Chronic Myocardial Ischemia Research Articles

Current perspective of stem cell therapies for cardiac regeneration

Despite recent advances in prevention and treatment of coronary artery disease, it remains the major cause of morbidity and mortality worldwide. There is an unmet need for treatment of ischemic cardiomyopathy caused by postmyocardial infarction, left ventricular remodeling or chronic myocardial ischemia. As a result, there is tremendous interest in developing stem cell therapies for prevention and treatment of ischemic cardiomyopathy. Although the mechanism remains unclear, the majority of preclinical studies demonstrate that different sources of cell-based therapy reduce the infarct size, and improve myocardial perfusion and contractile function. Recent results from randomized controlled clinical trials suggest that intracoronary or intramyocardial injection of bone marrow-derived cells may be a safe and feasible strategy for treatment of acute myocardial infarction as well as chronic myocardial ischemia. Furthermore, these studies have also provided initial evidence of clinical efficacy with modest, but...

Therapeutic potential of thymosin ß4 in acute and chronic ischemia

Acute cellular rejection of transplanted hearts has improved within the last years due to amelioration of the immunosuppressive treatment. However, the chronic rejection caused by cardiac allograft vasculopathy still remains a problem, limiting the survival time of the graft [1]. This vasculopathy is characterized by microcirculatory disturbance, caused by proliferation of smooth muscle cell, lymphocytes and macrophages [2]. Increasing vessel density and thereby enhancing micro- and macro circulation might be a therapeutic approach. Utilization of pro-angiogenic factors, such as VEGF, to improve perfusion in these grafts has the disadvantage of increasing vascular permeability. Moreover, VEGF-A may act as a pro-inflammatory cytokine [3]. In contrast, an anti-inflammatory factor providing pro-angiogenic properties might offer favourable outcome of transplant vasculopathy. Thymosin ß4, an endogenously occurring peptide of 5 kDa, has been demonstrated to be cardioprotective after acute myocardial ischemia, at least in part by reducing postischemic inflammation [4,5]. Furthermore, Thymosin ß4 is essential for coronary vessel development and provides angiogenesis during wound healing of the adult organism [6,7]. These results indicate an anti-inflammatory effect combined with a strong pro-angiogenic potential of Thymosin ß4, both required therapeutically, in particular in a transplant setting. To explore the vascular growth potential of Thymosin ß4, we designed an adeno-associated viral vector (AAV) containing Thymosin ß4 as transgene. The local over expression of Thymosin ß4 in a murine ischemic hindlimb model did not only increase capillarization, but also enhanced blood flow, in a strictly Akt dependent manner. Translation of the gene therapeutic approach to a pre clinical pig model of chronic myocardial ischemia confirmed the pro angiogenic and arteriogenic potential of the Thymosin ß4. Furthermore after 56 days of chronic myocardial ischemia global and regional myocardial as well as regional myocardial blood flow function were enhanced after Thymosin ß4 overexpression. We pursued the potential of Thymosin ß4 to vascularize transplant tissue in 2 models: In a dorsal skinfold chamber, which received engineered heart tissue propagated from neonatal rodent cardiomyocytes, vascularisation was significantly enhanced by exogenously applied Thymosin ß4 (in cooperation with T. Eschenhagen). Secondly, in an allogenic heart transplantation model (pig), where Thymosin ß4 is applied via AAV before transplantation, a better survival of cardiac grafts provided by reduced graft rejection was observed. Taken together, Thymosin ß4 might be a useful factor for chronic graft rejection, by reducing local inflammation and enhancing vascularization in the graft and thereby extent the survival time of the graft.

