Citations

Background: Prophylactic exclusion of the left atrial appendage (LAA) is often performed during cardiac surgery ostensibly to reduce the risk of stroke. However, the clinical impact of LAA closure in humans remains inconclusive. Methods: Of 10 633 adults who underwent coronary artery bypass grafting and valve surgery between January 2000 and December 2005, 9792 patients with complete baseline characteristics, surgery procedure, and follow-up data were included in this analysis. A propensity score–matching analysis based on 28 pretreatment covariates was performed and 461 matching pairs were derived and analyzed to estimate the association of LAA closure with early postoperative atrial fibrillation (POAF) (atrial fibrillation ≤30 days of surgery), ischemic stroke, and mortality. Results: In the propensity-matched cohort, the overall incidence of POAF was 53.9%. In this group, the rate of early POAF among the patients who underwent LAA closure was 68.6% versus 31.9% for those who did not undergo the procedure ( P <0.001). LAA closure was independently associated with an increased risk of early POAF (adjusted odds ratio, 3.88; 95% confidence interval, 2.89–5.20), but did not significantly influence the risk of stroke (adjusted hazard ratio, 1.07; 95% confidence interval, 0.72–1.58) or mortality (adjusted hazard ratio, 0.92; 95% confidence interval, 0.75–1.13). Conclusions: After adjustment for treatment allocation bias, LAA closure during routine cardiac surgery was significantly associated with an increased risk of early POAF, but it did not influence the risk of stroke or mortality. It remains uncertain whether prophylactic exclusion of the LAA is warranted for stroke prevention during non–atrial fibrillation-related cardiac surgery.

BackgroundAlthough sudden death (SD) is a rare complication after atrioventricular junction (AVJ) ablation and permanent pacemaker implantation, the risk factors leading to this SD remain unknown. The purpose of this study was to investigate SD and its risk factors after ablate‐and‐pace strategy for rate control in atrial fibrillation (AF) patients during long‐term follow‐up.HypothesisMethodsFrom January 2005 to December 2009, we enrolled into this study 517 AF patients with AVJ ablation and right ventricular pacemaker implantation. Patients were divided into 2 groups, SD and non‐SD. Cox proportional hazards models were used to assess potential risk factors for overall mortality and SD.ResultsDuring a mean follow‐up of 25.8 ± 18.6 months (range, 3 days to 63.8 months), 53 patients died (15 with SD). Cox proportional hazards models showed that the presence of congestive heart failure, New York Heart Association functional class, chronic renal failure, and nonsustained ventricular tachycardia were risk factors that predicted overall mortality. For SD, the presence of dilated cardiomyopathy and mitral stenosis were associated risk factors. SD was exclusively seen in patients who had narrow QRS complex or right bundle branch block prior to AVJ ablation and pacemaker implantation; SD was not seen in any patient with preexisting complete left bundle branch block.ConclusionsDilated cardiomyopathy, mitral stenosis, and baseline QRS morphology should be examined as potential risk factors for SD after AVJ ablation and pacemaker implantation.

Background— Left atrial (LA) compliance and contractility influence left ventricular stroke volume. We hypothesized that diminished LA compliance and contractile function occur early during the development of heart failure with preserved ejection fraction (HFpEF) and impair overall cardiac performance. Methods and Results— Cardiac magnetic resonance imaging, echocardiography, left ventricular and LA pressure-volume studies, and tissue analyses were performed in a model of early HFpEF (elderly dogs, renal wrap-induced hypertension, exogenous aldosterone; n=9) and young control dogs (sham surgery; n=13). Early HFpEF was associated with LA enlargement, cardiomyocyte hypertrophy, and enhanced LA contractile function (median active emptying fraction 16% [95% confidence interval, 13–24]% versus 12 [10–14]%, P =0.008; end-systolic pressure-volume relationship slope 2.4 [1.9–3.2]mm Hg/mL HFpEF versus 1.5 [1.2–2.2]mm Hg/mL controls, P =0.01). However, atrioventricular coupling was impaired and the curvilinear LA end-reservoir pressure-volume relationship was shifted upward/leftward in HFpEF (LA stiffness constant [β LA ] 0.16 [0.11–0.18]mm Hg/mL versus 0.06 [0.04–0.10]mm Hg/mL controls; P =0.002), indicating reduced LA compliance. Impaired atrioventricular coupling and lower LA compliance correlated with lower left ventricular stroke volume. Total fibrosis and titin isoform composition were similar between groups; however, titin was hyperphosphorylated in HFpEF and correlated with β LA . LA microvascular reactivity was diminished in HFpEF versus controls. LA microvascular density tended to be lower in HFpEF and inversely correlated with β LA . Conclusions— In early-stage hypertensive HFpEF, LA cardiomyocyte hypertrophy, titin hyperphosphorylation, and microvascular dysfunction occur in association with increased systolic and diastolic LA chamber stiffness, impaired atrioventricular coupling, and decreased left ventricular stroke volume. These data indicate that maladaptive LA remodeling occurs early during HFpEF development, supporting a concept of global myocardial remodeling.

