Eugen C. Palma

A minK-HERG complex regulates the cardiac potassium current I(Kr).

MinK is a widely expressed protein of relative molecular mass ∼15K that forms potassium channels by aggregation with other membrane proteins. MinK governs ion channel activation, regulation by second messengers,, and the function and structure of the ion conduction pathway,. Association of minK with a channel protein known as KvLQT1 produces a voltage-gated outward K+ current (IsK) resembling the slow cardiac repolarization current (IKs),. HERG, a human homologue of the ether-a-go-go gene of the fruitfly Drosophila melanogaster, encodes a protein that produces the rapidly activating cardiac delayed rectifier (IKr),. These two potassium currents, IKs and IKr, provide the principal repolarizing currents in cardiac myocytes for the termination of action potentials,. Although heterologously expressed HERG channels are largely indistinguishable from native cardiac IKr, a role for minK in this current is suggested by the diminished IKr in an atrial tumour line subjected to minK antisense suppression. Here we show that HERG and minK form a stable complex, and that this heteromultimerization regulates IKr activity. MinK, through the formation of heteromeric channel complexes, is thus central to the control of the heart rate and rhythm.

Cyclic AMP regulates the HERG K+ channel by dual pathways

Lethal cardiac arrhythmias are a hallmark of the hereditary Long QT syndrome (LQTS), a disease produced by mutations of cardiac ion channels [1]. Often these arrhythmias are stress-induced, suggesting a relationship between beta-adrenergic activation of adenylate cyclase and cAMP-dependent alteration of one or more of the ion channels involved in LQTS. Second messengers modulate ion channel activity either by direct interaction or through intermediary kinases and phosphatases. Here we show that the second messenger cAMP regulates the K(+) channel mutated in the LQT2 form of LQTS, HERG [2], both directly and indirectly. Activation of cAMP-dependent protein kinase (PKA) causes phosphorylation of HERG accompanied by a rapid reduction in current amplitude, acceleration of voltage-dependent deactivation, and depolarizing shift in voltage-dependent activation. In a parallel pathway, cAMP directly binds to the HERG protein with the opposing effect of a hyperpolarizing shift in voltage-dependent activation. The summation of cAMP-mediated effects is a net diminution of the effective current, but when HERG is complexed with with the K(+) channel accessory proteins MiRP1 or minK, the stimulatory effects of cAMP are favored. These findings provide a direct link between stress and arrhythmia by a unique mechanism where a single second messenger exerts complex regulation of an ion channel via two distinct pathways.

Atrial fibrillation ablation : Reaching the mainstream

Introduction and Aims: Ablation of atrial fibrillation (AF) has evolved rapidly in the decade since its inception. We aimed to review the results of this evolution as reflected in the published literature.

Insulation lead failure: Is it a matter of insulation coating, venous approach, or both?

Lead insulation material and implant route have a major impact on lead realiability and durability. We compare the incidence of lead insulation failure resulting from both the venous approach and insulation type. Two hundred ninty consecutive leads were followed for a mean period of 57 ± 30 months; leads with < 1 year follow‐up were excluded. There were 116 Silicone Rubber insulated leads and 174 with polyurethane (151 Pellethane 80A and 23 Pellethane 55D) insulation; 279 leads were bipolar and 11 unipolar; 274 leads were implanted in the ventricle and 66 in the atrium. The venous route was the subclavian vein for 170 leads (58%) and the cephalic vein for 120 leads (42%). Insulation failure was diagnosed when a single sign of oversensing, undersensing, failure to capture, early pulse battery depletion, and lead impedance < 250 Ω was present. Measurement of lead impedance was performed intraopera‐tively at implantation and during lead revision or pulse generator replacement. Lead failure caused by conductor coil fracture was not considered. There were 13 lead insulation failures, all among leads with polyurethane insulation (12 Pellethane 80A and 1 Pellethane 55D). Eleven failures (10%) occurred when the subclavian vein and 2 (3%) when the cephalic vein approach was used. The cumulative survival rate of polyurethane and silicone rubber insulated leads was 88.7% and 100%, respectively (P = 0.02); the cumulative survival rate of polyurethane insulated leads was 83.2% when the subclavian vein and 95.1% when the cephalic vein were used (P = 0.03). The mean time to polyurethane lead failure when the subclavian vein approach was used was 54 ± 17 months and when the cephalic route was 73 ± 4 months (P < 0.02). By multivariate analysis, the route of entry was found to be a significant variable related to polyurethane insulated lead failure (P < 0.05). At lead revision failure to capture was present in 7, over‐sensing in 4, and undersensing in 2 instances; impedance was < 250 Ω in all cases. Pellethane 80A insulated leads are prone to insulation failure, but more when the subclavian vein is used, rather than the cephalic vein.

Pacemakers and implantable cardioverter defibrillators: device longevity is more important than smaller size: the patient's viewpoint.

