scholarly journals Gene Polymorphisms of the Renin-Angiotensin System and Bleeding Complications of Warfarin: Genetic-Based Machine Learning Models

2021 ◽  
Vol 14 (8) ◽  
pp. 824
Author(s):  
Joo-Hee Kim ◽  
Jeong Yee ◽  
Byung-Chul Chang ◽  
Hye-Sun Gwak
Keyword(s):  
Machine Learning ◽  
Logistic Regression ◽  
Renin Angiotensin System ◽  
Bleeding Complications ◽  
Support Vector ◽  
Nucleotide Polymorphisms ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Risk Of Bleeding ◽  
Increased Risk

Background: This study aimed to investigate the effects of genetic variants and haplotypes in the renin–angiotensin system (RAS) on the risk of warfarin-induced bleeding complications at therapeutic international normalized ratios (INRs). Methods: Four single nucleotide polymorphisms (SNPs) of AGT, two SNPs of REN, three SNPs of ACE, four SNPs of AGTR1, and one SNP of AGTR2, in addition to VKORC1 and CYP2C9 variants, were investigated. We utilized logistic regression and several machine learning methods for bleeding prediction. Results: The study included 142 patients, among whom 21 experienced bleeding complications. We identified a haplotype, H2 (TCG), carrying three SNPs of ACE (rs1800764, rs4341, and rs4353), which showed a significant relation with bleeding complications. After adjusting covariates, patients with H2/H2 experienced a 0.12-fold (95% CI 0.02–0.99) higher risk of bleeding complications than the others. In addition, G allele carriers of AGT rs5050 and A allele carriers of AGTR1 rs2640543 had 5.0- (95% CI 1.8–14.1) and 3.2-fold (95% CI 1.1–8.9) increased risk of bleeding complications compared with the TT genotype and GG genotype carriers, respectively. The AUROC values (mean, 95% CI) across 10 random iterations using five-fold cross-validated multivariate logistic regression, elastic net, random forest, support vector machine (SVM)–linear kernel, and SVM–radial kernel models were 0.732 (0.694–0.771), 0.741 (0.612–0.870), 0.723 (0.589–0.857), 0.673 (0.517–0.828), and 0.680 (0.528–0.832), respectively. The highest quartile group (≥75th percentile) of weighted risk score had approximately 12.0 times (95% CI 3.1–46.7) increased risk of bleeding, compared to the 25–75th percentile group, respectively. Conclusion: This study demonstrated that RAS-related polymorphisms, including the H2 haplotype of the ACE gene, could affect bleeding complications during warfarin treatment for patients with mechanical heart valves. Our results could be used to develop individually tailored intervention strategies to prevent warfarin-induced bleeding.

Abstract 13174: Sex Differences in Clinical Characteristics, Management and Prognosis in Patients With Heart Failure With Preserved Ejection Faction: Insights From the CHART-2 Study

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Kanako Tsuji ◽  
Yasuhiko Sakata ◽  
Masanobu Miura ◽  
Soichiro Tadaki ◽  
Ryoichi Ushigome ◽  
...  
Keyword(s):  
Heart Failure ◽  
Sex Differences ◽  
Beta Blockers ◽  
Renin Angiotensin System ◽  
Class Iii ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Female Patients ◽  
Increased Risk ◽  
Patients With Heart Failure

