Modeling complex genetic and environmental influences on comorbid bipolar disorder with tobacco use disorder

Abstract Background Comorbidity of psychiatric and substance use disorders represents a significant complication in the clinical course of both disorders. Bipolar Disorder (BD) is a psychiatric disorder characterized by severe mood swings, ranging from mania to depression, and up to a 70% rate of comorbid Tobacco Use Disorder (TUD). We found epidemiological evidence consistent with a common underlying etiology for BD and TUD, as well as evidence of both genetic and environmental influences on BD and TUD. Therefore, we hypothesized a common underlying genetic etiology, interacting with nicotine exposure, influencing susceptibility to both BD and TUD. Methods Using meta-analysis, we compared TUD rates for BD patients and the general population. We identified candidate genes showing statistically significant, replicated, evidence of association with both BD and TUD. We assessed commonality among these candidate genes and hypothesized broader, multi-gene network influences on the comorbidity. Using Fisher Exact tests we tested our hypothesized genetic networks for association with the comorbidity, then compared the inferences drawn with those derived from the commonality assessment. Finally, we prioritized candidate SNPs for validation. Results We estimate risk for TUD among BD patients at 2.4 times that of the general population. We found three candidate genes associated with both BD and TUD (COMT, SLC6A3, and SLC6A4) and commonality analysis suggests that these genes interact in predisposing psychiatric and substance use disorders. We identified a 69 gene network that influences neurotransmitter signaling and shows significant over-representation of genes associated with BD and TUD, as well as genes differentially expressed with exposure to tobacco smoke. Twenty four of these genes are known drug targets. Conclusions This work highlights novel bioinformatics resources and demonstrates the effectiveness of using an integrated bioinformatics approach to improve our understanding of complex disease etiology. We illustrate the development and testing of hypotheses for a comorbidity predisposed by both genetic and environmental influences. Consistent with our hypothesis, the selected network models multiple interacting genetic influences on comorbid BD with TUD, as well as the environmental influence of nicotine. This network nominates candidate genes for validation and drug testing, and we offer a panel of SNPs prioritized for follow-up.http://deepblue.lib.umich.edu/bitstream/2027.42/112449/1/12881_2009_Article_575.pd

Coronary artery height differences and their effect on fractional flow reserve

Background: Fractional flow reserve (FFR) uses pressure-based measurements to assess the severityof a coronary stenosis. Distal pressure (Pd) is often at a different vertical height to that of the proximalaortic pressure (Pa). The difference in pressure between Pd and Pa due to hydrostatic pressure, mayimpact FFR calculation.Methods: One hundred computed tomography coronary angiographies were used to measure heightdifferences between the coronary ostia and points in the coronary tree. Mean heights were used to calculate the hydrostatic pressure effect in each artery, using a correction factor of 0.8 mmHg/cm. Thiswas tested in a simulation of intermediate coronary stenosis to give the “corrected FFR” (cFFR) andpercentage of values, which crossed a threshold of 0.8.Results: The mean height from coronary ostium to distal left anterior descending (LAD) was +5.26 cm,distal circumflex (Cx) –3.35 cm, distal right coronary artery-posterior left ventricular artery (RCA-PLV)–5.74 cm and distal RCA-posterior descending artery (PDA) +1.83 cm. For LAD, correction resulted in a mean change in FFR of +0.042, –0.027 in the Cx, –0.046 in the PLV and +0.015 in the PDA. Using 200 random FFR values between 0.75 and 0.85, the resulting cFFR crossed the clinical treatmentthreshold of 0.8 in 43% of LAD, 27% of Cx, 47% of PLV and 15% of PDA cases.Conclusions: There are significant vertical height differences between the distal artery (Pd) and its point of normalization (Pa). This is likely to have a modest effect on FFR, and correcting for this results in a proportion of values crossing treatment thresholds. Operators should be mindful of this phenomenon when interpreting FFR values

Impact of point-of-care pre-procedure creatinine and eGFR testing in patients with ST segment elevation myocardial infarction undergoing primary PCI: The pilot STATCREAT study

