Prediction of in-hospital adverse clinical outcomes in patients with pulmonary thromboembolism, machine learning based models.

Background: Pulmonary thromboembolism (PE) is the third leading cause of cardiovascular events. The conventional modeling methods and severity risk scores lack multiple laboratories, paraclinical and imaging data. Data science and machine learning (ML) based prediction models may help better predict outcomes. Materials and methods: In this retrospective registry-based design, all consecutive hospitalized patients diagnosed with pulmonary thromboembolism (based on pulmonary CT angiography) from 2011 to 2019 were recruited. ML based algorithms [Gradient Boosting (GB) and Deep Learning (DL)] were applied and compared with logistic regression (LR) to predict hemodynamic instability and/or all-cause mortality. Results: A total number of 1,017 patients were finally enrolled in the study, including 465 women and 552 men. Overall incidence of study main endpoint was 9.6%, (7.2% in men and 12.4% in women; p-value = 0.05). The overall performance of the GB model is better than the other two models (AUC: 0.94 for GB vs. 0.88 and 0.90 for DL and LR models respectively). Based on GB model, lower O2 saturation and right ventricle dilation and dysfunction were among the strongest adverse event predictors. Conclusion: ML-based models have notable prediction ability in PE patients. These algorithms may help physicians to detect high-risk patients earlier and take appropriate preventive measures.

Effects of Iron Sucrose and Erythropoietin on Transfusion Requirements in Patients with Preoperative Iron Deficiency Anemia Undergoing on-Pump Coronary Artery Bypass Graft.

Background: Preoperative anemia is an independent risk factor for higher rates of blood transfusion in cardiac surgery. This study aimed to evaluate the effects of intravenous iron sucrose and erythropoietin on transfusion requirements in patients with preoperative iron deficiency anemia (IDA) undergoing on-pump coronary artery bypass graft (CABG) surgery. Methods: In this open-label, randomized clinical trial, patients with preoperative IDA who were candidates for on-pump CABG were randomized into intervention (iron plus erythropoietin) or control groups. Iron sucrose was administered as a 200 mg intravenous dose and erythropoietin as a 100 IU/kg bolus 1 to 2 days before surgery. The primary outcome was the amount of blood transfusion during the first 4 postoperative days. Results: The study population consisted of 114 patients. The mean age was 64.11±8.18 years in the intervention group and 63.35±8.70 years in the control group. Twenty-seven patients (47.4%) in the intervention group and 25 (43.9%) in the control group were males. The number of red blood cell units transfused per patient exhibited a significant fall in the intervention group compared with the control group (P˂0.001). The ferritin level showed a significant rise in the intervention group on postoperative day 7 (P=0.027). The length of stay in the intensive care unit and the hospital was significantly lower in the intervention arm (P=0.041 and P=0.006, respectively). No adverse events were reported in both groups. Conclusion: The use of erythropoietin and iron sucrose 1 to 2 days before surgery significantly decreased the need for blood transfusion in patients with IDA undergoing CABG without any significant adverse events.

Compression stockings for treating vasovagal syncope (COMFORTS-II) trial: Rationale and design of a triple-blind, multi-center, randomized controlled trial.

BACKGROUND: Reduced venous return is an important trigger of vasovagal syncope (VVS). Elastic compression stockings (ECS) can modify venous return and be of therapeutic interest; however, evidence for ECS efficacy in VVS is scarce. This randomized controlled trial was designed to address the issue. METHODS: COMFORTS-II is a multicenter, triple-blind, parallel design, randomized controlled trial aimed to assess the efficacy of ECS in preventing VVS recurrences. Using central online randomization, 268 participants will be allocated to 2 arms (1:1 ratio), wearing intervention ECS (25-30 mm Hg pressure) or sham ECS (≤10 mm Hg pressure). All participants will receive standard VVS treatment in the form of education, and lifestyle modification recommendations (drinking 2-3 l/d of fluids and consuming 10 g/d-roughly half a tablespoon-of table salt). Adherence to ECS treatment will be evaluated through diary sheets, and compared between study arms. Follow-up continues for 1 year, and is conducted via a 24/7 phone line available to patients and trimonthly visits. The co-primary outcomes are proportion of participants with any syncopal recurrence and time to first syncopal episode. Secondary outcomes include frequency of VVS spells, time intervals between recurrences, and incidence of any patient-reported adverse effects. CONCLUSION: To the best of our knowledge, COMFORTS-II is the first clinical trial to assess ECS efficacy among patients with VVS, addressing an important gap in evidence for VVS treatments.