Background: The number of the patients with heart failure with preserved ejection fraction (HFpEF) has been rapidly increasing worldwide. However, sex differences in patients with HFpEF remain to be elucidated. Methods and Results: We examined sex differences in 3,124 consecutive patients with HFpEF (EF≥50%, mean 69.4years, 34.7% female) registered in our Chronic Heart Failure Analysis and Registry in the Tohoku District-2 (CHART-2) Study (N=10,219). Female patients, as compared with male patients, were characterized by higher age (72 vs. 68 years, P<0.01), higher LVEF (67 vs. 64%, P<0.01), higher heart rate (74 vs. 70bpm, PNYHA class III (14.1 vs. 7.0%, P<0.01), higher BNP levels (106 vs. 73pg/mL, P<0.01), lower prevalence of coronary artery disease (30 vs. 53%, P<0.01) and lower prescription rates of renin angiotensin system inhibitors (64.7 vs. 71.8%, P<0.01) and beta-blockers (37.8 vs. 43.9%, P<0.01). During the median 3.2-year follow-up, 147 female patients and 245 males died. Although there was no sex difference in all-cause mortality (13.6 vs. 12.0%, P=0.11), female patients more frequently died due to cardiovascular causes (53.7 vs. 39.2%, hazard ratio (HR): 1.62, 95% CI 1.20-2.18, P<0.01), and experienced more HF admissions (12.6 vs. 9.8%, HR: 1.35, 95% CI 1.08-1.68, P<0.01). Use of beta-blockers or renin-angiotensin system inhibitors was not associated with decreased incidence of death or HF admission in both sexes. In contrast, use of statins was associated with reduced incidence of all-cause death in both sexes (males and females; adjusted HR, 0.59 and 0.57; 95% CI 0.46-0.77 and 0.47-0.70, respectively, both P<0.01) and was also associated with reduced incidence of HF admission in males (adjusted HR: 0.67, 95%CI 0.53-0.85, P<0.01) but not in females (adjusted HR: 0.83, 95% CI 0.63-1.10, P=0.19). Conclusions: As compared with males, female patients with HFpEF were characterized by severer condition of HF and increased risk of cardiovascular death and HF admission. Although statin use was equally associated with improved mortality in both sexes, female patients with HFpEF may benefit from statins less than males in terms of reduction of HF admission.

MS555 GENETIC INTERACTIONS IN THE RENIN–ANGIOTENSIN SYSTEM CONFER INCREASED RISK OF STROKE

2010 ◽  
Vol 11 (2) ◽  
pp. 221
Author(s):  
A. Bazina ◽  
T. Bozina ◽  
J. Lovric ◽  
Z. Poljaković ◽  
N. Bozina ◽  
...  
Keyword(s):  
Renin Angiotensin System ◽  
Genetic Interactions ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Increased Risk

scholarly journals High Order Gene-Gene Interactions in Eight Single Nucleotide Polymorphisms of Renin-Angiotensin System Genes for Hypertension Association Study

2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
Cheng-Hong Yang ◽  
Yu-Da Lin ◽  
Shyh-Jong Wu ◽  
Li-Yeh Chuang ◽  
Hsueh-Wei Chang
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
Renin Angiotensin System ◽  
High Order ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Ras Genes ◽  
Snp Interaction

Several single nucleotide polymorphisms (SNPs) of renin-angiotensin system (RAS) genes are associated with hypertension (HT) but most of them are focusing on single locus effects. Here, we introduce an unbalanced function based on multifactor dimensionality reduction (MDR) for multiloci genotypes to detect high order gene-gene (SNP-SNP) interaction in unbalanced cases and controls of HT data. Eight SNPs of three RAS genes (angiotensinogen,AGT; angiotensin-converting enzyme,ACE; angiotensin II type 1 receptor,AT1R) in HT and non-HT subjects were included that showed no significant genotype differences. In 2- to 6-locus models of the SNP-SNP interaction, the SNPs ofAGTandACEgenes were associated with hypertension (bootstrapping odds ratio [Boot-OR] = 1.972~3.785; 95%, confidence interval (CI) 1.26~6.21;P<0.005). In 7- and 8-locus model, SNP A1166C ofAT1Rgene is joined to improve the maximum Boot-OR values of 4.050 to 4.483; CI = 2.49 to 7.29;P<1.63E−08. In conclusion, the epistasis networks are identified by eight SNP-SNP interaction models.AGT,ACE, andAT1Rgenes have overall effects with susceptibility to hypertension, where the SNPs ofACEhave a mainly hypertension-associated effect and show an interacting effect to SNPs ofAGTandAT1Rgenes.

scholarly journals The Identikit of Patient at Risk for Severe COVID-19 and Death: The Dysregulation of Renin-Angiotensin System as the Common Theme