Background: Contrast-induced acute kidney injury (CI-AKI) is a recognised complication during primary PCI that affects short and long term prognosis. The aim of this study was to assess the impact of point-of-care (POC) pre-PPCI creatinine and eGFR testing in STEMI patients. Methods 160 STEMI patients (STATCREAT group) with pre-procedure POC testing of Cr and eGFR were compared with 294 consecutive retrospective STEMI patients (control group). Patients were further divided into subjects with or without pre-existing CKD. Results: The incidence of CI-AKI in the whole population was 14.5% and not different between the two overall groups. For patients with pre-procedure CKD, contrast dose was significantly reduced in the STATCREAT group (124.6 ml vs. 152.3 ml, p = 0.015). The incidence of CI-AKI was 5.9% (n = 2) in the STATCREAT group compared with 17.9% (n = 10) in the control group (p = 0.12). There was no difference in the number of lesions treated (1.118 vs. 1.196, p = 0.643) or stents used (1.176 vs. 1.250, p = 0.78). For non-CKD patients, there was no significant difference in contrast dose (172.4 ml vs. 158.4 ml, p = 0.067), CI-AKI incidence (16.7% vs. 13.4%, p = 0.4), treated lesions (1.167 vs. 1.164, p = 1.0) or stents used (1.214 vs. 1.168, p = 0.611) between the two groups. Conclusions: Pre-PPCI point-of-care renal function testing did not reduce the incidence of CI-AKI in the overall group of STEMI patients. In patients with CKD, contrast dose was significantly reduced, but a numerical reduction in CI-AKI was not found to be statistically significant. No significant differences were found in the non-CKD group

Clinical Events After Deferral of LAD Revascularization Following Physiological Coronary Assessment

BACKGROUND Physicians are not always comfortable deferring treatment of a stenosis in the left anterior descending (LAD) artery because of the perception that there is a high risk of major adverse cardiac events (MACE). The authors describe, using the DEFINE-FLAIR (Functional Lesion Assessment of Intermediate Stenosis to Guide Revascularisation) trial, MACE rates when LAD lesions are deferred, guided by physiological assessment using fractional flow reserve (FFR) or the instantaneous wave-free ratio (iFR). OBJECTIVES The purpose of this study was to establish the safety of deferring treatment in the LAD using FFR or iFR within the DEFINE-FLAIR trial. METHODS MACE rates at 1 year were compared between groups (iFR and FFR) in patients whose physiological assessment led to LAD lesions being deferred. MACE was defined as a composite of cardiovascular death, myocardial infarction (MI), and unplanned revascularization at 1 year. Patients, and staff performing follow-up, were blinded to whether the decision was made with FFR or iFR. Outcomes were adjusted for age and sex. RESULTS A total of 872 patients had lesions deferred in the LAD (421 guided by FFR, 451 guided by iFR). The event rate with iFR was significantly lower than with FFR (2.44% vs. 5.26%; adjusted HR: 0.46; 95% confidence interval [CI]: 0.22 to 0.95; p = 0.04). This was driven by significantly lower unplanned revascularization with iFR and numerically lower MI (unplanned revascularization: 2.22% iFR vs. 4.99% FFR; adjusted HR: 0.44; 95% CI: 0.21 to 0.93; p = 0.03; MI: 0.44% iFR vs. 2.14% FFR; adjusted HR: 0.23; 95% CI: 0.05 to 1.07; p = 0.06). CONCLUSIONS iFR-guided deferral appears to be safe for patients with LAD lesions. Patients in whom iFR-guided deferral was performed had statistically significantly lower event rates than those with FFR-guided deferral. (c) 2019 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).Peer reviewe

Safety of the Deferral of Coronary Revascularization on the Basis of Instantaneous Wave-Free Ratio and Fractional Flow Reserve Measurements in Stable Coronary Artery Disease and Acute Coronary Syndromes