Investigating Lipid-Modulating Agents for Prevention or Treatment of COVID-19: JACC State-of-the-Art Review.

Coronavirus disease-2019 (COVID-19) is associated with systemic inflammation, endothelial activation, and multiorgan manifestations. Lipid-modulating agents may be useful in treating patients with COVID-19. These agents may inhibit viral entry by lipid raft disruption or ameliorate the inflammatory response and endothelial activation. In addition, dyslipidemia with lower high-density lipoprotein cholesterol and higher triglyceride levels portend worse outcomes in patients with COVID-19. Upon a systematic search, 40 randomized controlled trials (RCTs) with lipid-modulating agents were identified, including 17 statin trials, 14 omega-3 fatty acids RCTs, 3 fibrate RCTs, 5 niacin RCTs, and 1 dalcetrapib RCT for the management or prevention of COVID-19. From these 40 RCTs, only 2 have reported preliminary results, and most others are ongoing. This paper summarizes the ongoing or completed RCTs of lipid-modulating agents in COVID-19 and the implications of these trials for patient management.

Use of novel antithrombotic agents for COVID-19: Systematic summary of ongoing randomized controlled trials.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is associated with macro- and micro-thromboses, which are triggered by endothelial cell activation, coagulopathy, and uncontrolled inflammatory response. Conventional antithrombotic agents are under assessment in dozens of randomized controlled trials (RCTs) in patients with COVID-19, with preliminary results not demonstrating benefit in several studies. OBJECTIVES: Given the possibility that more novel agents with antithrombotic effects may have a potential utility for management of patients with COVID-19, we assessed ongoing RCTs including these agents with their potential mechanism of action in this population. METHODS: We searched clinicaltrials.gov and the World Health Organization International Clinical Trials Registry Platform to identify RCTs of novel antithrombotic agents in patients with COVID-19. RESULTS: Based on a systematic literature search, 27 RCTs with 10 novel antithrombotic agents (including nafamostat, dociparstat, rNAPc2, and defibrotide) were identified. The results from these trials have not been disseminated yet. The studied drugs in the ongoing or completed RCTs include agents affecting the coagulation cascade, drugs affecting endothelial activation, and mixed acting agents. Their postulated antithrombotic mechanisms of action and their potential impact on patient management are summarized. CONCLUSION: Some novel antithrombotic agents have pleiotropic anti-inflammatory and antiviral effects, which may help reduce the viral load or fibrosis, and improve oxygenation. Results from ongoing RCTs will elucidate their actual role in the management of patients with COVID-19.

Lipid-Modulating Agents for Prevention or Treatment of COVID-19 in Randomized Trials.

Coronavirus disease 2019 (COVID-19) is associated with systemic inflammation, endothelial activation, and multi-organ manifestations. Lipid modulating agents may be useful in treating patients with COVID-19. They may inhibit viral entry by lipid raft disruption or ameliorate the inflammatory response and endothelial activation. In addition, dyslipidemia with lower high-density lipoprotein cholesterol and higher triglycerides portends worse outcome in patients with COVID-19. Upon a systematic search, 40 RCTs with lipid modulating agents were identified, including 17 statin trials, 14 omega-3 fatty acids RCTs, 3 fibrates RCTs, 5 niacin RCTs, and 1 dalcetrapib RCT for management or prevention of COVID-19. This manuscript summarizes the ongoing or completed randomized controlled trials (RCTs) of lipid modulating agents in COVID-19 and the implications of these trials for patient management.

Comparison of Outcomes with Midodrine and Fludrocortisone for Objective Recurrence in Treating Syncope (COMFORTS trial): Rationale and design for a multi-center randomized controlled trial.

