Minocycline, a second-generation tetracycline compound, has been examined as a neuroprotectant in ␤-amyloid (A␤)-injected rat hippocampus. At 7 days post-injection, A␤ 1-42 caused a significant loss of granule cell layer neurons (28% reduction) compared to control uninjected hippocampus. Hippocampal injection of A␤ peptide also led to marked gliosis with numbers of microglia (increased by 26-fold) and immunoreactivity of astrocytes (increased by 11-fold) relative to control, as determined from immunohistochemical analysis. Intraperitoneal administration of minocycline significantly reduced neuronal loss induced by A␤ 1-42 (by 80%) and also diminished numbers of microglia (by 69%) and astrocytes (by 36%) relative to peptide alone. Peptide injection increased expression of cyclooxygenase-2 (COX-2) in most (about 70%) of granule cells, a subset (about 20%) of microglia, but not in astrocytes; in the presence of minocycline, COX-2 immunostaining was abolished in microglia. The results from this study suggest that minocycline may have efficacy in the treatment of AD.

No abstract

Background While several studies have evaluated predictors for atrial fibrillation (AF) recurrence following catheter ablation, there are limited data specific to cryoballoon ablation (CBA). Methods We analyzed a prospective registry of patients at a single institution who underwent CBA. Recurrence of AF (RAF) was defined as recurrence of AF by 12‐month follow‐up, excluding the 3‐month blanking period. Univariate analysis was performed to evaluate predictors of RAF. Receiver operating characteristic analysis was used to compare and evaluate the performance of various risk scores for discriminating risk of RAF. Results There were 542 patients included in the analysis with mean age 61.3 ± 10.6 years, 67.9% male, and 51.6% paroxysmal AF (PAF). Overall, only left atrial diameter (LAD) > 40 mm and ERAF (early recurrence of AF within 0‐3 month blanking period) were significant predictors of RAF. In the PAF specific subgroup, LAD > 40 mm, AF duration > 12 months, prior stroke or transient ischemic attack, ERAF, and having previously failed an antiarrhythmic drug were significant predictors of RAF. In persistent AF (PeAF) subgroup, obstructive sleep apnea (OSA) and ERAF were significant predictors of RAF. Out of clinical risk scores tested, BASEAF2 had the highest performance with area under the curve of 0.646 (95% confidence interval [0.548, 0.708]; P < .01). Conclusions In this single‐center retrospective study of CBA, we found only LAD > 40 mm and ERAF to be predictors of RAF. We identified OSA as a potential targetable risk factor in PeAF patients undergoing CBA. Out of risk scores tested for discriminating risk of RAF, BASEAF2 had the best performance.

Background - The mesenchymal stem cell (MSC), known to remodel in disease and have an extensive secretome, has recently been isolated from the human heart. However, the effects of normal and diseased cardiac MSCs on myocyte electrophysiology remain unclear. We hypothesize that in disease the inflammatory secretome of cardiac hMSCs remodels and can regulate arrhythmia substrates. Methods - Human cardiac MSCs (hMSCs) were isolated from patients with or without heart failure from tissue attached to extracted device leads and from samples taken from explanted/donor hearts. Failing hMSCs or non-failing hMSCs were co-cultured with normal human myocytes (hCM) derived from induced pluripotent stem cells. Using fluorescent indicators, APD, Ca2+ alternans, and spontaneous calcium release (SCR) incidence were determined. Results - Failing and non-failing hMSCs from both sources exhibited similar tri-lineage differentiation potential and cell surface marker expression as bone marrow hMSCs. Compared to non-failing hMSCs, failing hMSCs prolonged APD by 24% (p<0.001, n=15), increased Ca2+ alternans by 300% (p<0.001, n=18), and promoted SCR activity (n=14, p <0.013) in hCM. Failing hMSCs exhibited increased secretion of inflammatory cytokines IL-1β (98%, p<0.0001) and IL-6 (460%, p <0.02) compared to non-failing hMSCs. IL-1β or IL-6 in the absence of hMSCs prolonged APD but only IL-6 increased Ca2+ alternans and promoted SCR activity in hCM, replicating the effects of failing hMSCs. In contrast, non-failing hMSCs prevented Ca2+ alternans in hCM during oxidative stress. Finally, non-failing hMSCs exhibited >25 times higher secretion of IGF-1 compared to failing hMSCs. Importantly, IGF-1 supplementation or anti-IL-6 treatment rescued the arrhythmia substrates induced by failing hMSCs. Conclusions - We identified device leads as a novel source of cardiac hMSCs. Our findings show that cardiac hMSCs can regulate arrhythmia substrates by remodeling their secretome in disease. Importantly, therapy inhibiting (anti-IL-6) or mimicking (IGF-1) the cardiac hMSC secretome can rescue arrhythmia substrates.