2021 ◽  
Vol 10 (24) ◽  
pp. 5883
Author(s):  
Riccardo Sarzani ◽  
Massimiliano Allevi ◽  
Federico Giulietti ◽  
Chiara Di Pentima ◽  
Serena Re ◽  
...  
Keyword(s):  
Renin Angiotensin System ◽  
Adverse Outcomes ◽  
Virus Binding ◽  
Angiotensin System ◽  
Angiotensin Converting Enzyme 2 ◽  
Renin Angiotensin ◽  
Increased Risk ◽  
Metabolic Conditions ◽  
Patient At Risk

Since the first months of the coronavirus disease 2019 (COVID-19) pandemic, several specific physiologic traits, such as male sex and older age, or health conditions, such as overweight/obesity, arterial hypertension, metabolic syndrome, and type 2 diabetes mellitus, have been found to be highly prevalent and associated with increased risk of adverse outcomes in hospitalized patients. All these cardiovascular morbidities are widespread in the population and often coexist, thus identifying a common patient phenotype, characterized by a hyper-activation of the “classic” renin-angiotensin system (RAS) and mediated by the binding of angiotensin II (Ang II) to the type 1-receptor. At the same time, the RAS imbalance was proved to be crucial in the genesis of lung injury after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, where angiotensin-converting-enzyme-2 (ACE2) is not only the receptor for SARS-CoV-2, but its down-regulation through internalization and shedding, caused by the virus binding, leads to a further dysregulation of RAS by reducing angiotensin 1-7 (Ang 1-7) production. This focused narrative review will discuss the main available evidence on the role played by cardiovascular and metabolic conditions in severe COVID-19, providing a possible pathophysiological link based on the disequilibrium between the two opposite arms of RAS.

scholarly journals Real-world Evidence of Time-varying Effects of Renin-angiotensin System Inhibitors on Pneumonia and Related Deaths: A Territory-wide Cohort Study in 252,616 Patients With Diabetes (2002-2019)

2021 ◽  
Author(s):  
Aimin Yang ◽  
Mai Shi ◽  
Hongjiang Wu ◽  
Eric SH Lau ◽  
Baoqi Fan ◽  
...  
Keyword(s):  
Renin Angiotensin System ◽  
Chinese Patients ◽  
Cumulative Exposure ◽  
Time Varying ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Increased Risk ◽  
Patients With Diabetes ◽  
Reduced Risk

Abstract BackgroundDiabetes is associated with increased risk of respiratory infections. Renin-angiotensin system (RAS) inhibition with anti-fibrotic, anti-inflammatory effects may reduce pneumonia risk. Prior studies did not account for time-varying and cumulative exposure to RAS inhibitors (RASi), with short follow-up periods, nor compared angiotensin converting enzyme inhibitor (ACEi) and angiotensin receptor blocker (ARB) use in Asians. We investigated the association of long-term use of RASi with risk of pneumonia and related death in Chinese people with diabetes using electronic medical record (EMR) data.MethodsThis was a prospective analysis of EMR with overlap propensity-score weighting of a territory-wide cohort (n=252,616, 1.7 million person-years) and a register-based cohort (n=13,017, 0.1 million person-years) in Hong Kong. We compared new-users of RASi (ACEi/ARBs) following baseline assessment with non-RASi users and new-users of calcium-channel blockers as active comparator. The main outcome was first hospitalization and death from pneumonia. ResultsAmongst 252,616 patients with diabetes in the population-based cohort (mean age=61.0 [SD=12.2] years), 73,161 were new-ACEi-only users; 20,907 new-ARBs-only users; 38,778 ACEi/ARBs users; and 119,770 never-ACEi/ARBs users. Over a mean follow-up period of 6.7 years, 5.2% (n=13,057) of patients had pneumonia and 2.2% (n=5,480) died with pneumonia. Compared with non-RASi use, time-varying RASi exposure was associated with reduced risk of pneumonia (hazard ratio, HR, 95% CI): 0.78 (0.75-0.82) and pneumonia-related death (HR=0.49, 0.46-0.53). The respective HRs for ARBs-only were 0.70 (0.62-0.78) and 0.41 (0.33-0.52) and that of ACEi-only were 0.98 (0.91-1.05) and 0.77 (0.68-86). In the Aalen-additive hazards model, the effect of RASi use was time-invariant for pneumonia (P=0.340) and time-varying for related death (P<0.001) with prevention of 0.6 (0.2-0.9) and 1.4 (1.0-1.6) per-1000-person-years pneumonia events and related deaths, respectively.ConclusionsLong-term use of RASi, notably ARB, was associated with reduced risk of pneumonia and related deaths in Chinese patients with diabetes.

