Reduced CD26 expression is associated with improved cardiac function after acute myocardial infarction: insights from the REPERATOR study.

Peripheral blood mononuclear cells (MNC) enhance cardiac recovery and repair after myocardial infarction (MI). The SDF-1α/CXCR4 axis plays a major role in cell homing to infarcted myocardium and is negatively regulated by CD26. Therefore, we studied the expression of CD26 during MI and its effects on cardiac function. Blood samples from forty-two patients who underwent a primary percutaneous coronary intervention (PCI) for a first ST-elevated MI were collected during primary PCI, 1 week and 3 months after MI. Soluble CD26 (sCD26) and membrane bound CD26 expression on MNCs (mncCD26) were determined. Left ventricular function and infarct size were measured within 1 day, 1 week and 3 months follow up by magnetic resonance imaging. One week post MI, sCD26 was down regulated compared to baseline, while mncCD26 was higher at baseline and 1 week compared to 3 months. Increased mncCD26 expression at 1 week after MI was associated with decreased overall recovery of left ventricular function as measured by left ventricular end systolic volume index. Furthermore, the in vitro migration capacity of MNCs to SDF-1α was decreased 1 week post MI and the migration capacity to SDF-1α was negatively correlated with mncCD26 expression. CD26 inhibition with sitagliptin - a drug currently used in diabetic patients - resulted in improved in vitro migration capacities of MNCs. In conclusion, our preliminary results suggest that high cellular CD26 expression decreases the migration of MNCs towards SDF-1α and high cellular CD26 expression negatively influences cardiac function post MI. Treating patients shortly post MI with sitagliptin to inhibit CD26 may therefore increase MNC homing to the infarct area and could improve cardiac recovery and repair.

Early statin treatment prior to primary PCI for acute myocardial infarction: REPERATOR, a randomized placebo-controlled pilot trial.

OBJECTIVE: The aim of this pilot study was to determine whether early atorvastatin treatment will reduce left ventricle (LV) remodeling, infarct size, and improve microvascular perfusion. BACKGROUND: In animal studies, early statin therapy reduces reperfusion injury after a percutaneous coronary intervention (PCI) for acute myocardial infarction (AMI). METHODS: Forty-two consecutive patients (82% male, mean age 61.2 ± 9.8) who underwent a primary PCI for a first ST-elevated AMI were randomized for pretreatment with atorvastatin 80 mg (n = 20) or placebo (n = 22) and continued with the same dosage daily for 1 week. All patients received atorvastatin 80 mg once daily 7 days after primary PCI. The LV function and infarct size were measured by magnetic resonance imaging within 1 day, at 1 week, and 3 months follow up. The primary endpoint was the end-systolic volume index (ESVI) at 3 months. Secondary endpoints were global LV function measurements, myocardial infarct size, biochemical cardiac markers, TIMI flow, and ST-T elevation resolution. RESULTS: ESVI 3 months after AMI was 25.1 mL/m(2) in the atorvastatin arm and 25.0 mL/m(2) in the placebo arm (P = 0.74). The differences in change from baseline to 3 months follow up in global LV function and myocardial infarct size did not differ between both treatment arms. Furthermore, biochemical markers, TIMI flow, and ST-T elevation resolution did not differ between atorvastatin and placebo arm. CONCLUSIONS: In this pilot study, pretreatment with atorvastatin in an acute myocardial infarction does not result in an improved cardiac function, microvascular perfusion, or decreased myocardial infarct size.

Peripheral blood derived cell trafficking for cardiac regeneration.

Systemic available circulating cells play a role in cardiac maintenance and ameliorate cardiac recovery and repair after myocardial infarction. However, only a small number of cells will be incorporated during cardiac damage. Cell mobilization, homing to the ischemic myocardium and engraftment are complex processes depending on many adhesion molecules, proteases, chemokines and their receptors. Physiologic and pathophysiologic circumstances, cytokines, chemokines and certain drugs are able to influence these processes. For cardiovascular regeneration, understanding how mobilization and homing of blood derived cells is regulated and can be modulated as well as identification of cell populations able to regenerate the heart or reduce damage after myocardial infarction is essential for the development of successful cell based therapies.

Impaired recruitment of HHT-1 mononuclear cells to the ischaemic heart is due to an altered CXCR4/CD26 balance.