The large conductance Ca2+-activated K+ (BK) channels, abundantly expressed in coronary artery smooth muscle cells (SMCs), play a pivotal role in regulating coronary circulation. A large body of evidence indicates that coronary arterial BK channel function is diminished in both type 1 and type 2 diabetes. However, the consequence of coronary BK channel dysfunction in diabetes is not clear. We hypothesized that impaired coronary BK channel function exacerbates myocardial ischemia/reperfusion (I/R) injury in streptozotocin-induced diabetic mice. Combining patch-clamp techniques and cellular biological approaches, we found that diabetes facilitated the colocalization of angiotensin II (Ang II) type 1 receptors and BK channel α-subunits (BK-α), but not BK channel β1-subunits (BK-β1), in the caveolae of coronary SMCs. This caveolar compartmentation in vascular SMCs not only enhanced Ang II-mediated inhibition of BK-α but also produced a physical disassociation between BK-α and BK-β1, leading to increased infarct size in diabetic hearts. Most importantly, genetic ablation of caveolae integrity or pharmacological activation of coronary BK channels protected the cardiac function of diabetic mice from experimental I/R injury in both in vivo and ex vivo preparations. Our results demonstrate a vascular ionic mechanism underlying the poor outcome of myocardial injury in diabetes. Hence, activation of coronary BK channels may serve as a therapeutic target for cardiovascular complications of diabetes.

We previously reported that α2-adrenergic receptor (α2-AR) stimulation in Purkinje fibers in vitro prolongs action potential duration and suppresses β-adrenergic-induced delayed afterdepolarizations and sustained triggered activities. We examined the effects of α2-AR stimulation on reperfusion-induced ventricular arrhythmias [ventricular tachycardia/ventricular fibrillation (VT/VF)] in vivo. Arterial blood pressure, heart rate, surface electrocardiogram, and renal sympathetic nerve activities were recorded simultaneously in Sprague-Dawley rats. The incidence of VT/VF was 87.5% for controls, 50% for the β-blocker group, 72% for the α1-blocker group, and 12.5% for the α1 + β-blockers group (unopposed α2-adrenergic activation). Direct α2-AR stimulation with UK-14304 also prevented VT/VF. These effects were reversed by the α2-adrenergic antagonist yohimbine. Increases in renal sympathetic nerve activity were associated with left anterior descending coronary artery ligation and reperfusion (33 ± 1.5 and 62 ± 1.7% over baseline, respectively) in controls. Similar patterns were observed among all experimental groups irrespective of the incidence of VT/VF on reperfusion. We conclude that α2-AR stimulation has a potent antiarrhythmic effect on ischemia-reperfusion-induced VT/VF in vivo and that this effect is not centrally mediated.

PurposeAutoantibodies are implicated in the pathogenesis of cardiovascular diseases and cardiac arrhythmias. In this pilot study, we tested the hypothesis that autoantibodies are present in patients with postural orthostatic tachycardia syndrome (POTS).Experimental designSeven control subjects (6 F:1 M, average age 36.1 years) and ten patients with the diagnosis of POTS (7 F: 3 M, average age 35.1 years) provided informed consent and 30 mL of venous blood. Human heart membrane proteins were resolved by 2DE and immunoblotted against purified IgGs from controls and patients.ResultsEighteen protein spots immunoreactive specifically against patient IgGs were detected and they were excised from gels, trypsin‐digested, and analyzed by nanoLC‐electrospray MS/MS. Forty unique proteins were identified and these include proteins that are associated with cardiac hypertrophy (mimecan, myozenin), cardiac remodeling (periostin), cardiomyopathy (desmin, desmoplakin), cell survival (laminin), structural integrity (filamin), chaperone proteins (crystalline, HSP70), mitochondrial enzymes, and channel proteins. Ingenuity Pathway Analysis showed multiple pathways were involved including those that regulate energy metabolism, redox, fibrosis, cardiac hypertrophy, and degeneration.Conclusions and clinical relevanceAutoantibodies are present in patients with POTS. These autoantibodies cross‐react with a wide range of cardiac proteins and may induce alterations in cardiac function. Autoimmune pathogenetic mechanisms should be further explored in these patients.

