Bridging a Temporary High Risk of Sudden Arrhythmic Death. Experience with the Wearable Cardioverter Defibrillator (WCD)

The implantable cardioverter defibrillator (ICD) is able to reduce sudden arrhythmic death in patients who are considered to be at high risk. However, the arrhythmic risk may be increased only temporarily as long as the proarrhythmic conditions persist, left ventricular ejection fraction remains low, or heart failure prevails. The wearable cardioverter defibrillator (WCD) represents an alternative approach to prevent sudden arrhythmic death until either ICD implantation is clearly indicated or the arrhythmic risk is considered significantly lower or even absent. The WCD is also indicated for interrupted protection by an already implanted ICD, temporary inability to implant an ICD, and lastly refusal of an indicated ICD by the patient. The WCD is not an alternative to the ICD, but a device that may contribute to better selection of patients for ICD therapy. The WCD has the characteristics of an ICD, but does not need to be implanted, and it has similarities with an external defibrillator, but does not require a bystander to apply lifesaving shocks when necessary. The WCD was introduced into clinical practice about 8 years ago, and indications for its use are currently expanding. This article describes the technological aspects of the WCD, discusses current indications for its use, and reviews the clinical studies with the WCD. Additionally, data are reported on the clinical experience with the WCD based on 354 patients from Germany hospitalized between 2000 and 2008 who wore the WCD for a mean of 3 months. (PACE 2010; 33:353–367)     

Cardiac Resynchronization Therapy Device Implantation in Patients with Therapeutic International Normalized Ratios

Background: Many patients who need cardiac resynchronization therapy (CRT) require chronic anticoagulation. Current guidelines recommend discontinuation of warfarin and the initiation of anticoagulant “bridging” therapy during these procedures. We evaluated the safety of CRT‐device (CRT‐D) implantation without interruption of warfarin therapy. Methods: A total of 123 consecutive patients requiring CRT‐D therapy were enrolled, 49 identified as high risk for thromboembolic events who received either intravenous heparin, low molecular weight heparin, or warfarin therapy. The control group comprised 74 patients with low risk of thromboembolic events who required only cessation of warfarin perioperatively. Patients were evaluated at discharge and 15 and 30 days postoperatively for pocket hematomas, thromboembolic events, and bleeding. Patients’ length of stay was also catalogued. Results: Patients in the bridging arm had a significant increase in the rate of pocket hematomas (4.1%[control] vs 5.0%[warfarin] vs 20.7%[bridging], P = 0.03) and subsequent longer length of stay (1.6 ± 1.6 [control] vs 2.9 ± 2.7 [warfarin] vs 3.7 ± 3.2 [bridging], P < 0.001). Hematoma formation postoperatively was not different among patients undergoing an upgrade procedure versus those without preexisting cardiac rhythm devices (12% vs 6.2%, P = NS). Patients with a prosthetic mechanical mitral valve had a higher incidence of pocket hematoma formation (1.8% vs 20%, P = 0.03). Conclusions: Our findings suggest that implantation of CRT‐Ds without interruption of warfarin therapy in patients at high risk of thromboembolic events is a safe alternative to routine bridging therapy. This strategy is associated with reduced risk of pocket hematomas and shorter length of hospital stay. (PACE 2010; 400–406)     

The Effect of an 11.5-hr/Day Exposure Schedule on the Distribution and Toxicity of Inhaled Carbon Tetrachloride in the Rat