Long-term preservation of myocardial energetic in chronic hibernating myocardium

We previously reported that the myocardial energetic state, as defined by the ratio of phosphocreatine to ATP (PCr/ATP), was preserved at baseline (BL) in a swine model of chronic myocardial ischemia with mild reduction of myocardial blood flow (MBF) 10 wk after the placement of an external constrictor on the left anterior descending coronary artery. It remains to be seen whether this stable energetic state is maintained at a longer-term follow-up. Hibernating myocardium (HB) was created in minipigs (n = 7) by the placement of an external constrictor (1.25 mm internal diameter) on the left anterior descending coronary artery. Function was assessed with MRI at regular intervals until 6 mo. At 6 mo, myocardial energetic in the HB was assessed by (31)P-magnetic resonance spectrometry and myocardial oxygenation was examined from the deoxymyoglobin signal using (1)H-magnetic resonance spectrometry during BL, coronary vasodilation with adenosine, and high cardiac workload with dopamine and dobutamine (DpDb). MBF was measured with radiolabeled microspheres. At BL, systolic thickening fraction was significantly lower in the HB compared with remote region (34.4 ± 9.4 vs. 50.1 ± 10.7, P = 0.006). This was associated with a decreased MBF in the HB compared with the remote region (0.73 ± 0.08 vs. 0.97 ± 0.07 ml · min(-1) · g, P = 0.03). The HB PCr/ATP at BL was normal. DpDb resulted in a significant increase in rate pressure product, which caused a twofold increase in MBF in the HB and a threefold increase in the remote region. The systolic thickening fraction increased with DpDb, which was significantly higher in the remote region than HB (P < 0.05). The high cardiac workload was associated with a significant reduction in the HB PCr/ATP (P < 0.02), but this response was similar to normal myocardium. Thus HB has stable BL myocardial energetic despite the reduction MBF and regional left ventricular function. More importantly, HB has a reduced contractile reserve but has a similar energetic response to high cardiac workload like normal myocardium.

Does laser type impact myocardial function following transmyocardial laser revascularization?

Transmyocardial laser revascularization (TMR) is currently clinically performed with either a CO(2) or Ho:YAG laser for the treatment of severe angina. While both lasers provide symptomatic relief, there are significant differences in the laser-tissue interactions specific to each device that may impact their ability to enhance the perfusion of myocardium and thereby improve contractile function of the ischemic heart. A porcine model of chronic myocardial ischemia was employed. After collecting baseline functional data with cine magnetic resonance imaging (MRI) and dobutamine stress echo (DSE), 14 animals underwent TMR with either a CO(2) or Ho:YAG laser. Transmural channels were created with each laser in a distribution of 1/cm(2) in the ischemic zone. Six weeks post-treatment repeat MRI as well as DSE were obtained after which the animals were sacrificed. Histology was preformed to characterize the laser-tissue interaction. CO(2) TMR led to improvement in wall thickening in the ischemic area as seen with cine MRI (40.3% vs. baseline, P < 0.05) and DSE (20.2% increase vs. baseline, P < 0.05). Ho:YAG treated animals had no improvement in wall thickening by MRI (-11.6% vs. baseline, P = .67) and DSE (-16.7% vs. baseline, P = 0.08). Correlative semi-quantitative histology revealed a significantly higher fibrosis index in Ho:YAG treated myocardium versus CO(2) (1.81 vs. 0.083, P < 0.05). In a side-by-side comparison CO(2) TMR resulted in improved function of ischemic myocardium as assessed by MRI and echocardiography. Ho:YAG TMR led to no improvement in regional function likely due to concomitant increase in fibrosis in the lasered area.

Hiccups as a Sign of Chronic Myocardial Ischemia

Chronic myocardial ischemia often presents with a fairly typical history, but patients can present with atypical chest pain or pain referred to a less-typical location like the jaw, stomach, or back. Sometimes patients describe symptoms usually not attributed to heart disease, like indigestion or feeling cold and clammy, in the presence or absence of chest pain. One important clue to underlying coronary artery disease is the appearance of symptoms that are induced by effort and relieved by rest. This paper describes two unusual presentations of myocardial ischemia in patients whose main symptom was hiccups, the first intractable hiccups over months and the second effort-induced hiccups. Both also described atypical chest pain.