Machine learning to predict outcomes in patients with acute pulmonary embolism who prematurely discontinued anticoagulant therapy.

2021 ◽  
Author(s):  
Damian Mora ◽  
José Antonio Nieto ◽  
Jorge Mateo ◽  
Behnood Bikdeli ◽  
Stefano Barco ◽  
...  
Keyword(s):  
Machine Learning ◽  
Pulmonary Embolism ◽  
Logistic Regression ◽  
Anticoagulant Therapy ◽  
Roc Curve ◽  
Predictive Value ◽  
Support Vector ◽  
Calibration Plot ◽  
Composite Outcome ◽  
Increased Risk

Background: Patients with pulmonary embolism (PE) who prematurely discontinue anticoagulant therapy (<90 days) are at an increased risk for death or recurrences. Methods: We used the data from the RIETE registry to compare the prognostic ability of 5 machine-learning (ML) models and logistic regression to identify patients at increased risk for the composite of fatal PE or recurrent venous thromboembolism (VTE) 30 days after discontinuation. ML models included Decision tree, K-Nearest Neighbors algorithm, Support Vector Machine, Ensemble and Neural Network [NN]. A “full” model with 70 variables and a “reduced” model with 23 were analyzed. Model performance was assessed by confusion matrix metrics on the testing data for each model and a calibration plot. Results: Among 34,447 patients with PE, 1,348 (3.9%) discontinued therapy prematurely. Fifty-one (3.8%) developed fatal PE or sudden death and 24 (1.8%) had non-fatal VTE recurrences within 30 days after discontinuation. ML-NN was the best method for identification of patients experiencing the composite endpoint, predicting the composite outcome with an area under receiver operating characteristics (ROC) curve of 0.96 (95% confidence intervals [CI], 0.95-0.98), using either 70 or 23 variables captured before discontinuation. Similar numbers were obtained for sensitivity, specificity, positive predictive value, negative predictive value and accuracy. The discrimination of logistic regression was inferior (area under ROC curve, 0.76 [95% Cl 0.70-0.81]). Calibration plot showed similar deviations from the perfect line for ML-NN and logistic regression. Conclusions: ML-NN method very well predicted the composite outcome after premature discontinuation of anticoagulation and outperformed traditional logistic regression.

scholarly journals Role of renin-angiotensin system antagonists in the prevention of bevacizumab- and sunitinib-mediated cardiac dysfunction

2019 ◽  
Vol 316 (3) ◽  
pp. H446-H458 ◽  
Author(s):  
Viktoriya Mozolevska ◽  
Anna Schwartz ◽  
David Cheung ◽  
Vineet Goyal ◽  
Bilal Shaikh ◽  
...  
Keyword(s):  
Cardiac Dysfunction ◽  
Prophylactic Treatment ◽  
Cell Cancer ◽  
Renin Angiotensin System ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Prophylactic Administration ◽  
Increased Risk ◽  
Ras Inhibitors

