Postprandial induction of chaperone gene expression is rapid in mice.

Molecular chaperones assist in the biosynthesis and processing of proteins. Most chaperones are induced by physiological stresses. We have shown that dietary energy restriction decreases the mRNA and protein levels of many endoplasmic reticulum chaperones in the livers of mice. Here, we have investigated the response of chaperone mRNA to feeding. Control and 50% energy-restricted C3B10RF1 mice were deprived of food for 24 h, fed, and killed 0, 1.5, 5 or 12 h after feeding. Chaperone mRNAs were strongly induced as early as 1.5 h after feeding in control and energy-restricted mice. The integrated levels of these mRNA over 24 h were significantly lower in energy-restricted mice. The mRNA response to energy intake was mirrored over the course of days in the level of chaperone protein. A similar but smaller response to feeding was found in kidney and muscle. Puromycin and cycloheximide failed to inhibit the feeding response, suggesting that feeding releases chaperone expression from an unstable inhibitor. Studies with dibutyryl-cAMP- and glucagon-supplemented, normal and streptozotocin-diabetic mice suggest that glucagon and insulin may be mediators of the feeding response. Adrenalectomy enhanced the feeding induction, but dexamethasone administration had no effect. Thus, postprandial changes in insulin and glucagon may link chaperone gene expression to feeding, possibly in several tissues including liver.     

Marked Q-T prolongation due to encainide therapy

Summary Encainide is a type Ic antiarrhythmie agent. During encainide therapy, mild Q-T interval prolongation can be seen, usually associated with prolongation of the Q-R-S interval. The present case report describes an unusual and marked prolongation of the Q-T interval with no Q-R-S interval prolongation in a patient who was treated with encainide for atrioventricular nodal reentrant tachycardia. The drug metabolite profile in this patient's serum indicated an unusual elevation of the 3-methoxy-O-demethyl encainide metabolite, versus O-demethyl encainide. This elevated metabolite level suggests that 3-methoxy-O-demethyl encainide has a significant effect on prolongation of repolarization. An abnormal metabolism of encainide may be the underlying mechanism by which some patients would manifest an unusual prolongation of Q-T interval during encainide therapy.     

Femoral prosthesis implantation induces changes in bone stress that depend on the extent of porous coating

The objective of this study was to evaluate the effect of implantation of porous-coated anatomic medullary fitting prostheses on stress in the proximal femur. Three-dimensional finite element models of a cadaveric femur before and after implantation were used to evaluate the resulting changes in stress in the bone. Models of the femur were generated automatically from computed tomographic scan data with use of an innovative mesh-generation technique. The models were analyzed for three levels of porous coating (proximal, 5/8, and full), with the assumption of ideal ingrowth (perfect bonding) over porous areas and a frictionless, tension-free surface on smooth areas. All models were loaded and restrained to represent conditions of normal gait. The stresses predicted in the implanted femur are consistent with clinical observations of proximal cortical atrophy (normal stress reduced to 6-9% of normal at the calcar and 50–55% at mid-prosthesis) and of hypertrophy at the porous coating junctions (normal stress at the 5/8-coating junction, 123% of stress proximal to the junction) and hypertrophy near the distal tip of the prosthesis (anterior and posterior normal stresses 200–800% of normal). The fully coated prosthesis induced stresses in the bone near the tip of the prosthesis that were most like stresses in the normal femur (medial and lateral normal stress 105 and 102% of the stress in the normal femur). Below the collar, the normal stress associated with the proximally coated prosthesis was 6% greater than that produced with the other two levels of coating but still was only 2% of normal. The 5/8-coated prosthesis appeared to combine the worst features of the fully coated and proximally coated prostheses–greater stress-shielding at the calcar and higher stress near the tip of the prosthesis.     

SNP S1103Y in the cardiac sodium channel gene SCN5A is associated with cardiac arrhythmias and sudden death in a white family

Cardiac arrhythmias cause 400 000 sudden deaths annually in the United States alone. Mutations in the cardiac sodium channel gene SCN5A on chromosome 3p21 cause cardiac arrhythmias and sudden death. In this study, we define an SCN5A mutation, S1103Y, in a white family associated with syncope, ventricular fibrillation, and sudden death. A very recent study reported the same mutation in 13.2% of African Americans, but not in the white population. Our study shows that mutation S1103Y does exist in the white population, and it is associated with a considerable risk of syncope, ventricular arrhythmia, ventricular fibrillation, and sudden death in this population.     

