Uninterrupted rivaroxaban vs. uninterrupted vitamin K antagonists for catheter ablation in non-valvular atrial fibrillation.

AIMS: VENTURE-AF is the first prospective randomized trial of uninterrupted rivaroxaban and vitamin K antagonists (VKAs) in patients with non-valvular atrial fibrillation (NVAF) undergoing catheter ablation (CA). METHODS AND RESULTS: Trial size was administratively set at 250, the protocol-specified target. Events were independently and blindly adjudicated. We randomly assigned 248 NVAF patients to uninterrupted rivaroxaban (20 mg once-daily) or to an uninterrupted VKA prior to CA and for 4 weeks afterwards. The primary endpoint was major bleeding events after CA. Secondary endpoints included thromboembolic events (composite of stroke, systemic embolism, myocardial infarction, and vascular death) and other bleeding or procedure-attributable events. Patients were 59.5 ± 10 years of age, 71% male, 74% paroxysmal AF, and had a CHA2DS2-VASc score of 1.6. The average total heparin dose used to manage activated clotting time (ACT) was slightly higher (13 871 vs. 10 964 units; P < 0.001) and the mean ACT level attained slightly lower (302 vs. 332 s; P < 0.001) in rivaroxaban and VKA arms, respectively. The incidence of major bleeding was low (0.4%; 1 major bleeding event). Similarly, thromboembolic events were low (0.8%; 1 ischemic stroke and 1 vascular death). All events occurred in the VKA arm and all after CA. The number of any adjudicated events (26 vs. 25), any bleeding events (21 vs. 18), and any other procedure-attributable events (5 vs. 5) were similar. CONCLUSION: In patients undergoing CA for AF, the use of uninterrupted oral rivaroxaban was feasible and event rates were similar to those for uninterrupted VKA therapy. NAME OF THE TRIAL REGISTRY: Clinicaltrials.gov trial registration number is NCT01729871.

The utility of implantable loop recorders for diagnosing unexplained syncope in 100 consecutive patients: five-year, single-center experience.

INTRODUCTION: The purpose of this study was to retrospectively review the 5-year experience of a university hospital with implantable loop recorders (ILR) for the diagnosis of recurrent, unexplained syncope or presyncope. METHODS: One hundred patients with syncope or presyncope of unknown etiology (negative tilt-table test, electrophysiology study and neurologic workup) underwent prolonged monitoring with an ILR from March 2000 to December 2004. All implants were performed using a first-generation (manual activation) or second-generation (manual plus automatic activation) ILR. RESULTS: One hundred patients (70 women, 30 men) with a mean age of 68 +/- 18 years received the ILR. Twenty-three patients had coronary artery disease; 2 patients had dilated cardiomyopathy. Ten patients received a first-generation ILR, and 90 patients received a second-generation ILR. After 9 +/- 8 months' follow up, ILR interrogation identified an arrhythmogenic etiology to the syncope/presyncope in 45 patients with 55 events. Eight patients had a diagnosis by ILR less than 2 months from the date of implantation. Twenty-six patients had documented symptomatic bradycardia (asystole, sinus pauses, atrial fibrillation with long pauses); 11 patients had episodes of sinus tachycardia with heart rates of 130 to 140 beats/minute; 2 patients had atrial tachycardia; 5 patients had multiple episodes of nonsustained ventricular tachycardia (NSVT); 1 patient had sustained ventricular tachycardia, and 4 patients had paroxysmal supraventricular tachycardia. All arrhythmias were treated successfully by pacemaker/ICD implantation, radiofrequency catheter ablation and/or medications. One patient had seizure activity, which was detected by ILR as high-frequency noise. Two patients failed to activate their device, as it was a first-generation device. CONCLUSION: Five-year experience with the ILR in 100 consecutive patients confirms the utility of this device in the diagnosis of recurrent, infrequent, unexplained syncope or presyncope. It helped diagnose 45% of patients with unexplained syncope with negative electrophysiologic and neurologic workup. Most of these patients had an arrhythmogenic etiology to their syncope. Medical therapy, device therapy, and/or catheter ablation helped successfully treat all patients with an arrhythmogenic etiology detected by ILR.

Molecular mechanisms underlying K+ current downregulation in canine tachycardia-induced heart failure.

Heart failure (HF) is characterized by marked prolongation of action potential duration and reduction in cellular repolarization reserve. These changes are caused in large part by HF-induced K(+) current downregulation. Molecular mechanisms underlying these changes remain unclear. We determined whether downregulation of K(+) currents in a canine model of tachycardia-induced HF is caused by altered expression of underlying K(+) channel alpha- and beta-subunits encoding these currents. K(+) channel subunit expression was quantified in normal and failing dogs at the mRNA and protein levels in epicardial (Epi), midmyocardial (Mid), and endocardial (Endo) layers of left ventricle. Analysis of mRNA and protein levels of candidate genes encoding the transient outward K(+) current (I(to)) revealed marked reductions in canine cKv4.3 expression in HF in Epi (44% mRNA, 39% protein), Mid (52% mRNA, 34% protein), and Endo (49% mRNA, 73% protein) layers and a paradoxical enhancement (41% Epi, 97% Mid, 113% Endo) in cKv1.4 protein levels, without significant changes in Kv channel-interacting protein cKChIP2 expression. Expression of cKir2.1, the gene underlying inward rectifier K(+) current (I(K1)), was unaffected by HF at mRNA and protein levels despite significant reduction in I(K1), whereas canine ether-a-go-go-related gene (cERG), which encodes the rapidly activating component of the delayed rectifier current (I(K)), exhibited increased protein expression. HF was not accompanied by significant changes in cKvLQT1 or cMinK mRNA and protein levels. These data indicate that 1) downregulation of I(to) in HF is associated with decreased cKv4.3 and not cKv1.4 or cKChIP2, and 2) alterations in both the rapidly activating and slowly activating components of I(K) as well as I(K1) in nonischemic dilated cardiomyopathy are not caused by changes in either transcript or immunoreactive protein levels of relevant channel subunits, which suggests posttranslational modification of these currents by HF.

