Nonischemic Myocardium Research Articles

Impaired mitochondrial function in chronically ischemic human heart

Chronic ischemic heart disease is associated with myocardial hypoperfusion. The resulting hypoxia potentially inflicts damage upon the mitochondria, leading to a compromised energetic state. Furthermore, ischemic damage may cause excessive production of reactive oxygen species (ROS), producing mitochondrial damage, hereby reinforcing a vicious circle. Ischemic preconditioning has been proven protective in acute ischemia, but the subject of chronic ischemic preconditioning has not been explored in humans. We hypothesized that mitochondrial respiratory capacity would be diminished in chronic ischemic regions of human myocardium but that these mitochondria would be more resistant to ex vivo ischemia and, second, that ROS generation would be higher in ischemic myocardium. The aim of this study was to test mitochondrial respiratory capacity during hyperoxia and hypoxia, to investigate ROS production, and finally to assess myocardial antioxidant levels. Mitochondrial respiration in biopsies from ischemic and nonischemic regions from the left ventricle of the same heart was compared in nine human subjects. Maximal oxidative phosphorylation capacity in fresh muscle fibers was lower in ischemic compared with nonischemic myocardium (P < 0.05), but the degree of coupling (respiratory control ratio) did not differ (P > 0.05). The presence of ex vivo hypoxia did not reveal any chronic ischemic preconditioning of the ischemic myocardial regions (P > 0.05). ROS production was higher in ischemic myocardium (P < 0.05), and the levels of antioxidant protein expression was lower. Diminished mitochondrial respiration capacity and excessive ROS production demonstrate an impaired mitochondrial function in ischemic human heart muscle. No chronic ischemic preconditioning effect was found.

Expression of basigin in the early phase of acute myocardial ischemia in rats

Basigin may be involved in cardiovascular disease. In our previous study, suppression subtractive hybridization results indicated that basigin may be associated with the early phase of acute myocardial ischemia (AMI) within 1h. However, little is known regarding the expression of basigin in the early phase of AMI. The aim of the present study was to evaluate the temporal and spatial expression patterns of basigin mRNA and protein levels in AMI in rats. We constructed an AMI model in rats that received left anterior descending coronary artery ligation for 0, 15, 30, 60, 120 or 240min. Real‑time quantitative PCR and insitu hybridization (ISH) were conducted to reveal the basigin mRNA levels in the early ischemic myocardium (EIM) and non‑ischemic myocardium (NIM). The expression levels of basigin protein were detected using western blot analysis and immunohistochemistry. The expression levels of basigin mRNA and protein significantly changed in the EIM as early as 30min from ischemia, and the changes continued to be present throughout the ischemic period (P<0.05). The expression levels of basigin mRNA were significantly reduced, whilst those of the protein underwent a significant ~2-fold increase in the EIM. However, there were no significant differences in the basigin mRNA or protein expression levels from 0‑240min in the NIM (P>0.05). We failed to detect a signal for basigin mRNA in the myocardium by ISH. Our findings indicated that basigin may be involved in acute myocardial ischemia following continual ischemia for >30min.

Downregulation of Endogenous Intermedin Augmented Myocardial Injury in Rats with Ischemia/Reperfusion

Intermedin (IMD) plays an important regulatory role in cardiovascular function. We aimed to explore the protein expression of IMD and its receptors, calcitonin receptor-like receptor (CRLR) and receptor activity-modifying proteins (RAMPs), and the role of endogenous IMD in myocardial ischemia/reperfusion (I/R) injury in rats. The rat model of I/R was created by ligating cardiac left anterior descending artery. Western blot was used to determine protein expression of CRLR and RAMPs, and radioimmunoassay was used to detect IMD content. Compared with control, protein levels of CRLR and RAMPs in both ischemic and nonischemic region were upregulated at different stages of reperfusion. IMD protein content in nonischemic area myocardium also increased. However, IMD protein content in ischemic area downregulated at 3-, 6-, and 12-h reperfusion. In hypoxia/reoxygenation model of neonatal cardiomyocytes, IMD attenuated myocyte injury, and IMD receptor antagonist IMD17-47 aggravated myocyte impairment by blocking endogenous IMD. In conclusion, the downregulation of IMD at early stage of reperfusion might augment myocardium injury.

