Smoking and Respiratory Diseases in Patients with Coronary Microvascular Dysfunction.

BACKGROUND: Coronary microvascular disease (CMD) is common in patients with and without obstructive coronary artery disease, and is associated with adverse clinical outcomes. Respiratory-related variables are associated with pulmonary and systemic microvascular dysfunction, while evidence about their relationship with CMD is limited. We aim to evaluate respiratory-related variables as risk factors of CMD. METHODS: This is an observational, single-center study enrolling consecutive patients undergoing invasive evaluation of coronary microvascular function in the catheterization laboratory. Patients with evidence of obstructive coronary artery disease or with missing data were excluded. Associations between respiratory-related variables and indices of CMD were assessed using univariate and multivariate regression models. RESULTS: Overall, 266 patients (mean age 67 ± 11 years, 59% females) were included in the current analysis. Of those, 155 (58%) had evidence of CMD. Among the respiratory variables, independent predictors of CMD were current smoking (adjusted odds ratio [AOR] 2.5; 95% confidence interval [CI], 1.2-5; P = .01) and obstructive sleep apnea (AOR 5.7; 95% CI, 1.2-26; P = .03), while chronic obstructive pulmonary disease was not. Among ever-smokers, higher smoking pack-years was an independent risk factor for CMD (median 35 vs 25 pack-years, AOR 1.09; 95% CI, 1.04-1.13; P < .01), and was associated with higher rates of pathologic index of microcirculatory resistance and resistive reserve ratio. CONCLUSION: In patients undergoing invasive coronary microvascular evaluation, current smoking and obstructive sleep apnea are independently associated with CMD. Among smokers, higher pack-years is a strong predictor for CMD. Our findings should raise awareness for prevention and possible treatment options.

The impact of normal range estimated glomerular filtration rate on mortality in selected patients undergoing coronary angiography - a long-term follow-up.

BACKGROUND: Estimated glomerular filtration rate (eGFR) predicts mortality and adverse cardiovascular events in people with chronic kidney disease. The significance of eGFR within the normal range and its long-term effect on clinical adverse events is unknown. We examined the effect of normal range or mildly reduced eGFR on long-term mortality in a large prospective registry. METHODS: The study included consecutive patients undergoing clinically-driven coronary angiography who had an eGFR ≥60 ml/min/1.73 m2. Baseline clinical characteristics were assessed, and patients were followed-up for the occurrence of all-cause mortality. Cox regression analysis was used to evaluate the impact of eGFR. RESULTS: A total of 4186 patients were recruited. Median follow-up time was 2883 days (7.9 years). Mean age was 62.0 ± 11.3 years with 77.4% males. Clinical presentation included acute coronary syndrome and stable angina. In a multivariable model adjusted for possible confounding factors, decreasing eGFR within the normal and mildly reduced range was inversely associated with long-term all-cause mortality with a hazard ratio (HR) of 1.32 for every decrease of 10 ml/min/1.732 in eGFR. Compared to eGFR > 100 ml/min/1.732, there was a graded association between lower eGFR values and increased long term mortality with a HR of 1.16 (0.59-2.31) for eGFR 90-100 ml/min/1.732, HR 1.54 (0.81-2.91) for eGFR 80-90 ml/min/1.732, HR 2.62 (1.41-4.85) for eGFR 70-80 ml/min/1.732 and HR 2.93 (1.58-5.41) for eGFR 60-70 ml/min/1.732. CONCLUSION: eGFR within the normal and mildly reduced range is an independent predictor of long-term all-cause mortality in selected patients undergoing clinically driven coronary angiography.

Predictors of Outcomes Following Transcatheter Edge-to-Edge Mitral Valve Repair.