Evidence that the H1-H2 domain of alpha1 subunit of (Na++K+)-ATPase participates in the regulation of cardiac contraction.

(Na++K+)-ATPase (NKA) plays an important role in ion homeostasis and regulates cardiac contraction. To understand the molecular basis of its cardiac regulatory functions, we investigated whether the primary structure of the H1-H2 domain in alpha-1 (alpha1) subunit of the enzyme plays a role in myocardial contractile regulation. Here we show that site-specific binding to this 1 H1-H2 domain with a targeted antibody (SSA78) markedly augments intracellular Ca2+ transients and contraction of rat ventricular cardiomyocytes without inactivating NKA. In vivo SSA78 infusion in mice results in a positive inotropic effect with enhanced contractile function yet no change in relaxation, indicating a direct cardiac effect linked to the H1-H2 domain. Competitive immunofluorescent staining and flow cytometry reveal that SSA78 binding is antagonized by ouabain, supporting the interaction of SSA78 at one of the glycoside-effecter sites. These new findings suggest that the H1-H2 domain of 1 subunit of NKA is a critical determinant of enzyme biologic activity, which couples to enhanced myocyte calcium transient and inotropic action.

Utility of non-contact three-dimensional mapping of the left atrium for ablation of left atrial tachycardia.

A 78-year-old man with a highly symptomatic left atrial tachycardia, refractory to medical therapy, was referred for radiofrequency catheter ablation. Using a double trans-septal technique, two long sheaths were placed across the interatrial septum into the left atrium. Using a 64-electrode non-contact three-dimensional mapping technique, the left atrium was reconstructed and the focus localized to the right superior pulmonary vein ostium. Radiofrequency energy was applied and eliminated the ectopic focus. In summary, a three-dimensional non-contact mapping catheter can facilitate ectopic left atrial tachycardia ablation.

Pulmonary vein anatomy in patients undergoing catheter ablation of atrial fibrillation: lessons learned by use of magnetic resonance imaging.

BACKGROUND: This study sought to define the technique and results of magnetic resonance imaging (MRI) of pulmonary vein (PV) anatomy before and after catheter ablation of atrial fibrillation (AF). METHODS AND RESULTS: Twenty-eight patients with AF underwent ablation. Patients underwent gadolinium-enhanced MRI before and 6 weeks after their procedures. A control group of 27 patients also underwent MRI. Variant PV anatomy was observed in 38% of patients. AF patients had larger PV diameters than control subjects, but no difference was observed in the size of the PV ostia among AF patients. The PV ostia were oblong in shape with an anteroposterior dimension less than the superoinferior dimension. The left PVs had a longer "neck" than the right PVs. A detectable PV narrowing was observed in 24% of veins. The severity of stenosis was severe in 1 vein (1.4%), moderate in 1 vein (1.4%), and mild in 15 veins (21.1%). All patients were asymptomatic, and none required treatment. CONCLUSIONS: This study demonstrates that AF patient have larger PVs than control subjects and demonstrates the value of MRI in facilitating AF ablation. The benefits of preprocedural MRI of PVs include the ability to evaluate the number, size, and shape of the PVs. MRI also provides an assessment of the severity of PV stenosis.

Regulation of Kv4.3 current by KChIP2 splice variants: a component of native cardiac I(to)?

BACKGROUND: The transient outward potassium current (I(to)) encoded by the Kv4 family of potassium channels is important in the repolarization of cardiac myocytes. KChIPs are a recently identified group of Ca2+-binding accessory subunits that modulate Kv4-encoded currents. KChIP2 is the only family member expressed in the heart. METHODS AND RESULTS: We previously cloned 2 novel splice variants of KChIP2 from human heart, named KChIP2S and KChIP2T. The transmural distribution of KChIP2 mRNA and protein in human and canine left ventricle was examined using kinetic RT-PCR and Western blots in the same tissues. A steep gradient of mRNA with greater KChIP2 expression in the epicardium was observed. However, no gradient of immunoreactive protein was observed. Immunocytochemistry reveals KChIP2 expression in the t-tubules and the nucleus. The predominant effects of all 3 KChIP2 splice variants on hKv4.3-encoded current are to increase the density, slow the current decay in a Ca2+-dependent manner, and hasten recovery from inactivation in a splice variant-specific fashion. CONCLUSIONS: A family of KChIP2 proteins is expressed in human hearts that exhibits differential modulation of hKv4.3 current in a Ca2+-dependent fashion. The effect of KChIP2 on the biophysical properties of expressed Kv4.3 current and the absence of a gradient of protein across the ventricular wall suggest that KChIP2 is either not a requisite component of human or canine ventricular I(to) or that its functional effect is being affected or additionally modified by other factors present in myocardial cells.