BACKGROUND: The cornerstone of the treatment of vasovagal syncope (VVS) is lifestyle modifications; however, some patients incur life-disturbing attacks despite compliance with these treatments which underscores the importance of pharmacological interventions. METHODS: In this open-label multi-center randomized controlled trial, we are going to randomize 1375 patients with VVS who had ≥2 syncopal episodes in the last year into three parallel arms with a 2:2:1 ratio to receive midodrine, fludrocortisone, or no medication. All patients will be recommended to drink 2 to 3 liters of fluids per day, consume 10 grams of NaCl per day, and practice counter-pressure maneuvers. In medication arms, patients will start on 5 mg of midodrine TDS or 0.05 mg of fludrocortisone BD. After one week the dosage will be up-titrated to midodrine 30 mg/day and fludrocortisone 0.2 mg/day. Patient tolerance will be the principal guide to dosage adjustments. We will follow-up the patients on 3, 6, 9, and 12 months after randomization. The primary outcome is the time to first syncopal episode. Secondary outcomes include the recurrence rate of VVS, time interval between first and second episodes, changes in quality of life (QoL), and major and minor adverse drug reactions. QoL will be examined by the 36-Item Short Form Survey questionnaire at enrollment and 12 months after randomization. CONCLUSION: The COMFORTS trial is the first study that aims to make a head-to-head comparison between midodrine and fludrocortisone, against a background of lifestyle modifications for preventing recurrences of VVS and improving QoL in patients with VVS.

Recent Randomized Trials of Antithrombotic Therapy for Patients With COVID-19: JACC State-of-the-Art Review.

Endothelial injury and microvascular/macrovascular thrombosis are common pathophysiological features of coronavirus disease-2019 (COVID-19). However, the optimal thromboprophylactic regimens remain unknown across the spectrum of illness severity of COVID-19. A variety of antithrombotic agents, doses, and durations of therapy are being assessed in ongoing randomized controlled trials (RCTs) that focus on outpatients, hospitalized patients in medical wards, and patients critically ill with COVID-19. This paper provides a perspective of the ongoing or completed RCTs related to antithrombotic strategies used in COVID-19, the opportunities and challenges for the clinical trial enterprise, and areas of existing knowledge, as well as data gaps that may motivate the design of future RCTs.

A novel strategy for engineering of a smart generation of immune ribonucleases against EGFR+ cells.

The overexpression of epidermal growth factor receptor (EGFR) could result in the development of solid tumors of prostate, breast, gastric, colorectal, ovarian, and head and neck, leading to carcinoma. Antibody therapies are ideal methods to overcome malignant diseases. However, immunoribonucleases are a new generation of antibodies in which an RNase binds to a specific antibody and shows a stronger ability to terminate cancer cells. In this study, we engineered Rana pipiens RNase to bind to the scFv of human antiepidermal growth factor receptor antibody. The molecular dynamic simulations confirmed protein stability and the ability of scFv-ranpirnase (rantoxin) to bind to epidermal growth factor receptor protein. Then, the rantoxin construct was synthesized in a pCDNA 3.1 Neo vector. CHO-K1 cells were used as expression hosts and the construct was transfected. Cells were selected by antibiotic therapies using neomycin, 120 mg/ml, and the high-yield colony was screened by real-time polymerase chain reaction (PCR) methods. Then, the recombinant protein production was confirmed using the sodium dodecyl sulfate polyacrylamide gel electrophoresis and western blot analyses. The molecular dynamic simulation (MDS) confirmed that the I467, S468, Q408, and H409 amino acids of EGFR bonded well to rantoxin. As revealed by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and western blot analyses, the rantoxin production and PCR analysis showed that the T3 colony can produce rantoxin messenger RNA fourfold higher than the GAPDH gene. The immunotoxin function was assessed in A431 cancer cells and EGFR-negative HEK293 cells, and IC50  values were estimated to be 22.4 ± 3 and >620.4 ± 5 nM, respectively. The results indicated that the immunotoxins produced in this study had the potential for use as anticancer drugs.