Transcatheter edge-to-edge mitral valve repair is a viable alternative to surgery in patients with severe mitral regurgitation and high surgical risk. Yet the specific group of patients who would optimally benefit from this therapy remains to be determined. Selection of patients for transcatheter strategy is currently based on surgical prognostic scores and technical feasibility. Meanwhile, various clinical, anatomic, and procedural factors have been recently recognized as predictors of adverse outcomes following transcatheter edge-to-edge mitral valve repair, including device failure, recurrent mitral regurgitation, and mortality. Integration of these prognostic factors in the decision-making process of the heart team might improve patient management and outcomes. Herein, the authors review the different factors related to symptomatic status, comorbidity, serum biomarkers, echocardiographic findings, and procedural technique that have been identified as independent predictors of adverse outcome following transcatheter edge-to-edge mitral valve repair and discuss their potential application in everyday clinical practice.

Cardiac remodeling secondary to chronic volume overload is attenuated by a novel MMP9/2 blocking antibody.

OBJECTIVE: Monoclonal antibody derivatives are promising drugs for the treatment of various diseases due to their high matrix metalloproteinases (MMP) active site specificity. We studied the effects of a novel antibody, SDS3, which specifically recognizes the mature active site of MMP9/2 during ventricular remodeling progression in a mouse model of chronic volume overload (VO). METHODS: VO was induced by creating an aortocaval fistula (ACF) in 10- to 12-week-old C57BL male mice. The VO-induced mice were treated with either vehicle control (PBS) or with SDS3 twice weekly by intraperitoneal (ip) injection. The relative changes in cardiac parameters between baseline (day 1) and end-point (day 30), were evaluated by echocardiography. The effects of SDS3 treatment on cardiac fibrosis, cardiomyocyte volume, and cardiac inflammation were tested by cardiac staining with Masson's trichrome, wheat Germ Agglutinin (WGA), and CD45, respectively. Serum levels of TNFα and IL-6 with and without SDS3 treatment were tested by ELISA. RESULTS: SDS3 significantly reduced cardiac dilatation, left ventricular (LV) mass, and cardiomyocyte hypertrophy compared to the vehicle treated animals. The antibody also reduced the heart-to-body weight ratio of the ACF animals to values comparable to those of the controls. Interestingly, the SDS3 group underwent significant reduction of cardiac inflammation and pro-inflammatory cytokine production, indicating a regulatory role for MMP9/2 in tissue remodeling, possibly by tumor necrosis factor alpha (TNFα) activation. In addition, significant changes in the expression of proteins related to mitochondrial function were observed in ACF animals, these changes were reversed following treatment with SDS3. CONCLUSION: The data suggest that MMP9/2 blockage with SDS3 attenuates myocardial remodeling associated with chronic VO by three potential pathways: downregulating the extracellular matrix proteolytic cleavage, reducing the cardiac inflammatory responses, and preserving the cardiac mitochondrial structure and function.

Balloon dilatation and outcome among patients undergoing trans-femoral aortic valve replacement.

BACKGROUND: Balloon pre-dilatation before transcatheter aortic valve replacement (TAVR) is performed at the discretion of the treating physician. Clinical data assessing the implications of this step on procedural outcomes are limited. METHODS: We conducted a retrospective analysis of 1164 consecutive TAVR patients in the Israeli multicenter TAVR registry (Sheba, Rabin, and Tel Aviv Medical Centers) between the years 2008 and 2014. Patients were divided to those who underwent balloon pre-dilation (n=1026) versus those who did not (n=138). RESULTS: Rates of balloon pre-dilation decreased from 95% in 2008-2011 to 59% in 2014 (p for trend=0.002). Baseline characteristics between groups were similar except for more smoking (22% vs. 8%, p=0.008), less past CABG (18% vs. 26%, p=0.016), less diabetes mellitus (35% vs. 45%, p=0.01), and lower STS mortality scores (5.2±3.7 vs. 6.1±3.5, p=0.006) in the pre-dilatation group. The pre-dilation group included less patients with moderate to severely depressed LVEF (7% vs. 16%, p<0.001) and higher aortic peak gradients (76.9±22.7mmHg vs. 71.4±24.3mmHg, p=0.01). Stroke rates were comparable in both groups (2.5% vs. 3%, p=0.8), but pre-dilation was associated with lower rates of balloon post-dilatation (9% vs. 26%, p<0.001). On multivariate analysis, balloon pre-dilatation was not a predictor of device success or any post-procedural complications (p=0.07). CONCLUSIONS: Balloon pre-dilatation was not associated with procedural adverse events and may decrease the need for balloon post-dilatation. The results of the present study support the current practice to perform liberally balloon pre-dilatation prior to valve implantation.

