Amelioration of microvascular myocardial ischemia by gene transfer of vascular endothelial growth factor in rabbits

OBJECTIVES: Restoration of coronary blood flow by angiogenesis may offer a new approach to intractable ischemic heart disease. In the present study, we investigated the angiogenic effects of gene transfer of vascular endothelial growth factor 165 on microvascular myocardial ischemia. METHODS: A rabbit model of microvascular myocardial ischemia was created by plugging coronary microvessels with microspheres (15 microm in diameter, 2.8 x 10(5)/kg, n = 29). Gene transfer was performed by semi-selective intracoronary injection of recombinant adenovirus expressing vascular endothelial growth factor 165 forty minutes after microsphere injection (n = 9). RESULTS: Microsphere injection reduced myocardial perfusion (78% +/- 9% of baseline tissue flow) and diminished myocardial contraction (61% +/- 12% of the baseline ejection fraction) and cardiac performance (elevated left ventricular end-diastolic pressure and decreased systemic flow) in the acute phase. At 17 +/- 3 days, gene transfer of vascular endothelial growth factor 165 had had the following effects: (1) promoted coronary angiogenesis as evidenced by myocardial flow above the baseline (121% +/- 24%), (2) increased vascular density revealed by synchrotron radiation microangiography and histologic analysis, (3) ameliorated the degree of myocardial ischemia as evidenced by myocardial lactate content and the extent of histologic necrosis, and (4) restored heart function as evidenced by increased ejection fraction (95% +/- 10%), reduced left ventricular end-diastolic pressure, and restored body weight. CONCLUSIONS: In vivo vascular endothelial growth factor 165 gene transfer promoted angiogenesis and was an effective approach to treating microvascular myocardial ischemia.     

Radio frequency heating of chronic ovine infarct leads to sustained infarct area and ventricular volume reduction

OBJECTIVE: Myocardial infarct expansion and subsequent left ventricular remodeling are associated with increased incidence of congestive failure and mortality. Collagen is known to denature and contract when heated above 65 degrees C. We therefore tested the hypothesis that radio frequency heating of myocardial infarct tissue with application of a restraining patch causes a sustained reduction in myocardial infarct area and left ventricular volume. METHODS: Thirteen male Dorset sheep underwent surgical coronary artery ligation. At least 14 weeks later, animals were randomized to either radio frequency infarct heating (95 degrees C) with application of a restraining patch or a sham operation. Before treatment, after treatment, and 10 weeks later, left ventricular volume was measured with transdiaphragmatic echocardiography and myocardial infarct area was measured with an array of sonomicrometry crystals. RESULTS: Radio frequency infarct heating causes an acute decrease of 34% (-215 +/- 82 mm(2); P =.0002) in infarct area at end-diastole that is maintained at 10 weeks (-144 +/- 79 mm(2); P =.0002). Radio frequency infarct heating causes a downward trend in end-diastolic left ventricular volume measured by echocardiography of 20% (-15.7 +/- 6.3 mL; P = no significant difference) and end-systolic left ventricular volume of 32% (-17.1 +/- 9.8 mL; P =.09), which are significantly decreased at 10 weeks (-13.6 +/- 22.3 mL; P =.007 and -15.3 +/- 21.9 mL; P =.008, respectively). Radio frequency infarct heating causes an acute improvement in systolic function (P <.001), a sustained increase in left ventricular ejection fraction (+0.11%; P =.06), and preserved stroke volume. CONCLUSION: Radio frequency heating of chronic left ventricular myocardial infarct causes a sustained reduction in infarct area and left ventricular volume. This technique may beneficially reverse infarct expansion and left ventricular remodeling after myocardial infarction.     

Stromal cell-derived factor and granulocyte-monocyte colony-stimulating factor form a combined neovasculogenic therapy for ischemic cardiomyopathy

