Cardiac resynchronization therapy and atrial fibrillation

Cardiac resynchronization therapy (CRT) is an important advance for the treatment of end-stage heart failure (HF). About 15-50% of HF is complicated by atrial fibrillation (AF), associated with worsened outcomes. The presence of AF may interfere with optimal delivery of CRT due to competition with biventricular (BiV) capture by conducted beats. Pacing algorithms in newer devices may not ensure consistent CRT delivery during periods of rapid ventricular rates. Atrioventricular junction ablation with permanent pacing eliminates interference by conducted beats and provides complete BiV capture and is associated with improved outcomes. Catheter ablation of AF is another promising alternative to maintain sinus rhythm in patients with AF and HF. However, the optimal indications for CRT delivery for patients in this complex cohort remain to be assessed in randomized clinical trials

Atrial fibrillation after minimally invasive direct coronary artery bypass surgery

AbstractOBJECTIVESThe study compared the adjusted risk for developing atrial fibrillation (AF) after minimally invasive direct coronary artery bypass surgery (MIDCAB) and coronary artery bypass graft surgery (CABG).BACKGROUNDAtrial fibrillation results in increased morbidity and delays hospital discharge after CABG. Recently, MIDCAB has been explored as an alternative to CABG. Because of differences in surgical approach between the two procedures, the incidence of AF may differ.METHODSRandomly selected patients undergoing CABG and MIDCAB were examined. Baseline variables and postoperative course were recorded through review of medical record data.RESULTSThe MIDCAB patients were younger than CABG patients (64 ± 12 vs. 67 ± 10, p < 0.04) and had less extensive coronary artery disease (53% of MIDCAB vs. 3% of CABG had single-vessel disease, while 15% of MIDCAB vs. 69% of CABG had triple-vessel disease, p < 0.001 for overall group comparisons). No other differences in clinical or treatment data were noted. Postoperative AF occurred less often after MIDCAB (23% vs 39%, p = 0.02). Other significant factors associated with postoperative AF included age (p = 0.0024), prior AF (p = 0.0007), left main disease (p = 0.01), number of vessels bypassed (p = 0.009), absence of postoperative beta-blocker therapy (p = 0.0001), and a serious postoperative complication (p = 0.0018). Because of differences between CABG and MIDCAB patients, multivariate logistic analysis was performed to determine independent predictors of postoperative AF. The type of surgery (CABG vs. MIDCAB) was no longer a significant predictor of postoperative AF (estimated relative risk for AF in CABG vs. MIDCAB patients: 1.57, 95% confidence interval (0.82–2.52).CONCLUSIONSAlthough AF appears to be less common after MIDCAB than after CABG, the lower incidence is due to different clinical characteristics of patients undergoing these procedures

Activation of the endogenous coagulation system in patients with atrial flutter: Relationship to echocardiographic markers of thromboembolic risk

Background: Atrial thrombus formation in patients with atrial flutter raises concerns of stroke risk. We investigated patients with isthmus-dependent atrial flutter for coagulation abnormalities before and after cardioversion to sinus rhythm by catheter ablation, and evaluated the relationship of the abnormalities to the echocardiographic risk markers of stroke. Methods and results: Plasma samples were drawn prior to insertion of catheters, immediately after the procedure, and 24 hours afterwards. At baseline, coagulation abnormalities were found in 22 out of 25 patients (88%). von Willebrand factor antigen (vWF-Ag) and factor VIII:C were elevated in 17 patients (68%) and 15 patients (60%), respectively. At baseline, mean plasma levels of vWF-Ag (250.1 &#177; 144.4%) and factor VIII:C (215.0 &#177; 77.1%) were increased. Key markers of thrombin generation, thrombin-antithrombin III complex (TAT; 47.8 &#177; 30.9 &#956;g/L vs 14.5 &#177; 13.8 &#956;g/L; p < 0.05) and prothrombin fragments 1.2 (F1.2; 2.5 &#177; 0.5 nmoL/L vs 1.2 &#177; 1.0 nmoL/L) were significantly elevated in the presence of spontaneous echo contrast. Further, both markers of thrombin generation inversely correlated with left atrial appendage emptying velocity (r = -0.42 and -0.63, p < 0.05). Levels of TAT and F1.2 increased after conversion and ablation. Conclusions: Endothelial-dependent coagulation factors were enhanced in most patients with atrial flutter. Spontaneous echo contrast and decreased atrial contractility were associated with increased thrombin generation. After conversion and ablation, an increase in thrombin generation and fibrinolysis suggest a transient pro-thrombotic state. (Cardiol J 2010; 17, 4: 390-396

Firm finances, weather derivatives and geography

This paper considers some intellectual, practical and political dimensions of collaboration between human and physical geographers exploring how firms are using relatively new financial products – weather derivatives – to displace any costs of weather-related uncertainty and risk. The paper defines weather derivatives and indicates how they differ from weather insurance products before considering the geo-political, cultural and economic context for their creation. The paper concludes by reflecting on the challenges of research collaboration across the human–physical geography divide and suggests that while such initiatives may be undermined by a range of institutional and intellectual factors, conversations between physical and human geographers remain and are likely to become increasingly pertinent. The creation of a market in weather derivatives raises a host of urgent political and regulatory questions and the confluence of natural and social knowledges, co-existing within and through the geography academy, provides a constructive and creative basis from which to engage with this new market and wider discourses of uneven economic development and climate change

Thienopyridone Drugs Are Selective Activators of AMP-Activated Protein Kinase β1-Containing Complexes

SummaryThe AMP-activated protein kinase (AMPK) is an αβγ heterotrimer that plays a pivotal role in regulating cellular and whole-body metabolism. Activation of AMPK reverses many of the metabolic defects associated with obesity and type 2 diabetes, and therefore AMPK is considered a promising target for drugs to treat these diseases. Recently, the thienopyridone A769662 has been reported to directly activate AMPK by an unexpected mechanism. Here we show that A769662 activates AMPK by a mechanism involving the β subunit carbohydrate-binding module and residues from the γ subunit but not the AMP-binding sites. Furthermore, A769662 exclusively activates AMPK heterotrimers containing the β1 subunit. Our findings highlight the regulatory role played by the β subunit in modulating AMPK activity and the possibility of developing isoform specific therapeutic activators of this important metabolic regulator

The autophagy initiator ULK1 sensitizes AMPK to allosteric drugs

AMP-activated protein kinase (AMPK) is a metabolic stress-sensing enzyme responsible for maintaining cellular energy homeostasis. Activation of AMPK by salicylate and the thienopyridone A-769662 is critically dependent on phosphorylation of Ser108 in the β1 regulatory subunit. Here, we show a possible role for Ser108 phosphorylation in cell cycle regulation and promotion of pro-survival pathways in response to energy stress. We identify the autophagy initiator Unc-51-like kinase 1 (ULK1) as a β1-Ser108 kinase in cells. Cellular β1-Ser108 phosphorylation by ULK1 was dependent on AMPK β-subunit myristoylation, metabolic stress associated with elevated AMP/ATP ratio, and the intrinsic energy sensing capacity of AMPK; features consistent with an AMP-induced myristoyl switch mechanism. We further demonstrate cellular AMPK signaling independent of activation loop Thr172 phosphorylation, providing potential insight into physiological roles for Ser108 phosphorylation. These findings uncover new mechanisms by which AMPK could potentially maintain cellular energy homeostasis independently of Thr172 phosphorylation