Pulmonary Embolism and Right Heart Thrombi: A Single-Center Experience.

Background: The right heart thrombus (RHT) embolizes from deep venous thrombi and sits in the right atrium or the right ventricle. We aimed to determine the occurrence and prognosis of the RHT in patients with pulmonary embolism. Methods: We reviewed the cohort data of 622 patients with acute pulmonary embolism obtained from the registry of Tehran Heart Center. Demographic, physiological, clinical, and echocardiographic data, as well as clinical outcomes, were compared between patients with and without the RHT. Results: The study population comprised 622 patients, including 329 men (52.8%). The mean age of the patients was 60.2±17.0 years. Thirty patients (4.8%) had echocardiographically proven RHT. Baseline demographic and clinical characteristics were not different between the 2 groups. Right ventricular dysfunction was more prevalent in the RHT (+) group, and more patients in this group were treated with thrombolysis (P=0.013 and P<0.001, respectively). Overall, 3 out of 21 patients (14.2%) in the RHT (+) group vs 29 out of 306 patients (9.4%) in the RHT (-) group died at 1 month (P=0.445) and 5 out of 21 patients (23.8%) in the RHT (+) group vs 56 out of 307 patients (18.2%) in the RHT (-) group died at 1 year (P=0.562). Conclusion: The RHT is an influential complication in patients with pulmonary emboli, and it seems to increase the mortality rate of patients with acute pulmonary embolism.

Incidence and predictors of chronic thromboembolic pulmonary hypertension following first episode of acute pulmonary embolism.

INTRODUCTION: Late obstructive pulmonary artery remodeling presented as CTEPH portends adverse sequelae and therapeutic challenges. Although progressive dyspnea on exertion beyond three-month period of treatment with anticoagulants is a diagnostic cornerstone, uncertainty still surrounds early identification and risk factors. MATERIAL AND METHODS: We have conducted a prospective study among survivors of acute pulmonary embolism (PE) who were treated by anticoagulants for at least 3 months. Patients with preexisting pulmonary hypertension (PH), severe chronic obstructive pulmonary disease (COPD), and low ejection fraction (EF) in baseline echocardiography (EF < 30%) were excluded. Complete follow-up for 290 subjects were performed. According to a predetermined stepwise diagnostic protocol, patients with exertional Dyspnea and PH probable features in echocardiography underwent lung perfusion scan. RESULTS: Cumulative two-year incidence of CTEPH was 8.6% (n = 25). There was no patient with normal baseline right ventricular (RV) function in CTEPH group. In the same way, none of these patients had only segmental involvement in baseline CT angiography (CTA) in CTEPH group. Greater proportion of CTEPH group received fibrinolytic therapy, however the difference was not significant (2.6% vs 8 %, P = 0.16). Multivariate logistic regression demonstrated significant association of RV diameter, and PAP in baseline echocardiography as well as RV strain in CTA with development of CTEPH. Corresponding odds ratios were 1.147 (1.063-1.584) P < 0.0001) , 1.062 (1.019-1.106, P = 0.004), and 2.537 (1.041-6.674), P = 0.027), respectively. CONCLUSIONS: We found that incidence of CTEPH was relatively high in the present investigation. RV diameter, baseline PAP and RV dysfunction were independent predictors of CTEPH.

The Value of the GRACE Score for Predicting the SYNTAX Score in Patients with Unstable Angina/Non-ST Elevation Myocardial Infarction.

