Citations

Introduction: Percutaneous epicardial access (EAc) is increasingly performed as part of VT/PVC ablation, especially in those that have failed prior ablation. We aimed to delineate the outcomes of EAc. Methods: We retrospectively analyzed individuals undergoing EAc for arrhythmia ablation between June 2004 and July 2014. Acute procedural success was defined as elimination/non-inducibility of the clinical arrhythmia after ablation; clinical success was defined as absence of symptoms/arrhythmia. Results: Of 175 patients, 126 (72%) were male with a mean age of 52.8±15.7 years. Eighty-three (47.4%) patients had NICM, 25 (14.3%) had ICM and 34 (19.4%) had normal hearts. Baseline EF was 44±16%. Patients had failed an average of 1.7±1.2 antiarrhythmic drugs; 139 patients (79%) had failed prior endocardial (endo) ablation (average 1.3±1.1). Six (3.4%) had prior EAc and 18 (10.3%) prior cardiac surgery. The indication for ablation was VT or PVC in 113 (64.6%) and 60 (34.3%) patients, respectively. Successful access was obtained in 168 (98%) patients. Anterior access, inferior access, or both, was utilized in 89 (52.7%), 77 (45.6%) and 2 (1.2%) patients, respectively. There were an average of 2.7±2.2 VT/PVCs identified, and 1.6±1.1 ablated. Endo, epicardial (epi) or combined ablation was performed in 58 (33.1%), 14 (8%), and 100 (57.1%) patients, respectively; 3 did not undergo ablation. Procedural success was obtained in 158 of 173 (91.3%) patients for whom data was available. At 12 months, clinical success was maintained in 62% with no difference between endo, epi or combined ablation (figure). Cardiac tamponade requiring repeat EAc occurred in 12 (6.9%) patients. There were no procedural related deaths. Conclusion: Epicardial access is feasible in almost all patients with no prior cardiac surgery, and permits acute procedural success in 91.3% of patients, most of whom had failed previous ablation. Furthermore, complications are relatively infrequent in this complex cohort.

Background: Patients with chronic kidney disease are at increased risk for cardiovascular morbidity and mortality. We assessed the association between albuminuria and death or cardiovascular events among patients with stable coronary disease. Methods: We studied patients enrolled in the Prevention of Events with an ACE Inhibitor (PEACE) trial, in which patients with chronic stable coronary disease and preserved systolic function were randomized to trandolapril or placebo and followed for a median of 4.8 years. The urinary albumin to creatinine ratio (ACR) assessed in a core laboratory in 2977 patients at baseline and in 1339 patients at follow-up (mean 34 months) was related to estimated glomerular filtration rate (eGFR) and outcomes. Results: The majority of patients (73%) had a baseline albumin/creatinine ratio within the normal range. Independent of the eGFR and other baseline covariates, a higher albumin/creatinine ratio even within the normal range was associated with increased risks for all-cause mortality (p < 0.001) and cardiovascular death (p = 0.01). The effect of trandolapril therapy on outcomes was not significantly modified by the level of albuminuria. Nevertheless, trandolapril therapy was associated with a significantly lower mean follow-up ACR (12.5 ug/mg vs 14.6 ug/mg, p = 0.0002), after adjusting for baseline ACR, time between collections and other covariates. An increase in ACR over time was associated with increased risk of cardiovascular death (HR per log ACR 1.74, 95% confidence intervals 1.08–2.82). Conclusions: Albuminuria, even in low levels within the normal range, is an independent predictor of cardiovascular and all-cause mortality.

Background: Patients with sinus node dysfunction (SND) are at increased risk of atrial tachyarrhythmias, including atrial fibrillation (AF). Whether the presence of SND is also associated with worse outcomes among those with AF has not been well described. Methods: The ORBIT-AF registry enrolled patients with AF from a range of clinical practices across the US. SND was defined clinically, based on the presence of sinus bradycardia, severe sinus bradycardia, sinus arrest, sinoatrial exit block, or features of tachycardia-bradycardia syndrome. Descriptive statistics and multivariable logistic regression analysis were used to describe treatment patterns and outcomes for patients with and without SND and AF. Results: Overall, 1,710 (17.7%) patients had SND at enrollment. Patients with SND had lower left-ventricular ejection fractions, higher CHA 2 DS 2 -VASc risk scores, and more prior cerebrovascular events. Patients with SND had more severe symptoms (EHRA class IV: 17.5% vs. 13.9%; p=0.007) and poorer quality of life (median AFEQT 77.5 vs. 81.1; p=0.008) as compared to those without. SND patients were more frequently treated with oral anticoagulants (79.2% vs. 75.9%, p=0.004) and had more often received interventional therapy for AF (16.1% vs. 10.5%, p<0.0001). There were no differences in the current AF management strategy between patients with SND and those without [rate control (69.7% vs. 67.7%), rhythm control (30.0% vs. 32.0%); P=0.11]. After adjustment, significantly more patients with SND had progressed from paroxysmal AF at baseline to persistent or permanent AF at any follow-up or persistent AF at baseline to permanent AF at any follow-up than those without (OR 1.23, 95% CI 1.01-1.49, p=0.035). Conclusion: Sinus node dysfunction is associated worse symptoms, lower quality of life, and higher risk of progression to permanent AF. However, SND is not associated with increased risk of all-cause hospitalization, incident stroke, or all-cause death.