Extracranial carotid artery stenosis and outcomes of patients undergoing transcatheter aortic valve replacement.

BACKGROUND: Transcatheter aortic valve replacement (TAVR) is an alternative to open cardiac surgery in selected patients with severe aortic stenosis (AS). Carotid artery stenosis (CAS) has been associated with an increased risk of stroke following cardiac surgery, although the association between CAS and outcomes following TAVR is unclear. We therefore sought to study the prognostic impact of CAS on outcomes of patients undergoing TAVR. METHODS: Consecutive patients (n=312) with severe symptomatic AS who underwent a carotid Doppler study immediately prior to TAVR were followed prospectively. Major adverse cardiovascular event (MACE) rates were stratified by the presence of CAS, defined in accordance with current practice guidelines. RESULTS: Carotid atherosclerosis (CA, defined as any carotid plaque) was present in 301 (96.5%) of patients and CAS (peak systolic velocity [PSV]≥125cm/s; ≥50% diameter stenosis) in 97 (31.1%) patients. Severe CAS (PSV≥230cm/s; ≥70% stenosis, or near occlusion) was found in 20 (6.4%) patients. At long-term follow-up (248±205days), composite (20.9% vs. 19.6%, p=0.50) and individual (all-cause mortality, stroke, myocardial infarction, readmission for heart failure [19.5%% vs. 14.4%%, p=0.24; 3.3% vs. 2.1%, p=0.47; 1.4% vs. 0%, p=0.22; and 7.9% vs. 8.2%, p=0.84 respectively]) MACE rates did not differ significantly between patients without versus those with CAS. By multivariate analysis, CAS was not independently predictive of late MACE rates (HR=0.85, [95%CI 0.50-1.78], p=0.85). CONCLUSIONS: CAS was not associated with worse outcomes following TAVR. The relative prognostic significance of CAS in patients considered for either surgical or transcatheter valve replacement merits further research.

Sustained Elevation of Vascular Endothelial Growth Factor and Angiopoietin-2 Levels After Transcatheter Aortic Valve Replacement.

BACKGROUND: Transcatheter aortic valve replacement (TAVR) exposes the systemic vasculature to increased mechanical forces. Endothelial adaptation to mechanical stimuli is associated with angiogenic activation through various growth factors. We studied the potential angiogenic shift evoked by TAVR. METHODS: From a cohort of 69 consecutive patients undergoing TAVR, we excluded patients with conditions known to affect angiogenic factors, and serum vascular endothelial growth factor (VEGF) and angiopoietin (Ang)-1 and Ang-2 were assessed by ELISA. We assessed in vitro the properties of endothelial cells after exposure to serum collected from patients undergoing TAVR using adhesion, migration, and Matrigel angiogenesis assays. The correlation between changes in angiogenic factors and cardiac functions was evaluated on 30- day echocardiograms. RESULTS: The study population consisted of 46 patients (82 ± 5 years). Two days after TAVR the post/pre TAVR ratio of VEGF, Ang-1, and Ang-2 was 5.38 ± 4 (P < 0.001), 1.05 ± 0.49 (P = 0.27), and 4.65 ± 2.01 (P < 0.001), respectively. The increase in VEGF and Ang-2 showed a significant correlation (r = 0.609; P < 0.001), but no correlation was found with hemolysis or tissue injury markers. Patients with relatively low levels of VEGF or an Ang-2 rise had more severe aortic stenosis and coronary disease at baseline. Exposure of endothelial cells to post-TAVR serum induced adhesion, migration, and tube formation compared with pre-TAVR serum. An increase in VEGF levels correlated with improvement in pulmonary systolic pressure and a right ventricular fractional area change at 30 days, (r = 0.54 and r = 0.48, respectively; P < 0.01). CONCLUSIONS: Sustained elevation of VEGF and Ang-2 levels occur after TAVR, reflecting a systemic angiogenic shift. A rise in VEGF levels is associated with a decrease in pulmonary blood pressure in patients undergoing TAVR.