OBJECTIVE: Ischemic heart failure is an increasingly prevalent global health concern with major morbidity and mortality. Currently, therapies are limited, and novel revascularization methods might have a role. This study examined enhancing endogenous myocardial revascularization by expanding bone marrow-derived endothelial progenitor cells with the marrow stimulant granulocyte-monocyte colony-stimulating factor and recruiting the endothelial progenitor cells with intramyocardial administration of the potent endothelial progenitor cell chemokine stromal cell-derived factor. METHODS: Ischemic cardiomyopathy was induced in Lewis rats (n = 40) through left anterior descending coronary artery ligation. After 3 weeks, animals were randomized into 4 groups: saline control, granulocyte-monocyte colony-stimulating factor only (GM-CSF only), stromal cell-derived factor only (SDF only), and combined stromal cell-derived factor/granulocyte-monocyte colony-stimulating factor (SDF/GM-CSF) (n = 10 each). After another 3 weeks, hearts were analyzed for endothelial progenitor cell density by endothelial progenitor cell marker colocalization immunohistochemistry, vasculogenesis by von Willebrand immunohistochemistry, ventricular geometry by hematoxylin-and-eosin microscopy, and in vivo myocardial function with an intracavitary pressure-volume conductance microcatheter. RESULTS: The saline control, GM-CSF only, and SDF only groups were equivalent. Compared with the saline control group, animals in the SDF/GM-CSF group exhibited increased endothelial progenitor cell density (21.7 +/- 3.2 vs 9.6 +/- 3.1 CD34 + /vascular endothelial growth factor receptor 2-positive cells per high-power field, P = .01). There was enhanced vascularity (44.1 +/- 5.5 versus 23.8 +/- 2.2 von Willebrand factor-positive vessels per high-power field, P = .007). SDF/GM-CSF group animals experienced less adverse ventricular remodeling, as manifested by less cavitary dilatation (9.8 +/- 0.1 mm vs 10.1 +/- 0.1 mm [control], P = .04) and increased border-zone wall thickness (1.78 +/- 0.19 vs 1.41 +/- 0.16 mm [control], P = .03). (SDF/GM-CSF group animals had improved cardiac function compared with animals in the saline control group (maximum pressure: 93.9 +/- 3.2 vs 71.7 +/- 3.1 mm Hg, P < .001; maximum dP/dt: 3513 +/- 303 vs 2602 +/- 201 mm Hg/s, P < .05; cardiac output: 21.3 +/- 2.7 vs 13.3 +/- 1.3 mL/min, P < .01; end-systolic pressure-volume relationship slope: 1.7 +/- 0.4 vs 0.5 +/- 0.2 mm Hg/microL, P < .01.) CONCLUSION: This novel revascularization strategy of bone marrow stimulation and intramyocardial delivery of the endothelial progenitor cell chemokine stromal cell-derived factor yielded significantly enhanced myocardial endothelial progenitor cell density, vasculogenesis, geometric preservation, and contractility in a model of ischemic cardiomyopathy.     

Matrix metalloproteinase inhibition modifies left ventricular remodeling after myocardial infarction in pigs

BACKGROUND: Global and regional shape changes that occur within the left ventricular wall after myocardial infarction have been termed infarct expansion. A potential mechanism for this postinfarction remodeling is activation of the matrix metalloproteinases. Accordingly, the present study examined the effects of matrix metalloproteinase inhibition on left ventricular global geometry after myocardial infarction in pigs. METHODS: Myocardial infarction was created in pigs by means of occlusion of the first and second obtuse marginal branches of the circumflex coronary artery, resulting in a uniform left ventricular free wall infarct size of 21% +/- 2%. At 5 days after infarction, the pigs were randomized to undergo broad-spectrum matrix metalloproteinase inhibition (n = 9; PD166793, 20 mg. kg(-1). d(-1) by mouth) or myocardial infarction alone (n = 8). Ten pigs served as noninfarction control animals. Left ventricular end-diastolic area, determined by means of echocardiography, was measured 8 weeks after infarction. RESULTS: Left ventricular end-diastolic area increased in both the myocardial infarction plus broad-spectrum matrix metalloproteinase inhibition and myocardial infarction only groups compared to reference control animals (3.7 +/- 0.2 cm(2)), but was reduced with broad-spectrum matrix metalloproteinase inhibition compared to myocardial infarction alone (4.5 +/- 0.2 vs 4.9 +/- 0.2 cm(2), respectively; P <.05). Regional radial stress within the infarct region increased in both infarction groups when compared to values obtained from reference control animals (599 +/- 152 g/cm(2)), but was attenuated in the myocardial infarction plus broad-spectrum matrix metalloproteinase inhibition group compared to the myocardial infarction alone group (663 +/- 108 vs 1242 +/- 251 g/cm(2), respectively; P <.05). Similarly, regional myocardial stiffness increased in both the myocardial infarction plus broad-spectrum matrix metalloproteinase inhibition and the myocardial infarction only groups compared with that observed in reference control animals (14 +/- 1 rkm, P <.05) but was lower with broad-spectrum matrix metalloproteinase inhibition than with myocardial infarction alone (42 +/- 6 vs 68 +/- 10 rkm, respectively; P <.05). CONCLUSIONS: Matrix metalloproteinase inhibition reduced postinfarction left ventricular dilation, reduced regional myocardial wall stress, and modified myocardial material properties. These unique findings suggest that increased myocardial matrix metalloproteinase activation after infarction contributes directly to the left ventricular remodeling process.     

Combined autologous cellular cardiomyoplasty with skeletal myoblasts and bone marrow cells in canine hearts for ischemic cardiomyopathy

