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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.
Résumé
Introduction
Le remplacement valvulaire aortique par cathétérisme (RVAC) expose le système vasculaire à des forces mécaniques accrues. L’adaptation de l’endothélium aux stimuli mécaniques est associée à une activation angiogénique sous l’effet de divers facteurs de croissance. Cette étude porte sur un éventuel déséquilibre de l’angiogenèse provoqué par le RVAC.
Méthodes
Parmi les 69 patients consécutifs ayant subi un RVAC, ceux qui présentaient des troubles connus pour influer sur les facteurs angiogéniques ont été exclus. Les taux sériques de facteur de croissance de l’endothélium vasculaire (VEGF) ainsi que d’angiopoïétine-1 et d’angiopoïétine-2 ont été déterminés au moyen de la méthode ELISA. Les propriétés des cellules endothéliales ont été évaluées in vitro au moyen de tests d’adhésion, de migration et d’angiogenèse sur Matrigel, après exposition au sérum recueilli chez les patients ayant subi un RVAC. La corrélation entre les changements au chapitre des facteurs angiogéniques et des fonctions cardiaques a été évaluée à l’aide d’échocardiogrammes sur 30 jours.
Résultats
La population à l’étude se composait de 46 patients (82 ± 5 ans). Deux jours après le RVAC, le ratio post/pré-RVAC des taux de VEGF, d’angiopoïétine-1 et d’angiopoïétine-2 s’établissait respectivement comme suit : 5,38 ± 4 (P < 0,001); 1,05 ± 0,49 (P = 0,27) et 4,65 ± 2,01 (P < 0,001). Il existait une nette corrélation entre l’augmentation des taux de VEGF et d’angiopoïétine-2 (r = 0,609; P < 0,001), mais aucune corrélation n’a été établie avec l’hémolyse ou les marqueurs de lésions tissulaires. Les patients dont le taux de VEGF était relativement bas ou dont le taux d’angiopoïétine-2 a augmenté présentaient une sténose aortique et une coronaropathie plus importantes au départ. L’exposition des cellules endothéliales au sérum post-RVAC a entraîné l’adhésion, la migration et la formation de tubes comparativement à l’exposition au sérum pré-RVAC. L’augmentation du taux de VEGF était corrélée avec une amélioration de la pression systolique pulmonaire et une variation fractionnaire de surface du ventricule droit à 30 jours (r = 0,54 et r = 0,48, respectivement; P < 0,01).
Conclusions
Une élévation soutenue des taux de VEGF et d’angiopoïétine-2 a suivi le RVAC, reflétant un déséquilibre général de l’angiogenèse. Une hausse du taux de VEGF est associée à une diminution de la pression sanguine pulmonaire chez les patients qui subissent un RVAC.
Transcatheter aortic valve implantation (TAVR) is associated with an abrupt increase in cardiac output and blood pressure, which are considered good prognostic factors.
Exposure of the endothelium to increased shear stress was previously shown to induce a protective angiogenic activation through various growth factors such as vascular endothelial growth factor (VEGF), which is a pivotal regulator of endothelial homeostasis.
Aging impairs transcriptional regulation of vascular endothelial growth factor in human microvascular endothelial cells: implications for angiogenesis and cell survival.
In the present study, we assessed the effect of TAVR on the systemic levels of VEGF as well as those of angiopoietin (Ang)-1 and Ang-2, which are both known to alter in response to hemodynamic changes.
Additionally, we evaluated the correlation between VEGF/Ang-1/Ang-2 levels and post-TAVR echocardiographic functional parameters.
Methods
Patients
Sixty-nine consecutive patients undergoing transfemoral TAVR under local anesthesia and monitored anesthesia care were enrolled. The investigation conformed to the principles outlined in the Declaration of Helsinki. Before inclusion, informed consent was obtained from each patient as approved by the institutional ethics committee. The diagnosis of aortic stenosis was based on clinical, echocardiographic, and hemodynamic criteria.
2008 focused update incorporated into the ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (writing committee to revise the 1998 guidelines for the management of patients with valvular heart disease) endorsed by the Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons.