Angiogenesis in chronic ischemic porcine myocardium after transfer of VEGF₁₆₅ and angiopoietin-1 mediated by recombinant adeno-associated viral vector

To study the effects of combination of angiopoietin-1 (ANG-1) and vascular endothelial growth factor₁₆₅ (VEGF₁₆₅) gene transfer mediated by recombinant adeno-associated viral vector on the neovascularization in chronic ischemic porcine myocardium. An ameroid constrictor was implanted around the left circumflex coronary artery (LCX) via endoscopy. Six weeks later, coronary angiography revealed that the myocardial ischemia was established by gradual occlusion of the left circumflex coronary artery (LCX). Sixteen swine with the total occlusion or partial stenosis (> 85 %) of the LCX were divided into 4 groups (4 in each group): group I, group II and group IV (control) received direct myocardium injection of rAAV₂ VEGF₁₆₅, rAAV₂ ANG-1 or PBS alone, respectively; group III received rAAV₂ VEGF₁₆₅ and rAAV₂ ANG-1. Selective coronary angiography and ultrasonography were performed perioperatively to evaluate the cardiac function and the formation of collateral circulation. The expression of VEGF₁₆₅ and ANG-1 proteins were assessed using ELISA or Western blot. The degree of angiogenesis was assessed by use of immunohistochemical analysis. Angiography showed that the occlusion of all LCX was completed or exceeded 95% 6 weeks after ameroid constrictor implantation, indicating the successful establishment of animal model. The expression levels of VEGF₁₆₅ in group I and III and ANG-1 in groups II and III began to increase at d7 after transfection and reached the peak at d14; then decreased gradually to the normal level after 3 months. The expression levels of VEGF₁₆₅ in group II and group IV or that of ANG-1 protein in group I and group IV had no markedly changes at different time after transfection. There were significant increase in capillary density and arteriole density and more side branch vessels formed in group III compared with other groups. Echocardiographic measurements showed that the left ventricular systolic function of animals in groups I, II and III increased significantly after gene transfection, especially in group III; but there was no changes in group IV. Myocardial perfusion and the left ventricular systolic function are improved after rAAV₂ VEGF₁₆₅ or rAAV₂ ANG-1 transfection, which is associated with the angiogenesis in porcine model of chronic myocardial ischemia.

Cell-Based Therapy for Chronic Ischemic Heart Disease-A Clinical Perspective

In patients with ischemic heart disease, the goal of cell therapy is to improve perfusion and function of the damaged heart muscle. For this review, we selected articles that reported the findings from the major clinical studies of cardiovascular stem cell therapy in patients with chronic ischemic heart disease. Because of the current status of development of clinical investigation in this field, all relevant studies were included. Initial clinical trials have shown that adult cell-based therapy is safe and may improve the quality of life and the functional status of patients with chronic myocardial ischemia. Adult bone marrow mononuclear cells have been most frequently used in cardiac cell therapy trials to date, but new cell types are now being assessed in both preclinical and clinical studies. Although not well defined, mechanisms underlying the benefits associated with cell therapy are most likely multiple and include a paracrine effect. Cell therapy in patients with chronic ischemic heart disease has been shown to be safe and feasible. Initial data have shown that cell therapy with autologous bone marrow cells is associated with modest functional improvements. This finding needs to be confirmed in subsequent phase 2 and 3 trials.

