Pharmacokinetic Evaluation of Intravenous Vitamin C: A Classic Pharmacokinetic Study.

PURPOSE: Intravenous vitamin C (IVC) is used in a variety of disorders with limited supporting pharmacokinetic data. Herein we report a pharmacokinetic study in healthy volunteers and cancer participants with IVC doses in the range of 1-100 g. METHODS: A pharmacokinetic study was conducted in 21 healthy volunteers and 12 oncology participants. Healthy participants received IVC infusions of 1-100 g; oncology participants received IVC infusions of 25-100 g. Serial blood and complete urine samples were collected pre-infusion and for 24 h post-infusion. Pharmacokinetic parameters were computed using noncompartmental methods. Adverse events were monitored during the study. RESULTS: In both cohorts, IVC exhibited first-order kinetics at doses up to 75 g. At 100 g, maximum concentration (Cmax) plateaued in both groups, whereas area under the concentration-time curve (AUC) only plateaued in the healthy group. IVC was primarily excreted through urine. No saturation of clearance was observed; however, the mean 24-h total IVC excretion in urine for all doses was lower in oncology participants (89% of dose) than in healthy participants at 100 g (99%). No significant adverse events were observed; thus, maximum tolerated dose (MTD) was not reached. CONCLUSION: IVC followed first-order pharmacokinetics up to 75 g and at up to 100 g had complete renal clearance in 24 h. IVC up to 100 g elicited no adverse effects or significant physiological/biochemical changes and appears to be safe. These data can be used to rectify existing misinformation and to guide future clinical trials. REGISTRATION: ClinicalTrials.gov identifier number NCT01833351.

Stronger influence of growth rate than severity of drought stress on mortality of large ponderosa pines during the 2012-2015 California drought.

Forests in the western United States are being subject to more frequent and severe drought events as the climate warms. The 2012-2015 California drought is a recent example, whereby drought stress was exacerbated by a landscape-scale outbreak of western pine beetle (Dendroctonus brevicomis) and resulted in widespread mortality of dominant canopy species including ponderosa pine (Pinus ponderosa). In this study, we compared pairs of large surviving and beetle-killed ponderosa pines following the California drought in the southern Sierra Nevadas to evaluate physiological characteristics related to survival. Inter-annual growth rates and tree-ring stable isotopes (∆13C and δ18O) were utilized to compare severity of drought stress and climate sensitivity in ponderosa pines that survived and those that were killed by western pine beetle. Compared to beetle-killed trees, surviving trees had higher growth rates and grew in plots with lower ponderosa pine basal area. However, there were no detectable differences in tree-ring ∆13C, δ18O, or stable isotope sensitivity to drought-related meteorological variables. These results indicate that differences in severity of drought stress had little influence on local, inter-tree differences in growth rate and survival of large ponderosa pines during this drought event. Many previous studies have shown that large trees are more likely to be attacked and killed by bark beetles compared to small trees. Our results further suggest that among large ponderosa pines, those that were more resistant to drought stress and bark beetle attacks were in the upper echelon of growth rates among trees within a stand and across the landscape.

Anatomical and electrical remodeling with incomplete left atrial appendage ligation: Results from the LAALA-AF registry.

BACKGROUND: The anatomical, electrical, and clinical impact of incomplete Lariat left atrial appendage ligation remains unclear. METHODS: We studied LAA anatomy pre- and postligation using contrast enhanced-computed tomography (CT) scans in 91 patients with atrial fibrillation (AF) who subsequently underwent catheter ablation (CA). RESULTS: Eleven patients had an incomplete exclusion (12%) with a central leak ranging from 1 to 5 mm. Despite incomplete ligation; the LAA volume were reduced by 67% postprocedurally when compared to preprocedure. In 7 patients with a leak between 1 and 3 mm, there was a 77% reduction in LAA volume beyond the ligation site suggestive of remodeling of the LAA. In 4 patients with larger (4-5 mm) leak the LAA remnants (LAARs) were slightly larger than those with smaller leaks on follow-up CT scan. Three out of the 4 demonstrated LAA electrical activity during CA and underwent isolation of the LAA ostium. Follow-up imaging showed two of these LAARs completely sealed with no communication with the left atrium. There was no significant difference in the AF recurrence rates between the patients who had a leak versus those with complete ligation (4 of 11 [36%] vs. 22 of 80 [27%]; P  =  0.6). Oral anticoagulation was discontinued in all patients with small leaks and 2 patients with large leaks that sealed completely upon follow-up imaging. There were no strokes or TIAs at 12 months. CONCLUSION: Despite incomplete LAA ligation by Lariat device there is significant anatomical and electrical remodeling that resulted in reduction in LAA size, volume, and electrical activity.

