Progress in research into the genes associated with venous thromboembolism

BACKGROUND: Venous thromboembolism(VTE), including both deep vein thrombosis(DVT) and pulmonary embolism(PE), is a common, lethal disorder that affects hospitalized and nonhospitalized patients. This study aimed to review the progress in the research into VTE.DATA SOURCES: We reviewed the studies about VTE and verified different genetic polymoriphisms of VTE.RESULTS: The pathogenesis of VTE involves hereditary and acquired factors. Many studies indicated that the disorder of coagulation and fibirnolytic system is of utmost importance to this disease. Genetic polymoriphism-related VTE demonstrated significant differences among geographies and ethnicities.CONCLUSION: VTE has many risk factors, but genetic factors play an important role.

Increasing angiotensin-converting enzyme(ACE)2/ACE axes ratio alleviates early pulmonary vascular remodeling in a porcine model of acute pulmonary embolism with cardiac arrest

BACKGROUND:Acute pulmonary embolism(APE)with cardiac arrest(CA)is characterized by high mortality in emergency due to pulmonary arterial hypertension(PAH).This study aims to determine whether early pulmonary artery remodeling occurs in PAH caused by massive APE with CA and the protective effects of increasing angiotensin-converting enzyme(ACE)2-angiotensin(Ang)(1-7)-Mas receptor axis and ACE-Ang II-Ang II type 1 receptor(AT1)axis(ACE2/ACE axes)ratio on pulmonary artery lesion after return of spontaneous circulation(ROSC).METHODS:To establish a porcine massive APE with CA model,autologous thrombus was injected into the external jugular vein until mean arterial pressure dropped below 30 mmHg(1 mmHg=0.133 kPa).Cardiopulmonary resuscitation and thrombolysis were delivered to regain spontaneous circulation.Pigs were divided into four groups of five pigs each:control group,APE-CA group,ROSC-saline group,and ROSC-captopril group,to examine the endothelial pathological changes and expression of ACE2/ACE axes in pulmonary artery with or without captopril.RESULTS:Histological analysis of samples from the APE-CA and ROSC-saline groups showed that pulmonary arterioles were almost completely occluded by accumulated endothelial cells.Western blotting analysis revealed a decrease in the pulmonary arterial ACE2/ACE axes ratio and increases in angiopoietin-2/angiopoietin-1 ratio and expression of vascular endothelial growth factor(VEGF)in the APE-CA group compared with the control group.Captopril significantly suppressed the activation of angiopoietin-2/angiopoietin-1 and VEGF in plexiform lesions formed by proliferative endothelial cells after ROSC.Captopril also alleviated endothelial cell apoptosis by increasing the B-cell lymphoma-2(Bcl-2)/Bcl-2-associated X(Bax)ratio and decreasing cleaved caspase-3 expression.CONCLUSION:Increasing the ACE2/ACE axes ratio may ameliorate pulmonary arterial remodeling by inhibiting the apoptosis and proliferation of endothelial cells after ROSC induced by APE.

Extracorporeal Membrane Oxygenation Improving Survival and Alleviating Kidney Injury in a Swine Model of Cardiac Arrest Compared to Conventional Cardiopulmonary Resuscitation

Background： Acute kidney injury （AKI） frequently occurs in cardiopulmonary resuscitation patients. Studies comparing the effects of extracorporeal membrane oxygenation （ECMO） with conventional cardiopuhnonary resuscitation （CCPR） on AKI were rare. This study aimed to compare the effects of ECMO with those of CCPR on survival rate and AKI and explore the underlying mechanisms in a swine model of cardiac arrest （CA）. Methods： Sixteen male pigs were treated with ventricular fibrillation to establish CA model and then underwent CCPR （CCPR group, n = 8） or ECMO during cardiopulmonary resuscitation （ECPR group, n = 8）. The study endpoints were 6 h after return of spontaneous circulation （ROSC） or death. Serum and urine samples were collected at baseline and during the 6 h after ROSC. The biomarkers of AKI were detected by enzyme-linked immunosorbent assay. The apoptosis of renal tubular epithelial cells was discovered by transmission electron microscope （TEM） and terminal deoxynucleotidyl transferase dUTP nick end labeling assay. Apoptosis-related genes were detected by immune-staining and Western blotting. Data were compared by Student＇s t-test. Results： All pigs in ECPR group were successfully resuscitated with a higher 6-h survival rate （8/8） compared to CCPR group （6/8）. The expressions ofAKl biomarkers including neutrophil gelatinase-associated lipocalin （NGAL）, tissue inhibitor ofmetalloproteinase2 （TIMP2）, insulin-like growth factor-binding protein 7 （IGFBP7）, liver fatty acid-binding protein （LFABP）, and kidney injury molecule l （Kim-1） were all increased along with the time after ROSC in both groups and lower in ECPR group compared with CCPR group. Especially, products of urinary T1MP and IGFBP levels （TIMP＊IGFBP） were significantly lower at ROSC4 （0.58 ± 0.10 ng^2/ml^2 vs. 1.18 ± 0.38 ng^2/ml^2, t = 4.33, P =0.003） and ROSC6 （1.79 ±0.45 ng2^/ml^2 vs. 3.00 ±0.44 ng^2/ml^2, t = 5.49, P 〈 0.001）; urinary LFABP was significantly lower at ROSC6 （0.74 ± 0.06 pg/ml vs. 0.85 4±0.11 pg/ml, t = 2.41, P = 0.033）; and urinary Kim-1 was significantly lower at ROSC4 （0.66 ± 0.09 pg/ml vs. 0.83 ± 0.06 pg/ml, t = 3.99, P = 0.002） and ROSC6 （0.73 ± 0.12 pg/ml vs. 0.89 ± 0.08 pg/ml, t = 2.82, P = 0.016）. Under light microscope and TEM, the morphological injures in renal tissues were found to be improved in ECPR group. Moreover, apoptosis was also alleviated in ECPR group. Conclusions： Compared with CCPR, ECMO improves survival rate and alleviates AKI in a swine model of CA. The mechanism of which might be via downregulating AKI biomarkers and apoptosis in kidney.