BACKGROUND: In patients with unstable angina/non-ST-elevation myocardial infarction (UA/NSTEMI), Global Registry for Acute Coronary Events (GRACE) score is a valid tool for risk stratification. The Synergy between PCI with Taxus and Cardiac Surgery (SYNTAX) score is an angiographic scoring system to guide the decision-making between coronary artery bypass grafting (CABG) surgery and percutaneous coronary intervention (PCI). The aim of the present study was to assess the accuracy of the GRACE score in predicting the severity and extent of coronary artery stenosis by SYNTAX score. METHODS: A total of 330 patients with acute coronary syndrome (ACS) were enrolled in the study. For every patient, the GRACE score was calculated. All patients underwent coronary angiography within 2 days and the SYNTAX scoring system was used to evaluate the severity and extent of coronary stenotic lesions. Based on ROC curve analysis, the cut-off value of GRACE score that could predict SYNTAX score ≥ 23 was calculated. RESULTS: GRACE score was 107.12 ±â€¯34.4 in patients with SYNTAX SCORE < 23 and 134.80 ±â€¯48.3 in patients with SYNTAX score ≥ 23 (p value = 0.001). A positive correlation was observed between the GRACE score and angiographic SYNTAX score (r = 0.34 p < 0.001). We found that a GRACE score of 109 is the optimal cut-off to predict SYNTAX score ≥ 23 with a sensitivity of 73.5% and specificity of 60% (p < 0.001). Its negative predictive value was 94.0%. CONCLUSION: GRACE score had significant but modest value to predict the severity and extent of coronary artery stenosis in patients with ACS.

Mean Platelet Volume and Major Adverse Cardiac Events following Percutaneous Coronary Intervention.

BACKGROUND: Mean platelet volume (MPV) has been introduced as a simple and accurate method for assessing platelet function, which can be used as a prognostic marker for cardiovascular events. We investigated whether pre-procedural MPV could predict major adverse cardiac events (MACE) in candidates for elective percutaneous coronary intervention (PCI). METHODS: In this large retrospective cohort, we reviewed the clinical and follow-up data of 4199 candidates (mean age = 59.9 ± 10.3 years; female patients = 1440 [34.3%]) for elective PCI due to unstable angina (UA) or non-ST segment elevation myocardial infarction (NSTEMI). The primary endpoint of the study was the incidence of MACE defined as in-hospital mortality, cardiac death, nonfatal MI, target lesion revascularization (TLR) or target vessel revascularization (TVR). Based on the MPV level tertiles, patients were categorized into three groups for further comparison. RESULTS: Higher MPV was significantly associated with older age (P<0.001), hypertension (P<0.001), diabetes mellitus (P=0.003), history of previous CABG (P<0.001) and lower levels of serum triglyceride (P<0.001). The frequency of 1-year MACE was 176 (4.1%) with no significant difference between the MPV tertile groups. The highest MPV tertile could significantly predict MACE in the univariable model (hazard ratio = 1.51, 95% confidence interval: 1.05-2.17; P=0.026). In the adjusted model, the highest MPV tertile was a borderline predictor for MACE (hazard ratio = 1.62, 95% CI: 0.98-2.68; P=0.057). CONCLUSION: High MPV was associated with cardiovascular risk factors and older age while high MPV was a borderline independent predictor for 1-year MACE in the candidates for elective PCI.

Relationship between Vitamin D Levels and the Incidence of Post Coronary Artery Bypass Graft Surgery Atrial Fibrillation.

Background: Postoperative atrial fibrillation (POAF) is probably a consequence of inflammation. Vitamin D is known for its anti-inflammatory properties. The aim of this study was to evaluate the effects of vitamin D levels on the incidence of POAF. Methods: In a prospective cohort study, patients were monitored for the occurrence of POAF during the first 5 days after coronary artery bypass grafting surgery in Tehran Heart Center. Those with concomitant valvular surgeries were excluded. Thereafter, they were divided into 2 groups: with or without POAF. Vitamin D levels were assessed in all the patients. The relationship between the vitamin D level and the incidence of POAF was evaluated and compared between the groups using the Mann-Whitney U test. Results: The study population comprised of 156 patients. The mean age was 62.8±8.6 years, and 105 (67.3%) patients were male. Of the 156 patients, 29 (19%) developed POAF. The median preoperative vitamin D level was 15.3 in the group with POAF and 25.3 in the group without POAF (P=0.07). Conclusion: Our results demonstrated no significant relationship between vitamin D levels and the occurrence of POAF.

Catheter-Directed Thrombolysis in Acute Iliofemoral Deep Vein Thrombosis with or without Stenting: A Case Series.