Suitability and eligibility for TAVR was determined by our heart team. Excluded were patients assigned to TAVR because of aortic regurgitation and those with comorbidities that might significantly affect serum VEGF/Ang-1/2 levels, including recent (< 3 months) myocardial infarction/stroke, recent vascular intervention, severe chronic kidney disease (stage ≥ 4), chronic pulmonary disease, carotid artery occlusion, and active cancer. Additionally, patients with postprocedural complications (ie, myocardial infarction, stroke, major vascular complications [requiring intervention], thromboembolism, bleeding [requiring blood perfusion], respiratory failure, sepsis, or valve failure) were also excluded.
Blood samples were collected from all patients 1 day before (baseline) and 2 and 30 days after the procedure. One month after discharge, all patients were assessed by a cardiologist in the hospital's outpatient cardiology clinic. Medical interviews and physical examinations were performed, blood samples were collected, and electrocardiographic recordings were obtained. Echocardiography was performed at baseline and at 30 days after TAVR. Procedural end points, device success, and adverse events were considered according to the Valve Academic Research Consortium-2 definitions.
For measurement of serum VEGF/Ang-1/Ang-2 levels, human VEGF (Antigenix America, Huntington Station, NY), human Ang-1 (R&D Systems, Minneapolis, MN), and human Ang-2 (R&D systems) enzyme-linked immunosorbent assay (ELISA) was employed according to the manufacturer's instructions. Per-patient normalization of VEGF and Ang1/2 concentrations to platelet counts were evaluated based on blood counts obtained at each time point, as previously recommended.
Correlation of plasma and serum vascular endothelial growth factor levels with platelet count in colorectal cancer: clinical evidence of platelet scavenging?.
The humoral effects of TAVR on endothelial cells were studied in vitro by applying patient sera collected before and after TAVR on human umbilical vein endothelial cells (HUVECs) (Promocell, Biological Industries, Cromwell, CT). Cells were cultured in endothelial cell growth medium (Promocell, Biological Industries) in a humidified 5% CO2 atmosphere at 37°C. Alternatively, medium was supplemented with 20% serum collected for 48 hours from patients undergoing TAVR. Cells from passages 4-6 were used for the experiments described here.
Flow cytometry analysis
HUVECs (106/well) were collected, washed with phosphate buffered saline (PBS), and stained for 30 minutes at 4°C with fluorescein isothiocyanate (FITC) monoclonal antihuman vascular cell adhesion molecule-1 (VCAM-1) or FITC monoclonal antihuman intracellular adhesion molecule-1 (ICAM-1) (Affymetrix eBioscience, San Diego, CA) antibodies. Cells were then washed with PBS and acquired using FACSCalibur (BD Biosciences, San Jose, CA).
Adhesion assay
HUVECs (104/well) were seeded for 30 minutes on 96-well immunoplates precoated with fibronectin (Chemicon International, Temicula, CA). Fibronectin-coated wells served as background. Nonadherent cells were washed away with PBS, and adherent cells were quantified by XTT-based colorimetry (Biological Industries).
Migration assay
A migration assay was performed as previously described.
The transient receptor potential vanilloid 2 cation channel is abundant in macrophages accumulating at the peri-infarct zone and may enhance their migration capacity towards injured cardiomyocytes following myocardial infarction.
Briefly, HUVECs (105/well) were seeded on top of 8-μm Transwell inserts (Greiner Bio-One, Monroe, NC) in 24-well plates and allowed to migrate toward patients' sera in the bottom side of the inserts for 4 hours at 37°C and 5% CO2. Alternatively, sera were supplemented with bevacizumab (100 ng/mL).
The inserts were then taken out, the upper sides were scraped with cotton wool, and migrating cells in the lower side were fixed with cold ethanol for 10 minutes. Cells were then stained with Coomassie blue and counted in 4 random fields/insert under light microscopy (×10).