OBJECTIVES: Cellular cardiomyoplasty with isolated skeletal myoblasts and bone marrow mononuclear cells is an encouraging therapeutic strategy for heart failure. We investigated the achievements accomplished with combined cell therapy of skeletal myoblast and bone marrow mononuclear cell transplantation to the ischemic canine myocardium. METHODS: Autologous skeletal myoblasts (1 x 10(8)) and autologous bone marrow mononuclear cells (3 x 10(6)) were injected directly into the damaged myocardium of canine hearts that had undergone 2 weeks of left anterior descending coronary artery ligation. Treatment groups were as follows: skeletal myoblasts plus bone marrow mononuclear cells (combined cell therapy, n = 4), myoblasts (n = 4), bone marrow mononuclear cells (n = 4), and medium only (n = 4). In similarly designed supporting experiments, angiogenic factor expression was evaluated by enzyme-linked immunosorbent assay after cell transplantation in rat hearts that had undergone left anterior descending coronary artery ligation. RESULTS: Four weeks after cell implantation, echocardiography demonstrated better cardiac performance with reduced left ventricular dilation and significantly improved ejection fraction in the combined cell therapy group compared with that seen in the other groups (pretreatment, 37.7% +/- 1.1%, vs combined cell therapy, 55.4% +/- 8.6%; myoblasts, 47.4% +/- 7.4%; bone marrow mononuclear cells, 44.4% +/- 6.7%; medium only [control], 34.4% +/- 5.4%; P < .05). A significantly high number of neovessels were observed in the group receiving combined cell therapy only (combined cell therapy, 45.5 +/- 12 x 10(2)/mm2; myoblasts, 26.5 +/- 8 x 10(2)/mm2; bone marrow mononuclear cells, 30.7 +/- 15 x 10(2)/mm2; medium only [control], 7.1 +/- 1 x 10(2)/mm2; P < .05). Immunostained sections expressed the skeletal specific marker myosin heavy chain, although they did not express the cardiac specific marker troponin T. Results of enzyme-linked immunosorbent assay showed the highest expression of vascular endothelial growth factor (combined cell therapy, 2.9 +/- 0.7 ng/g tissue; myoblasts, 0.24 +/- 0.7 ng/g tissue; bone marrow mononuclear cells, 1.9 +/- 0.2 ng/g tissue; medium only [control], 0.19 +/- 0.004 ng/g tissue; P < .05) and hepatocyte growth factor in the combined cell therapy hearts. CONCLUSIONS: Combined autologous cellular therapy induced both myogenesis and angiogenesis with enhancement of cardiac performance and reduction of cardiac remodeling, suggesting a capable strategy for treating severe ischemic cardiomyopathy clinically.     

Coronary artery plaque burden and perioperative cardiac risk.

BACKGROUND: Electron-beam computed tomography-derived coronary calcium score correlates with the morphologic severity of coronary artery disease, reflecting both global atherosclerotic plaque formation and coronary artery luminal narrowing. The current study examines the impact of coronary atherosclerotic plaque burden, measured by coronary calcium score, on the potential for perioperative myocardial cell injury, as assessed by cardiac troponin T elevations in patients undergoing elective vascular surgery. The authors further investigated whether perioperative myocardial cell injury in those patients adversely affects noninvasive measures of left ventricular systolic function, such as ejection fraction and wall motion score. METHODS: Fifty-one consecutive patients scheduled for vascular surgery were enrolled in this prospective study. In addition to standard preoperative evaluation, including patient history and physical examination, electron-beam computed tomography scan, 12-lead electrocardiography, and transthoracic echocardiography were performed on the day before surgery. Subsequent evaluations on postoperative days 2 and 7 included transthoracic echocardiography and 12-lead electrocardiography. Cardiac troponin T determinations were performed on the day before surgery, immediately preoperatively, and on postoperative days 1, 2, 3, and 7. RESULTS: The median coronary calcium score of the 51 patients was 997.0 (25th percentile, 202.5; 75th percentile, 1,949.5). Cardiac troponin T elevations exclusively occurred in patients with a coronary calcium score greater than 1,000. The six patients (12%) with perioperative cardiac troponin T elevations had a 2.5-fold higher coronary calcium score than those without cardiac troponin T elevation (P = 0.021). In these patients, the ejection fraction decreased from 61 +/- 10% to 52 +/- 13% (mean +/- SD) on postoperative day 2 and was 54 +/- 16% on postoperative day 7 (P = 0.022). CONCLUSION: A high electron-beam computed tomography coronary calcium score, reflecting substantial coronary plaque burden, carries an increased risk for myocardial cell injury after vascular surgery. In these patients, myocardial damage may result in deterioration of global systolic left ventricular function.     

Adenoviral-mediated transfer of vascular endothelial growth factor 121 cDNA enhances myocardial perfusion and exercise performance in the nonischemic state

BACKGROUND: Angiogenic gene therapy has been demonstrated to enhance perfusion to ischemic tissues, but it is unknown whether the administration of angiogenic growth factors will increase blood flow to nonischemic tissues. This study investigates whether enhanced myocardial perfusion can be mediated by adenovirus-mediated transfer of vascular endothelial growth factor 121 cDNA to nonischemic myocardium. METHODS: New Zealand White rabbits received adenovirus (5 x 10(10) particle units) encoding for vascular endothelial growth factor 121 (n = 14) or a control vector without a transgene (n = 13) or saline solution (n = 9) via direct myocardial injection. Fluorescent microsphere perfusion studies and histologic analyses were performed 4 weeks later. In a parallel study, exercise treadmill testing was performed to assess the functional effects of this therapy in Sprague-Dawley rats. RESULTS: Microsphere assessment of myocardial perfusion in rabbits 4 weeks after adenovirus-encoding vascular endothelial growth factor administration was greater than that for rats injected with control vector without a transgene or saline solution (3.2 +/- 0.5 vs 2.7 +/- 0.7 and 2.4 +/- 0.4, respectively; P <.03). The endothelial cell count per high power field was increased in animals injected with adenovirus-encoding vascular endothelial growth factor versus animals injected with control vector without a transgene or saline solution (147 +/- 27 vs 123 +/- 14 and 125 +/- 16 cells, respectively), although this did not reach statistical significance (P =.12). Rats treated with adenovirus-encoding vascular endothelial growth factor also demonstrated prolonged exercise tolerance compared with rats injected with control vector without a transgene or saline solution (exhaustion time: 26 +/- 5 minutes vs 19 +/- 2 minutes and 20 +/- 3 minutes, respectively; P =.006). CONCLUSIONS: Adenovirus encoding-mediated transfer of vascular endothelial growth factor 121 induces an enhancement in regional perfusion in nonischemic myocardium that corresponds to changes in exercise tolerance. Adenovirus-encoding vascular endothelial growth factor therapy may be useful for inducing angiogenesis in the nonischemic state, such as for prophylactic therapy of early coronary artery disease.     