Leonurine (SCM-198) improves cardiac recovery in rat during chronic infarction

Leonurine, an alkaloid typically found in Herba leonuri, is known to have both antioxidant and cardioprotective properties. In the present study, we investigated the cardioprotective mechanism of leonurine the in vivo rat model of chronic myocardial ischemia and in vitro H9c2 cardiac myocyte model of oxidative stress. Myocardial ischemia was induced by ligating the left anterior descending coronary artery. Rats were divided into sham, myocardial ischemia + saline, and myocardial ischemia + leonurine (15 mg/kg/day). Cardiac function was recorded by catheterization. Apoptosis-related factor vascular endothelial growth factor (VEGF), survivin, Bcl-2 and Bax and pro-survival signaling pathways Akt, hypoxia inducible factor (HIF)-1α were measured by Western blotting or RT-PCR. Our results showed leonurine significantly improved myocardial function as evidenced by the decreased left ventricle end-diastolic pressure and the increased + dP/dt. Interestingly, leonurine increased the phosphorylation of Akt, the protein and gene expression of Bcl-2, but it reduced the protein and gene expression of Bax in vivo. Meanwhile leonurine significantly increased Akt phosphorylation in a concentration-dependent manner in H9c2 cardiac myocyte induced by oxidative stress in vitro, which was abolished by a phosphoinositide 3-kinase (PI3K) inhibitor, LY294002. Furthermore, leonurine not only increased the expression of HIF-1α but also the expression of survivin and VEGF. The results of present study demonstrated, for the first time that leonurine has potent anti-apoptotic effects after chronic myocardial ischemia mediated by activating the PI3K/Akt signaling pathway. Angiogenic mechanisms may be partially responsible for such an effect, which needs to be studied further.

Resveratrol Improves Myocardial Perfusion in a Swine Model of Hypercholesterolemia and Chronic Myocardial Ischemia

Resveratrol may provide protection against coronary artery disease. We hypothesized that supplemental resveratrol will improve cardiac perfusion in the ischemic territory of swine with hypercholesterolemia and chronic myocardial ischemia. Yorkshire swine were fed either a normal diet (control, n=7), a hypercholesterolemic diet (HCC, n=7), or a hypercholesterolemic diet with supplemental resveratrol (100 mg/kg/d orally, HCRV, n=7). Four weeks later, an ameroid constrictor was placed on the left circumflex artery. Animals underwent cardiac MRI and coronary angiography 7 weeks later before euthanasia and tissue harvest. Total cholesterol was lowered about 30% in HCRV animals (P<0.001). Regional wall motion analysis demonstrated a significant decrease in inferolateral function from baseline to 7 weeks in HCC swine (P=0.04). There was no significant change in regional function in HCRV swine from baseline to 7 weeks (P=0.32). Tissue blood flow during stress was 2.8-fold greater in HCRV swine when compared with HCC swine (P=0.04). Endothelium-dependent microvascular relaxation response to Substance P was diminished in HCC swine, which was rescued by resveratrol treatment (P=0.004). Capillary density (PECAM-1 staining) demonstrated fewer capillaries in both HCC and HCRV swine versus control swine (P=0.02). Immunoblot analysis demonstrated significantly greater expression in HCRV versus HCC swine of the following markers of angiogenesis: VEGF (P=0.002), peNOS (ser1177) (P=0.04), NFkB (P=0.004), and pAkt (thr308) (P=0.001). Supplemental resveratrol attenuates regional wall motion abnormalities, improves myocardial perfusion in the collateral dependent region, preserves endothelium-dependent coronary vessel function, and upregulates markers of angiogenesis associated with the VEGF signaling pathway.

Effects of neuropeptide Y on collateral development in a swine model of chronic myocardial ischemia

We investigated the role of neuropeptide Y (NPY), abundant in the myocardial sympathetic nervous system and endothelial cells, in angiogenesis during chronic myocardial ischemia. Adult male Yorkshire swine underwent ameroid constrictor placement on the proximal left circumflex coronary artery. After 3 weeks, an osmotic pump was placed to deliver either placebo (control, n = 8) or NPY 3–36 (NPY, n = 8) to the collateral dependent region. Five weeks after pump placement, after cardiac catheterization and hemodynamic assessment, the heart was harvested for analysis. NPY treated animals demonstrated increased mean arterial pressures and improved left ventricular function (+ d P/d t). Cardiac catheterization demonstrated a significant increase in the blush score in the NPY group ( p < 0.001). Blood flow to the ischemic myocardium was not different between groups at rest or during ventricular pacing. Immunohistochemical double staining for CD-31 and smooth muscle actin demonstrated an increase in capillary and arteriole formation in NPY treated animals ( p = 0.02 and p < 0.001). Immunoblotting showed a significant upregulation of DPPIV ( p = 0.009) and NPY receptors 1 ( p = 0.008), 2 ( p = 0.02) and 5 ( p = 0.03) in the NPY treated group. Additionally, there was significant upregulation of VEGF ( p = 0.04), eNOS ( p = 0.014), phospho-eNOS (ser1177) ( p = 0.02), and PDGF ( p < 0.001) in NPY treated group. The anti-angiogenic factors endostatin and angiostatin were significantly decreased in NPY treated animals (endostatin, p = 0.03; angiostatin, p = 0.04). Exogenous NPY 3-36 resulted in improved myocardial function and increased angiogenesis and arteriogenesis by stimulating growth factor, pro-angiogenic receptor upregulation, and decreasing anti-angiogenic expression, but did not increase blood flow to the ischemic myocardium. NPY may act as a good adjunct to primary agents of therapeutic angiogenesis.