Abstract 235: Ischemia-Reperfusion Injury Decreases Myocardial Hydration Potential Without Changing Flow Resistance in the Interstitial Matrix

Interstitial edema is an early response to myocardial ischemia, leading to fibrosis and remodeling in several heart failure conditions. We aimed to clarify whether osmotic, frictional, or mechanical forces drive fluid accumulation. Equilibrium and dynamic interstitial hydration parameters were determined, compared, and analyzed using osmotic stress approaches in explants from ischemic and nonischemic myocardial regions of pig heart. They were isolated after injury induced by ligating 3-4 branches of the left anterior descending coronary artery, for 85 min followed by 3 hours’ reperfusion. Their volume changed (Δ V max ) linearly with colloidosmotic pressure in both ischemic and nonischemic areas, yielding interstitial compliance values of 1.04 ± 0.09 and 1.08 ± 0.05 µl/g/ mmHg , which do not differ significantly, and hydration potentials from the abscissa intercepts at Δ V max = 0, of -121.4 ± 28 and -14.7 ± 7.6 mmHg, which do (mean ± SE, n = 5 , P-value = 0.001). These hydration potential differences manifest ex-vivo influx rates 8.5 ± 2.7- fold slower in ischemic than nonischemic myocardium. Surprisingly, interstitial flow resistance values derived from net-flow rates at an imposed pressure difference of 216 mmHg were 0.23 ± 0.08 and 0.19 ± 0.01 µl -1 . g. min and did not differ significantly between the areas. The similarity in interstitial compliance and fluid resistance indicates that the more negative hydration potential and faster efflux rates in at-risk regions after reperfusion are due to increased hydrostatic pressure rather than decreased osmotic or frictional forces. Tissue distends due to interstitial fluid accumulation against matrix mechanical forces, including elastic recoil of the collagen elastin mesh and fibroblast action, consistent with impaired drainage and persistent diastolic-like conditions during reperfusion of at-risk areas in vivo . These results indicate changes in pressure gradient magnitude and may have clinical and therapeutic implications; for example, reversal of paracrine interstitial flows during early remodeling

Local Arginase Inhibition during Early Reperfusion Mediates Cardioprotection via Increased Nitric Oxide Production

Consumption of L-arginine contributes to reduced bioavailability of nitric oxide (NO) that is critical for the development of ischemia-reperfusion injury. The aim of the study was to determine myocardial arginase expression and activity in ischemic-reperfusion myocardium and whether local inhibition of arginase within the ischemic myocardium results in increased NO production and protection against myocardial ischemia-reperfusion. Anesthetized pigs were subjected to coronary artery occlusion for 40 min followed by 4 h reperfusion. The pigs were randomized to intracoronary infusion of vehicle (n = 7), the arginase inhibitor N-hydroxy-nor-L-arginine (nor-NOHA, 2 mg/min, n = 7), the combination of nor-NOHA and the NO synthase inhibitor NG-monomethyl-L-arginine (L-NMMA, 0.35 mg/min, n = 6) into the jeopardized myocardial area or systemic intravenous infusion of nor-NOHA (2 mg/min, n = 5) at the end of ischemia and start of reperfusion. The infarct size of the vehicle group was 80±4% of the area at risk. Intracoronary nor-NOHA reduced infarct size to 46±5% (P<0.01). Co-administration of L-NMMA abrogated the cardioprotective effect mediated by nor-NOHA (infarct size 72±6%). Intravenous nor-NOHA did not reduce infarct size. Arginase I and II were expressed in cardiomyocytes, endothelial, smooth muscle and poylmorphonuclear cells. There was no difference in cytosolic arginase I or mitochondrial arginase II expression between ischemic-reperfused and non-ischemic myocardium. Arginase activity increased 2-fold in the ischemic-reperfused myocardium in comparison with non-ischemic myocardium. In conclusion, ischemia-reperfusion increases arginase activity without affecting cytosolic arginase I or mitochondrial arginase II expression. Local arginase inhibition during early reperfusion reduces infarct size via a mechanism that is dependent on increased bioavailability of NO.