AIMS: Mononuclear cells (MNCs) from patients with hereditary haemorrhagic telangiectasia type 1 (HHT1), a genetic disorder caused by mutations in endoglin, show a reduced ability to home to infarcted mouse myocardium. Stromal cell-derived factor-1alpha (SDF-1alpha) and the chemokine receptor CXCR4 are crucial for homing and negatively influenced by CD26. The aim of this study was to gain insight into the impaired homing of HHT1-MNCs. METHODS AND RESULTS: CXCR4 and CD26 expression on MNCs was determined by flow cytometry. Transwell migration to SDF-1alpha was used to analyse in vitro migration. Experimentally induced myocardial infarction in mice, followed by tail vein injection of MNCs, was applied to study homing in vivo. HHT1-MNCs expressed elevated levels of CXCR4, but this was counterbalanced by high levels of CD26, resulting in decreased migration towards an SDF-1alpha gradient in vitro. Migration was enhanced by inhibiting CD26 with Diprotin-A. While MNCs from healthy controls responded to transforming growth factor-beta stimulation by increasing CXCR4 and lowering CD26 expression levels, HHT1-MNCs did not react as efficiently: in particular, CD26 expression remained high. Inhibiting CD26 on MNCs increased the homing of human cells into the infarcted mouse heart. Interestingly, the defect in homing of HHT1-MNCs was restored by pre-incubating the HHT1-MNCs with Diprotin-A before injection into the tail vein. CONCLUSION: We show that a decreased homing of HHT1-MNCs is caused by an impaired ability of the cells to respond to SDF-1alpha. Our results suggest that modulating CD26 levels using inhibitors like Diprotin-A can restore homing in cases where increased expression of CD26 contributes to the underlying pathological mechanism.

Balance between angiopoietin-1 and angiopoietin-2 is in favor of angiopoietin-2 in atherosclerotic plaques with high microvessel density.

INTRODUCTION: Atherosclerotic plaque microvessels are associated with plaque hemorrhage and rupture. The mechanisms underlying plaque angiogenesis are largely unknown. Angiopoietin (Ang)-1 and -2 are ligands of the endothelial receptor Tie-2. Ang-1 induces formation of stable vessels, whereas Ang-2 destabilizes the interaction between endothelial cells and their support cells. We studied the expression patterns of Ang-1 and -2 in relation to plaque microvessels. METHODS AND RESULTS: Carotid endarterectomy specimens were studied (n = 100). Microvessel density (MVD) was correlated with the presence of macrophages and with a (fibro)atheromatous plaque phenotype. A negative correlation was observed between Ang-1 expression and MVD. A positive correlation was observed between the ratio of Ang-2/Ang-1 and MVD. Ang-2 expression was correlated with matrix metalloproteinase-2 (MMP-2) activity. Immunohistochemical staining of Ang-1 was observed in smooth muscle cells, whereas Ang-2 was detected in endothelial cells, smooth muscle cells and macrophages. CONCLUSIONS: In plaques with high MVD, the local balance between Ang-1 and Ang-2 is in favor of Ang-2. Plaque Ang-2 levels are associated with MMP-2 activity. Ang-2-induced MMP-2 activity might play a role in the development of (unstable) plaque microvessels.

Endoglin has a crucial role in blood cell-mediated vascular repair.

BACKGROUND: Endoglin, an accessory receptor for transforming growth factor-beta in vascular endothelial cells, is essential for angiogenesis during mouse development. Mutations in the human gene cause hereditary hemorrhagic telangiectasia type 1 (HHT1), a disease characterized by vascular malformations that increase with age. Although haploinsufficiency is the underlying cause of the disease, HHT1 individuals show great heterogeneity in age of onset, clinical manifestations, and severity. METHODS AND RESULTS: In situ hybridization and immunohistochemical analysis of mouse and human hearts revealed that endoglin is upregulated in neoangiogenic vessels formed after myocardial infarction. Microvascularity within the infarct zone was strikingly lower in mice with reduced levels of endoglin (Eng+/-) compared with wild-type mice, which resulted in a greater deterioration in cardiac function as measured by magnetic resonance imaging. This did not appear to be because of defects in host inflammatory cell numbers in the infarct zone, which accumulated to a similar extent in wild-type and heterozygous mice. However, defects in vessel formation and heart function in Eng+/- mice were rescued by injection of mononuclear cells from healthy human donors but not by mononuclear cells from HHT1 patients. CONCLUSIONS: These results establish defective vascular repair as a significant component of the origin of HHT1. Because vascular damage or inflammation occurs randomly, it may also explain disease heterogeneity. More generally, the efficiency of vascular repair may vary between individuals because of intrinsic differences in their mononuclear cells.