Effects of selective cyclooxygenase-2 and nonselective cyclooxygenase inhibition on ischemic myocardium

We explored effects of nonselective cyclooxygenase and selective cyclooxygenase 2 inhibition on collateral development in a model of chronic myocardial ischemia. We hypothesized that cyclooxygenase 2 inhibitors would negatively effect angiogenic and inflammatory pathways. Yorkshire swine were made chronically ischemic by placing an ameroid constrictor on the left circumflex coronary artery. Swine were divided into 3 groups and given no drug (control, n=7), a nonselective cyclooxygenase inhibitor (naproxen 400 mg daily, n=7), or a selective cyclooxygenase 2 inhibitor (celecoxib 200 mg daily, n=7). After 7 weeks, coronary angiography was performed. Myocardial function and microvascular reactivity were assessed. Serum and myocardial tissue were analyzed for prostaglandin levels and markers of inflammation and angiogenesis. The celecoxib group demonstrated significantly increased mean arterial pressure and decreased left ventricular function. Myocardial perfusion in the celecoxib group was similar to control value but less than in the naproxen group. Coronary microvascular contraction in the collateral-dependent territory was increased in the naproxen group but minimally affected in the celecoxib group. Oxidative stress and apoptosis were increased in the celecoxib group. Expression of angiogenic markers vascular endothelial growth factor and phospho-endothelial nitric oxide synthase (ser1177) and tissue levels of prostacyclin were decreased in both celecoxib and naproxen groups. The naproxen group had diminished endostatin expression. Selective and nonselective cyclooxygenase inhibition are more complex in effect than previously published, but they did not decrease collateral-dependent blood flow to the myocardium in our model of chronic myocardial ischemia.

A clinically relevant swine model of metabolic syndrome and chronic myocardial ischemia

A clinically relevant swine model of metabolic syndrome and chronic myocardial ischemia

Temporal and Spatial Changes in Collateral Formation and Function During Chronic Myocardial Ischemia

We investigated time dependence and spatial progression of cardiac function and angiogenesis signaling in a porcine model of chronic myocardial ischemia. Yorkshire mini-swine (n = 7/group) were subjected to chronic myocardial ischemia by placing an ameroid constrictor on the left circumflex coronary artery under general anesthesia. Swine were sacrificed after either 4 or 7 weeks of ischemia. Myocardial function, angiographic evidence of angiogenesis, microvessel function, molecular signaling, and levels of apoptosis and oxidative stress were assessed. Flow reserve was significantly increased at 7 versus 4 weeks. Myocardial function (+dP/dt) improved 1.5-fold by 7 weeks. In the ischemic territory, microvessels at 4 weeks displayed abnormal contraction responses to serotonin, which diminished at 7 weeks. Delta-like ligand 4 protein expression decreased at 7 weeks; expression of vascular endothelial growth factor (VEGF) and phospho-endothelial nitric acid synthase (eNOS) increased. The number of apoptotic cells was decreased at 7 weeks, and antiapoptotic markers heat shock protein (HSP) 27 and HSP 90 were upregulated at 7 weeks. There was an increase in proliferating endothelial cells at 7 weeks as compared with 4 weeks. In the adjacent normal ventricle, microvessels demonstrated smaller contraction responses to endothelin-1 and serotonin at 7 weeks. There was an increase in protein peroxidation in the ischemic territory at 7 weeks. Over time, myocardial perfusion, function, and angiogenic signaling improved in the ischemic myocardium and adjacent normal territory compared with what is observed shortly after coronary occlusion.