Therapeutic angiogenesis with intramyocardial administration of basic fibroblast growth factor

BACKGROUND: Basic fibroblast growth factor (bFGF) induces endothelial cell and smooth muscle cell proliferation and stimulates angiogenesis. This study was designed to evaluate the effects of intramyocardial administration of bFGF on myocardial blood flow, angiogenesis, and ventricular function in a canine acute infarction model. METHODS: Myocardial infarction was induced in 12 dogs by ligation of the left anterior descending coronary artery. Within 5 minutes after coronary occlusion, 100 microg of human recombinant bFGF in 1 mL of saline was injected into the infarct and border zone in 6 dogs, whereas saline alone was used in 6 control dogs. Myocardial blood flow was determined with colored microspheres before and immediately after coronary ligation and again 3, 7, 14, and 28 days after treatment and it was expressed as percent of normal. Angiogenesis was evaluated by immunohistochemical studies 28 days later. Cardiac function was evaluated by repeated echocardiographic measurement. RESULTS: Treatment with bFGF significantly increased the endocardial blood flow in the border zone (7 days after infarction, 75%+/-7% and 41% +/-7% in the bFGF and control groups, respectively, p<0.01) as well as epicardial blood flow in the infarcted zone. Treatment with bFGF significantly increased the capillary density (39.7+/-2.3 and 22.7+/-1.1 vessels per visual field in the bFGF and control groups, respectively, p<0.01) as well as arteriolar density in the border zone. Treatment with bFGF significantly reduced the change in ratio of thickness of the infarcted wall to the normal wall (44%+/-6% and 26% +/-5% in the bFGF and control groups, respectively, p<0.05). It improved the left ventricular ejection fraction (7 days after infarction, 0.54+/-0.02 and 0.37+/-0.03 in the bFGF and control groups, respectively, p<0.01). CONCLUSIONS: Intramyocardial administration of bFGF increased the regional myocardial blood flow, reduced thinning of the infarcted region, and improved ventricular function in acute myocardial infarction. Intramyocardial administration of bFGF may be a new therapeutic approach for patients with acute myocardial infarction.     

Prevascularization with gelatin microspheres containing basic fibroblast growth factor enhances the benefits of cardiomyocyte transplantation

OBJECTIVE: The effects of cell transplantation on the ischemic failing heart have already been documented. However, the area in and around infarct regions is not a good environment for cells to survive in because they are exposed to poor conditions in which certain requirements cannot be adequately supplied. We therefore designed a study to investigate the efficacy of prevascularization in ischemic regions before cell transplantation. METHODS: Rats with myocardial infarction were randomized into 4 groups: 11 rats received a culture medium injection to the left ventricular wall (control group), 11 received fetal cardiomyocyte transplantation (TX group), 11 received gelatin hydrogel microspheres incorporating basic fibroblast growth factor (FGF group), and 11 received basic fibroblast growth factor pretreatment sequentially, followed by cardiomyocyte transplantation (FGF-TX group). Four weeks later, left ventricular function was assessed by means of echocardiography and cardiac catheterization. RESULTS: In the FGF and FGF-TX groups neovascularization was found in the scar tissue 1 week later. The TX, FGF, and FGF-TX groups showed better fractional shortening than the control group (TX, FGF, FGF-TX, and control: 28% +/- 4.4%, 24% +/- 8.6%, 27% +/- 7.3%, and 17% +/- 4.6%, respectively; P <.01). Left ventricular maximum time-varying elastance was higher in the FGF-TX group than in the TX and FGF groups (FGF-TX, TX, and FGF: 0.52 +/- 0.23, 0.30 +/- 0.08, and 0.27 +/- 0.20 mm Hg/microL, respectively; P <.01). Histologically, more transplanted cells survived in the FGF-TX group than in the TX group. CONCLUSIONS: Prevascularization with basic fibroblast growth factor-incorporated microspheres enhances the benefits of cardiomyocyte transplantation. We expect that this system will contribute to regeneration medicine through its extensive application to other growth factors.     

