Recently, treatment of beta2 (β2)-adrenergic receptor (β2-AR) agonists with myeloid cytokines such as granulocyte-colony stimulating factor (G-CSF) have been reported to enhance stem/progenitor cell mobilization and proliferation in ischemic myocardium. However, whether the combination therapy of G-CSF and clenbuterol (selective β2-AR agonist) contributes to improved left ventricular (LV) function remains uncertain. Therefore, we investigated whether this combination therapy induced bone marrow derived stem/progenitor cell mobilization, recruitment, neovascularization, and altered LV function after acute myocardial infarction (MI). Clenbuterol administered in conjunction with C-CSF improves LV function through stem/progenitor cell mobilization and neovascularization. Male Sprague-Dawley rats were infarcted by placing a permanent ligature around the proximal left coronary artery. Rats with acute MI were treated with single clenbuterol (Clen), high dose Clen, and G-CSF + Clen. The G-CSF was given for 5 days and Clen for two weeks. We evaluated LV function and LV remodeling with echocardiography and hemodynamic measurements 3 weeks post MI. Treatment with G-CSF + Clen increased (p<0.05) LV ejection fraction from 34 ± 2 to 46 ± 3 % and LV dP/dt from 4503 ± 283 to 5789 ± 394 mmHg/s. Treatment with G-CSF + Clen increased the percentage of CD34+ cells in the peripheral blood, appearing to correlate with improvements in LV function and hemodynamics. Treatment with G-CSF + Clen increased (p<0.05) in microvessel density in endocardial regions of both the infarct (0.03 vs. 0.11 microvessels/μm2) and peri-infarct zones (0.03 vs 0.09 microvessels/μm2) suggesting that G-CSF + Clen increased neovascularization in rats with ischemic heart failure after MI. Combination therapy (G-CSF and clenbuterol) improved LV function 3 weeks after MI and that combination of G-CSF + Clen might augment stem/progenitor cell migration from the bone marrow to the peripheral blood and contribute tissue healing in rats with acute MI. These data raise the possibility that enhancing endogenous bone marrow derived stem/progenitor cell mobilization may be a new treatment for ischemic heart failure after MI.

Granulocyte macrophage colony-stimulating factor (GM-CSF) promotes infarct expansion and inappropriate collagen synthesis in a myocardial infarction (MI). This study was designed to determine if treatment with anti-GM-CSF will inhibit macrophage migration, preserve function, and limit left ventricular (LV) remodeling in the rat coronary artery ligation model. Treatment with a monoclonal antibody to GM-CSF (5 mg/kg) was initiated 24 hours before coronary artery ligation and continued every 3 days for 3 weeks. Left coronary arteries of rats were ligated, animals were recovered, and cardiac function was evaluated 3 weeks postligation. Tissue samples were processed for histochemistry. Anti-GM-CSF treatment increased LV ejection fraction (37 ± 3% vs 47 ± 5%) and decreased LV end systolic diameter (0.75 ± 0.12 vs 0.59 ± 0.05 cm) with no changes in LV systolic pressure (109 ± 4 vs 104 ± 5 mm Hg), LV end diastolic pressure (22 ± 4 vs 21 ± 2 mm Hg), LV end diastolic diameter (0.96 ± 0.04 vs 0.92 ± 0.05 cm), or the time constant of LV relaxation tau (25.4 ± +2.4 vs 22.7 ± 1.4 milliseconds) (P < 0.05). Significantly lower numbers of tissue macrophages and significant reductions in infarct size were found in the myocardium of antibody-treated animals (81 ± 21.24 vs 195 ± 31.7 positive cells per 0.105 mm, compared with controls. These findings suggest that inhibition of macrophage migration may be beneficial in the treatment of heart failure after MI.