Although anticancer systemic therapy agents clearly lead to improved survival in patients with cancer, these can come at the cost of serious complications including cardiotoxicity. Two types of targeted systemic therapies currently in use for colorectal cancer (CRC) and renal cell cancer (RCC), respectively, include the vascular endothelial growth factor inhibitor bevacizumab (BVZ) and the tyrosine kinase inhibitor sunitinib (SNT). Despite the beneficial effects of BVZ and SNT in improving clinical outcomes in the settings of CRC and RCC, there is an increased risk of cardiac dysfunction. The aim of the present study was to determine whether prophylactic administration of renin-angiotensin system (RAS) inhibitors would attenuate the cardiotoxic side effects of BVZ or SNT in a chronic in vivo murine model. A total of 194 wild-type C57Bl/6 male mice received: 1) 0.9% saline, 2) BVZ (10 mg·kg−1·wk−1), or 3) SNT (40 mg·kg−1·day−1) for 4 wk. Within each arm, mice received daily prophylactic treatment with hydralazine (0.05 mg/ml), aliskiren (50 mg/kg), perindopril (4 mg/kg), or valsartan (2 mg/kg). Although hydralazine effectively lowered blood pressure in BVZ- or SNT-treated mice, it did not prevent left ventricular systolic dysfunction. Prophylactic administration of aliskiren, perindopril, or valsartan prevented adverse cardiovascular remodeling in mice treated with either BVZ or SNT. The addition of RAS antagonists also downregulated expression of phosphorylated p38 and Bcl-2-like 19-kDa interacting protein 3 in SNT-treated mice. In our chronic in vivo murine model, RAS antagonists partially attenuated the development of BVZ- or SNT-mediated cardiac dysfunction. Future clinical studies are warranted to investigate the cardioprotective effects of prophylactic treatment with RAS inhibitors in the settings of CRC and RCC. NEW & NOTEWORTHY In the evolving field of cardio-oncology, bevacizumab and sunitinib improve clinical outcomes in the settings of metastatic colorectal cancer and renal cell cancer, respectively. These anticancer drugs, however, are associated with an increased risk of cardiotoxicity. The prophylactic administration of renin-angiotensin system antagonists is partially cardioprotective against bevacizumab- and sunitinib-mediated cardiac dysfunction.

scholarly journals Renin–angiotensin system blocker discontinuation and adverse outcomes in chronic kidney disease

2020 ◽  
Author(s):  
Carl P Walther ◽  
Wolfgang C Winkelmayer ◽  
Peter A Richardson ◽  
Salim S Virani ◽  
Sankar D Navaneethan
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Renin Angiotensin System ◽  
Cox Proportional Hazards ◽  
Adverse Outcomes ◽  
Converting Enzyme Inhibitors ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Risk Of Death ◽  
Increased Risk

Abstract Background Treatment with renin–angiotensin system inhibitors (RASIs), angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) is the standard of care for those with chronic kidney disease (CKD) and albuminuria. However, ACEI/ARB treatment is often discontinued for various reasons. We investigated the association of ACEI/ARB discontinuation with outcomes among US veterans with non-dialysis-dependent CKD. Methods We performed a retrospective cohort study of patients in the Veterans Affairs healthcare system with non-dialysis-dependent CKD who subsequently were started on ACEI/ARB therapy (new user design). Discontinuation events were defined as a gap in ACEI/ARB therapy of ≥14 days and were classified further based on duration (14–30, 31–60, 61–90, 91–180 and &gt;180 days). This was treated as a time-varying risk factor in adjusted Cox proportional hazards models for the outcomes of death and incident end-stage kidney disease (ESKD), which also adjusted for relevant confounders. Results We identified 141 252 people with CKD and incident ACEI/ARB use who met the inclusion criteria; these were followed for a mean 4.87 years. There were 135 356 discontinuation events, 68 699 deaths and 6152 incident ESKD events. Discontinuation of ACEI/ARB was associated with a higher risk of death [hazard ratio (HR) 2.3, 2.0, 1.99, 1.92 and 1.74 for those discontinued for 14–30, 31–60, 61–90, 91–180 and &gt;180 days, respectively]. Similar associations were noted between ACEI and ARB discontinuation and ESKD (HR 1.64, 1.47, 1.54, 1.65 and 1.59 for those discontinued for 14–30, 31–60, 61–90, 91–180 and &gt;180 days, respectively). Conclusions In a cohort of predominantly male veterans with CKD Stages 3 and 4, ACEI/ARB discontinuation was independently associated with an increased risk of subsequent death and ESKD. This may be due to the severity of illness factors that drive the decision to discontinue therapy. Further investigations to determine the causes of discontinuations and to provide an evidence base for discontinuation decisions are needed.

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