Passive ventricular constraint to improve left ventricular function and mechanics in an ovine model of heart failure secondary to acute myocardial infarction

OBJECTIVE: This study investigated the effects on global cardiac function and myocardial energetics of limiting progressive dilatation after infarction by means of a woven polyester jacket cardiac support device. We hypothesized that placement of the cardiac support device results in a decrease in myocardial wall stress and improvement in cardiac function and myocardial energetics. METHODS: To investigate the effect of passive constraint on left ventricular function and mechanics, a total of 10 sheep were studied with pressure-volume analysis and magnetic resonance imaging. A baseline study was followed by the creation of an anterior infarct. After 1 week, the animals underwent a second study. The cardiac support device was then placed over the epicardium in 5 sheep; the remaining animals served as controls. A terminal study was performed at 2 months after the infarct. RESULTS: The cardiac support device group at the terminal study exhibited a decrease in end-diastolic volume (control 110.3 +/- 19.8 mL vs cardiac support device 67.6 +/- 4.7 mL, P =.006) and an improved ejection fraction (control 15.5% +/- 5.7% vs cardiac support device 29.46% +/- 4.42%, P =.008) relative to the control group. Myocardial energetics were also enhanced in the cardiac support device group, as evidenced by the significant improvements in potential energy (control 2015 +/- 503 mL. mm Hg/beat vs cardiac support device 885 +/- 220 mL. mm Hg/beat, P =.006), efficiency (control 39.4% +/- 13.6% vs cardiac support device 59.8% +/- 8.5%, P =.044), and oxygen consumption (control 0.072 +/- 0.013 mL O(2)/beat vs cardiac support device 0.052 +/- 0.007 mL O(2)/beat, P =.034). CONCLUSION: Passive constraint with the cardiac support device after infarct prevents further remodeling and may stimulate reverse remodeling in heart failure secondary to acute myocardial infarction. These results suggest that in human beings placement of the cardiac support device after a large anterior myocardial infarction may be effective in halting the remodeling process that often leads to end-stage heart failure. If proved effective, placement of a cardiac support device after large heart attacks has the potential to decrease the incidence of heart failure that results after large myocardial infarctions.     

Coronary Artery Plaque Burden and Perioperative Cardiac Risk

Background : Electron-beam computed tomography-derived coronary calcium score correlates with the morphologic severity of coronary artery disease, reflecting both global atherosclerotic plaque formation and coronary artery luminal narrowing. The current study examines the impact of coronary atherosclerotic plaque burden, measured by coronary calcium score, on the potential for perioperative myocardial cell injury, as assessed by cardiac troponin T elevations in patients undergoing elective vascular surgery. The authors further investigated whether perioperative myocardial cell injury in those patients adversely affects noninvasive measures of left ventricular systolic function, such as ejection fraction and wall motion score.

Methods : Fifty-one consecutive patients scheduled for vascular surgery were enrolled in this prospective study. In addition to standard preoperative evaluation, including patient history and physical examination, electron-beam computed tomography scan, 12-lead electrocardiography, and transthoracic echocardiography were performed on the day before surgery. Subsequent evaluations on postoperative days 2 and 7 included transthoracic echocardiography and 12-lead electrocardiography. Cardiac troponin T determinations were performed on the day before surgery, immediately preoperatively, and on postoperative days 1, 2, 3, and 7.

Results : The median coronary calcium score of the 51 patients was 997.0 (25th percentile, 202.5; 75th percentile, 1,949.5). Cardiac troponin T elevations exclusively occurred in patients with a coronary calcium score greater than 1,000. The six patients (12%) with perioperative cardiac troponin T elevations had a 2.5-fold higher coronary calcium score than those without cardiac troponin T elevation (P = 0.021). In these patients, the ejection fraction decreased from 61 +/- 10% to 52 +/- 13% (mean +/- SD) on postoperative day 2 and was 54 +/- 16% on postoperative day 7 (P = 0.022).     

The effect of leukocyte-depleted blood cardioplegia in patients with severe left ventricular dysfunction: a randomized, double-blind study

BACKGROUND: The propensity for leukocytes to cause reperfusion injury in patients undergoing heart surgery is widely accepted. Reperfusion injury may result in myocardial damage and unfavorable operative outcome, especially in patients with severely reduced ejection fractions. This study was performed to evaluate the impact of leukocyte filtration on the postoperative course of patients undergoing coronary bypass surgery. METHODS: Thirty-two patients with coronary artery disease and left ventricular ejection fraction less than 35% were included in this double-blind, randomized study. Two serial leukocyte removal filters (Pall BC1B filter [Pall Biomedical, Portsmouth, England], group F, 15 patients) or two dummy filters (group C, 17 patients) were connected to the blood cardioplegia line. Leukocyte count, hemodynamic measurement, and transesophageal echocardiography were performed before and after cardiopulmonary bypass. Cardiac-specific enzymes were analyzed from arterial blood during the first 72 hours and from coronary sinus blood 30 and 60 minutes after aortic unclamping. RESULTS: Patient characteristics were similar in the two groups (ejection fraction 20.9% +/- 4.3% in group C and 21.1% +/- 4.8% in group F; P =.773). No early death or perioperative myocardial infarction occurred. Leukocyte count, hemodynamic parameters, cardiac troponin T, cardiac troponin I, and creatine kinase MB mass levels in arterial blood were similar in the two groups. Group F showed lower release of cardiac troponin T from the coronary sinus 30 minutes after unclamping of the aorta (group F, 0.263 +/- 0.12 ng/mL; group C, 0.6 +/- 0.32 ng/mL; P =.005). Lower doses of dopamine were necessary after cardiopulmonary bypass (group F, 0.36 +/- 0.11 mg x kg(-1) x min(-1); group C, 0.49 +/- 0.14 mg x kg(-1) x min(-1); P =.003). A moderate increase in ejection fraction was observed at 30 minutes in both groups (group F, 30.3% +/- 6.2%; group C, 28.0% +/- 6.3%; P =.239) and a significant increase at 60 minutes in group F (group F, 32.5% +/- 6.0%; group C, 27.4% +/- 7.5%; P =.012). CONCLUSIONS: These results indicate that serial leukocyte filters connected to the blood cardioplegia line decrease myocardial cell injury and may therefore help to improve outcome of patients with severely depressed ejection fractions undergoing coronary artery bypass grafting.     