Reperfusion-triggered stress protein response in the myocardium is blocked by post-conditioning. Systems biology pathway analysis highlights the key role of the canonical aryl-hydrocarbon receptor pathway

Ischaemic post-conditioning (IPost-Co) exerts cardioprotection by diminishing ischaemia/reperfusion injury. Yet, the mechanisms involved in such protection remain largely unknown. We have investigated the effects of IPost-Co in cardiac cells and in heart performance using molecular, proteomic and functional approaches. Pigs underwent 1.5 h mid-left anterior descending balloon occlusion and then were sacrificed without reperfusion (ischaemia; n= 7), subjected to 2.5 h of cardiac reperfusion and sacrificed (n= 5); or subjected to IPost-Co before reperfusion and sacrificed 0.5 h (n= 4) and 2.5 h (n= 5) afterwards. A sham-operated group was included (n= 4). Ischaemic and non-ischaemic myocardium was obtained for molecular/histological analysis. Proteomic analysis was performed by two-dimensional electrophoresis followed by matrix-assisted laser desorption/ionization-time-of-flight identification. Potential protein networks involved were identified by bioinformatics and Ingenuity Pathway Analysis (IPA). Cardiac function was assessed by echocardiography. IPost-Co diminished (up to 2.5 h) reperfusion-induced apoptosis of both the intrinsic and extrinsic pathways whereas it did not affect reperfusion-induced Akt/mammalian target of rapamycin (mTOR)/P70S6K activation. Proteomic studies showed that IPost-Co reverted 43% of cardiac cytoplasmic protein changes observed during ischaemia and ischaemia + reperfusion. Systems biology assessment revealed significant changes in the aryl-hydrocarbon receptor (AhR) pathway (cell damage related). Bioinformatic data were confirmed since the expression of HSP90, AhR, ANRT, and β-tubulin (involved in AhR-signalling transduction) were accordingly modified after IPost-Co. IPost-Co rescued 52% of the left ventricle-at-risk compared with reperfusion alone and resulted in a ≈30% relative improvement in left ventricular ejection fraction (P <0.05). IPost-Co improves cardiac function post-myocardial infarction and reduces reperfusion-induced cell damage by down-regulation of the AhR-signalling transduction pathway ultimately leading to infarct size reduction.

Cysteinyl Leukotriene Signaling Aggravates Myocardial Hypoxia in Experimental Atherosclerotic Heart Disease

BackgroundCysteinyl-leukotrienes (cys-LT) are powerful spasmogenic and immune modulating lipid mediators involved in inflammatory diseases, in particular asthma. Here, we investigated whether cys-LT signaling, in the context of atherosclerotic heart disease, compromises the myocardial microcirculation and its response to hypoxic stress. To this end, we examined Apoe−/− mice fed a hypercholesterolemic diet and analysed the expression of key enzymes of the cys-LT pathway and their receptors (CysLT1/CysLT2) in normal and hypoxic myocardium as well as the potential contribution of cys-LT signaling to the acute myocardial response to hypoxia.Methods and principal findingsMyocardial biopsies from Apoe−/− mice demonstrated signs of chronic inflammation with fibrosis, increased apoptosis and expression of IL-6, as compared to biopsies from C57BL/6J control mice. In addition, we found increased leukotriene C4 synthase (LTC4S) and CysLT1 expression in the myocardium of Apoe−/− mice. Acute bouts of hypoxia further induced LTC4S expression, increased LTC4S enzyme activity and CysLT1 expression, and were associated with increased extension of hypoxic areas within the myocardium. Inhibition of cys-LT signaling by treatment with montelukast, a selective CysLT1 receptor antagonist, during acute bouts of hypoxic stress reduced myocardial hypoxic areas in Apoe−/− mice to levels equal to those observed under normoxic conditions. In human heart biopsies from 14 patients with chronic coronary artery disease mRNA expression levels of LTC4S and CysLT1 were increased in chronic ischemic compared to non-ischemic myocardium, constituting a molecular basis for increased cys-LT signaling.ConclusionOur results suggest that CysLT1 antagonists may have protective effects on the hypoxic heart, and improve the oxygen supply to areas of myocardial ischemia, for instance during episodes of sleep apnea.

