Increased body mass index, age, and left atrial size are associated with altered intracardiac atrial electrograms in persistent atrial fibrillation patients.

BACKGROUND: There are limited studies evaluating whether atrial fibrillation (AF) patients with increased BMI, age, and left atrial (LA) size have altered intracardiac electrogram (EGM) morphology. METHODS: We analyzed left atrial intracardiac EGMs acquired during invasive electrophysiology study in 54 patients with AF. EGM correlations were assessed among AF risk factors including age, left atrial size, and BMI. RESULTS: BMI correlated positively with DF (r2 = 0.17, p = 0.009) and MP (r2 = 0.16, p = 0.01) with dominant frequency (DF) and mean spectral profile (MP) greater among obese individuals. Age was negatively associated with mean amplitude (r2 = 0.42, p < 0.001) and width (r2 = 0.32, p < 0.001); age was positively correlated with MP (r2 = 0.24, p < 0.001). LA size was negatively correlated with mean amplitude (r2 = 0.18, p = 0.03) and width (r2 = 0.23, p = 0.01); LA size was positively correlated with DF (r2 = 0.22, p = 0.01) and MP (r2 = 0.23, p = 0.01). Mean amplitude and width were decreased among subjects with a severely enlarged LA; DF and MP were increased in those with severely enlarged LA. The associations with BMI and LA size remained significant in multiple regression models that included age, male gender, time since AF diagnosis, and LVEF. CONCLUSIONS: EGM morphology of AF patients with increased BMI, older age, and an enlarged LA possessed decreased amplitude and decreased width and increased DF and MP. These findings suggest that atrial remodeling due to increased age, LA size, and BMI is associated with differences in local atrial activation, decreased refractoriness, and more heterogeneous activation. These novel findings point out clinical risk factors for atrial fibrillation that may affect electrogram characteristics.

Data presentation in rodent stroke studies and the predictive value of confidence intervals.

The clinical failure of neuroprotective agents stems partly from inappropriate statistical presentation of preclinical data, which causes an overestimation of effect size and underpowered clinical studies. We searched for studies utilizing neuroprotective agents in a rodent middle cerebral artery occlusion model. We identified all experimental groups demonstrating statistically significant claims of neuroprotection within these studies and calculated the mean, 95% confidence intervals (CI), and meta-analyses of effect size for each agent. The lower limits of the CI (LLCI) of effect size were less than 0.2 in 161/221 (73%) of all experimental groups, corresponding to small effects. After meta-analysis, 29/60 (48%) and 11/18 (61%) of the agents had an effect size LLCI<0.2 for infarct volume and neurological function, respectively. This difference was statistically significant (p<0.05). These results suggest that the preclinical neuroprotective effect size of many of these drugs is small, although that of neurological function is smaller and is thus a more conservative and appropriate estimate of effect.

Preclinical evaluation of the neuroprotective effect of soluble complement receptor type 1 in a nonhuman primate model of reperfused stroke.

OBJECT: Postischemic cerebral inflammatory injury has been extensively investigated in an effort to develop effective neuroprotective agents. The complement cascade has emerged as an important contributor to postischemic neuronal injury. Soluble complement receptor Type 1 (sCR1), a potent inhibitor of complement activation, has been shown to reduce infarct volume and improve functional outcome after murine stroke. Given numerous high-profile failures to translate promising antiinflammatory strategies from the laboratory to the clinic and given the known species-specificity of the complement cascade, the authors sought to evaluate the neuroprotective effect of sCR1 in a nonhuman primate model of stroke. METHODS: A total of 48 adult male baboons (Papio anubis) were randomly assigned to receive 15 mg/kg of sCR1 or vehicle. The animals were subjected to 75 minutes of middle cerebral artery occlusion/reperfusion. Perioperative blood samples were analyzed for total complement activity by using a CH50 assay. Infarct volume and neurological scores were assessed at the time the animals were killed, and immunohistochemistry was used to determine cerebral drug penetration and C1q deposition. An interim futility analysis led to termination of the trial after study of 12 animals. Total serum complement activity was significantly depressed in the sCR1-treated animals compared with the controls. Immunostaining also demonstrated sCR1 deposition in the ischemic hemispheres of treated animals. Despite these findings, there were no significant differences in infarct volume or neurological score between the sCR1--and vehicle-treated cohorts. CONCLUSIONS: A preischemic bolus infusion of sCR1, the most effective means of administration in mice, was not neuroprotective in a primate model. This study illustrates the utility of a translational primate model of stroke in the assessment of promising antiischemic agents prior to implementation of large-scale clinical trials.

High dose magnesium infusions are not associated with increased pressor requirements after carotid endarterectomy.

INTRODUCTION: Although magnesium provides cerebral protection in animal stroke models, magnesium therapy has significant side effects in humans. Therefore, we sought to examine the incidence of alpha-agonist treated hypotension in our ongoing, prospective, randomized, double-blind, placebo-controlled Phase I/IIa dose escalation study of magnesium therapy in patients undergoing carotid endarterectomy. METHODS: Eighty patients undergoing elective carotid endarterectomy were randomly assigned to a placebo control group (n = 38) or to one of the three intravenous magnesium groups. Magnesium levels were obtained before induction, and then 15 minutes, 1 hour, 2 hours, 6 hours, 12 hours, and 24 hours after a loading dose and infusion. After surgery, a target systolic blood pressure range was chosen, and the amount and duration of phenylephrine needed to maintain that pressure was compared across treatment groups. RESULTS: All treatment groups achieved levels significantly different from baseline at 12 and 24 hours (P < 0.01). Magnesium treatment did not significantly increase the proportion of patients requiring pressure support. For those requiring pressure support, the amount and average duration of phenylephrine required was not different between control patients and those receiving magnesium, even when the individual minimum systolic blood pressures required were subdivided on the basis of dose of magnesium administered. CONCLUSION: There were no significant differences detected in the 1) percentage of patients requiring pressor support, 2) the duration of postoperative pressor support, or 3) the amount of phenylephrine support needed between controls and magnesium treated patients. The percentage of patients requiring pressure support depended on the minimum systolic blood pressure ordered after surgery.