Comparison of vascular endothelial growth factor and fibroblast growth factor-2 in a swine model of endothelial dysfunction.

OBJECTIVE: Growth factor based angiogenesis, with or without cell therapy, is a promising therapeutic modality for patients with coronary artery disease. We compared the relative efficacies of surgically delivered vascular endothelial growth factor (VEGF) and fibroblast growth factor-2 (FGF-2) in a swine model of hypercholesterolemia-induced endothelial dysfunction which captures many of the pathophysiologic abnormalities of human coronary disease. METHODS: Yucatan mini-swine (20-30 kg), fed a high cholesterol diet (total 20 weeks), underwent circumflex ameroid placement to create chronic myocardial ischemia, followed three weeks later by perivascular administration of VEGF (2 microg; n=6), FGF-2 (100 microg; n=6), or placebo (n=7) in the ischemic territory. Normocholesterolemic animals (n=7) served as controls. Four weeks later, endothelial function, collateral-dependent perfusion, as well as myocardial protein and mRNA levels of angiogenic mediators were assessed. RESULTS: Endothelial dysfunction was observed in all hypercholesterolemic animals as impaired microvessel relaxation in response to adenosine diphosphate and VEGF. VEGF administration improved baseline-adjusted collateral-dependent perfusion at rest (-0.03+/-0.05 vs -0.12+/-0.04, VEGF vs placebo, p=0.09), but FGF-2 delivery caused a significantly greater improvement in perfusion compared to either group (+0.15+/-0.03, p<0.05 vs HC-placebo and HC-VEGF) at rest. Molecular analysis revealed increased eNOS expression (135%+/-8%, p=0.03 vs placebo) in all growth factor treated animals and increased expression of FGF-2 receptor, FGFR1 (65+/-26%, p=0.04 vs placebo), in FGF-2 treated animals. No significant changes were demonstrated in other angiogenic mediators including Akt, Syndecan-4. CONCLUSIONS: In the setting of hypercholesterolemic endothelial dysfunction, FGF-2 is more effective than VEGF at enhancing collateral-dependent perfusion and thus, may be a better candidate than VEGF for angiogenic therapy in patients with end-stage CAD.     

Myocardial protection with insulin cardioplegia: who can really benefit?

AIM: The aim of the study was to evaluate the effects on myocardial protection of insulin-enriched warm blood cardioplegia (IWBC) in coronary artery bypass grafting (CABG) and in subgroups of patients with associated cardiac co-morbidities. METHODS: Between May 2000 and December 2002, 268 consecutive patients underwent CABG with warm blood cardioplegia (group A) or IWBC (10 UI/L) (group B). Hospital outcome, ECG, echocardiography and biochemical markers of ischemia were compared. Differences between subgroups of patients with unstable angina (UA), ventricular hypertrophy (VH) and diabetes were assessed. RESULTS: Hospital mortality, incidence of postoperative myocardial infarction and low output syndrome, IABP requirement, postoperative atrial fibrillation, in-hospital and in-ITU stay, postoperative recovery of left ventricular function and enzyme leakage did not show differences between the 2 groups; inotropic support was lower in IWBC. Moreover, patients with UA and IWBC showed a lower troponin I (TnI) (12 h: 0.82+/-0.57 ng/mL vs 2.56+/-1.18, P < 0.0001; 24 h: 0.71+/-0.64 vs 2.16+/-1.52, P < 0.0001; 48 h: 0.69+/-1.13 vs 1.79+/-1.43, P = 0.001; 72 h: 0.44+/-0.83 vs 1.01+/-1.02, P = 0.001), lower incidence of atrial fibrillation (4.2% versus 60.6%; P < 0.0001) and intraoperative defibrillation (0% versus 27.3%; P = 0.007). Furthermore, patients with VH treated with IWBC showed lower level of TnI (12 h: 0.41+/-0.32 ng/mL vs 2.93+/-0.67, P < 0.0001; 24 h: 0.37+/-0.45 vs 2.40+/-1.28, P < 0.0001; 48 h: 0.22+/-0.18 vs 1.95+/-1.33, P < 0.0001; 72 h: 0.12+/-0.12 vs 1.31+/-1.56, P < 0.0001), lower atrial fibrillation (6.5% vs 48%, P < 0.0001) and ventricular defibrillation (0% vs 20%, P = 0.011). CONCLUSIONS: Insulin addiction to blood cardioplegia does not show any benefit in the global population and in diabetics; nevertheless, better myocardial protection can be demonstrated in patients with unstable angina and left ventricular hypertrophy.     