Differential Effects of Colchicine on Cardiac Cell Viability in an in vitro Model Simulating Myocardial Infarction.

OBJECTIVES: We aimed to examine the effects of colchicine, currently in clinical trials for acute myocardial infarction (AMI), on the viability of cardiac cells using a cell line model of AMI. METHODS: HL-1, a murine cardiomyocyte cell line, and H9C2, a rat cardiomyoblast cell line, were incubated with TNFα or sera derived from rats that underwent AMI or sham operation followed by addition of colchicine. In another experiment, HL-1/H9C2 cells were exposed to anoxia with or without subsequent addition of colchicine. Cell morphology and viability were assessed by light microscopy, flow cytometry and Western blot analyses for apoptotic markers. RESULTS: Cellular viability was similar in both sera; however, exposing both cell lines to anoxia reduced their viability. Adding colchicine to anoxic H9C2, but not to anoxic HL-1, further increased their mortality, at least in part via enhanced apoptosis. Under any condition, colchicine induced detachment of H9C2 cells from their culture plates. This phenomenon did not apply to HL-1 cells. CONCLUSIONS: Colchicine enhanced cardiomyoblast mortality under in vitro conditions mimicking AMI and reduced their adherence capability. HL-1 was not affected by colchicine; nevertheless, no salvage effect was observed. We thus conclude that colchicine may not inhibit myocardial apoptosis following AMI.

Effect of vitamin D analogues on acute cardiorenal syndrome: a laboratory rat model.

BACKGROUND: Vitamin D has been shown to induce beneficial effects on cardiovascular and renal morbidity by regulating inflammation and tissue fibrosis. OBJECTIVES: To evaluate the effect of vitamin D analogues on cardiac function and fibrosis in an animal model of cardiorenal syndrome. METHODS: Unilateral nephrectomy was performed and myocardial infarction induced in rats. The rats were treated with vitamin D receptor activator (VDRA, paricalcitol, 40 ng/250 g x 3/week) versus a vehicle. A third group of animals, which served as the control, underwent sham surgery and received no treatment. After 4 weeks of treatment, cardiac function and fibrosis were assessed by trans-thoracic echo and histology, respectively. As a parameter of systemic inflammation, previously shown to be altered in acute coronary syndrome, T regulatory (Treg) cell levels were measured by flow cytometry. Renal dysfunction was documented by standard laboratory tests. RESULTS: After 4 weeks of treatment, no significant improvement in cardiac function parameters was noted following VDRA administration. VDRA treatment did not significantly alter Treg cell systemic levels. Consistently, despite a trend toward less extent of myocardial fibrosis, we found no clear beneficial effects of VDRA on myocardial tissue inflammation and remodeling. CONCLUSIONS: Vitamin D treatment showed no beneficial effects on cardiac function parameters and fibrosis in an animal model of cardiorenal syndrome.

Accelerated renal fibrosis in cardiorenal syndrome is associated with long-term increase in urine neutrophil gelatinase-associated lipocalin levels.