Introduction: Copeptin has demonstrated a role in early rule out for acute myocardial infarction in combination with a negative troponin. However, the value of copeptin in patients with a positive troponin is not established. Hypothesis: The addition of a baseline copeptin at chest pain presentation will improve risk stratification in patients with mild troponin elevation. Methods: The multi-center CHOPIN trial enrolled 2071 acute chest pain patients. All subjects with ST segment elevations were excluded from this analysis. Of the remaining patients, 124 had a mildly elevated troponin (defined by < 2x URL) and were included in the study cohort. Baseline cTnI and copeptin levels were drawn on presentation, and another cTnI at 2 hours. Copeptin ≤14 pmol/l and troponin deltas ≤10% from baseline were considered positive. Two independent blinded cardiologists adjudicated AMI diagnosis. The value of a baseline copeptin in this cohort was assessed using AMI incidence, odds ratio, sensitivity, and negative predictive value (NPV). Results: Of the 124 patients in the study cohort, 73 (59%) had an elevated copeptin and an associated AMI incidence of 25% (18 AMIs). The remaining 51 patients (41%) were copeptin negative and diagnosed with 3 AMIs, an incidence of 5.9% (p = 0.006, figure 1). A positive copeptin increased the likelihood of AMI diagnosis with an odds ratio of 5.3 (95% CI: 1.5-19.2). The sensitivity and NPV for AMI were 86% and 94%, both of which were higher than the delta troponin (table 1). When an initial copeptin was combined with the delta troponin the sensitivity and NPV for AMI improved to 100%. Conclusion: Use of copeptin in chest pain patients with mild troponin elevation provides further risk stratification. The combination of copeptin with a delta troponin may aid in earlier AMI rule out in this subset of patients. This approach could be especially relevant as the increasing use of high sensitivity troponin assays leads to greater rates of mild troponin elevations.

Abstract Introduction: A test that detects cancer signal across multiple cancer types and predicts signal (tissue) origin (SO) could aid in more efficient diagnostic workup and shorten time to cancer diagnosis in individuals with signs and symptoms.Methods: The Circulating Cell-free Genome Atlas (CCGA; NCT02889978) study is a prospective, longitudinal, multicenter, case-control study to develop and validate a multi-cancer detection test. The 2nd CCGA substudy utilized a targeted methylation-based cell-free DNA assay and machine learning algorithm and included assessment of test performance (sensitivity and SO prediction accuracy) in a subgroup of participants with clinically presenting cancers (CPCs) that were undiagnosed prior to blood draw. Specificity was assessed in the noncancer group and subgroups with confounding (nonmalignant) conditions (CCs; eg, cirrhosis) and noncancer participants enrolled in hematology clinics (HCs).Results: Specificity was 99.5% (95% confidence interval: 98.2-99.9%; 396/398), 93.8% (71.7-99.7%; 15/16), and 99.3% (96.0-100.0%; 136/137) for the noncancer group, CCs subgroup, and HCs subgroup, respectively. Overall sensitivity among those with CPCs was 66.4% (62.2-70.3%; 344/518). Sensitivity of cancer signal detection increased with increasing clinical stage (Table). SO prediction accuracy was 91.7% (88.3-94.3%; 300/327) among CPC participants with cancers detected, excluding those with multiple or unknown primaries. The test demonstrated prognostic value as detected cancer participants had worse survival probability than those not detected. Conclusions: This multi-cancer detection test detected cancer signals and predicted SO in individuals with CPCs with high specificity. These findings support further clinical development of this multi-cancer detection test that could accelerate the diagnostic resolution of symptomatic cancers. Table. Sensitivity by Clinical Stage Across Cancer Type in Clinically Presenting CancersClinical StagePositive Test/Total Cancer; Sensitivity (95% CI)All*344/518; 66.4% (62.2-70.3%)I33/122; 27.0% (20.0-35.5%)II60/102; 58.8% (49.1-67.9%)III103/121; 85.1% (77.7-90.4%)IV136/147; 92.5% (87.1-95.8%)Not expected to be staged9/21; 42.9% (24.5-63.5%)Non-informative2/4; 50.0% (15.0-85.0%)CI, confidence interval.*One participant who had a positive test result had multiple primaries with clinical stage I and not-expected-to-be-staged. Citation Format: Alan H. Bryce, Minetta C. Liu, Michael V. Seiden, David D. Thiel, Donald Richards, Carlos Becerra, Kathryn N. Kurtzman, Xiaoji Chen, Tony Wu, Quan Zhang, Jingjing Gao, Nan Zhang, Earl Hubbell, Arash Jamshidi, Eric T. Fung, Eric A. Klein. Performance of a cell-free DNA-based multi-cancer detection test as a tool for diagnostic resolution of symptomatic cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB058.

