Perfusion Of Ischemic Myocardium Research Articles

Cinnamaldehyde protects cardiomyocytes from oxygen-glucose deprivation/reoxygenation-induced lipid peroxidation and DNA damage via activating the Nrf2 pathway.

Rapid restoration of perfusion in ischemic myocardium is the most direct and effective treatment for coronary heart disease but may cause myocardial ischemia/reperfusion injury (MIRI). Cinnamaldehyde (CA, C9H8O), a key component in the well-known Chinese medicine cinnamomum cassia, has cardioprotective effects against MIRI. This study aimed to observe the therapeutic effect of CA on MIRI and to elucidate its potential mechanism. H9C2 rat cardiomyocytes were pretreated with CA solution at 0, 10, and 100 μM, respectively and subjected to oxygen-glucose deprivation/reoxygenation (OGD/R). Then the cell viability, the NF-κB and caspase3 gene levels, the reduced glutathione (GSH)/oxidized glutathione (GSSG) ratio, superoxide dismutase (SOD) level, reactive oxygen species (ROS) generation, 4-hydroxynonenal (4-HNE), and malondialdehyde (MDA) were detected. The severity of DNA damage was assessed by tail moment (TM) values using alkaline comet assay. Besides, the DNA damage-related proteins and the key proteins of the Nrf2 pathway were detected by western blot. CA treatment increased the cell viability, GHS/GSSG ratio, SOD level, PARP1, Nrf2, PPAR-γ, and HO-1 protein levels of H9C2 cardiomyocytes, while reducing NF-κB, caspase3, ROS level, 4-HNE and MDA content, γ-H2AX protein level, and TM values. Inhibition of the Nrf2 pathway reversed the effect of CA on cell viability and apoptosis of OGD/R induced H9C2 cardiomyocytes. Besides, 100 μM CA was more effective than 10 μM CA. In the OGD/R-induced H9C2 cardiomyocyte model, CA can protect cardiomyocytes from MIRI by attenuating lipid peroxidation and repairing DNA damage. The mechanism may be related to the activation of the Nrf2 pathway.

LncRNA PART1 Attenuates Myocardial Ischemia-Reperfusion Injury by Regulating TFAP2C/DUSP5 Axis via miR-302a-3p.

Myocardial ischemia-reperfusion injury (MIRI) refers to the damage of cardiac function caused by restoration of blood flow perfusion in ischemic myocardium. However, long non-coding RNA prostate androgen regulated transcript 1 (PART1)'s role in MIRI remain unclear. Immunofluorescence detected LC3 expression. Intermolecular relationships were verified by dual luciferase reporter assay. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, flow cytometry and transferase-mediated dUTP nick-end labeling (TUNEL) assays analyzed cell viability and apoptosis. The release of lactate dehydrogenase was tested via enzyme-linked immunosorbent assay (ELISA). Left anterior descending coronary artery surgery induced a MIRI mouse model. Infarct area was detected by 2,3,5-triphenyltetrazolium chloride staining. Hematoxylin and eosin staining examined myocardial injury. ELISA evaluated myocardial marker (creatine kinase MB) level. PART1 was decreased in hypoxia/reoxygenation (H/R) induced AC16 cells and MIRI mice. PART1 upregulation attenuated the increased levels of Bax, beclin-1 and the ratio of LC3II/I, and enhanced the decrease of Bcl-2 and p62 expression in H/R-treated cells. PART1 upregulation alleviated H/R-triggered autophagy and apoptosis via miR-302a-3p. Mechanically, PART1 targeted miR-302a-3p to upregulate transcription factor activating enhancer-binding protein 2C (TFAP2C). TFAP2C silencing reversed the protected effects of miR-302a-3p inhibitor on H/R treated AC16 cells. We further established TFAP2C combined to dual-specificity phosphatase 5 (DUSP5) promoter and activated DUSP5. TFAP2C upregulation suppressed H/R-stimulated autophagy and apoptosis through upregulating DUSP5. Overexpressed PART1 reduced myocardial infarction area and attenuated MIRI in mice. PART1 improved the autophagy and apoptosis in H/R-exposed AC16 cells through miR-302a-3p/TFAP2C/DUSP5 axis, which might provide novel targets for MIRI treatment.