BACKGROUND: Cardiac events are the main cause of death among patients with end-stage renal failure. Even a mild renal disease is currently considered a major risk factor for cardiovascular complications following myocardial infarction (MI). The aim of the present study was to detect histological, sera and urine characteristics of kidney injury in cardiorenal syndrome (CRS) compared to chronic kidney disease (CKD) with an intact cardiac function. METHODS: We employed a rat model for CRS, in which an acute MI (AMI) was induced 4 weeks after establishment of subtotal nephrectomy. Four weeks later, left ventricular function was assessed by echocardiography and changes in renal performance were examined using histological and biochemical parameters. RESULTS: Increased interstitial fibrosis as well as renal inflammation were observed in renal sections derived from CRS rats, compared to subtotal nephrectomy (CKD)-only animals. Moreover, we found that even though AMI on the background of CKD was not associated with a further decrease in creatinine clearance or a further increase in sera BUN levels compared to CKD only, a significant long-term elevation in urine neutrophil gelatinase-associated lipocalin (Ngal) levels was detectable post-MI induction. CONCLUSIONS: AMI in the CKD setting is associated with accelerated renal fibrosis and long-term elevated urine Ngal values, suggesting that cardiac dysfunction contributes to accelerated intrinsic kidney injury in CKD. The data indicate that elevated urine Ngal may potentially serve as an early non-invasive laboratory parameter for a left ventricular dysfunction-related renal injury.

Islet-1 gene delivery improves myocardial performance after experimental infarction.

OBJECTIVE: The LIM-homeobox transcription factor Isl1 plays a crucial role during heart embryogenesis and later on gives rise to adult resident cardiac stem cells. In this study, we aimed to discover new extra cardiac populations of Isl1 stem cells. We then investigated endogenous Isl1 kinetics after myocardial infarction (MI), and the effect of intra-myocardial gene transfer of naked DNA encoding Isl1 on functional recovery after MI. METHODS: We used the transgenic mice Isl1/cre/Z/EG for lineage tracing of extra cardiac Isl1 stem cells. Non transgenic mice were used to study Isl1 kinetics post-MI by RT-PCR and FACS analysis. MI was induced in non transgenic mice by permanent ligation of the left anterior descending coronary artery (LAD). Naked DNA encoding Isl1 was injected to the peri-infarct region. Evaluation of cardiac performance was conducted by echocardiogram. Analysis of myocardial fibrosis and number of vessels was performed on histological cryosections. RESULTS AND CONCLUSIONS: Isl1 gives rise to subpopulations of progenitors in both the bone marrow and spleen, and is re-expressed in the spleen and left ventricle following MI. Intramyocardial gene transfer of Isl1 to the border zone of the infarcted hearts resulted in partial salvage of left ventricular function, enhanced vascularization, and reduced myocardial fibrosis. The Isl1 gene appears to be an attractive reparative target for future management of myocardial dysfunction.

A potential role for islet-1 in post-natal angiogenesis and vasculogenesis.

The LIM-homeobox transcription factor islet-1 (Isl1) marks a cell population which gives rise to myocardial, pacemaker, endothelial and smooth muscle cells, which are derived from the secondary heart field during heart embryogenesis. Isl1+ precursors have the potential of self-renewal and differentiation into endothelial, cardiomyocyte and smooth muscle lineages. The primary objective of this study was to determine whether retroviral gene delivery of Isl1 to endothelial cells and mesenchymal stem cells (MSCs) could promote angiogenic and vasculogenic properties. To this end, endothelial cells and rat MSCs were retrovirally transduced to express Isl1. Isl1 expression in endothelial cells resulted in enhanced proliferation and adhesion to fibronectin. In addition, increased IL-1b and VEGF secretion was evident in Isl1 transduced endothelial cells, concomitant with increased migratory and tube formation properties of the endothelial cells. Isl1 expression in MSCs promoted their vasculogenic properties and resulted in enhanced in vitro tube formation. Finally, Isl1 expressing endothelial cells induced enhanced in vivo vascularisation in C57BL/6J mice. These data suggest, for the first time, that Isl1 promotes postnatal angiogenesis and vasculogenesis by improving the angiogenic properties of endothelial cells and MSCs.

B-type natriuretic peptide enhances vasculogenesis by promoting number and functional properties of early endothelial progenitor cells.