Iliofemoral deep vein thrombosis (IFDVT) is a potentially devastating condition comprising a quarter of all cases of lower extremity DVT. It can lead to serious consequences such as pulmonary embolism, limb malperfusion, and post-thrombotic syndrome (PTS), which is a chronic sequela of IFDVT. We herewith present 18 IFDVT cases managed with catheter-directed thrombolysis at our hospital. Nine of these patients underwent stenting of the involved iliac veins. The remaining 9, who did not receive stenting, had a residual stenosis of more than 50% in the common femoral or iliac veins following the procedure. Based on a final residual stenosis of less than 50% in the iliac veins, we had 9 successful (patients with stenting) and 9 unsuccessful procedures (patients without stenting). In subsequent follow-ups at a median follow-up of 39.5 months, using the Villalta score, while only 2 out of the 9 patients who underwent stenting suffered PTS, 4 patients among the other 9 patients comprising the non-stenting group developed PTS. Our results support the notion that stenting might have a role in decreasing the PTS risk in patients undergoing catheter-directed thrombolysis.

Effects of Parenteral Vitamin D on the Biomarkers of the Endothelial Function in Patients with Type 2 Diabetes and Ischemic Heart Disease: A Randomized Clinical Trial.

Vitamin D deficiency is associated with cardiovascular and metabolic diseases. Cardiovascular diseases, in turn, are responsible for mortality of patients with type 2 diabetes (T2D). We investigated whether a single parenteral dose of 25(OH) Vit D could improve the endothelial function in T2D patients with ischemic heart disease. A randomized, placebo-controlled, and double-blind trial was performed on 112 patients randomly divided into vitamin D (n = 55) and placebo (n = 57) groups. A randomization table was used to administer a single dose of either vitamin D (300000 IU) or a matching placebo, intramuscularly. The levels of 25(OH) Vit D, intercellular adhesion molecule 1 (ICAM-1), and vascular cell adhesion molecule 1 (VCAM-1) were measured at baseline and at 8 weeks. In the supplemented group, the level of serum 25(OH) Vit D was increased significantly (29.6 ± 20.8 vs. 44.5 ± 19.2 ng/mL; P < 0.05), whereas no changes were observed in the placebo group. Within the supplemented group, before and after vitamin D intervention no significant changes in the levels of ICAM-1 and VCAM-1 were observed. The marginal means of the outcome variables (ICAM-1, VCAM-1, and 25(OH) Vit D) were compared between the groups using ANCOVA, adjusted for the baseline of each variable itself: no significant difference was seen in the markers of the endothelial function. A single parenteral dose of vitamin D in T2D patients with ischemic heart disease failed to show improvement in endothelial function.

Comparative Analysis of Peripheral Alkaline Phytase Protein Structures Expressed in E. coli.

BACKGROUND: Degradation of phytic acid to inorganic phosphate in domestic animals' diets requires thermostable phytase. Although Basillus subtilis phytase shows a potential to be degraded phytate complex in high temperature, the enzyme activities and yields need to be increased to make them possible for industrial application. METHODS: The phytase gene from Bacillus subtilis DR8886 was isolated from Dig Rostam hot mineral spring in Iran and cloned into pET21(+) and pET32(+). Expression was induced with 1.5 mM IPTG and the proteins were purified. RESULTS: The recombinant protein affected by thioredoxin (Trx) from pET32a-PhyC was estimated to constitute about 31% of the total soluble protein in the cells; its concentration was 3.5 µg/ml, and its maximal phytase activity was 15.9 U/ml, whereas the recombinant phytase from pET21a-PhyC was estimated to comprise about 19% of the total soluble protein; its concentration was 2.2 µg/ml, and its maximal phytase activity was 69 U/ml. The molecular masses of recombinant phytase with and without Trx were about 60 kDa and 42 kDa, respectively. Zymography confirmed that the recombinant enzymes were active. Although the concentration of the alkaline phytase expressed by pET32a was approximately 59% greater than that expressed by pET21, its phytase activity was approximately 77% less. CONCLUSION: This study showed that the peripheral gene (Trx) encoded by the pET32a (+) vector are the principal reason for the decrease in recombinant phytase enzyme activity.