Abstract Transfemoral access has long been the main access site for cerebral angiography and neurointerventional procedures. Radial access is accepted as an alternative to the traditional transfemoral approach. Ulnar access may be undertaken if the radial artery is occluded or small caliber, or when radial artery preservation is needed. The safety and feasibility of ulnar access for neuroangiographic procedures has been demonstrated. 1-3 In this operative video, we demonstrate ulnar artery access in a patient in whom radial artery preservation was desired. We further elaborate on the technical nuances of this access. This nontraditional access site offers the same advantages as radial access, avoiding the need to switch to femoral artery access. A preoperative Allen's test is not necessary. Ultrasound imaging is used to aid in the identification and successful puncture of the ulnar artery. A medial to lateral approach for ulnar artery puncture is advised to avoid injury to the ulnar nerve. Careful application of wrist closure bands avoids hematoma accumulation. The patient gave informed consent for the procedure and video recording. Institutional review board approval was deemed unnecessary. Video. © University at Buffalo, May 2021. Used with permission.

Background: Benchmarking international cancer survival differences is necessary to evaluate and improve healthcare systems. Our aim was to assess the potential regional differences in outcomes among patients with metastatic colorectal cancer (mCRC) participating in international randomized clinical trials (RCTs). Design: Countries were grouped into 11 regions according to the World Health Organization and the EUROCARE model. Meta-analyses based on individual patient data were used to synthesize data across studies and regions and to conduct comparisons for outcomes in a two-stage random-effects model after adjusting for age, sex, performance status, and time period. We used mCRC patients enrolled in the first-line RCTs from the ARCAD database, which provided enrolling country information. There were 21,509 patients in 27 RCTs included across the 11 regions. Results: Main outcomes were overall survival (OS) and progression-free survival (PFS). Compared with other regions, patients from the United Kingdom (UK) and Ireland were proportionaly over-represented, older, with higher performance status, more frequently male, and more commonly not treated with biological therapies. Cohorts from central Europe and the United States (USA) had significantly longer OS compared with those from UK and Ireland ( p = 0.0034 and p < 0.001, respectively), with median difference of 3–4 months. The survival deficits in the UK and Ireland cohorts were, at most, 15% at 1 year. No evidence of a regional disparity was observed for PFS. Among those treated without biological therapies, patients from the UK and Ireland had shorter OS than central Europe patients ( p < 0.001). Conclusions: Significant international disparities in the OS of cohorts of mCRC patients enrolled in RCTs were found. Survival of mCRC patients included in RCTs was consistently lower in the UK and Ireland regions than in central Europe, southern Europe, and the USA, potentially attributed to greater overall population representation, delayed diagnosis, and reduced availability of therapies.