Calpain inhibition improves collateral-dependent perfusion in a hypercholesterolemic swine model of chronic myocardial ischemia

PurposeCalpain overexpression is implicated in aberrant angiogenesis. We hypothesized that calpain inhibition (MDL28170) would improve collateral perfusion in a swine model with hypercholesterolemia and chronic myocardial ischemia. MethodsYorkshire swine fed a high cholesterol diet for 4 weeks underwent surgical placement of an ameroid constrictor to their left circumflex coronary artery. Three weeks later, animals received no drug, high cholesterol control group (n = 8); low-dose calpain inhibition (0.12 mg/kg; n = 9); or high-dose calpain inhibition (0.25 mg/kg; n = 8). The heart was harvested after 5 weeks. ResultsMyocardial perfusion in ischemic myocardium significantly improved with high-dose calpain inhibition at rest and with demand pacing (P = .016 and .011). Endothelium-dependent microvessel relaxation was significantly improved with low-dose calpain inhibition (P = .001). There was a significant increase in capillary density, with low-dose calpain inhibition and high-dose calpain inhibition (P = .01 and .01), and arteriolar density with low-dose calpain inhibition (P = .001). Calpain inhibition significantly increased several proangiogenic proteins, including vascular endothelial growth factor (P = .02), vascular endothelial growth factor receptor 1 (P = .003), vascular endothelial growth factor receptor 2 (P = .003), and talin, a microvascular structural protein (P = .0002). There was a slight increase in proteins implicated in endothelial-dependent (nitric oxide mediated) relaxation, including extracellular signal-regulated kinase, phosphorylated extracellular signal-regulated kinase, and inducible nitric oxide synthase with calpain inhibition. ConclusionsIn the setting of hypercholesterolemia, calpain inhibition improved perfusion, with a trend toward increased collateralization on angiography and increased capillary and arteriolar densities in ischemic myocardium. Calpain inhibition also improved endothelium-dependent microvessel relaxation and increased expression of proteins implicated in angiogenesis and vasodilatation.

Bone marrow–derived CMPs and GMPs represent highly functional proangiogenic cells: implications for ischemic cardiovascular disease

AbstractClinical studies using bone marrow–derived proangiogenic cells (PACs) have demonstrated modest improvements of function and/or perfusion of ischemic myocardium or skeletal muscle. Because the identities of these PACs and their functional ability to promote neovascularization remain poorly understood, it is possible that a subset of robust PACs exists but is obscured by the heterogeneous nature of this cell population. Herein, we found that common myeloid progenitors (CMPs) and granulocyte-macrophage progenitors (GMPs) preferentially differentiate into PACs compared with megakaryocyte-erythrocyte progenitors, hematopoietic stem cells, and common lymphoid progenitors. In vivo hindlimb ischemia studies and Matrigel plug assays verified the enhanced neovascularization properties uniquely associated with PACs derived from CMPs and GMPs. Taken together, these observations identify CMPs and GMPs as key bone marrow progenitors for optimal PAC function in vitro and in vivo and provide a foundation for novel therapeutic approaches to modulate angiogenesis.

High-fat diet alters prostanoid balance and perfusion in ischemic myocardium of naproxen-treated swine

The effect of nonsteroidal anti-inflammatory drugs (NSAIDs) on the cardiovascular system remains controversial, especially in patients with cardiovascular comorbidities. We used a swine model of chronic myocardial ischemia to investigate whether hypercholesterolemia alters the cardiovascular effects of the nonselective NSAID naproxen. Yorkshire swine were fed normal chow (NAP; n = 7) or a high-fat diet (HF-NAP; n = 8). Chronic myocardial ischemia was created in all animals by left circumflex ameroid constrictor placement. All swine were started on oral naproxen (440 mg/day) at the time of ameroid placement. After 7 weeks, myocardial perfusion and microvessel reactivity in the ischemic territory were assessed. Tissue levels of prostanoid metabolites 11-dehydrothromboxane B2 (11-d-TXB₂) and 6-keto-prostaglandin F1-α (6-k-PGF(1α)) were measured. Tissue was analyzed for capillary density and protein expression. Myocardial perfusion was significantly decreased in the HF-NAP group both at rest and during ventricular pacing. Microvessel relaxation responses to sodium nitroprusside and adenosine 5'-diphosphate were similar between groups. Tissue 11-d-TXB₂ levels were similar between groups, but tissue 6-k-PGF(1α) was significantly decreased in the HF-NAP group (P = .001). Expression of thromboxane synthase was significantly higher in the HF-NAP group (P = .02), while prostacyclin synthase expression was significantly decreased in the HF-NAP group (P = .04). Capillary density was higher in the HF-NAP group (P = .005). Proangiogenic vascular endothelial growth factor (VEGF; P = .0002) and Akt (P = .01) were downregulated in the HF-NAP group. A high-fat diet impairs tissue perfusion in ischemic myocardium of naproxen-treated swine by shifting the prostanoid balance to favor production of thromboxane over prostacyclin. Dietary modification may improve myocardial blood flow and alter the safety profile in chronically ischemic cardiac patients taking naproxen.