Matrigel assay
HUVECs (2 × 105/well) were seeded on 24-well plates coated with 200 μL Matrigel (BD Biosciences). Alternatively, VEGF receptor 2 (VEGFR2) inhibitor (50 nM) SU5416 was added to cultures.
SU5416 Is a potent and selective inhibitor of the vascular endothelial growth factor receptor (Flk-1/KDR) that inhibits tyrosine kinase catalysis, tumor vascularization, and growth of multiple tumor types.
Cell organization was scored after 12 hours by microscopy (×40), and the number of closed tubules and branching points were determined, as previously described.
Comparison between groups was performed using the unpaired/paired Student t test for comparison between 2 groups, and 1-way analysis of variance for multiple comparisons (normal distribution) and the Pearson χ2 test for the continuous and categorical variables, respectively. Spearman's Rho correlation was used to evaluate the correlations (non-normal distribution). Level of significance was set at P < 0.05. Results are expressed as mean ± standard deviation. For box plots, center lines show the medians; box limits indicate the 25th and 75th percentiles; whiskers extend to the fifth and 95th percentiles, and outliers are represented by dots.
Results
Patients
From an initial cohort of 69 consecutive patients undergoing transfemoral TAVR, we excluded 23 patients (recent percutaneous coronary intervention [n = 16], major bleeding [n = 4], renal failure [n = 1], transient ischemic attack [n = 1], procedural failure [n = 1]). The final study population consisted of 46 patients (19 women) with a mean age of 82 ± 5 years, New York Heart Association class 2-4, and a mean EuroSCORE of 16 ± 10. At baseline, the mean aortic valve pressure gradient was 47 ± 14 mm Hg, and the mean aortic valve area was 0.73 ± 0.18 cm2. The demographic and clinical features of the included patients are presented in Supplemental Table S1.
Serum VEGF/Ang-1/Ang-2 levels after TAVR
Sera were collected before TAVR (day 0) and on days 2 and 30 after the procedure; levels of VEGF/Ang-1/Ang-2 were assessed by ELISA. Two days after TAVR, levels of VEGF, Ang-1, and Ang-2 were 5.38 fold ± 4 fold (P < 0.001), 1.05 fold ± 0.49 fold (P = 0.27), and 4.65 fold ± 2.01 fold (P < 0.001) compared with baseline levels. On day 30, levels of VEGF, Ang-1, and Ang-2 were 4.03 fold ± 3.2 fold (P < 0.001), 1.01 fold ± 0.4 fold (P = 0.13), and 5.11 fold ± 2.25 fold (P < 0.001) compared with baseline levels (Fig. 1A). Serum VEGF levels normalized to platelet count (pg/million) showed similar findings. Of note, the increase in VEGF levels significantly correlated with those of Ang-2 (r = 0.609; P < 0.001) (Fig. 1B).
Figure 1Ang-1, Ang-2, and vascular endothelial growth factor (VEGF) levels 2 and 30 days after transcatheter aortic valve replacement (TAVR). Sera of patients undergoing TAVR were collected 2 and 30 days after the procedure and (A) angiopoietin (Ang)-1, (B) Ang-2, and (C) VEGF levels were assessed by enzyme-linked immunoassay. (D) The correlation between the change (day 2/day 0 ratio) of Ang-2 and VEGF (∗P < 0.01; ∗∗P < 0.001).
For assessment of postprocedural anemia, tissue injury, or inflammation after intervention as potential triggers for the rise of angiogenic factors, we followed the levels of hemoglobin, bilirubin, lactate dehydrogenase, creatine phosphokinase (CPK), and C-reactive protein (CRP). We did not find a significant correlation between the levels of any of these factors and those of VEGF or Ang-2 (Supplemental Table S2).
We then assessed the background vascular morbidity of patients with a low vs high post-TAVR elevation of VEGF and Ang-2 based on the median day 2/day 0 ratio (3.95 and 4.05, respectively) (Supplemental Table S3). Patients with a low VEGF level or Ang-2 rise after TAVI had worse baseline aortic stenosis parameters as well as more advanced coronary artery disease compared with patients who exhibited higher VEGF or Ang-2 elevations.
