MI improved LV function, reduced scar size, and increased scar thickness and microvessel density in post-MI rats. Exercise at a higher intensity could have further small effects. LIE may be beneficial, but it would not be sufficient to improve MI. Moderate-intensity and high-intensity running upregulated the expression of VEGF protein and increased microvessels, which may have partly improved cardiac function after MI in this study.

Cardioprotective effect of therapeutic hypothermia at 34 °C against ischaemia/reperfusion injury mediated by PI3K and nitric oxide in a rat isolated heart model

AimTherapeutic hypothermia (TH) is widely used as a cardioprotective treatment for cardiac arrest. TH at 30–32°C during ischaemia and reperfusion has a cardioprotective effect. The aims of the study were to examine whether TH at 34°C with late induction (immediately after the start of reperfusion) has a cardioprotective effect and to determine if this effect is mediated by nitric oxide (NO) and phosphatidylinositol 3′-kinase (PI3K). MethodsLangendorff perfusion of Sprague–Dawley rat hearts was initiated at 75mmHg at 37°C. Left ventricle infarct sizes were evaluated by triphenyltetrazolium chloride staining after Langendorff perfusion in 6 groups (each n=7): control group; ischaemia group, with 34°C TH during ischaemia for 30min and reperfusion for 180min; reperfusion group, with 34°C TH induced solely during the reperfusion period; the l-NAME (NO synthase inhibitor), LY294002, and wortmannin (PI3K inhibitors) groups, which were treated similarly to the reperfusion group with the addition of each compound. ResultsTH reduced the left ventricle infarct size from 54.2±14.8% of the control group to 11.9±6.3% (ischaemia group, p<0.001) and to 23.5±10.5% (reperfusion group, p<0.001). l-NAME, LY294002, and wortmannin reversed the cardioprotective effect of TH induced during reperfusion to 42.5±10.6% (p=0.009), 40.9±4.1% (p=0.021), and 51.9±13.0% (p<0.001), respectively. Circulatory temperatures reached 34°C within 5min in all groups subjected to TH. ConclusionsTH of 34°C showed a cardioprotective effect even with late initiation of cooling during reperfusion. The effect was mediated by NO and PI3K.

Albiglutide, a Long Lasting Glucagon-Like Peptide-1 Analog, Protects the Rat Heart against Ischemia/Reperfusion Injury: Evidence for Improving Cardiac Metabolic Efficiency

BackgroundThe cardioprotective effects of glucagon-like peptide-1 (GLP-1) and analogs have been previously reported. We tested the hypothesis that albiglutide, a novel long half-life analog of GLP-1, may protect the heart against I/R injury by increasing carbohydrate utilization and improving cardiac energetic efficiency.Methods/Principal FindingsSprague-Dawley rats were treated with albiglutide and subjected to 30 min myocardial ischemia followed by 24 h reperfusion. Left ventricle infarct size, hemodynamics, function and energetics were determined. In addition, cardiac glucose disposal, carbohydrate metabolism and metabolic gene expression were assessed. Albiglutide significantly reduced infarct size and concomitantly improved post-ischemic hemodynamics, cardiac function and energetic parameters. Albiglutide markedly increased both in vivo and ex vivo cardiac glucose uptake while reducing lactate efflux. Analysis of metabolic substrate utilization directly in the heart showed that albiglutide increased the relative carbohydrate versus fat oxidation which in part was due to an increase in both glucose and lactate oxidation. Metabolic gene expression analysis indicated upregulation of key glucose metabolism genes in the non-ischemic myocardium by albiglutide.Conclusion/SignificanceAlbiglutide reduced myocardial infarct size and improved cardiac function and energetics following myocardial I/R injury. The observed benefits were associated with enhanced myocardial glucose uptake and a shift toward a more energetically favorable substrate metabolism by increasing both glucose and lactate oxidation. These findings suggest that albiglutide may have direct therapeutic potential for improving cardiac energetics and function.

The cardioprotection induced by lipopolysaccharide involves phos-phoinositide 3-kinase/Akt and high mobility group box 1 pathways

Objective The mechanisms by which lipopolysaccharide (LPS) pretreatment induces cardioprotection following ischaemia/reperfusion (I/R) have not been fully elucidated. We hypothesized that activation of phosphoinositide 3-kinase (PI3K)/Akt and high mobility group box 1 (HMGBx1) signaling plays an important role in LPS-induced cardioprotection. Methods In in vivo experiments, age- and weight-matched male C57BL/10Sc wild type mice were pretreated with LPS before ligation of the left anterior descending coronary followed by reperfusion. Infarction size was examined by triphenyltetrazolium chloride (TTC) staining. Akt, phospho-Akt, and HMGBx1 were assessed by immunoblotting with appropriate primary antibodies. In situ cardiac myocyte apoptosis was examined by the TdT-mediated dUTP nick-end labeling (TUNEL) assay. In an in vitro study, rat cardiac myoblasts (H9c2) were subdivided into two groups, and only one was pretreated with LPS. After pretreatment, the cells were transferred into a hypoxic chamber under 0.5% O 2. Levels of HMGBx1 were assessed by immunoblot. Results In the in vivo experiment, pretreatment with LPS reduced the at risk infarct size by 70.6% and the left ventricle infarct size by 64.93% respectively. Pretreatment with LPS also reduced cardiac myocytes apoptosis by 39.1% after ischemia and reperfusion. The mechanisms of LPS induced cardioprotection involved increasing PI3K/Akt activity and decreasing expression of HMGBx1. In the in vitro study, pretreatment with LPS reduced the level of HMGBx1 in H9c2 cell cytoplasm following hypoxia. Conclusion The results suggest that the cardioprotection following I/R induced by LPS pretreatment involves PI3K/Akt and HMGBx1 pathways.