Extracorporeal Cardiac Shock Wave Therapy Ameliorates Clinical Symptoms and Improves Regional Myocardial Blood Flow in a Patient with Severe Coronary Artery Disease and Refractory Angina

Different therapeutic options are being used for chronic coronary artery disease (CAD). We report about a 51-year-old female with CAD and refractory angina pectoris despite maximally tolerated medical therapy and after both percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG). The patient received cardiac shock wave therapy (CSWT) over a period of 6 month. There was no arrhythmia during or after treatment; enzyme levels were normal at all times. PET imaging showed a substantial improvement of myocardial stress perfusion. Since the patient reported that she now was fully capable to deal with her everyday life, further treatment options were postponed. Our case report suggests that ultrasound-guided CSWT is able to improve symptoms and perfusion in ischemic myocardium.

Functional Characteristics of Coronary Vasomotor Function Following Intramyocardial Gene Therapy with Naked DNA Encoding for Vascular Endothelial Growth Factor165

Vascular endothelial growth factor (VEGF) is a potent angiogenic factor. VEGF gene therapy improves perfusion of ischemic myocardium in experimental models and possibly in patients with end-stage coronary artery disease. In addition to its proliferative and migratory effect on endothelial cells, it also activates and up-regulates endothelial nitric oxide synthase (eNOS). Therefore, the authors investigated coronary endothelium-dependent vasodilatation in patients before and after VEGF gene therapy. The effect of intracoronary acetylcholine infusion on coronary diameter was assessed at baseline and after 3 months follow-up in patients with end-stage coronary artery disease treated with VEGF gene and in controls scheduled for elective percutaneous transluminal coronary angioplasty (PTCA) (acetylcholine test at diagnostic angiography and before a subsequently scheduled PTCA). Five out of six VEGF patients experienced a reduction in anginal complaints. Angiographic evidence for improved collateral filling was evident in two out of six patients. The vasoconstrictive response to acetylcholine was partly converted into dilatation. In contrast, the acetylcholine response in control patients remained vasoconstrictive. In conclusion, VEGF gene therapy has an important beneficial effect on the functional characteristics of the myocardial vascular network. Therefore, this therapy can potentially play an important role in all stages of the atherosclerotic process.

Radiofrequency transmyocardial revascularization in experiment

Conducted benchmark analysis of influence to mechanical punctures, transmyocardial radiofrequency influence and lazer radiating on myocardium. Study is conducted on 284 rats. Transmyocardial revascularization (ТМR) was executed with use intramuscular needle, Nd:YAG lazer, radiofrequency generator with needle electrode. Study of vascular density and myocardial perfusion was conducted through 1, 2, 4 and 8 weeks. Maximum increasing vascular density was observed on 4 week. In groups with radiofrequency TMR and Nd:YAG TMR specific vascular volume is enlarged in 5 once (26,9 ± 1,9% and 22,2 ± 1,7%, accordingly; Р < 0,05) in contrast with the checking group (4,9 ± 1,6%). In the group with mechanical ТМР specific vascular volume is enlarged small (6,1 ± 1,3%). Increasing an accumulation 99mTc-myoview in the group with radiofrequency TMR occurred on 8 week by comparing with the checking group, it has formed 2,82 ± 0,31% (Р < 0,05) and 1,68 ± 0,21% accordingly. Conclusion: Analysis of vascular density points to alike efficiency of lazer and radiofrequency transmyocardial revascularization. Radiofrequency ТМR causes an increasing vascular density and improvement myocardial perfusion in ischemic myocardium.