Similar patterns of myocardial metabolism and perfusion in patients with type 2 diabetes and heart disease of ischaemic and non-ischaemic origin

Type 2 diabetes and insulin resistance are often associated with the co-occurrence of coronary atherosclerosis and cardiac dysfunction. The aim of this study was to define the independent relationships between left ventricular dysfunction or ischaemia and patterns of myocardial perfusion and metabolism in type 2 diabetes. Twenty-four type 2 diabetic patients--12 with coronary artery disease (CAD) and preserved left ventricular function and 12 with non-ischaemic heart failure (HF)--were enrolled in a cross-sectional study. Positron emission tomography (PET) was used to assess myocardial blood flow (MBF) at rest, after pharmacological stress and under euglycaemic hyperinsulinaemia. Insulin-mediated myocardial glucose disposal was determined with 2-deoxy-2-[(18)F]fluoroglucose PET. There was no difference in myocardial glucose uptake (MGU) between the healthy myocardium of CAD patients and the dysfunctional myocardium of HF patients. MGU was strongly influenced by levels of systemic insulin resistance in both groups (CAD, r = 0.85, p = 0.005; HF, r = 0.77, p = 0.01). In HF patients, there was an inverse association between MGU and the coronary flow reserve (r = -0.434, p = 0.0115). A similar relationship was observed in non-ischaemic segments of CAD patients. Hyperinsulinaemia increased MBF to a similar extent in the non-ischaemic myocardial of CAD and HF patients. In type 2 diabetes, similar metabolic and perfusion patterns can be detected in the non-ischaemic regions of CAD patients with normal cardiac function and in the dysfunctional non-ischaemic myocardium of HF patients. This suggests that insulin resistance, rather than diagnosis of ischaemia or left ventricular dysfunction, affects the metabolism and perfusion features of patients with type 2 diabetes.

Higher frequencies of BCRP+ cardiac resident cells in ischaemic human myocardium

Several cardiac resident progenitor cell types have been reported for the adult mammalian heart. Here we characterize their frequencies and distribution pattern in non-ischaemic human myocardial tissue and after ischaemic events. We obtained 55 biopsy samples from human atria and ventricles and used immunohistological analysis to investigate two cardiac cell types, characterized by the expression of breast cancer resistance protein (BCRP)/ABCG2 [for side population (SP) cells] or c-kit. Highest frequencies of BCRP+ cells were detected in the ischaemic right atria with a median of 5.40% (range: 2.48-11.1%) vs. 4.40% (1.79-7.75%) in the non-ischaemic right atria (P = 0.47). Significantly higher amounts were identified in ischaemic compared with non-ischaemic ventricles, viz. 5.44% (3.24-9.30%) vs. 0.74% (0-5.23%) (P = 0.016). Few numbers of BCRP+ cells co-expressed the cardiac markers titin, sarcomeric α-actinin, or Nkx2.5; no co-expression of BCRP and progenitor cell marker Sca-1 or pluripotency markers Oct-3/4, SSEA-3, and SSEA-4 was detected. C-kit+ cells displayed higher frequencies in ischaemic (ratio: 1:25 000 ± 2500 of cell counts) vs. non-ischaemic myocardium (1:105 000 ± 43 000). Breast cancer resistance protein+/c-kit+ cells were not identified. Following in vitro differentiation, BCRP+ cells isolated from human heart biopsy samples (n = 6) showed expression of cardiac troponin T and α-myosin heavy-chain, but no full differentiation into functional beating cardiomyocytes was observed. We were able to demonstrate that BCRP+/CD31- cells are more abundant in the heart than their c-kit+ counterparts. In the non-ischaemic hearts, they are preferentially located in the atria. Following ischaemia, their numbers are elevated significantly. Our data might provide a valuable snapshot at potential progenitor cells after acute ischaemia in vivo, and mapping of these easily accessible cells may influence future cell therapeutic strategies.