In vitro assessment of the systemic angiogenic propensity after TAVR
Whether a rise in VEGF and Ang-2 levels reflect a systemic proangiogenic propensity after TAVR was evaluated by applying pre- and post-TAVR sera to HUVEC cultures. We first assessed endothelial activation through surface expression of adhesion molecules VCAM-1 and ICAM-1 using flow cytometry. We found an increased expression of 3.2 fold ± 0.8 fold (P < 0.005) and 1.8 fold ± 0.4 fold (P < 0.05), respectively, after exposing endothelial cells to patient sera 2 days after TAVR, compared with baseline patient sera (Fig. 2A). The expression of VCAM-1 and ICAM-1 was even more intensified using serum from patients 30 days after TAVR (5 fold ± 1.8 fold and 6.1 fold ± 1.5 fold, respectively; P < 0.005). Accordingly, the capacity of HUVECs exposed to serum of patients 30 days after TAVR to adhere to fibronectin was increased compared with cells treated with pre-TAVR serum (2.5 fold ± 0.8 fold compared with baseline; P < 0.005) (Fig. 2B).
Figure 2Adhesion capacity of human umbilical vein endothelial cells (HUVECs) exposed to serum of patients undergoing transcatheter aortic valve replacement (TAVR). Sera of patients undergoing TAVR were collected 2 and 30 days after the procedure and applied to HUVEC cultures. After 48 hours, vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) expression was assessed by flow cytometry. (A) Representative cytometric measurements of a single patient are presented. Additionally, cells were allowed to adhere to fibronectin-coated plates for 30 minutes, and nonadherent cells were washed away. (B) Adherent cells were quantified by XTT colorimetry (∗P < 0.05; ∗∗P < 0.005).
We next assessed the capacity of HUVECs to migrate toward sera of patients undergoing TAVR using the Transwell migration assay (Greiner Bio-One, Monroe, NC). We observed an increased migration toward sera of patients collected 30 days after TAVR compared with serum of patients before undergoing TAVR (2.94 fold ± 1.02 fold; P < 0.001), which correlated with VEFG levels (r = 0.65; P < 0.01) but not with Ang-2 levels (r = 0.21; P = 0.58) (Fig. 3A). Pretreatment of post-TAVR serum with anti-VEGF antibody and bevacizumab (100 ng/mL) markedly abolished the increased migration (Fig. 3B). The ability of HUVECs to form cord-like structures in vitro was assessed by Matrigel assay (Fig. 3C). After 12 hours, cultures exposed to post-TAVR sera showed significantly higher angiogenic capacity compared with cultures exposed to pre-TAVR sera, as assessed by the number of branching points (P < 0.001) (Fig. 3D) and closed tubules (P < 0.001) (Fig. 3E). The reaction was significantly inhibited in the presence of the VEGFR2 inhibitor SU5416 (50 nM).
Figure 3Migration and network formation capacities of human umbilical vein endothelial cells (HUVECs) exposed to serum of patients undergoing transcatheter aortic valve replacement (TAVR). For migration assay, HUVECs were seeded on 8-μm Transwell inserts and allowed to migrate toward different patients' sera. Cell number was determined in 4 random fields/insert under light microscopy (×10). The number of migrating cells (A) correlated with post-TAVR (30 days) vascular endothelial growth factor (VEGF) but not angiopoietin (Ang)-2 levels and (B) diminished in the presence of anti-VEGF bevacizumab (100 ng/mL). For network formation assay, sera of patients undergoing TAVR were collected 2 and 30 days after the procedure and applied to HUVEC cultures. Alternatively, SU5416 (50 nM) was added to cultures. After 48 hours, cells were collected and seeded on Matrigel-coated plates for 24 hours. (C) Representative microscopy of a single patient. (D) The number of closed tubules as well as (E) branching points were determined in 4 random fields/slide (×40) (∗P < 0.01; ∗∗P < 0.001).