Perfusion of Ischemic Myocardium during Anesthesia with Sevoflurane

Sevoflurane produces direct vasodilation of coronary arteries in vitro and decreases coronary vascular resistance in vivo, pharmacologic properties that may contribute to the development of "coronary steal." This investigation examined the effects of sevoflurane on the distribution of regional myocardial perfusion in chronically instrumented dogs with steal-prone coronary artery anatomy. Dogs were chronically instrumented for measurement of aortic and left ventricular pressure, diastolic coronary blood flow velocity and subendocardial segment length. After recovery from surgery, dogs underwent repetitive, brief, left anterior descending coronary artery (LAD) occlusions via an implanted hydraulic vascular occluder to enhance collateral development. A progressive left circumflex coronary artery (LCCA) stenosis was also obtained using an ameroid constrictor. After development of LCCA stenosis, the LAD was totally occluded to produce a model of multivessel coronary artery disease. Systemic hemodynamics, regional contractile function and myocardial perfusion measured with radioactive microspheres were assessed in the conscious state and during sevoflurane anesthesia at 1.0 and 1.5 MAC with and without restoration of arterial blood pressure and heart rate to conscious levels. Total LAD occlusion with simultaneous LCCA stenosis increased heart rate, mean arterial pressure, left ventricular systolic and end-diastolic pressures, end-diastolic segment length, and rate-pressure product in conscious dogs. Subsequent administration of sevoflurane caused dose-related decreases in arterial pressure, left ventricular systolic pressure, double product, and peak rate of increase of left ventricular pressure at 50 mmHg. Perfusion of normal myocardium was unchanged during sevoflurane anesthesia. In contrast, sevoflurane caused dose-dependent decreases in blood flow to myocardium supplied by the stenotic LCCA, which returned to control levels after restoration of heart rate and arterial pressure. No reduction in collaterally derived blood flow to the occluded region was produced by 1.0 or 1.5 MAC sevoflurane. No redistribution of blood flow away from the occluded LAD region to normal or stenotic myocardium occurred during sevoflurane anesthesia. In fact, increases in the ratio of blood flow between occluded and normal zones or occluded and stenotic zones were observed in the subepicardium during 1.5 MAC sevoflurane with maintenance of the heart rate and arterial pressure at conscious levels. The results demonstrate that sevoflurane does not reduce or abnormally redistribute myocardial blood flow derived from coronary collateral vessels in a chronically instrumented canine model of multivessel coronary artery obstruction.

Effects of Pharmacological Treatment of Acute Myocardial Infarction on Left Ventricular Function

Impairment of left ventricular function is a major consequence of acute myocardial infarction. Several interventions have been proposed to reduce the extent of myocardial tissue undergoing necrosis after cornoracy artery occlusion. Therapy for patients with acute myocardial infarction has long relied on interventions aimed at reducing oxygen consumption, such as administration of beta-blockers and nitrates. However, despite clinical evidence that these interventions can reduce mortality or prevent left ventricular dilatation, no clear benefit has been observed on left ventricular function. Over the past few years, treatment of acute myocardial infarction has radically changed. Availability of several thrombolytic agents has made reperfusion of ischemic myocardium a routine procedure. Early reperfusion has been shown to be the most powerful intervention to reduce infarct size and minimize left ventricular dysfunction in experimental preparations. Several clinical trials have also demonstrated that patients with acute myocardial infarction may greatly benefit from early thrombolysis, as this procedure is associated with improvement of global and regional left ventricular function and reduction in mortality. However, in spite of its obvious advantages, reperfusion might result in a paradoxical tissue damage that may blunt the net beneficial effect of restoring perfusion of ischemic myocardium. Reperfusion-mediated myocardial injury has been shown to occur in several experimental preparations and it has been proposed that generation of toxic oxygen metabolites at the moment of reflow is responsible for the occurrence of this phenomenon. Indeed, administration of free radical scavengers may significantly reduce the extent of reperfusion injury and improve contractile recovery in experimental preparations.(ABSTRACT TRUNCATED AT 250 WORDS)

Alterations in myocardial perfusion during exercise after isosorbide dinitrate infusion in patients with coronary disease: Assessment by thallium-201 scintigraphy