Variations of Postresuscitation Lung Function after Thrombolysis Therapy in a Cardiac Arrest Porcine Model Caused by Pulmonary Thromboembolism

Background： Study of lung function in survivor from cardiac arrest （CA） caused by pulmonary thromboembolism （PTE） was rare. The aim of this study was to investigate the variations ofpostresuscitation lung function after thrombolysis treatment in a CA porcine model caused by PTE. Methods： After 2 min of untreated CA, pigs of 10-12 weeks with a weight of 30±2 kg （n = 24） were treated with recombinant human tissue plasminogen activator （50 mg）. Cardiopulmonary resuscitation （CPR） and ventilation were initiated after drug administration. Pulmonary function and arterial blood gas parameters were measured at baseline, return of spontaneous circulation （ROSC） immediately, and 1 h, 2 h, 4 h, and 6 h after ROSC. Results： The dynamic lung compliance decreased significantly at ROSC immediately and 1 h after ROSC compared to baseline （21.86 ±2.00 vs. 26.72± 2.20 ml/mmHg and 20.38 ± 1.31 vs. 26.72 ± 2.20 ml/mmHg, respectively; P 〈 0.05; 1 mmHg = 0.133 kPa）. Compared with baseline, airway resistance increased significantly at ROSC immediately and 1 h after ROSC （P 〈 0.05）. Respiratory index also increased after ROSC and showed significant differences among baseline, ROSC immediately, and 2 h after ROSC （P 〈 0.05）. Oxygen delivery decreased at ROSC immediately compared to baseline （P 〈 0.05）. The oxygenation index decreased significantly at any time after ROSC compared to baseline （P 〈 0.05）. Extravascular lung water index and pulmonary vascular permeability index （PVP1） showed significant differences at ROSC immediately compared to baseline and 1 h after ROSC （P 〈 0.05）; PVPI at ROSC inamediately was also different from 6 h after ROSC （P 〈 0.05）. Ventilation/perfusion ratios increased after ROSC （P 〈 0.05）. Histopathology showed fibrin effusion, bleeding in alveoli, and hemagglutinatiun in pulmonary artery. Conclusions： Lung function remains abnormal even after CPR with thrombolysis therapy; it is essential to continue anticoagulation and symptomatic treatment after ROSC.

Study of Cardiac Arrest Caused by Acute Pulmonary Thromboembolism and Thrombolytic Resuscitation in a Porcine Model

Background： The success rate of resuscitation in cardiac arrest （CA） caused by pulmonary thromboembolism （PTE） is low. Furthermore, there are no large animal models that simulate clinical CA. The aim of this study was to establish a porcine CA model caused by PTE and to investigate the pathophysio[ogy of CA and postresuscitation. Methods： This model was induced in castrated male pigs （30 ± 2 kg; n = 21 ） by injecting thrombi （10-15 ml） via the left external jugular vein. Computed tomographic pulmonary angiography （CTPA） was performed at baseline, CA, and return of spontaneous circulation （ROSC）. After CTPA during CA, cardiopulmonary resuscitation （CPR） with thrombolysis （recombinant tissue plasminogen activator 50 mg） was initiated. Hemodynamic, respiratory, and blood gas data were monitored. Cardiac troponins T, cardiac troponin I, creatine kinase-MB, myoglobin, and brain natriuretic peptide （BNP） were measured by enzymeqinked immunosorbent assay. Data were compared between baseline and CA with paired-sample t-test and compared among different time points for survival animals with repeated measures analysis of variance. Results： Seventeen animals achieved CA after emboli injection, while four achieved CA after 5-8 ml more thrombi. Nine animals survived 6 h after CPR. CTPA showed obstruction of the pulmonary arteries. Mean aortic pressure data showed occurrence of CA caused by PTE （Z = -2.803, P = 0.002）. The maximal rate of mean increase of left ventricular pressure （dp/dtmax） was statistically decreased （t = 6,315, P = 0.000, variation coefficient = 0.25）, and end-tidal carbon dioxide partial pressure （PetCO2） decreased to the lowest value （t - 27.240, P = 0.000）. After ROSC （n = 9）, heart rate （HR） and mean right ventricular pressure （MRVP） remained different versus baseline until 2 h after ROSC （HR, P = 0.036; MRVP, P - 0.027）. Myoglobin was statistically increased from CA to 1 h after ROSC （P - 0.036, 0.026, 0,009, respectively）, and BNP was increased from 2 h to 6 h after ROSC （P 0.012, 0.014, 0.039, respectively）. Conclusions： We established a porcine model of CA caused by PTE. The dp/dtmax and PetCO2 may be important for the occurrence of CA, while MRVP may be more important in postresuscitation.