OBJECTIVES The aim of this study was to investigate the clinical outcomes of patients deferred from coronary revascularization on the basis of instantaneous wave-free ratio (iFR) or fractional flow reserve (FFR) measurements in stable angina pectoris (SAP) and acute coronary syndromes (ACS). BACKGROUND Assessment of coronary stenosis severity with pressure guidewires is recommended to determine the need for myocardial revascularization. METHODS The safety of deferral of coronary revascularization in the pooled per-protocol population (n = 4,486) of the DEFINE-FLAIR (Functional Lesion Assessment of Intermediate Stenosis to Guide Revascularisation) and iFR-SWEDEHEART (Instantaneous Wave-Free Ratio Versus Fractional Flow Reserve in Patients With Stable Angina Pectoris or Acute Coronary Syndrome) randomized clinical trials was investigated. Patients were stratified according to revascularization decision making on the basis of iFR or FFR and to clinical presentation (SAP or ACS). The primary endpoint was major adverse cardiac events (MACE), defined as the composite of all-cause death, nonfatal myocardial infarction, or unplanned revascularization at 1 year. RESULTS Coronary revascularization was deferred in 2,130 patients. Deferral was performed in 1,117 patients (50%) in the iFR group and 1,013 patients (45%) in the FFR group (p <0.01). At 1 year, the MACE rate in the deferred population was similar between the iFR and FFR groups (4.12% vs. 4.05%; fully adjusted hazard ratio: 1.13; 95% confidence interval: 0.72 to 1.79; p = 0.60). A clinical presentation with ACS was associated with a higher MACE rate compared with SAP in deferred patients (5.91% vs. 3.64% in ACS and SAP, respectively; fully adjusted hazard ratio: 0.61 in favor of SAP; 95% confidence interval: 0.38 to 0.99; p = 0.04). CONCLUSIONS Overall, deferral of revascularization is equally safe with both iFR and FFR, with a low MACE rate of about 4%. Lesions were more frequently deferred when iFR was used to assess physiological significance. In deferred patients presenting with ACS, the event rate was significantly increased compared with SAP at 1 year. (C) 2018 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation.Peer reviewe

Comparison of bivalirudin with heparin versus abciximab with heparin for primary percutaneous coronary intervention in “Real World” practice

Objective: We aimed to carry out a “real world” comparison of bivalirudin plus unfractionated heparin (UFH) versus abciximab plus UFH in patients undergoing primary percutaneous coronary intervention (PPCI) for ST elevation myocardial infarction (STEMI). Methods: We included patients who had abciximab or bivalirudin during their PPCI in our unit between Sept 2009 and Nov 2011. Results: The study included 516 and 484 patients in the bivalirudin and abciximab group respectively. There were more women in the bivalirudin group (29% vs 20%, p 0.001), while cardiogenic shock (6.4% vs 10.1%, p 0.04) and thrombectomy device use (76.6% vs 82%, p 0.04) were lower in the bivalirudin group. The primary composite end point of 30-day mortality, 30-day definite stent thrombosis or non-CABG major bleeding was similar between the bivalirudin and abciximab groups (7.8% vs 9.5%, OR 0.8, 95% CI 0.5 to 1.2, p 0.4). There was also no difference in in-hospital mortality (4.1% vs 4.3%, p 0.9), 30-day mortality (5.2% vs 6.4%, p 0.5), 1-year mortality (9.1% vs 9.9%, p 0.7), 30-day stent thrombosis (1% vs 0.4%, p 0.5) and non-CABG bleeding (2.7 vs 3.7%, p 0.4) between the bivalirudin and abciximab group respectively. On Cox proportional hazard analysis after adjusting for all the co-variates, the use of bivalirudin was not a predictor of 30-day mortality (HR 1.13, 95% CI 0.7–1.9, p 0.7). Conclusion: In this “real-world” observational study, there was no significant difference in the clinical outcome of PPCI for patients who had abciximab or bivalirudin after initial pre-treatment with UFH

Serial Fractional Flow Reserve Measurements Post Coronary Chronic Total Occlusion Percutaneous Coronary Intervention