Optimal timing for first-pass stress CT myocardial perfusion imaging

CT-based myocardial perfusion imaging (CTP) has been shown to accurately detect myocardial perfusion defects when compared to SPECT. When performing single-phase first-pass stress CTP, timing is of major importance. The aim of this study was to provide guidance for optimal timing of single-phase first-pass stress CTP acquisitions. 16 patients (12 male, age, 69 ± 8 years) with known or suspected coronary artery disease underwent invasive coronary angiography with fractional flow reserve (FFR) measurements using a pressure wire as well as a time-resolved CTP protocol under adenosine stress, performed on a dual-Source CT scanner over a period of 30 s. From the CTP data, time-attenuation curves have been determined both in known ischemic myocardium with a corresponding coronary artery stenosis as proven by a FFR below 0.75 in invasive coronary angiography, as well as in non-ischemic reference myocardium during pharmacological stress. Furthermore, contrast enhancement in the ascending aorta was determined. The time point for an optimal contrast (i.e., difference in Hounsfield Units, HU) between ischemic and normal myocardium was determined. Under pharmacological stress using adenosine, a maximum mean HU difference between ischemic and non-ischemic myocardium (17.7-22.5 HU) was observed 24-32 s after injection of contrast medium. The maximal attenuation difference between normal and ischemic myocardium ranged from 15 to 77 HU in the analyzed patient cohort. When applying a bolus-tracking technique with an automatic contrast detection in the proximal ascending aorta, the optimal time frame for stress CTP was between 8 and 16 s after contrast enhancement in the aorta exceeds 100 HU, or between 7 and 15 s using a threshold of 150 HU. For first-pass CT myocardial perfusion imaging there is a time frame of approximately 8 s for optimal differentiation of ischemic and non-ischemic myocardium, which will be helpful to optimize single-phase CTP scans.

Ischemia-Reperfusion Increases Transfection Efficiency of Intracoronary Adenovirus Type 5 in Pig Heart In Situ

Efficiency of intracoronary (IC) adenoviral vector transfection is impaired by the vascular endothelium. Ischemia and substances that increase vascular permeability (sodium nitroprusside, nitroglycerin) may augment adenoviral vector transfection efficiency (TE). We tested whether TE of adenoviral vector following IC infusion is improved by nitrates or by ischemia. Fluoroscopically guided angioplasty balloon catheters occluded the coronary artery in Yorkshire pigs and delivered adenoviral type 5 vector encoding the luciferase gene (Ad5Luc, 10(11) viral particles). TE (luciferase activity) was minimal and was not augmented by IC co-administration of 50 μg/min sodium nitroprusside to nonischemic myocardium. Two (but not one) 3-min episodes of occlusion tended to increase luciferase activity (p=0.06), and luciferase activity was further increased by IC co-administration of nitroglycerin (p<0.001). After 75 min of coronary artery occlusion, luciferase activity was greater than with shorter periods of ischemia, and was significantly greater in the ischemia-reperfused zone compared to the border zone 3 and 14 days after infusion; there was no transfection in nonischemic myocardium. IC delivery of Ad5Luc into post-ischemic myocardium caused no local inflammation or hemodynamic instability. We conclude that the uptake of IC Ad5 to ischemic reperfused myocardium validates use of IC Ad5 delivery protocols in future human gene therapy trials in patients following myocardial ischemia.

Mapping molecular agents distributions in whole mice hearts using born-normalized optical projection tomography.

To date there is a lack of tools to map the spatio-temporal dynamics of diverse cells in experimental heart models. Conventional histology is labor intensive with limited coverage, whereas many imaging techniques do not have sufficiently high enough spatial resolution to map cell distributions. We have designed and built a high resolution, dual channel Born-normalized near-infrared fluorescence optical projection tomography system to quantitatively and spatially resolve molecular agents distribution within whole murine heart. We validated the use of the system in a mouse model of monocytes/macrophages recruitment during myocardial infarction. While acquired, data were processed and reconstructed in real time. Tomographic analysis and visualization of the key inflammatory components were obtained via a mathematical formalism based on left ventricular modeling. We observed extensive monocyte recruitment within and around the infarcted areas and discovered that monocytes were also extensively recruited into non-ischemic myocardium, beyond that of injured tissue, such as the septum.

Reduced microvascular density in non-ischemic myocardium of patients with recent non-ST-segment-elevation myocardial infarction

BackgroundMyocardial microvascular dysfunction has been implicated in the pathogenesis of myocardial infarction (MI). We tested the hypothesis that patients with MI have lower microvasculature density in myocardium remote from the site of infarction than patients with similar extent of coronary artery disease (CAD) without MI and examined the relationship between myocardial capillary length density and plasma levels of angiogenesis-related biomarkers. MethodsWe analyzed biopsies from non-ischemic left ventricular (LV) myocardium and measured plasma levels of angiogenesis-related biomarkers in patients undergoing coronary artery bypass graft surgery, 57 without previous MI (no-MI) and 27 with recent non-ST-segment-elevation MI (NSTEMI). Comparison was made with biopsies from 31 aortic stenosis (AS) patients and 6 patients with “normal” LV without CAD. ResultsMyocardial microvascular density of NSTEMI patients was approximately half the density of no-MI patients, and similar to AS patients. Whereas the reduced microvascular density of AS patients was accounted for by their cardiomyocyte hypertrophy, this was not the case for NSTEMI patients, who had higher diffusion radius/cardiomyocyte width ratio than no-MI, “normal” LV, and AS patients. NSTEMI patients had lower plasma levels of carboxymethyl lysine and low molecular weight fluorophores, higher vascular endothelial growth factor (VEGF) receptor-1/VEGF-A ratio, and higher endostatin and hepatocyte growth factor levels than no-MI patients. ConclusionsRecent MI was associated with reduced microvasculature density in myocardium remote from the site of infarction and alteration in plasma levels of angiogenesis-related biomarkers.