Activity of the vascular large conductance Ca2+-activated K+ (BK) channel is tightly regulated by its accessory β1 subunit (BK-β1). Downregulation of BK-β1 expression in diabetic vessels is associated with upregulation of the forkhead box O subfamily transcription factor-3a (FOXO-3a)–dependent F-box–only protein (FBXO) expression. However, the upstream signaling regulating this process is unclear. Overproduction of reactive oxygen species (ROS) is a common finding in diabetic vasculopathy. We hypothesized that ROS signaling cascade facilitates the FOXO-3a/FBXO-mediated BK-β1 degradation and leads to diabetic BK channel dysfunction. Using cellular biology, patch clamp, and videomicroscopy techniques, we found that reduced BK-β1 expression in streptozotocin (STZ)-induced diabetic mouse arteries and in human coronary smooth muscle cells (SMCs) cultured with high glucose was attributable to an increase in protein kinase C (PKC)-β and NADPH oxidase expressions and accompanied by attenuation of Akt phosphorylation and augmentation of atrogin-1 expression. Treatment with ruboxistaurin (a PKCβ inhibitor) or with GW501516 (a peroxisome proliferator–activated receptor δ activator) reduced atrogin-1 expression and restored BK channel-mediated coronary vasodilation in diabetic mice. Our results suggested that oxidative stress inhibited Akt signaling and facilitated the FOXO-3a/FBXO-dependent BK-β1 degradation in diabetic vessels. Suppression of the FOXO-3a/FBXO pathway prevented vascular BK-β1 degradation and protected coronary function in diabetes.

Rationale: Activity of the large conductance Ca 2+ -activated K + (BK) channels is profoundly modulated by its β 1 subunit (BK-β 1 ). However, BK-β 1 expression is downregulated in diabetic vessels. The ubiquitin–proteasome system (UPS) is a major mechanism of intracellular protein degradation. Whether UPS participates in BK-β 1 downregulation in diabetic vessels is unknown. Objective: We hypothesize that UPS facilitates vascular BK-β 1 degradation in diabetes. Methods and Results: Using patch clamp and molecular biological approaches, we found that BK-β 1 –mediated channel activation and BK-β 1 protein expression were reduced in aortas of streptozotocin-induced diabetic rats and in human coronary arterial smooth muscle cells (CASMCs) cultured in high glucose. This was accompanied by upregulation of F-box only protein (FBXO)-9 and FBXO-32 (atrogin-1), the key components of the Skp1-Cullin-F-box (SCF) type ubiquitin ligase complex. BK-β 1 expression was suppressed by the FBXO activator doxorubicin but enhanced by FBXO-9 small interfering RNA or by the proteasome inhibitor MG-132. Cotransfection of atrogin-1 in HEK293 cells significantly reduced Flag-hSlo-β 1 expression by 2.16-fold, compared with expression of Flag-hSlo-β 1 V146A (a mutant without the PDZ-binding motif). After cotransfection with atrogin-1, the ubiquitination of Flag-hSlo-β 1 was increased by 1.91-fold, compared with that of hSlo-β 1 V146A, whereas cotransfection with atrogin-1ΔF (a nonfunctional mutant without the F-box motif) had no effect. Moreover, inhibition of Akt signaling attenuated the phosphorylation of forkhead box O transcription factor (FOXO)-3a and enhanced atrogin-1 expression, which in turn suppressed BK-β 1 protein levels in human CASMCs. Conclusions: Downregulation of vascular BK-β 1 expression in diabetes and in high-glucose culture conditions was associated with FOXO-3a/FBXO-dependent increase in BK-β 1 degradation.