OBJECTIVE: To test the hypothesis that B-type natriuretic peptide (BNP) acts as a potent vasculogenic agent by enhancing the number, proliferation, adhesion, and migration of endothelial progenitor cells (EPCs). BACKGROUND: BNP is a neurohormonal peptide that predicts outcome and used for treatment in chronic heart failure patients. It has been shown to promote angiogenesis in experimental animals. EPCs have been demonstrated to contribute to postnatal angiogenesis and vasculogenesis. METHODS: The number of EPC colony forming units (CFU) and levels of N-terminal ProBNP were assayed in patients with severe, yet controlled, New York Heart Association (NYHA) II-IV heart failure. The in vitro effects of BNP on early EPC-CFU numbers, proliferation, migration, adhesive, and vascular tube formation capacities were studied using human and murine systems. The effects of in vivo BNP administration on Sca-1/Flk-1 progenitors and on vasculogenesis in the hindlimb ischemia model were then assayed in wild-type mice. RESULTS: A significant correlation was found between circulating N-terminal ProBNP levels and EPC-CFU numbers. We observed a dose-dependent effect of BNP on the numbers of CFU and proliferation capacity of human EPCs as well as on their adhesive, migratory, and tube formation properties, in vitro. Systemic BNP administration to mice led to a significant increase in bone marrow Sca-1/Flk-1 EPCs and improvement in blood flow and capillary density in the ischemic limbs of mice. CONCLUSIONS: BNP promotes vessel growth by increasing the number of endothelial progenitors and enhancing their functional properties. These provasculogenic properties of BNP could account for some of its beneficial effects in chronic heart failure patients and may be harnessed for the purpose of improving collateral formation in ischemic subjects.

Hypoxia-inducible factor-1alpha and -2alpha additively promote endothelial vasculogenic properties.

OBJECTIVE: While both play a role in the transcriptional response of hypoxic endothelial cells (ECs), hypoxia-inducible factor-1alpha (HIF-1alpha) and HIF-2alpha differ in their transactivation sites, pointing at potentially different target genes. We studied the discrete and common effects of HIF-1alpha and HIF-2alpha on the cytokine expression and vasculogenic properties of ECs. METHODS AND RESULTS: H5V and bovine aortic ECs were transfected to express HIF-1alpha, HIF-2alpha or both. Overexpression of HIF-1alpha or HIF-2alpha and, to a greater extent, cotransfection of HIF-1alpha and HIF-2alpha resulted in EC activation, as revealed by analysis of the adhesion capacities and adhesion molecule surface expression of ECs. From the paracrine aspect, conditioned medium from HIF-expressing ECs was found to promote the migration and tube formation capacity of wild-type ECs, mostly following HIF-1alpha and HIF-2alpha coexpression. Antibody arrays revealed altered expression of multiple cytokines, pointing at consistent additive effects of HIF-1alpha and HIF-2alpha on angiogenic protein expression. Finally, HIF-1alpha and HIF-2alpha additively promoted vessel formation in vivo, as demonstrated by a Matrigel angiogenesis assay. CONCLUSION: Our results further clarify the functional roles of HIF-1alpha and HIF-2alpha in ECs and for the first time demonstrate a common contribution of HIF-1alpha and HIF-2alpha to vasculogenesis.

Constitutive expression of HIF-1alpha and HIF-2alpha in bone marrow stromal cells differentially promotes their proangiogenic properties.

Bone marrow stromal cells (BMSCs) contain progenitors capable of participating in postnatal angiogenesis. Hypoxia-inducible factors (HIFs) mediate endothelial activation by driving the expression of multiple angiogenic factors. We explored the potential of HIF-1alpha and HIF-2alpha modification in BMSCs, as a tool to improve cell-based angiogenic therapy. BMSCs were retrovirally transduced to express stable forms of HIF-1alpha and HIF-2alpha. HIF-1alpha and, to a greater extent, HIF-2alpha overexpression promoted differentiation of BMSCs to the endothelial lineage, evident by CD31 and Tie-2 expression and improved adhesive properties. Whereas chemotaxis toward stromal-derived factor 1 was higher in both HIF-alpha-expressing BMSCs, enhanced migration toward vascular endothelial growth factor was found only following overexpression of HIF-2alpha, supported by a robust expression of its receptor, Flk-1. HIF-alpha expression was associated with upregulation of angiogenic proteins and improved tube formation. Cytokine arrays of endothelial cells stimulated by medium collected from HIF-alpha-expressing BMSCs revealed further angiogenic activation and improved adhesive capacity. Eventually, delivery of HIF-2alpha-transduced BMSCs induced a more robust angiogenic response, compared with sham-transduced or HIF-1alpha-transduced BMSCs in the corneal micropocket angiogenesis model. Our results support the use of HIF-alpha genes, particularly HIF-2alpha, to augment the efficacy of future cell-based therapy. Disclosure of potential conflicts of interest is found at the end of this article.