Background: Recent studies have shown granulocyte-macrophage colony-stimulating factor (GM-CSF) promotes infarct expansion and inappropriate collagen synthesis in the infarcted ventricle. Thus suggesting, enhanced proliferation of monocytes and macrophages at the time of acute myocardial infarction (MI) may have deleterious effects on left ventricular (LV) remodeling. This study was designed to determine if blocking the effects of GM-CSF alters LV remodeling and hemodynamics in rats with acute MI. Hypothesis: Pretreatment of rats with GM-CSF antibody prior to MI will inhibit monocyte and macrophage migration limiting LV remodeling and preserving LV function. Methods: Acute MI was created by ligating the left coronary artery of rats; treatment with the GM-CSF antibody (5 mg/kg) was initiated 24 h prior to coronary ligation. Closed chest echocardiography and solid-state micromanometers were used to measure outcome variables 3 weeks after ligation. N=6–10 in each group. Results: The GM-CSF antibody increased (P<0.05) LV ejection fraction (37±3 vs 47±5%) and decreased (P<0.05) LV end-systolic diameter (0.75±0.12 vs. 0.59 ±0.05 cm) with no changes in LV systolic pressure (109 ± 4 vs 104 ± 5 mmHg), LV-end diastolic pressure (22 ± 4 vs 21 ± 2 mmHg), LV-end diastolic diameter (0.96 ± 0.04 vs. 0.92 ± 0.05 cm), or Tau (25.4+2.4 vs. 22.7±1.4 msec). Conclusion: We report improvements in LV ejection fraction and partial reversal of LV remodeling using an antibody against GM-CSF initiated 24 hours prior to MI. These findings suggest that inhibition of monocyte and marcophage migration may be beneficial in the treatment of heart failure after MI. Background: Recent studies have shown granulocyte-macrophage colony-stimulating factor (GM-CSF) promotes infarct expansion and inappropriate collagen synthesis in the infarcted ventricle. Thus suggesting, enhanced proliferation of monocytes and macrophages at the time of acute myocardial infarction (MI) may have deleterious effects on left ventricular (LV) remodeling. This study was designed to determine if blocking the effects of GM-CSF alters LV remodeling and hemodynamics in rats with acute MI. Hypothesis: Pretreatment of rats with GM-CSF antibody prior to MI will inhibit monocyte and macrophage migration limiting LV remodeling and preserving LV function. Methods: Acute MI was created by ligating the left coronary artery of rats; treatment with the GM-CSF antibody (5 mg/kg) was initiated 24 h prior to coronary ligation. Closed chest echocardiography and solid-state micromanometers were used to measure outcome variables 3 weeks after ligation. N=6–10 in each group. Results: The GM-CSF antibody increased (P<0.05) LV ejection fraction (37±3 vs 47±5%) and decreased (P<0.05) LV end-systolic diameter (0.75±0.12 vs. 0.59 ±0.05 cm) with no changes in LV systolic pressure (109 ± 4 vs 104 ± 5 mmHg), LV-end diastolic pressure (22 ± 4 vs 21 ± 2 mmHg), LV-end diastolic diameter (0.96 ± 0.04 vs. 0.92 ± 0.05 cm), or Tau (25.4+2.4 vs. 22.7±1.4 msec). Conclusion: We report improvements in LV ejection fraction and partial reversal of LV remodeling using an antibody against GM-CSF initiated 24 hours prior to MI. These findings suggest that inhibition of monocyte and marcophage migration may be beneficial in the treatment of heart failure after MI.

Background: Recent clinical trials utilizing cell-based therapies for acute myocardial infarction (MI) have reported disappointing Results: Because of this, we are proposing the use of a viable 3-dimensional fibroblast construct (3DFC) on the infracted heart. The 3DFC patch provides a matrix support structure and growth factor stimulation for new cell and blood vessel growth. This study was designed to compare implanting the 3DFC at the time of the acute MI in rats versus 3 weeks after coronary ligation when the rat is in heart failure. Methods: Acute MI is created by ligating the left coronary artery of rats; the 3DFC is implanted at the time of the MI versus 3 weeks later. N=8–12 in each group. Results: With implanting the 3DFC at the time of the MI vs. 3 weeks later, there are increases (P<0.05) in LV ejection fraction (EF): 40 vs 21%, systolic displacement of the infarcted anterior wall (64 vs 43%), and myocardial blood flow (37 vs 116% ml/kg/min). While implanting 3DFC at the time of the MI improves LV remodeling by decreasing (P<0.05) LV end-diastolic dimension 19%, implanting the 3DFC with the rat in heart failure does not alter LV remodeling; LV end-diastolic dimension does not change. Implanting the 3DFC at either time does not alter LV hemodynamics. Conclusion: We report improvements in LV function and myocardial blood flow in both acute MI and chronic heart failure treated with a 3DFC patch. This patch partially reverses LV remodeling only if implanted during an acute MI. Our conclusion is that improving matrix support and myocardial blood flow prevents adverse LV remodeling only in an acute MI; it does not reverse LV remodeling in chronic heart failure.