Plasma angiopoietin-1 level, left ventricular ejection fraction, and multivessel disease predict development of 1-year major adverse cardiovascular events in patients with acute ST elevation myocardial infarction—a pilot study.
the correlation between VEGF and Ang-2 levels and key echocardiographic functional parameters was assessed 30 days after TAVR (Supplemental Table S4). No correlation was found between VEGF or Ang-2 levels and left ventricular (LV) systolic/diastolic or valvular function. A significant correlation was observed between serum VEGF, but not Ang-2 and the decrease in estimated pulmonary artery pressure (EPASP) after TAVR (r = 0.54; P < 0.01). Furthermore, VEGF levels positively correlated with the improvement in right ventricular (RV) function as assessed by fractional area change (FAC) (r = 0.48; P < 0.01) and tricuspid annular plane systolic excursion (r = 0.36; P = 0.07). Patients who showed a relatively high VEGF elevation (ratio greater than the median of 3.95 fold) after TAVI showed a EPASP decrease of 0.8 fold ± 0.29 fold on day 30, as opposed to patients with a low VEGF elevation (< 3.95 fold) who showed no improvement at 30 days (1.1 fold ± 0.26 fold) (P < 0.001). Also, patients with a high VEGF elevation showed a prominent improvement in FAC of 1.31 fold ± 0.4 fold compared with those with a low VEGF elevation (1.07 fold ± 0.2 fold) (P < 0.03).
Discussion
In the present study, we showed a systemic proangiogenic shift after TAVR, reflected by a sustained elevation of serum VEGF and Ang-2 levels. Relatively low VEGF and Ang-2 elevations were associated with more prominent underlying vascular morbidity. The proangiogenic propensity of post-TAVR serum was demonstrated in vitro. Eventually, the VEGF increase correlated with improvement of pulmonary hypertension after TAVR.
Different mechanisms may account for VEGF and Ang-2 increases in patients undergoing TAVR. Both factors are secreted by various cells that participate in wound healing and play a role in the recruitment of inflammatory cells and angiogenesis during tissue repair.
Yet, a rise in VEGF and Ang-2 levels after wound healing generally occurs during the first week after wounding, peaking differently during that period depending on various factors (eg, wound type, age), and then decline to normal levels.
failed to show a significant increase in our study. Additionally, although the increased postprocedural levels of CPK and CRP (as markers of tissue injury and inflammation) returned to baseline values within a few days after TAVR, VEGF and Ang-2 elevation was sustained after 30 days. The drop in hemoglobin levels that characterize the post-TAVR course also tended to resolve within days and did not correlate with VEGF or Ang-2 levels. Interestingly, transient depression of both systolic and diastolic LV function was reported despite the relief of chronic pressure overload, perhaps because of myocardial stunning,
Nevertheless, postprocedural ventricular dysfunction was shown to occur within the first postoperative hours, followed by rapid recovery of contractility and normalization of heart failure biomarkers.
Although aortic stenosis is accompanied by diverse flow abnormalities and hemodynamic disturbances, aortic valve replacement may increase arterial wall shear stress and reduce intima-media thickness.
demonstrated an increased wall shear stress as well as improved flow-mediated vasodilation after TAVR. Interestingly, these findings were accompanied by an alteration in the level of endothelial microparticles, which seem to hold diverse roles in endothelial activation and function.
In fact, endothelial cells are strongly influenced by changes in mechanical stresses, which substantially alter their signal transduction and humoral and structural properties.
VEGF signalling was recently shown to play a pivotal role in arterial endothelium survival after activation of flow-mediated mechanosignalling pathways.
Additionally, VEGF and Ang-2 both have a critical role in the cross talk between endothelial cells and other cells (ie, pericytes, fibroblasts, smooth muscle cells) that take part in the vascular adaption to hemodynamic changes.
The observed changes in serum VEGF and Ang-2 levels after TAVR in our study might ensue, at least in part, from the vigorous hemodynamic and shear stress changes applied to the vascular endothelium after the relief of the aortic valve pressure gradient.