Drug modification of angiogenesis in a rat cornea model.

PURPOSE: To evaluate the influence of some widely used antiglaucoma agents on angiogenesis in a novel rat cornea model. METHODS: Angiogenesis was induced in 32 rats by slow-release polymer pellets containing basic fibroblast growth factor (bFGF) placed in a corneal micropocket. Angiogenesis was later measured and compared in groups of rats given one of four antiglaucoma drug therapies and one control group. The drugs were commercially available preparations of prostaglandins, beta-blockers, alpha-2 agonists, and carbonic anhydrase inhibitors given for 7 days in a manner similar to that used in humans. Growth was measured by calculating the maximum linear vessel growth divided by pellet-limbus distance. RESULTS: Biomicroscopic observation disclosed that all tested animals showed an induction of neovascular reactions in their corneal stroma. The growth index results for the control, latanoprost, dorzolamide, brimonidine, and timolol malate groups were 1.65 +/- 0.16, 1.98 +/- 0.18, 1.85 +/- 0.19, 2.03 +/- 0.38, and 1.65 +/- 0.14, respectively, confirming the hypothesis that topically delivered antiglaucoma drugs modify the normal angiogenic response. Of them, the prostaglandins showed the most prominent angiogenic stimulatory effect (P = 0.03). CONCLUSIONS: This modified micropocket assay of corneal angiogenesis in rats demonstrated the stimulatory effect of several widely used topically delivered antiglaucoma medications on the angiogenic process. The results indicate that the selection of drugs for treating different ophthalmic diseases should take into account their influence on angiogenic processes.

Endothelial progenitor cells as therapeutic vectors in cardiovascular disorders: from experimental models to human trials.

Cell-based therapy approaches for the restoration of blood flow in ischemic organs has recently received growing interest. A considerable number of reports have documented the presence of circulating, bone marrow-derived endothelial progenitor cells (EPC) in adult peripheral blood. These putative cells are thought to participate in postnatal growth of new blood vessels. Mounting evidence from animal studies point to potential therapeutic applications of EPCs in the treatment of a wide range of cardiovascular (CV) disorders, while preliminary results from the pilot clinical trials still remain equivocal. Here, we review the experimental data that has accumulated so far from animal and clinical studies regarding the potential importance of EPCs. In addition, we discuss the potential hurdles as well as future options of EPC-based therapy.

[Endothelial progenitor cells (EPCs)--new tools for diagnosis and therapy].

Accumulating evidence suggests that postnatal bone marrow is a source of cells that can participate in postnatal neovascularization and vascular homeostasis. Among these cells, a scarce population of endothelial progenitor cells (EPCs) have the capacity to migrate to the peripheral circulation, proliferate and differentiate into mature endothelial cells in response to stimulating signals emanating from vascular injuries or during tumor growth. Questions persist, however, regarding the precise panel of cell surface markers that defined EPCs, as well as the different mechanisms stimulating or inhibiting their mobilization and differentiation. In the last decade, EPCs number and function have been correlated with risk factors for cardiovascular and peripheral vascular diseases. The authors review experimental results obtained from both animal studies and recent clinical trials, which point to the importance of EPCs potential as diagnostic markers and therapeutic tools in ischemic diseases. Furthermore, the article discusses the risk of potentially harmful side effects of altered EPCs number and functional properties, a critical barrier to overcome while bringing progenitor cell therapy to the clinical arena.