J004 Darbepoetin- protects heart against ischemia-reperfusion: role of BCL-2 family proteins

Heart can usually survive a short period of ischemia, but when this period is too long, damages of the cardiac tissue became irreversible and are possibly exacerbated by blood reperfusion. Loss of cardiac myocytes via apoptosis is believed to contribute to the continuous decline of ventricular function described in heart failure. Limiting theses deleterious responses is of major importance in cardiac surgery and for the treatment of coronary thrombosis. The purpose of this study was to assess the short and long term cardioprotective effects of the long lasting effect erythropoietin analogue darbepoetin-α (DA) in a myocardial ischemia-reperfusion model in rat and ; to investigate the signaling pathway through which DA potentially limits apoptosis of cardiomyocytes. Rat were subjected to 40 min left coronary artery ligation followed by 3h, 72 h or 4 weeks reperfusion and they received either DA (3 or 30 μg/kg) or vehicle i.v. prior ischemia. Left ventricle (LV) function was assessed by echocardiography prior surgery and after reperfusion. Hearts were collected for histological analysis, protein analysis and reactive oxygen species (ROS) production. In DA3 and DA30 72hrs groups, both LV shortening fraction and LV ejection fraction were higher vs. control (P<0.05), matching with histological analysis revealing a relative LV infarct size 72h post ischemia of 40 ± 5 % in control vs. 27 ± 3 and 17 ± 2 % in DA3 and DA30, respectively. DA treatment lowered ROS production, the activity of caspase 3 in 3 h and 72 h reperfusion groups, and activated the JAK2/AkT signaling pathway and then increased both phosphorylated Bad and GSk3β proteins. This was consistent with the decrease of Bad-Bcl-Xl in DA30 group, suggesting an increased level of Bcl-Xl protein. Similar results were obtained in DA-treated rats reperfused 4 weeks ; in which cardiac fibrosis was significantly lower than that in control group. DA pre-treatment limited in a dose dependent manner the early and late I/R-induced heart injury in rat. Anti-apoptotic effects mediated through the activation the survival kinase Akt that regulates the Bcl-2 family proteins and activates GSK-3β is central in the DA cardioprotective mechanism.

Prenatal Nicotine Exposure Increases Heart Susceptibility to Ischemia/Reperfusion Injury in Adult Offspring

In the present study we tested the hypothesis that prenatal nicotine exposure increases heart susceptibility to ischemia/reperfusion (I/R) injury in adult offspring. Nicotine was administered to pregnant rats via subcutaneous osmotic minipumps throughout gestation. Nicotine treatment resulted in a rapid and transient decrease in food-intake and a moderate decrease in maternal body weight gain. Hearts were isolated from adult male and female offspring and subjected to I/R in a Langendorff preparation. Nicotine significantly attenuated left ventricle (LV) developed pressure, heart rate, and coronary flow rate in female but not male hearts at baseline. Additionally, nicotine significantly increased LV infarct size and attenuated postischemic recovery of LV function in both male and female offspring with more pronounced effects in females. In female but not male hearts, nicotine significantly decreased the postischemic coronary flow rate. However, coronary nitric oxide release was decreased in male but not female hearts. Caspase-3, -8, and -9 levels were not significantly changed in either female or male hearts. However, nicotine caused a significant decrease in protein levels of protein kinase (PK) Cepsilon in both male and female hearts and a decrease in PKCdelta levels in female hearts only. Control studies of maternal food restriction showed that a moderate decrease in maternal body weight gain had no effect on female hearts but significantly improved postischemic recovery of LV function in male hearts. The results suggest that prenatal nicotine exposure causes in utero programming of the PKC isozyme gene expression pattern in the developing heart and increases heart susceptibility to I/R injury in adult offspring.

PPARδ Activation Normalizes Cardiac Substrate Metabolism and Reduces Right Ventricular Hypertrophy in Congestive Heart Failure

Previously, it was shown that selective deletion of peroxisome proliferator activated receptor delta (PPARdelta) in the heart resulted in a cardiac lipotoxicity, hypertrophy, and heart failure. The aim of the present study was to determine the effects of chronic and selective pharmacological activation of PPARdelta in a model of congestive heart failure. PPARdelta-specific agonist treatment (GW610742X at 30 and 100 mg/kg/day for 6-9 weeks) was initiated immediately postmyocardial infarction (MI) in Sprague-Dawley rats. Magnetic resonance imaging/spectroscopy was used to assess cardiac function and energetics. A 1-(13)C glucose clamp was performed to assess relative cardiac carbohydrate versus fat oxidation. Additionally, cardiac hemodynamics and reverse-transcription polymerase chain reaction gene expression analysis was performed. MI rats had significantly reduced left ventricle (LV) ejection fractions and whole heart phosphocreatine/adenosine triphosphate ratio compared with Sham animals (reduction of 43% and 14%, respectively). However, GW610742X treatment had no effect on either parameter. In contrast, the decrease in relative fat oxidation rate observed in both LV and right ventricle (RV) following MI (decrease of 58% and 54%, respectively) was normalized in a dose-dependent manner following treatment with GW610742X. These metabolic changes were associated with an increase in lipid transport/metabolism target gene expression (eg, CD36, CPT1, UCP3). Although there was no difference between groups in LV weight or infarct size measured upon necropsy, there was a dramatic reduction in RV hypertrophy and lung congestion (decrease of 22-48%, P<0.01) with treatment which was associated with a >7-fold decrease (P<0.05) in aterial natriuretic peptide gene expression in RV. Diuretic effects were not observed with GW610742X. In conclusion, chronic treatment with a selective PPARdelta agonist normalizes cardiac substrate metabolism and reduces RV hypertrophy and pulmonary congestion consistent with improvement in congestive heart failure.