Objective: Diabetes is a common among patients with atrial fibrillation (AF). However, little is known on the impact of diabetes on symptoms, health status, care and outcomes among AF patients. We assessed whether symptoms, health status, care and outcomes differ between AF patients with and without diabetes. Methods: This observational cohort study included 9,749 patients with AF from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation registry, a prospective, nationwide, multicenter outpatient registry of patients with incident and prevalent AF enrolled at 174 sites between June 2010 and August 2011. The outcomes were symptoms, health status, and AF treatment, as well as 2-year risks of death, readmission, thrombomebolic events, heart failure (HF) and AF progression. Results: Among AF patients; those with diabetes (29.5%) were younger and more likely to have hypertension, chronic kidney disease, HF, coronary heart disease, and stroke. Patients with diabetes had a lower Atrial Fibrillation Effects on Quality of Life score (80.6 [IQR: 62.5 - 92.6] vs. 82.4 [IQR: 67.6 -93.5]; P = 0.025), but a higher CHA 2 DS 2 -VASc score (5 [IQR: 4 - 6] vs. 4 [2 - 5]; P <0.0001) and were more likely to receive anticoagulation ( P <0.001). Diabetes was associated with higher mortality, with a greater overall (adjusted hazard ratio [aHR]: 1.63 [95% CI: 1.04-2.56] for age<70 vs. 1.25 [1.09-1.44] for age ≥70) and cardiovascular (2.20 [1.22-3.98] for age<70 vs. 1.24 [1.02-1.51] for age ≥70) mortality risks before age 70 years. Diabetes conferred a higher risk of non-cardiovascular (CV) death (1.29 [1.06-1.56]), sudden cardiac death (1.53 [1.04-2.26]), hospitalization (1.15 [1.09-1.22]), CV hospitalization (1.13 [1.05-1.22]) and non-CV and non-bleeding-related hospitalization (1.19 [1.10-1.30]); but no increase in risks of thromboembolic events, bleeding related hospitalization, new-onset HF, and AF progression. The use of oral anticoagulants (OAC) modifies the relation of diabetes and all-cause hospitalization, with a higher risk among those on OAC (1.21 [1.12-1.29]). Conclusions: Among patients with AF, diabetes was associated with worse AF symptoms and lower quality of life, as well an increased risk of death and hospitalizations, but not with the risk of thromboembolic or bleeding events.

Introduction Fat embolism (FE) induced by iv injection of triolein (T) causes vasculitis, septal inflammation and fibrosis in rat lungs at 48 hrs that is mitigated by two drugs acting on the renin‐angiotensin system (RAS): captopril and losartan (1). The histopathological changes found at this time are also ameliorated by treatment with the renin inhibitor aliskiren as the associated increase in mast cell numbers (2). This study examines whether captopril and losartan also prevent the increase in mast cell number at this time. Methods Sprague‐Dawley rats (280–300g) were treated with 0.2 ml iv (T) n=31 or saline n=7. One hour later 0.2 ml of saline (n=7) ip, aliskiren (50 mg/kg n=6), (100 mg/kg n=6), captopril (150 mg/kg n=6) or losartan (10 mg/kg n=6) were given. Saline treated rat (n=7) receive ip, one hour later, the same dose of saline. 48 hours later all the rats were necropsied after isofluorane anesthesia, lungs fixed in 10% formalin and H&E stained for morphology, Masson trichrome for fibrosis and CD 117 for mast cells. Two pathologists unaware of slides identity took at random 10 photographs of all the slides at 400× and separately counted the mast cells. Results As previously reported, 48 hours after triolein the lungs showed severe histopathological damage that was prevented by all three of the RAS drugs (1–3) and was associated with an increase in the number of mast cells (3). Aliskiren treatment reduced their numbers confirming previous findings (3,4). A significant reduction was also induced by losartan but not by captopril despite its protective effects on lung histopathology. Conclusions Mast cells may be involved in the pathological damage found after FE as suggested by their increase in number in the lungs after T and their reduction during protective treatment with aliskiren. Aliskiren and losartan also reduced their number. However, the lack of effect of captopril on mast cell number at this acute time period may suggest that some other pathways are involved in the time course of mast cell recruitment, such as angiotensin (1–7). Support or Funding Information Supported by the Catherine T Geldmacher Foundation, St. Louis, MO This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

The prohormone convertases PC1/3 and PC2 are eukaryotic serine proteases involved in proteolytic maturation of peptide hormone precursors and implicated in a variety of pathological conditions, including obesity, diabetes, and neurodegenerative diseases. In this work, we screened 45 compounds obtained by derivatization of a 2,5‐dideoxystreptamine scaffold. We found four promising PC1/3 competitive inhibitors and three PC2 inhibitors exhibiting various inhibition mechanisms with sub‐ and low micromolar inhibitory potency against a fluorogenic substrate. Low micromolar concentrations of certain compounds blocked the processing of the physiological substrate proglucagon. Interestingly, we identified compounds that were able to stimulate both 87 kDa PC1/3 and PC2 activity. Molecular modeling studies revealed interactions of the PC1/3 inhibitors with the active site that suggest structural modifications to further enhance potency. In support of experimental data suggesting that PC2 inhibition likely occurs via an allosteric mechanism, we identified several possible allosteric binding sites using computational searches. This work was supported by DA050854 to Iris Lindberg.