Effect of Combination Therapy With Bone-Marrow Mononuclear Cells Implantation and Fasudil on Angiogenesis in Myocardial Ischemia

The present study was to investigate whether combination therapy with bone marrow mononuclear cells (MNCs) and Rho-kinase inhibitor, fasudil, shows to enhance angiogenesis and ameliorates cardiac function compared with MNCs alone in a canine model of chronic myocardial infarction. Immediately after aspiration of BM, a model of chronic myocardial ischemia was created by LAD ligation in adult beagles, and then BM-MNCs or medium alone (control) was injected into the LAD risk area. Fasudil was administered by orally (30 mg/kg/day) in combination therapy with BM-MNCs and fasudil.

Cardiac shock wave therapy ameliorates left ventricular remodeling after myocardial ischemia–reperfusion injury in pigs in vivo

Left ventricular (LV) remodeling after acute myocardial infarction (AMI) is associated with a poor prognosis and an impaired quality of life. We have shown earlier that low-energy extracorporeal cardiac shock wave (SW) therapy improves chronic myocardial ischemia in pigs and humans and also ameliorates LV remodeling in a pig model of AMI induced by permanent coronary ligation. However, in the current clinical setting, most of the patients with AMI receive reperfusion therapy. Thus, in this study we examined whether our SW therapy also ameliorates LV remodeling after myocardial ischemia-reperfusion (I/R) injury in pigs in vivo. Pigs were subjected to a 90-min ischemia and reperfusion using a balloon catheter and were randomly assigned to two groups with or without SW therapy to the ischemic border zone (0.09 mJ/mm(2), 200 pulses/spot, 9 spots/animal, three times in the first week) (n = 15 each). Four weeks after I/R, compared with the control group, the SW group showed significantly ameliorated LV remodeling in terms of LV enlargement (131 +/- 9 vs. 100 +/- 7 ml), reduced LV ejection fraction (28 +/- 2 vs. 36 +/- 3%), and elevated left ventricular end-diastolic pressure (11 +/- 2 vs. 4 +/- 1 mmHg) (all P <0.05, n = 8 each). The SW group also showed significantly increased regional myocardial blood flow (-0.06 +/- 0.11 vs. 0.36 +/- 0.13 ml/min/g, P < 0.05), capillary density (1.233 +/- 31 vs. 1.560 +/- 60/mm(2), P < 0.001), and endothelial nitric oxide synthase activity (0.24 +/- 0.03 vs. 0.41 +/- 0.05, P < 0.05) in the ischemic border zone compared with the control group (n = 7 each). These results indicate that our SW therapy is also effective in ameliorating LV remodeling after myocardial I/R injury in pigs in vivo.

Acute administration of cannabidiol in vivo suppresses ischaemia‐induced cardiac arrhythmias and reduces infarct size when given at reperfusion

Cannabidiol (CBD) is a phytocannabinoid, with anti-apoptotic, anti-inflammatory and antioxidant effects and has recently been shown to exert a tissue sparing effect during chronic myocardial ischaemia and reperfusion (I/R). However, it is not known whether CBD is cardioprotective in the acute phase of I/R injury and the present studies tested this hypothesis. Male Sprague-Dawley rats received either vehicle or CBD (10 or 50 microg kg(-1) i.v.) 10 min before 30 min coronary artery occlusion or CBD (50 microg kg(-1) i.v.) 10 min before reperfusion (2 h). The appearance of ventricular arrhythmias during the ischaemic and immediate post-reperfusion periods were recorded and the hearts excised for infarct size determination and assessment of mast cell degranulation. Arterial blood was withdrawn at the end of the reperfusion period to assess platelet aggregation in response to collagen. CBD reduced both the total number of ischaemia-induced arrhythmias and infarct size when administered prior to ischaemia, an effect that was dose-dependent. Infarct size was also reduced when CBD was given prior to reperfusion. CBD (50 microg kg(-1) i.v.) given prior to ischaemia, but not at reperfusion, attenuated collagen-induced platelet aggregation compared with control, but had no effect on ischaemia-induced mast cell degranulation. This study demonstrates that CBD is cardioprotective in the acute phase of I/R by both reducing ventricular arrhythmias and attenuating infarct size. The anti-arrhythmic effect, but not the tissue sparing effect, may be mediated through an inhibitory effect on platelet activation.

