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Wireless remote monitoring with automatic clinician alerts as compared with standard in-office follow-up significantly reduced the time to a clinical decision in response to clinical events and was associated with a significant reduction in mean length of CV hospital stay. (Clinical Evaluation of Remote Notification to Reduce Time to Clinical Decision [CONNECT]; NCT00402246).

The voltage-gated Kv1.3 K ϩ channel is a novel target for immunomodulation of autoreactive effector memory T (T EM ) cells that play a major role in the pathogenesis of autoimmune diseases. We describe the characterization of the novel peptide ShK(L5) that contains L-phosphotyrosine linked via a nine-atom hydrophilic linker to the N terminus of the ShK peptide from the sea anemone Stichodactyla helianthus. ShK(L5) is a highly specific Kv1.3 blocker that exhibits 100-fold selectivity for Kv1.3 (K d ϭ 69 pM) over Kv1.1 and greater than 250-fold selectivity over all other channels tested. ShK(L5) suppresses the proliferation of human and rat T EM cells and inhibits interleukin-2 production at picomolar concentrations. Naive and central memory human T cells are initially 60-fold less sensitive than T EM cells to ShK(L5) and then become resistant to the peptide during activation by up-regulating the calcium-activated K Ca 3.1 channel. ShK(L5) does not exhibit in vitro cytotoxicity on mammalian cell lines and is negative in the Ames test. It is stable in plasma and when administered once daily by subcutaneous injection (10 g/kg) attains "steady state" blood levels of ϳ300 pM. This regimen does not cause cardiac toxicity assessed by continuous EKG monitoring and does not alter clinical chemistry and hematological parameters after 2-week therapy. ShK(L5) prevents and treats experimental autoimmune encephalomyelitis and suppresses delayed type hypersensitivity in rats. ShK(L5) might prove useful for therapy of autoimmune disorders.

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Traditional right ventricular (RV) pacing for the management of bradyarrhythmias has been pursued successfully for decades, although there remains debate regarding optimal pacing site with respect to both hemodynamic and clinical outcomes. The deleterious effects of long-term RV apical pacing have been well recognized. This has generated interest in approaches providing more physiological stimulation, namely, His bundle pacing (HBP). This paper reviews the anatomy of the His bundle, early clinical observations, and current approaches to permanent HBP. By stimulating the His-Purkinje network, HBP engages electrical activation of both ventricles and may avoid marked dyssynchrony. Recent studies have also demonstrated the potential of HBP in patients with underlying left bundle branch block and cardiomyopathy. HBP holds promise as an attractive mode to achieve physiological pacing. Widespread adaptation of this technique is dependent on enhancements in technology, as well as further validation of efficacy in large randomized clinical trials.

Kv1.3 potassium channels maintain the membrane potential of effector memory (T EM ) T cells that are important mediators of multiple sclerosis, type 1 diabetes mellitus, and rheumatoid arthritis. The polypeptide ShK-170 (ShK-L5), containing an N-terminal phosphotyrosine extension of the Stichodactyla helianthus ShK toxin, is a potent and selective blocker of these channels. However, a stability study of ShK-170 showed minor pH-related hydrolysis and oxidation byproducts that were exacerbated by increasing temperatures. We therefore engineered a series of analogs to minimize the formation of these byproducts. The analog with the greatest stability, ShK-192, contains a nonhydrolyzable phosphotyrosine surrogate, a methionine isostere, and a C-terminal amide. ShK-192 shows the same overall fold as ShK, and there is no evidence of any interaction between the N-terminal adduct and the rest of the peptide. The docking configuration of shows the N-terminal para-phosphonophenylalanine group lying at the junction of two channel monomers to form a salt bridge with Lys 411 of the channel. ShK-192 blocks Kv1.3 with an IC 50 of 140 pM and exhibits greater than 100-fold selectivity over closely related channels. After a single subcutaneous injection of 100 g/kg, ϳ100 to 200 pM concentrations of active peptide is detectable in the blood of Lewis rats 24, 48, and 72 h after the injection. ShK-192 effectively inhibits the proliferation of T EM cells and suppresses delayed type hypersensitivity when administered at 10 or 100 g/kg by subcutaneous injection once daily. ShK-192 has potential as a therapeutic for autoimmune diseases mediated by T EM cells.

The strategic use of remote pacemaker interrogation follow-up detects actionable events that are potentially important more quickly and more frequently than transtelephonic rhythm strip recordings. The use of transtelephonic rhythm strips for pacemaker follow-up is of little value except for battery status determinations. (PREFER [Pacemaker Remote Follow-up Evaluation and Review]; NCT00294645).

BackgroundWe developed and validated a heart failure (HF) risk score combining daily measurements of multiple device-derived parameters.MethodsHeart failure patients from clinical studies with implantable devices were used to form two separate data sets. Daily HF scores were estimated by combining changes in intra-thoracic impedance, atrial fibrillation (AF) burden, rapid rate during AF, %CRT pacing, ventricular tachycardia, night heart rate, heart rate variability, and activity using a Bayesian model. Simulated monthly follow-ups consisted of looking back at the maximum daily HF risk score in the preceding 30 days, categorizing the evaluation as high, medium, or low risk, and evaluating the occurrence of HF hospitalizations in the next 30 days. We used an Anderson–Gill model to compare survival free from HF events in the next 30 days based on risk groups.ResultsThe development data set consisted of 921 patients with 9790 patient-months of data and 91 months with HF hospitalizations. The validation data set consisted of 1310 patients with 10 655 patient-months of data and 163 months with HF hospitalizations. In the validation data set, 10% of monthly evaluations in 34% of the patients were in the high-risk group. Monthly diagnostic evaluations in the high-risk group were 10 times (adjusted HR: 10.0; 95% CI: 6.4–15.7, P < 0.001) more likely to have an HF hospitalization (event rate of 6.8%) in the next 30 days compared with monthly evaluations in the low-risk group (event rate of 0.6%).ConclusionAn HF score based on implantable device diagnostics can identify increased risk for HF hospitalization in the next 30 days.