We studied the effect of intravenous isosorbide dinitrate (ISDN) on myocardial perfusion of patients with coronary artery disease, by using exercise thallium-201 (TI-201) myocardial scintigraphy. A control study was conducted initially to assess regional myocardial perfusion rate. Left ventricular myocardium was divided into six parts: anterior, lateral, apical, inferior, posterior, and septal segments. The segmental myocardial perfusion was characterized according to TI-201 initial uptake index (IUI) of relative distribution and redistribution index (RDI) of TI-201 washout. The normal limit of IUI and RDI was established from the data of 17 persons with normal coronary arteries, and then the IUI ≤ 84% and the RDI ≥ 1.12 was defined as abnormal. Based on IUI and RDI, each segment was characterized into three types: A type = IUI ≦ 84%, RDI ≧ 1.12; B type = IUI ≦ 84%, RDI < 1.12; and C type = IUI > 84%, RDI < 1.12. ISDN was given as a dose of 0.1 mg/kg/hr, and then treadmill testing was repeated for the same duration of exercise time using the same protocol as in the control period. The segments of A type showed a significant improvement in IUI and RDI after receiving ISDN infusion, while the B and C type segments showed no change. It was also shown that the improvement of IUI and RDI of the A type segments was not as marked in multivessel disease as in cases of single-vessel disease. The results of our study suggest that ISDN particularly improves myocardial perfusion in ischemic myocardium, and the degree of improvement is influenced by myocardial viability and the severity of coronary artery disease.

Contrasting effects of pharmacologic vasodilation on true collateral and overlap perfusion in ischemic myocardium

1. 1. The effects of chromonar (3.5 and 7.0 mg/kg i.v.), a selective coronary vasodilator, on true collateral blood flow and overlap flow (noncollateral perfusion due to overlapping end arteries of adjacent coronary vessels) were measured independently in anesthetized dogs following acute coronary occlusion. 2. 2. Collateral flow in the ischemic zone was significantly ( P<0.05) reduced by chromonar in a doserelated manner while transmural overlap flow was increased. 3. 3. True collateral flow was distributed primarily to the subepicardium and chromonar produced a significant reduction in both subepicardial and subendocardial perfusion. Overlap perfusion was distributed equally across the left ventricular wall and chromonar increased perfusion to both subepicardium and subendocardium. 4. 4. The results indicate that there are two independent sources of perfusion of ischemic myocardium and that pharmacologic vasodilation with chromonar produces opposite effects on each: a steal of true collateral blood flow and an increase in overlap perfusion.

Effect of acute ischemia, nitroglycerin and nitroprusside on regional myocardial thickening, stress and perfusion. Experimental echocardiographic studies.

The purposes of this study were to demonstrate that echocardiography can be used to demonstrate the systolic wall thinning of acutely ischemic myocardium, and to compare the effects of nitroglycerin and nitroprusside on systolic thinning, wall stress and perfusion of ischemic myocardium. In 37 dogs, the ratio of end-systolic-to-end-diastolic posterior wall thickness fell from 1.30 +/- 0.02 to 0.88 +/- 0.01 ((p less than 0.001) after circumflex coronary occlusion; perfusion of the area supplied by the occluded artery fell from 98.2 +/- 7.5 ml/100 g/min to 36.5 +/- 2.9 ml/100 g/min (p less than 0.001). Nitroglycerin and nitroprusside were given to lower mean arterial pressure by 7% and 15%. Despite the reduction in coronary perfusion pressure, transmural perfusion, endocardial/epicardial perfusion ratio and systolic thinning remained constant. Both drugs reduced the ischemic "wall stress index" (ventricular pressure x ventricular diameter/wall thickness) by almost 50%. Thus, both nitroglycerin and nitroprusside were equally beneficial in this model of acute myocardial ischemia.

Effect of Inosine on Ventricular Regional Perfusion and Infarct Size after Coronary Occlusion

In 16 dogs inosine was infused at 0.5 mmol/min i.v. for 5 min beginning 15 min after coronary occlusion. Tracer microspheres were used to estimate flow in subepicardium and subendocardium of nonischemic, central ischemic, and borderline ischemic muscle. Estimates of flow before occlusion, 5 min after occlusion, during inosine infusion, 30 min after infusion and 60 min after infusion were obtained. Coronary occlusion reduced flow in the central ischemic regions by 75-95%. The reduction in flow was greatest in subendocardium. In the borderline regions subendocardial flow was reduced by 30% while subepicardial flow was unaffected. The major effects of inosine were seen in nonischemic and borderline ischemic regions. Flow in borderline subendocardium returned to its pre-occlusion value, and flow in nonischemic myocardium increased by approximately 60-80%. However, only in the ischemic regions was the increase in flow sustained for the entire 60 min. In 20 dogs infarct size was determined using nitro blue tetrazolium stain. In 10 controls infarct size was 20.1%, while in 10 inosine-treated dogs infarct size was 15.2% of left ventricular weight (p less than 0.01). Thus, following coronary occlusion inosine infusion was associated with an increase in perfusion of ischemic myocardium and a reduction in infarct size.