“Cardiac K ATP ”

Understanding the etiology of and development of appropriate treatment for myocardial ischemia and associated sudden cardiac death is a major goal of cardiovascular research. In a recent review,1 a compelling case is presented that sarcolemmal ATP-sensitive potassium (KATP) channels are an excellent target for antiarrhythmic therapy. Because opening of cardiac KATP channels shortens the action potential and reduces the refractory period, its activation can establish an arrhythmogenic substrate, supporting reentry. Hence, inhibition of KATP could be an ideal way to stop or even prevent arrhythmias: these channels tend to be closed under normal circumstances and to open only when cell metabolism is inhibited; therefore, any agents that inhibit KATP activity should specifically target channels only during ischemia, leaving nonischemic myocardium unaffected. On the other hand, activation of cardiac KATP channels has consistently been shown to protect the heart from damage during ischemia by limiting Ca entry.2 Finding a way to balance these opposing effects on the heart before, during, and after an ischemic event remains an intractable issue. Until recently, efforts to manipulate cardiac KATP have generally been conducted under a single underlying assumption, namely that cardiac KATP channels are structurally and functionally the same throughout the heart. However, recent studies, including the new report of Bao and colleagues3 in this issue, reveal that “cardiac KATP” is not a single entity and is more accurately a collection of structurally distinct channels. The relative density of each one varies regionally in the heart, may differ between species, and may be under dynamic control. Article see p 926 KATP channels are expressed in many different excitable tissues, where they couple cell energetic status with membrane excitability and function.4 In different tissues, KATP channels exhibit different properties. This …

Loss of fibulin-2 protects against progressive ventricular dysfunction after myocardial infarction

Remodeling of the cardiac extracellular matrix (ECM) is an integral part of wound healing and ventricular adaptation after myocardial infarction (MI), but the underlying mechanisms remain incompletely understood. Fibulin-2 is an ECM protein upregulated during cardiac development and skin wound healing, yet mice lacking fibulin-2 do not display any identifiable phenotypic abnormalities. To investigate the effects of fibulin-2 deficiency on ECM remodeling after MI, we induced experimental MI by permanent coronary artery ligation in both fibulin-2 null and wild-type mice. Fibulin-2 expression was up-regulated at the infarct border zone of the wild-type mice. Acute myocardial tissue responses after MI, including inflammatory cell infiltration and ECM protein synthesis and deposition in the infarct border zone, were markedly attenuated in the fibulin-2 null mice. However, the fibulin-2 null mice had significantly better survival rate after MI compared to the wild-type mice as a result of less frequent cardiac rupture and preserved left ventricular function. Up-regulation of TGF-β signaling and ECM remodeling after MI were attenuated in both ischemic and non-ischemic myocardium of the fibulin-2 null mice compared to the wild type counterparts. Increase in TGF-β signaling in response to angiotensin II was also lessened in cardiac fibroblasts isolated from the fibulin-2 null mice. The studies provide the first evidence that absence of fibulin-2 results in decreased up-regulation of TGF-β signaling after MI and protects against ventricular dysfunction, suggesting that fibulin-2 may be a potential therapeutic target for attenuating the progression of ventricular remodeling.

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.