Short and long-term outcomes of percutaneous left atrial appendage suture ligation: Results from a US multicenter evaluation.

BACKGROUND: Published studies of epicardial ligation of left atrial appendage (LAA) have reported discordant results. OBJECTIVE: The purpose of this study was to delineate the safety and efficacy of LAA closure with the LARIAT device. METHODS: This is a multicenter registry of 712 consecutive patients undergoing LAA ligation with LARIAT at 18 US hospitals. The primary end point was successful suture deployment, no leak by intraprocedural transesophageal echocardiography (TEE), and no major complication (death, stroke, cardiac perforation, and bleeding requiring transfusion) at discharge. A leak of 2-5 mm on follow-up TEE was the secondary end point. RESULTS: LARIAT was successfully deployed in 682 patients (95.5%). A complete closure was achieved in 669 patients (98%), while 13 patients (1.8%) had a trace leak (<2 mm). There was 1 death related to the procedure. Ten patients (1.44%) had cardiac perforation necessitating open heart surgery, while another 14 (2.01%) did not need surgery. The risk of cardiac perforation decreased significantly after the introduction of a micropuncture (MP) needle for pericardial access. Delayed complications (pericarditis requiring >2 weeks of treatment with nonsteroidal anti-inflammatory drugs/colchicine and pericardial and pleural effusion after discharge) occurred in 34 (4.78%) patients, and the risk decreased significantly with the periprocedural use of colchicine. Follow-up TEE (n = 480) showed a leak of 2-5 mm in 6.5% and a thrombus in 2.5%. One patient had a leak of >5 mm. CONCLUSION: LARIAT effectively closes the LAA and has acceptable procedural risks with the evolution of the use of the micropuncture needle for pericardial access and the use of colchicine for mitigating the postinflammatory response associated with LAA ligation and pericardial access.

Electrolyte and hemodynamic changes following percutaneous left atrial appendage ligation with the LARIAT device.

PURPOSE: The left atrial appendage (LAA) is a well-known source of atrial natriuretic peptide (ANP) and therefore plays an important role in homeostasis. The neurohormonal impact of epicardial exclusion of the LAA with the LARIAT procedure is unknown. In this proof-of-concept study, we postulated that LAA exclusion would impact homeostasis as evidenced by changes in electrolytes and blood pressure (BP). METHODS: A total of 76 patients who underwent successful LAA exclusion were enrolled in this retrospective observational study utilizing a prospective registry. Electrolytes, BP, and heart rate (HR) were monitored before LARIAT and post-LARIAT (24 and 72 h and 6 months). RESULTS: There was a significant reduction of systolic BP (mmHg) at 24 h (113.3 ± 16.0; p < 0.0001) and 72 h (119.0 ± 18.4 mmHg; p < 0.0001) post-LARIAT when compared with pre-LARIAT BP (138.2 ± 21.3). The reduction in systolic BP persisted at 6-month follow-up (128.8 ± 17.3; p = 0.0005). There was significant reduction in serum sodium (mmol/L) at 24 h (135.4 ± 3.6; p < 0.0001) and 72 h (136.3 ± 3.7; p < 0.001) post-LARIAT when compared to pre-LARIAT (138.7 ± 3.2). The reduction in sodium was not persistent at 6-month follow-up (138.4 ± 3.3; p = 0.453). CONCLUSIONS: LAA exclusion results in an early and persistent decrease in systolic BP. Additionally, there is an early decline in serum sodium, which normalizes at long-term follow-up. The underlying mechanism leading to these changes is not entirely clear; however, it is likely related to neurohormonal changes post LAA exclusion.