Echocardiographic analysis with a two-dimensional strain of chronic myocardial ischemia induced with ameroid constrictor in the pig

Despite much progress in the medical management of myocardial ischemia, several problems remain and experimental models help to improve our understanding of the pathophysiology involved in this domain. The ameroid constrictor model is the most widely used to create ischemia but evaluation of patent ischemia is still under debate. In the present study, we describe the potential of a two-dimensional (2D) strain for experimentally evaluating myocardial ischemia in the pig. An ameroid constrictor was placed around the circumflex artery in 30 pigs. Angiography showed 90% stenosis at one and two months. Left ventricular function was moderately altered and associated with mitral valve insufficiency in 30% of cases. Longitudinal and circumference strains were dramatically modified in the ischemic inferior-lateral zone compared to the healthy anterior zone (P<0.01) at one and two months. We correlated these results to myocardial ischemia by using contrast echocardiography, which showed a significant reduction in myocardial perfusion in the ischemic zone compared to the uninjured area, and by using histological analysis. We showed that evaluation of the 2D strain could be an interesting approach for assessing myocardial ischemia after ameroid constrictor implantation. The 2D strain represents a useful tool for the evaluation of experimental models of myocardial ischemia.

Aquaporin-1 expression and angiogenesis in rabbit chronic myocardial ischemia is decreased by acetazolamide

Aquaporin-1 (AQP1) is a water channel protein expressed in endothelial and epithelial cells of many tissues, including the vasculature, where it serves to increase water permeability of the cell membrane. Prior studies have also reported that AQP1 plays a central role in tumor angiogenesis by promoting endothelial cell migration. To investigate whether AQP1 might also influence vascular angiogenesis in ischemic myocardium, the expression level of AQP1 for 21 days post myocardial infarction in rabbit hearts was observed. Aquaporin-1 mRNA and protein levels in day 3, and peaked on day 7 post surgery. This correlated well with the pattern of neovascularization and increased water content of infarct border tissue, and suggested that AQP1 may be involved in myocardial angiogenesis in response to ischemia injury. These AQP1-induced changes were tempered by acetazolamide, a carbonic anhydrase inhibitor, which acted by downregulating AQP1 expression. Acetazolamide treatment did not significantly affect the expression of vascular endothelial growth factor in the tissues studied. Our findings indicate a novel role for AQP1 in postnatal angiogenesis, which has implications in diverse pathophysiological conditions including wound healing, tumor metastasis, and organ regeneration.

Anti-Angiogenic Effect of Resveratrol in a Swine Model of Chronic Myocardial Ischemia and Hypercholesterolemia: Role of Angiostatin and VE-Cadherin

Anti-Angiogenic Effect of Resveratrol in a Swine Model of Chronic Myocardial Ischemia and Hypercholesterolemia: Role of Angiostatin and VE-Cadherin

Pharmacotherapy for end-stage coronary artery disease

Importance of the field: Coronary artery disease remains the leading cause of mortality in the industrialized world. Despite advances in surgical and catheter-based interventions, a select number of patients remain with no options for invasive therapy. The goal of this review is to discuss the current status of pharmacotherapeutic interventions to treat end-stage coronary artery disease.Areas covered in this review: Literature review on the topic of therapeutic angiogenesis from 1980 to 2009.What the reader will gain: Insight into current therapeutic strategies employed to manage end-stage coronary artery disease.Take home message: A promising approach focuses on augmenting the endogenous angiogenic response to chronic myocardial ischemia via the use of growth factors.