We found improved angiogenic properties of endothelial cells exposed to post-TAVR serum in vitro, namely, adhesion, migration, and network formation capacities. VEGF/VEGFR2 is a well-established regulator of endothelial cell activation, adhesion, and migration.
Although Ang-1/Tie-2 signalling maintains the quiescent phenotype of endothelial cells, activated endothelial cells liberate stored pools of Ang-2, which antagonize Ang-1 signalling to facilitate endothelial sensitivity to exogenous cytokines.
Accordingly, we found a marked reduction in endothelial cell migration and network formation capacities on inhibition of VEGF.
Previous studies have shown that the endothelial angiogenic and vasodilatory responses, including VEGF and angiopoietin signalling, tend to diminish with aging in association with increasing vascular morbidity (ie, atherosclerosis, hypertension).
Aging impairs transcriptional regulation of vascular endothelial growth factor in human microvascular endothelial cells: implications for angiogenesis and cell survival.
We found an increased severity of aortic stenosis and coronary artery disease among patients with relatively low VEGF or Ang-2 secretion capacity. Furthermore, we found that the magnitude of VEGF response after aortic valve opening directly correlated with improvement of pulmonary hypertension after 1 month. In line with this finding, VEGF positively correlated with improvement in RV function. No correlation was found between VEGF levels and LV diastolic function; thus, VEGF correlation to EPASP was unlikely to emanate in diastolic improvement. Few recent studies have pointed at an improvement in pulmonary hypertension as a key prognostic factor after TAVR, negatively correlating with aortic regurgitation and mortality.
VEGF was previously shown to ameliorate pulmonary hypertension through inhibition of endothelial apoptosis, stimulation of nitric oxide production, and angiogenesis.
In line with these studies, a positive correlation between VEGF levels and RV function has been recently demonstrated in patients with pulmonary hypertension.
Eventually, given the advanced age of patients undergoing TAVR, those with a relatively higher capacity to secrete VEGF in response to mechanical stimuli after TAVR could be those who hold a higher potential to reduce pulmonary blood pressure after TAVR.
Study limitations
An increase in VEGF and Ang-2 levels apparently emanates from various sources in the postprocedural setting. We thus excluded major comorbidities, recent procedures, and anesthetic factors previously known to affect VEGF or Ang-2 levels. As described earlier, we believe that regardless of the diverse VEGF/Ang-2 origins, the sustained elevation of these angiogenic factors demonstrated in this study represents a substantial vascular response to TAVR, with potential prognostic significance. We focused on serum VEGF and angiopoietins levels; however, multiple factors are obviously altered after TAVR. Indeed, the present in vitro strategy allowed us to evaluate fluctuations in the net humoral effects on homogeneous cell cultures of primary endothelium. Finally, the nature of our study limited us to a relatively small number of patients. We analyzed paired samples of each patient before and after TAVR, and as such, we did not include separate non-TAVR controls. Further studies will be needed to determine the proangiogenic response after TAVR and its prognostic value.
Disclosures
The authors have no conflicts of interest to disclose.
Aging impairs transcriptional regulation of vascular endothelial growth factor in human microvascular endothelial cells: implications for angiogenesis and cell survival.
2008 focused update incorporated into the ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (writing committee to revise the 1998 guidelines for the management of patients with valvular heart disease) endorsed by the Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons.
Correlation of plasma and serum vascular endothelial growth factor levels with platelet count in colorectal cancer: clinical evidence of platelet scavenging?.
The transient receptor potential vanilloid 2 cation channel is abundant in macrophages accumulating at the peri-infarct zone and may enhance their migration capacity towards injured cardiomyocytes following myocardial infarction.
SU5416 Is a potent and selective inhibitor of the vascular endothelial growth factor receptor (Flk-1/KDR) that inhibits tyrosine kinase catalysis, tumor vascularization, and growth of multiple tumor types.
Plasma angiopoietin-1 level, left ventricular ejection fraction, and multivessel disease predict development of 1-year major adverse cardiovascular events in patients with acute ST elevation myocardial infarction—a pilot study.
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