Electrophysiological determinants of antidromic reentry induced during atrial extrastimulation. Insights from a pacing model of Wolff-Parkinson-White syndrome

The electrophysiology of antidromic reentry, a less common phenomenon than orthodromic reentry, remains a poorly understood aspect of the Wolff-Parkinson-White (WPW) syndrome. We used a pacing model of ventricular preexcitation in patients without WPW, so that electrophysiological events in the normal pathway during atrial extrastimulation (A1-A2 technique) could be precisely delineated without the obscuring effect of an actual accessory pathway. Ventricular preexcitation was simulated by an A1-V1 sequential basic drive with A2-V2 extrastimulation at progressively shorter A1-A2 (equal to V1-V2) coupling intervals. At each coupling interval tested within the zone of atrioventricular (A-V) nodal effective refractory period (since anterograde block of A2 was considered mandatory for manifestation of antidromic reentry), responses were assessed after A2 alone (method I), V2 alone (method II), and A2 plus V2 (method III, the complete preexcitation model). The entire pacing protocol was performed at two A-V intervals, short (50 msec) and long (150-180 msec), thereby simulating different proximities between the A pacing site and "accessory pathway" location. Of 47 consecutive unmedicated patients screened for the study protocol, 38 failed to meet minimal prerequisites for possible initiation of antidromic reentry because of failure in 18 (38% of total) to achieve anterograde A-V nodal block of A2, even though 1:1 ventriculoatrial conduction to cycle lengths less than or equal to 500 msec (less than or equal to 400 msec in 12) was present; and poor or absent ventriculoatrial conduction in the others. The nine remaining candidates underwent the full pacing protocol. Antidromic reentry (retrograde atrial response following V2 in method III) was observed in only two cases (4% of total), and both were associated with retrograde His-Purkinje system delays (documented by method II) occurring in tandem with a long A-V interval, thereby allowing for completion of retrograde A-V nodal recovery after penetration by A2. Indeed, such a prolonged recovery time prevented initiation of antidromic reentry in six of the nine patients (proven by intact ventriculoatrial conduction in method II). Retrograde A-V nodal block of V2, independent of A2, prevented an antidromic echo in one case. Findings in our model help to clarify the various factors, including specific anterograde and retrograde A-V nodal properties; anatomic relation between the accessory and normal pathways; and the retrograde His-Purkinje system delays, that must prevail in a concerted fashion to permit the initiation of antidromic reentry during the A1-A2 technique in patients with the WPW syndrome.     

Electrophysiologic mechanisms of orthodromic tachycardia initiation during ventricular pacing in the Wolff-Parkinson-White syndrome

Orthodromic tachycardia is the most common arrhythmia in patients with Wolff-Parkinson-White syndrome. It is often initiated during incremental ventricular pacing that requires the onset of retrograde block along the normal pathway (that is, atrioventricular [AV] node-His-Purkinje system) with concomitant retrograde atrial activation by way of the accessory pathway. However, the site of retrograde block, that is, the AV node versus the His-Purkinje system, during incremental ventricular pacing and, hence, the mechanism of orthodromic tachycardia initiation have not been systematically elucidated. The mechanisms of orthodromic tachycardia induction were studied in 17 patients with Wolff-Parkinson-White syndrome using a specially designed pacing protocol. A beat by beat analysis indicated that the retrograde His-Purkinje system block was the most common initiating mechanism of orthodromic tachycardia in 14 of the 17 cases. In two cases, AV node block preceded the onset of orthodromic tachycardia, whereas the data in the remaining case suggested that both mechanisms were operative but at different pacing cycle lengths. The orthodromic tachycardia induction with His-Purkinje system block occurred within the first two cycles in most cases. When orthodromic tachycardia initiation was delayed beyond the first two cycles of the ventricular train it represented either a 2:1 block in the His-Purkinje system; a linking phenomenon in the His-Purkinje system; or a block in the AV node. These data have methodologic, mechanistic and therapeutic implications for patients with the Wolff-Parkinson-White syndrome.     

Safety and efficacy of radiofrequency energy catheter ablation of atrial fibrillation in patients with pacemakers and implantable cardiac defibrillators

BACKGROUND: Catheter ablation has significantly transformed the clinical management of atrial fibrillation (AF). The safety and efficacy of this procedure are not well understood in patients with pacemakers and defibrillators. OBJECTIVES: The purpose of this study was to study the impact of radiofrequency catheter ablation of AF in patients with pacemakers and implantable cardiac defibrillators. METHODS: We studied 86 patients with pacemakers and defibrillators (group I) and a similar number of age- and gender-matched controls (group II) who underwent AF ablation between 1999 and 2004. Clinical and procedural variables were compared between the two groups. In group I, various generator and lead parameters were compared before and after the procedure. Resurgence of clinical AF after 2 months was considered recurrence. RESULTS: Both groups were similar with regard to age, gender, body mass index, and type of AF. Group I had a higher incidence of diabetes (17% vs 6%, P = .03), coronary artery disease (25% vs 13%, P = .05), less prolonged AF (31 +/- 21 vs 45 +/- 30 months, P <.001), lower left ventricular ejection fraction (49 +/- 13% vs 52 +/- 9%, P = .03), and left ventricular end-diastolic dimensions (4.97 +/- 0.81 vs 4.72 +/- 0.67, P = .03). No changes in the sensing and pacing thresholds, impedance of atrial and ventricular leads, or defibrillator coil impedance after AF ablation were observed in group I. Atrial lead dislodgment was seen in two patients. Transient abnormal but "expected" pulse generator behavior was seen in 25% of patients without permanent malfunction. Stroke (1% vs 1%, P = 1.000), pulmonary vein stenosis (2% vs 1%, P = .77), and AF recurrence rates at 12 months were similar between groups I and II, respectively (19% vs 21%, P = .73). CONCLUSION: AF ablation is safe and efficacious in patients with pacemakers and defibrillators.