Background: The aim of this study was to evaluate the functional result of chronic total occlusion percutaneous coronary intervention (PCI) measured by fractional flow reserve (FFR) immediately post the index procedure and at short-term follow-up. Methods and Results: This was a prospective single-center observational study. Consecutive patients with right coronary artery chronic total occlusion scheduled for elective PCI were included. FFR measurements were performed immediately after successful PCI and at 4 months follow-up. Twenty-six patients completed baseline and follow-up measurements. Mean age was 61.2±9.7 years, 88.5% of the patients were male, and 19.2% were diabetic. The mean FFR immediately after successful chronic total occlusion PCI was 0.82±0.10 and significantly increased to 0.89±0.07 at 4 months (P<0.001). The FFR increased in 77% of the patients with a mean absolute increase of 0.07±0.08. The incidence of FFR ≤0.80 immediately after PCI was significantly higher amongst patients with subintimal versus intraplaque recanalization (23% versus 12%; P=0.03). At 4 months, FFR ≤0.80 was found only in 2 patients with subintimal recanalization. At follow-up, 42.7% of the patients continued to have an FFR <0.90. Conclusions: Post chronic total occlusion PCI, FFR increased significantly at short-term follow-up compared with measurements post index procedure. Because FFR remained <0.90 in many cases, further efforts should be made to optimize procedural results

CASTLE score versus J-CTO score for the prediction of technical success in chronic total occlusion percutaneous revascularisation

Aims: We sought to compare the efficiency of the novel EuroCTO (CASTLE) score with the commonly used Multicentre CTO Registry in Japan (J-CTO) score in predicting procedural success of percutaneous coronary intervention (PCI) for coronary chronic total occlusions (CTOs). Methods and results: We evaluated 660 consecutive CTO PCIs (mean age 66±11 years, 84% male). The mean J-CTO and EuroCTO (CASTLE) scores were 1.86±1.2 and 1.74±1.2, respectively. Antegrade wire escalation, antegrade dissection re-entry and retrograde approach were used in 82%, 14% and 37% of cases, respectively. Receiver operating characteristic analysis demonstrated equal overall discriminatory capacity between the two scores (AUC 0.698, 95% CI: 0.653-0.742, p<0.001 for J-CTO vs AUC 0.676, 95% CI: 0.627-0.725, p<0.001 for EuroCTO; AUC difference: 0.022, p=0.5). However, for more complex procedures (J-CTO ≥3 or EuroCTO [CASTLE] ≥4]), the predictive capacity of the EuroCTO (CASTLE) score appeared superior (AUC 0.588, 95% CI: 0.509-0.668, p=0.03 for EuroCTO [CASTLE] score vs AUC 0.473, 95% CI: 0.393-0.553, p=NS for the J-CTO score, AUC difference: 0.115, p=0.04). Conclusions: In this study, the novel EuroCTO (CASTLE) score was comparable to the J-CTO score in predicting CTO PCI outcome with a superior discriminatory capacity for the more complex cases

Contemporary management of stent thrombosis: Predictors of mortality and the role of new‐generation drug‐eluting stents

Objectives: We sought to evaluate mortality predictors and the role of new-generation drug-eluting stents (NG-DES) in stent thrombosis (ST) management. Background: No data are available regarding the outcome of patients with ST after interventional management that includes exclusively NG-DES. Methods: Patients with definite ST of DES or BMS who underwent urgent/emergent angiography between 2015 and 2018 at our institution were considered for the study. After excluding patients who achieved TIMI-flow<2 after intervention or received an old-generation stent, 131 patients were included. Management classification was stent or non-stent treatment (medical management, thromboaspiration, balloon-angioplasty). Follow-up was performed to document all-cause death (ACD) and target-lesion-revascularization (TLR) that was used for censorship. Results: Mode of presentation was STEMI in 88% and UA/NSTEMI in 12%. Type of ST was early, late, and very late in 11, 4, and 85%, respectively. Eighty four patients received stent and 47 non-stent treatment. After 926 ± 34 days, 21 ACDs, 7 TLRs and no cases of definite, recurrent ST were observed. Univariate predictors of in-hospital mortality were LVEF and presentation with shock or cardiac arrest. For patients discharged alive, non-stent treatment (HR 4.2, p = .01), TIMI-2 flow (HR 7.4, p = .002) and GFR < 60 mL/min (HR 3.8, p = .01) were independent predictors of ACD. The stent-treatment group had significantly better ACD-free survival after discharge, both unadjusted (p = .022) and adjusted (p = .018). Conclusions: After ST management, different predictors were observed for in-hospital mortality and mortality in patients discharged alive. The better outcome with NG-DES treatment is a novel observation, warranting further studies to elucidate if it is associated with stent-related or patient-related factors