The supportive value of pre-bypass L-glutamate loading in patients undergoing coronary artery bypass grafting

AIM: Experimental studies have demonstrated that an exogenous supply of glutamate improves mechanical function and recovery of ischemic myocardium. The aim of the present study was to investigate the effect of myocardial pre-bypass loading with glutamate on myocardial protection during global ischemia and reperfusion of patients undergoing coronary artery bypass grafting (CABG). METHODS: The study was double blinded. Twenty patients undergoing elective CABG were randomized to receive L-glutamate (n = 10) or normal saline (n = 10). Intracellular levels of glutamate, ATP and lactate were measured in left ventricular biopsies collected 10 min after aortic clamp release. Hemodynamic data, and postoperative release of CK-MB and troponin T were also measured. RESULTS: Pre-bypass administration of glutamate resulted in myocardial glutamate loading since glutamate levels were significantly higher in the glutamate group of patients than in controls (18.6 +/- 3.1 versus 8.7 +/- 1.2 microg/g tissue, P < 0.001). In the same group ATP levels were also significantly higher (2.4 +/- 0.7 versus 1.5 +/- 0.4 microg/g tissue, P < 0.05) and lactate levels significantly less than in controls (6.9 +/- 1.9 versus 12.0 +/- 2.1 microg/g tissue, P < 0.001). Glutamate patients had statistically significantly superior post-bypass hemodynamic performance (cardiac index, left ventricular stroke work index, systemic vascular resistance and pulmonary vascular resistance). Statistically significantly lower levels of CK-MB (6 h postoperative), total and peak CK-MB, troponin T (24 h postoperative), and total troponin T were found in the glutamate group. CONCLUSIONS: The results of this preliminary study indicate that pre-bypass intravenous administration of glutamate in patients undergoing CABG has a supportive effect on myocardial metabolism during global ischemia and reperfusion, improves patients' postoperative hemodynamic performance and reduces postoperative cardiac enzyme release.     

Gene therapy with adenovirus-mediated myocardial transfer of vascular endothelial growth factor 121 improves cardiac performance in a pacing model of congestive heart failure

BACKGROUND: Myocardial ischemia is the most common cause of congestive heart failure. Angiogenic therapy has recently been demonstrated to enhance myocardial perfusion in the ischemic setting. We therefore hypothesized that administration of adenovirus encoding for vascular endothelial growth factor could be used to enhance myocardial function in a pacing-induced model of heart failure. METHODS: Yorkshire swine underwent a left thoracotomy with placement of a ventricular epicardial pacing system. Animals received adenovirus coding either for the 121-amino-acid isoform of vascular endothelial growth factor (Ad(CU)VEGF121.1 group, n = 8) or a null vector coding for no genes (AdNull group, n = 8). The adenovirus was administered in the left ventricular free wall as 10 transepicardial injections of 100 microL each (total dose of 10(11) particle units). After a 1-week recovery period, animals were paced at a rate of 230 beats/min for 7 days to induce heart failure. Transthoracic echocardiographic and sonomicrometric measurements were performed before pacing (baseline), on termination of pacing (day 0), and then weekly for 3 weeks. RESULTS: The fractional area change was significantly decreased in AdNull animals at day 0 after pacing compared with the Ad(CU)VEGF121.1 animals (29% +/- 14% vs 46% +/- 8%, P =.02). The fractional area change recovered to baseline values within 7 days in the Ad(CU)VEGF121.1 animals (62% +/- 7%) but remained significantly impaired in the AdNull group compared with that in the Ad(CU)VEGF121.1 animals up to day 21 (P =.04). Similarly, fractional wall thickening demonstrated a decrease at day 0 after pacing that was greater (P <.05) in the AdNull group compared with that in the Ad(CU)VEGF121.1 group in 5 of 6 segments. Fractional wall thickening returned to levels approximating prepacing values in all segments within 7 days in the Ad(CU)VEGF121.1 group but remained significantly impaired compared with prepacing fractional wall thickening (P <.05) in the AdNull group in 5 of 6 segments up to day 21 after pacing. Segmental shortening, as measured by sonomicrometry, also was significantly decreased at day 7 in the AdNull group compared with that in the Ad(CU)VEGF121.1 group (10% +/- 4% vs 16% +/- 3%, P =.004) and remained significantly impaired (P <.05) in the AdNull group at day 14 and 21 when compared with baseline values. CONCLUSION: Preservation of cardiac performance and a more rapid recovery of myocardial function can be achieved in a model of pacing-induced cardiomyopathy with adenovirus-mediated administration of vascular endothelial growth factor compared with that seen in a null virus control group. These data suggest that angiogenic therapy may be useful clinically in treating cardiomyopathy.     

Blood warm reperfusion: a necessary adjunct to heart-valve surgery in low-risk patients?