The size of pacemakers and implantable cardioverter defibrillators (ICDs) has been diminishing progressively. If two devices are otherwise identical in components, features and technology, the one with a larger battery should have a longer service life. Therefore, patients who receive smaller devices may require more frequent surgery to replace the devices. It is uncertain whether this tradeoff for smaller size is desired by patients. We surveyed 156 patients to determine whether patients prefer a larger, longer‐lasting device, or a smaller device that is less noticeable but requires more frequent surgery. The effects of subgroups were evaluated; these included body habitus, age, gender, and patients seen at time of pulse generator replacement (PGR), initial implant, or follow‐up. Among 156 patients surveyed, 151 expressed a preference. Of these, 90.1% preferred the larger device and 9.9% the smaller device (P < 0.0001). Among thin patients, 79.5% preferred a larger device. Ninety percent of males and 89.2% of females selected the larger device. Among younger patients (≤72 years), 89.6% preferred the larger device, as did 90.5% of older patients (>72 years). Of patients undergoing PGR or initial implants, 95% favored the larger device, as did 86% of patients presenting for follow‐up. The vast majority of patients prefer a larger device to reduce the number of potential replacement operations. This preference crosses the spectrum of those with a previously implanted device, those undergoing initial implants, those returning for routine follow‐up, and patients of various ages, gender, and habitus.

A Left Hemiblock Improves Cardiac Resynchronization Therapy Outcomes in Patients With a Right Bundle Branch Block

The current recommendation for cardiac resynchronization therapy (CRT) in congestive heart failure (CHF) patients is based on QRS duration, not on QRS morphology.

Value of Pre-Hospital Discharge Defibrillation Testing in Recipients of Implanted Cardioverter Defibrillators

Opinions vary regarding the need to perform defibrillation testing prior to hospital discharge in recipients of state‐of‐the‐art cardioverter defibrillators (ICDs). Our protocol is to perform predischarge ICD testing 1 day after implant. This report includes 682 consecutive implants. Adverse observations at testing were grouped into (1) risk of defibrillation failure, (2) surgical complications, (3) sensing/pacing issues or narrow defibrillation margin warranting closer follow‐up, or (4) findings correctable by device reprogramming. Among the 682 patients, 63% had single‐chamber and 37% dual‐chamber or biventricular ICDs. In 48 patients (7%) there were 69 concerns and/or interventions, with overlaps among the four categories, including one failure to defibrillate (0.15%), and six other patients at risk. Surgical complications included 11 hematomas (1.6%), and six lead dysfunctions. Closer follow‐up was indicated in 19 patients (2.7%), for high pacing thresholds in seven, sensing issues in seven, and <10 J defibrillation margin in five. Device reprogramming was needed in 31 patients (4.5%), for tachycardia detection and therapy settings in 12, and for pacing/sensing functions in 22 patients. In eight patients ventricular fibrillation could not be induced. There was no morbidity or mortality due to testing. The state‐of‐the‐art ICDs delivering biphasic shocks are remarkably reliable. The routine pre‐hospital discharge defibrillation testing of such ICDs may be optional and left to the physicians’ discretion.

Runaway pulse generator malfunction resulting from undetected battery depletion.

VIJAYARAMAN, P., et al.: Runaway Pulse Generator Malfunction Resulting from Undetected Battery Depletion. Runaway pacemaker is an uncommon, potentially lethal circuit malfunction characterized by sudden onset of erratic pacing at rapid nonphysiological rates. Two patients with a single chamber pacemaker (Medtronic ST 8331 and 8419) presented with episodic dizziness. ECG revealed recurrent decrescendo amplitude episodes of runaway stimuli at 2,400 and 2,600 ppm, approximately 3 seconds in duration, separated by pacing at 62.5 and 65 ppm, respectively. Fortunately the runaway stimuli were subthreshold and did not result in capture of the ventricle. Emergency pulse generator replacement was uneventful. Both leads were normal and both pulse generators had low battery voltages at 1.488 and 1.78 V, respectively.

Lead Stuck (Frozen) in Header: Salvage by Bone Cutter Versus Other Techniques

It is occasionally difficult to disconnect leads from headers at the time of pulse generator replacement without injuring the fragile leads. Over a 2.5‐year period we encountered this problem in six cases (1.7% of pulse generator replacements). The posterior portion of the header was clipped off using an orthopedic bone cutter in four cases. The cut was aligned with the deep end of the lead socket in the header. A metal rod was then used to push the lead out of the socket. Bench testing of alternative methods was done on previously explanted pulse generators that were firmly held in a vice. Motorized microtools were used to drill holes from the end of the header to the deep end of the socket; or with a rotary saw attachment to slice off the back of the header, allowing a retained lead to be pushed out. The latter was also done with a hand held razor saw, and attempts were made with a scalpel. Lead removal in the clinical cases was accomplished quickly in the four cases using the bone‐cutter, without trauma to the lead. Bench testing results varied. The bone cutter was the most efficient method for most brands, but was ineffective on one. The motorized tool was difficult to position, produced sprays of plastic particles, and would have been risky in a clinical setting. The razor saw was difficult to use safely, or efficiently, except in some headers that resisted the bone cutter. The scalpel failed except in one “soft header” pacemaker. An orthopedic bone cutter is a useful tool for removing a retained lead from a pulse generator header. Different header designs and materials necessitate knowledge of several lead detachment methods.

Histopathological correlation of ablation lesions guided by noncontact mapping in a patient with peripartum cardiomyopathy and ventricular tachycardia.

PALMA, E.C., et al.: Histopathological Correlation of Ablation Lesions Guided by Noncontact Mapping in a Patient with Peripartum Cardiomyopathy and Ventricular Tachycardia. A patient with peripartum cardiomyopathy developed a nearly incessant nonsustained VT. Guided by a noncontact mapping system, the tachycardia was mapped to the mid‐septum of the right ventricle and ablated. Despite transient success, the tachycardia recurred and the patient subsequently died of multiorgan failure. Histopathological correlation of the ablation site revealed a nontransmural lesion that may have contributed to the failure of the ablation.