Endocardial (Watchman) vs epicardial (Lariat) left atrial appendage exclusion devices: Understanding the differences in the location and type of leaks and their clinical implications.

BACKGROUND: Watchman and Lariat left atrial appendage (LAA) occlusion devices are associated with LAA leaks postdeployment. OBJECTIVE: The purpose of this study was to compare the incidence, characteristics, and clinical significance of these leaks. METHODS: We performed a multicenter prospective observational study of all patients who underwent LAA closure. Baseline, procedural, and imaging variables along with LAA occlusion rates at 30-90 days and 1-year postprocedure were compared. RESULTS: A total of 478 patients (219 with the Watchman device and 259 with the Lariat device) with successful implants were included. Patients in the Lariat group had a higher CHADS2 (congestive heart failure, hypertension, age >74 years, diabetes, stroke) score and a larger left atrium and LAA. A total of 79 patients (17%) had a detectable leak at 1 year. More patients in the Watchman group had a leak compared with those in the Lariat group (46 [21%] vs 33 [14%]; P = .019). All the leaks were eccentric (edge effect) in the Watchman group and concentric (gunny sack effect) in the Lariat group. The size of the leak was larger in the Watchman group than in the Lariat group (3.10 ± 1.5 mm vs 2.15 ± 1.3 mm; P = .001). The Watchman group had 1 device embolization requiring surgery and 2 pericardial effusions requiring pericardiocentesis. In the Lariat group, 4 patients had cardiac tamponade requiring urgent surgical repair. Three patients in each group had a cerebrovascular accident and were not associated with device leaks. CONCLUSION: The Lariat device is associated with a lower rate of leaks at 1 year as compared with the Watchman device, with no difference in rates of cerebrovascular accident. There was no correlation between the presence of residual leak and the occurrence of cerebrovascular accident.

Sequential Percutaneous LAA Ligation and Pulmonary Vein Isolation in Patients with Persistent AF: Initial Results of a Feasibility Study.

INTRODUCTION: Left atrial appendage (LAA) ligation results in LAA electrical isolation and a decrease in atrial fibrillation (AF) burden. This study assessed the feasibility of combined percutaneous LAA ligation and pulmonary vein isolation (PVI) in patients with persistent AF. METHODS AND RESULTS: A total of 22 patients with persistent AF underwent LAA ligation with the LARIAT device followed by PVI. PVI was confirmed with the demonstration of both entrance and exit block. Patients (n = 10) in sinus rhythm pre- and post-LAA ligation underwent P-wave analysis. Monitoring for AF was performed at 1, 3, and 6 months postablation. LAA ligation was successful in 21 of 22 (95%) patients. The procedure was aborted in one patient due to pericardial adhesions. PVI was performed in 20 of 21 patients. One patient converted to atrial flutter with a controlled ventricular response after LAA ligation and refused subsequent PVI. Demonstration of entrance and exit block was achieved in 19 of 20 patients. At 3 months, 13 of 19 (68.4%) patients were in sinus rhythm. Four patients underwent a second PVI. At 6 months, 15 of 20 (75%) patients were in sinus rhythm. There was a significant decrease in P-wave duration and P-wave dispersion after LAA ligation. Complications with LAA ligation included pericarditis, a delayed pleural effusion, and a late pericardial effusion. CONCLUSIONS: Staged LAA ligation and PVI is feasible and decreases P-wave dispersion. Randomized studies are needed to assess the efficacy of LAA ligation as adjunctive therapy to PVI for maintaining sinus rhythm in patients with persistent AF.

Left Atrial Appendage Ligation and Ablation for Persistent Atrial Fibrillation: The LAALA-AF Registry.