AIM: The aim of this prospective, randomized study was to determine whether blood warm reperfusion improves myocardial protection provided by cold crystalloid cardioplegia in patients undergoing first-time elective heart-valve surgery, using cardiac troponin I release as the criterion for evaluating the adequacy of myocardial protection. METHODS: Seventy patients with a left ventricular ejection fraction greater than 40% were randomly assigned to 1 of 2 myocardial protection strategies: 1) cold crystalloid cardioplegia with no reperfusion or 2) cold crystalloid cardioplegia followed by 2-minute blood warm reperfusion before aortic unclamping. Cardiac troponin I concentrations were measured in serial venous blood samples drawn immediately prior to cardiopulmonary bypass and after aortic unclamping at 6, 9, 12, and 24 h. RESULTS: Randomization produced 2 equivalent groups. The total amount of cardiac troponin I released (7.17+/- 14.8 mg in the crystalloid cardioplegia with no reperfusion group and 5.82+/-4.66 mg in the crystalloid cardioplegia followed by blood warm reperfusion group) was not different (P > 0.2). Cardiac troponin I concentration did not differ for any sample in either of the 2 groups. The total amount of cardiac troponin I released was higher in patients who required inotropic support (9.14 +/-16.2 mg) than those who did not (4.73+/-4.52 mg; P = 0.009). CONCLUSIONS: Our study shows that adding blood warm reperfusion to cold crystalloid cardioplegia provides no additional myocardial protection in low-risk patients undergoing heart-valve surgery.     

Promoting angiogenesis protects severely hypertrophied hearts from ischemic injury

BACKGROUND: Myocardial hypertrophy is associated with progressive contractile dysfunction, increased vulnerability to ischemia-reperfusion injury, and is, therefore, a risk factor in cardiac surgery. During the progression of hypertrophy, a mismatch develops between the number of capillaries and cardiomyocytes per unit area, suggesting an increase in diffusion distance and the potential for limited supply of oxygen and nutrients. We hypothesized that promoting angiogenesis in hypertrophied hearts increases microvascular density, thereby improves tissue perfusion and substrate availability, maintains myocardial function, and improves postischemic recovery. METHODS: Left ventricular hypertrophy was created in 10-day-old rabbits by aortic banding and progression was monitored by echocardiography. At 4 weeks (compensated hypertrophy), 2 microg of vascular endothelial growth factor (VEGF) or placebo was administered intrapericardially. After 2 weeks, microvascular density, coronary flow (CF), and glucose uptake (GU) were measured. Tolerance to ischemia was determined by cardiac function measurements before and after ischemia-reperfusion using an isolated heart preparation. RESULTS: Microvascular density increased significantly following VEGF treatment (1.43 +/- 0.08/nuclei/field vs 1.04 +/- 0.06/nuclei/field untreated hypertrophy). Concomitantly, there was an increase in CF (7 +/- 0.5 vs 5 +/- 0.4 mL/min/g) and GU (1.24 +/- 0.2 vs 0.69 +/- 0.2 micromoles/g/30 minutes; p 相似文献   

Pharmacologic inhibition of intracellular caspases after myocardial infarction attenuates left ventricular remodeling: a potentially novel pathway

OBJECTIVE: Myocyte death occurs by necrosis and caspase-mediated apoptosis in the setting of myocardial infarction. In vitro studies suggest that caspase activation within myocytes causes contractile protein degradation without inducing cell death. Thus, caspase activation may evoke left ventricular remodeling through 2 independent processes post-myocardial infarction. However, the effects of caspase activation on left ventricular geometry post-myocardial infarction remain unclear. This project applied broad-spectrum caspase inhibition to a chronic porcine model of myocardial infarction. METHODS: Coronary snares and sonomicrometry crystals in remote and area-at-risk regions were placed in pigs (n = 22, 34 kg). Geometric measurements at end diastole and end systole, including left ventricular area by echocardiography and interregional distance by sonomicrometry, were obtained at baseline. Coronary occlusion was instituted for 60 minutes, followed by reperfusion and repeated geometric measurements at 7 days, including left ventriculography. At reperfusion, pigs were randomized to saline (n = 12) or caspase inhibition (n = 10, IDN6734, 2 mg/kg intravenously, then 2 mg x kg x h for 24 hours) at a dose that achieved desired plasma concentrations (790 +/- 142 ng/mL) as predicted by prior pharmacokinetic studies. RESULTS: Infarct size and 24-hour troponin-I values were not significantly different between the saline and caspase inhibition groups (51% +/- 8% vs 42% +/- 6% and 189 +/- 20 ng/mL vs 152 +/- 26 ng/mL, respectively, P >.10). At 7 days, end-diastole volume was increased in both groups compared with reference control values (47 +/- 1 mL, P <.05), but it was decreased with caspase inhibition (72 +/- 4 mL) compared with saline (84 +/- 4 mL, P <.05). Similarly, end-diastole and end-systole areas increased by 32% +/- 3% and 81% +/- 16% in the saline group but were attenuated with caspase inhibition (19% +/- 3% and 31% +/- 10%, respectively, P <.05). End-diastole interregional distance increased by 30% +/- 7% in the saline group but was attenuated with caspase inhibition (12% +/- 5%, P <.05). CONCLUSION: Despite equivalent degrees of myocardial injury, caspase inhibition reduced post-myocardial infarction left ventricular remodeling as evidenced by multiple, independent assessments of left ventricular dilation. Thus, caspase activation alters left ventricular geometry in the absence of significant effects on myocardial injury.