Resveratrol preserves myocardial function and perfusion to adjacent non-ischemic myocardium in a swine model of metabolic syndrome and chronic myocardial ischemia

Resveratrol preserves myocardial function and perfusion to adjacent non-ischemic myocardium in a swine model of metabolic syndrome and chronic myocardial ischemia

Hypercholesterolemia and chronic ischemia alter myocardial responses to selective cyclooxygenase-2 inhibition

Cyclooxygenase-2 inhibitors have been implicated in adverse cardiac events. We hypothesize that hypercholesterolemia and ischemia may alter the myocardial response to the cyclooxygenase-2 inhibitor celecoxib. Yorkshire swine fed normal chow (CX, n = 6) or high-cholesterol diet (HCX, n = 6) underwent placement of an Ameroid constrictor on the left circumflex artery and were started on celecoxib (200 mg/day). After 7 weeks, ischemic and nonischemic myocardium was analyzed for thrombogenic ratio (thromboxane content divided by prostacyclin content), total protein oxidative stress, and expression of prostacyclin synthase, thromboxane synthase, myeloperoxidase, and superoxide dismutase. Cardiac function, tissue perfusion, and vessel density were measured. HCX animals were significantly hypercholesterolemic compared with CX animals. Thrombogenic ratio was significantly higher in the HCX group than in the CX group, but prostacyclin and thromboxane synthase expression was similar in all tissues. Myocardial perfusion was decreased in the HCX group compared with the CX group. Total oxidative stress, myeloperoxidase, and superoxide dismutase were increased in ischemic tissue compared with nonischemic tissues, but there was no diet-induced difference between groups. There was no difference in capillary or arteriolar density between groups. Left ventricular contractility was greater in the HCX group than in the CX group, but there was no significant difference in heart rate, mean arterial pressure, or left ventricular pressure. Hypercholesterolemic patients using celecoxib may be at higher risk for thrombotic events than those with normal cholesterol, but the relationship between dyslipidemia, ischemia, and cyclooxygenase-2 inhibition is likely much more complicated than originally thought.

Acute T3 treatment protects the heart against ischemia-reperfusion injury via TRα1 receptor

We have previously shown that acute thyroid hormone treatment could limit reperfusion injury and increase post-ischemic recovery of function. In the present study, we further explore potential initiating mechanisms of this response. Thus, isolated rat hearts were subjected to 30 min zero-flow global ischemia (I) followed by 60-min reperfusion (R). Reperfusion injury was assessed by post-ischemic recovery of left ventricular developed pressure (LVDP%) and LDH release. T3 at a dose of 60 nM which had no effect on contractile function of non-ischemic myocardium, significantly increased LVDP% [48% (2.9) vs. 30.2% (3.3) for untreated group, P < 0.05] and reduced LDH release [8.3 (0.3) vs. 10 (0.42) for untreated group, P < 0.05] when administered at R. T4 (60 and 400 nM) had no effect on contractile function either in non-ischemic or ischemic myocardium. Administration of debutyl-dronedarone (DBD), a TRα1 antagonist abolished the T3-limiting effect on reperfusion injury: Thus, co-administration of T3 and DBD resulted in significantly lower LVDP%, [23% (4.7) vs. 48% (2.9) for T3 group, P < 0.05] and higher LDH release [9.9 (0.3) vs. 8.3 (0.3), for T3 group, P < 0.05]. In conclusion, acute T3 and not T4 treatment will be able to protect against reperfusion injury. T3 can exert this beneficial effect on ischemic myocardium at a dose that has no effects on non-ischemic myocardium. Acute T3-limiting effect on reperfusion injury is mediated, at least in part, via TRα1 receptor.

Right ventricular dysfunction following acute myocardial infarction in the absence of pulmonary hypertension in the mouse.

BackgroundCardiac remodelling after AMI is characterized by molecular and cellular mechanisms involving both the ischemic and non-ischemic myocardium. The extent of right ventricular (RV) dilatation and dysfunction and its relation to pulmonary hypertension (PH) following AMI are unknown. The aim of the current study was to evaluate changes in dimensions and function of the RV following acute myocardial infarction (AMI) involving the left ventricle (LV).MethodsWe assessed changes in RV dimensions and function 1 week following experimental AMI involving the LV free wall in 10 mice and assessed for LV and RV dimensions and function and for the presence and degree of PH.ResultsRV fractional area change and tricuspidal annular plane systolic excursion significantly declined by 33% (P = 0.021) and 28% (P = 0.001) respectively. Right ventricular systolic pressure measured invasively in the mouse was within the normal values and unchanged following AMI.ConclusionAMI involving the LV and sparing the RV induces a significant acute decline in RV systolic function in the absence of pulmonary hypertension in the mouse indicating that RV dysfunction developed independent of changes in RV afterload.