OBJECTIVES: This study was intended to evaluate the impact of adding the left atrial appendage (LAA) closure system (LARIAT) procedure to conventional atrial fibrillation (AF) ablation in patients with persistent AF. BACKGROUND: Percutaneous endoepicardial LARIAT may result in both mechanical and electrical exclusion of the LAA and aid in improving the outcomes of catheter ablation by eradicating the LAA triggers and altering the substrate. METHODS: We performed a prospective observational study of patients with persistent AF referred for AF ablation. Patients underwent LAA ligation with LARIAT procedure before undergoing AF ablation (LARIAT group). Age- and sex-matched persistent AF patients undergoing AF ablation during the same time frame were included in the control group (ablation-only group). RESULTS: A total of 138 patients were included in the study, with 69 patients in the LARIAT group. The mean age of the population was 67 ± 10 years, with 96 (70%) men. Left atrial (LA) size, CHADS2, CHADSVasc, and HAS-BLED scores were higher in the LARIAT group when compared with the ablation-only group. There were no differences in the type of lesions during AF ablation between the groups. The primary outcome of freedom from AF at 1 year off antiarrhythmic therapy after 1 ablation procedure was higher in the LARIAT group (45 [65%] vs. 27 [39%]; p = 0.002). More patients in the ablation-only group underwent repeat ablation because of AF recurrence (11 [16%] vs. 23 [33%]; p = 0.018). CONCLUSIONS: In patients with persistent AF, addition of LAA ligation with the LARIAT device to conventional ablation appears to improve the success rate of AF ablation.

Initial experience with post Lariat left atrial appendage leak closure with Amplatzer septal occluder device and repeat Lariat application.

BACKGROUND: Left atrial appendage (LAA) ligation with the Lariat device is a therapeutic option to prevent thromboembolic stoke in patients with nonvalvular atrial fibrillation (AF) at high risk for systemic thromboembolization and bleeding related to use of anticoagulation. In rare cases, this procedure could leave the LAA incompletely ligated with continued risk of stroke. OBJECTIVE: The purpose of this study was to investigate the incidence and characteristics of LAA leak following ligation using the Lariat device and the feasibility of leak closure with the Amplatzer septal occluder device or a repeat Lariat application. METHODS: Seventy-one consecutive patients who underwent LAA ligation by the Lariat device were followed-up with transesophageal echocardiography to evaluate for the presence of appendage leaks, characterization of the leaks, and the presence of any thrombus. Patients with LAA leaks underwent definite closure of the leak. RESULTS: Six patients had LAA leaks with a mean leak size of 4.3 ± 0.6 mm. All leaks were concentric in nature. None of the patients had LAA thrombus. Leaks in 5 of these patients were successfully closed using an Amplatzer septal occluder device (St. Jude Medical); the leak in the sixth patient was closed using a repeat Lariat procedure. CONCLUSION: LAA leaks from incomplete ligation of the LAA following the Lariat procedure are not uncommon and could be successfully closed with an Amplatzer septal occluder device or a repeat Lariat procedure.

Embryology and Anatomy of the Left Atrial Appendage: Why Does Thrombus Form?

The left atrial appendage (LAA) is a long tubular structure that opens into the left atrium. In patients with atrial fibrillation, the LAA develops mechanical dysfunction and fibroelastotic changes on the endocardial surface. The complex anatomy of the LAA makes it a good site for relative blood stasis. In addition, systemic factors exacerbate the hypercoagulable state, eventually resulting in endothelial dysfunction, release of tissue factor, and production of inflammatory cytokines and oxidative free radicals, and eventually initiating the coagulation cascade. Thus, the LAA is susceptible to thrombus formation and is the most common source of systemic thromboembolism.

IntraCameral right coronary artery: detection by 64 slice coronary computed tomographic angiography and implications for radiofrequency ablation of atrial dysrhythmias.

An intracameral or intracavitary course for a coronary artery is a rare anomaly. Nevertheless, it carries a significant impact for invasive cardiac procedures that require right atrial catheterization, pacemaker implantation, or electrophysiologic study such as radiofrequency ablation. If a coronary artery were to be damaged within the atrial chamber by catheter manipulation at the time of heart catheterization, serious complications might ensue. We describe the first reported case of an intracameral right coronary artery identified with multidetector 64-slice coronary computed tomographic angiography performed prior to pulmonary venous antral isolation for atrial fibrillation.