The Effect of an 11.5-hr/Day Exposure Schedule on the Distributionand Toxicity of Inhaled Carbon Tetrachloride in the Rat. PAUSTENBACH,D. J., CHRISTIAN, J. E., CARLSON, G. P., AND BORN, G. S. (1986),Fundam. Appl. Toxicol. 6,472–483. This study evaluatedthe differences in toxicity and tissue distribution for 16 groupsof male rats repeatedly exposed to 100 ppm of ¹⁴CCl₄ vaporsfor 8 or 11.5 hr/day for periods of 1 to 10 days. Serum sorbitoldehydrogenase (SDH) was also evaluated for its sensitivity atdetecting CCl₄-induced hepatotoxicity. Following 1, 2, 3, 4,5, 7, 11, and 14 days, one group of rats from each exposureschedule was sacrificed and ¹⁴C activity in seven tissues andserum SDH levels were measured. To compare the effects of CCl₄on the liver and kidney following repeated exposure to the twoschedules, one group of rats was exposed for 8 hr/day for 10of 12 consecutive days and another for 11.5 hr/thy for 7 of12 consecutive days so that each group received essentiallythe same dose (8000 ppm-hr) of CCl₄. The 11.5- hr/day exposureschedule, compared to rats exposed 8-hr/day, produced minorchanges in the distribution and concentration of ¹⁴C (CCl₄ equivalents)in various tissues. Following 1 and 2 weeks of exposure to eitherschedule, the fat, liver, lungs and adrenals had the highestconcentration of CCl₄ equivalents. There were no significantdifferences in CCl₄-induced hepatotoxicity or nephrotoxicitybetween rats exposed to the two schedules following either 1or 2 weeks of exposure as measured by histopathology. In contrast,rats exposed 11.5 hr/day had significantly higher SDH levelsthan those exposed to the 8-hr/thy schedule; thus suggestingthat the 11.5-hr schedule did produce a measurably greater degreeof hepatotoxicity, although it was too subtle to detect pathologically.Rats exposed for a fourth and fifth thy during the second weekof the 11.5-hr schedule had a significantly greater concentrationof ¹⁴C activity in the fat than rats exposed to the 8-hr/dayschedule as well as severe fatty infiltration of the liver andhigher serum SDH activity. This study demonstrated that SDHis a very useful assay for detecting subtle changes in liverinjury as compared to histopathology. It was also shown thateven at relatively low vapor concentrations, modest changesin dosage regimen, like those involving unusual (e.g., 10- orl2-hr/ day) work schedules, can have a measurable effect onthe distribution of the chemical and the degree of toxicity.These results support published recommendations which suggestthat for persons working long shifts, occupational exposurelimits for systemic toxicants with half-lives between 4 and200 hr be reduced so that these persons will have the same marginof safety from any adverse effects.     

Side reaction during the deprotection of (S-acetamidomethyl)cysteine in a peptide with a high serine and threonine content

The acetamidomethyl (Acm) group is a widely used protecting group for the thiol of cysteine during the SPPS process. We prepared the amino terminal loop of the snake α-neurotoxin, [Cys³, Cys²³, Ser¹⁷(1–24) amide, from the linear peptide [Cys(Acm)^3,23,Ser¹⁷](1–24) amide obtained by SPPS. Three different methods of deprotection of Cys(Acm) and disulfide bond formation were used: iodine, thallium(III) trifluoroacetate and mercuric acetate/potassium ferricyanide. The iodine method failed to yield the expected peptide, and gave instead the mono-iodinated tyrosine analog. The disulfide cyclized peptide obtained by thallium(III) or Hg(II) procedures displayed a MW value observed by mass spectrometry that was higher than the calculated value. The difference (MW_obs - MW_calc) corresponded to a multiple of the Acm moiety, which is shifted intra-and/or intermoleculary. Furthermore, we observed, in addition to the Acm shift in the disulfide cyclized decapeptide with a high Ser and Thr content (model peptide II), the dimerization phenomenon in the Tl(TFA)₃ process. Therefore we conclude that a side reaction, a S–O(Ser,Thr) Acm shift, occured during the Cys(Acm) deprotection. This shift was supported by the demonstration of Ser(O-Acm) formation in the reaction of Boc-(L)-Cys(Acm) with Tl(TFA)₃ in the presence of an equimolar amount of (L)Ser. We report here the efficiency of a trivalent alcohol, glycerol, as scavenger in the both Tl(TFA)₃ and mercuric/ferricyanide methods, in an attempt to circumvent this side-reaction during the disulfide bond formation step starting from a bis-Cys(Acm) peptide with a high Ser and Thr content, such as the N-terminal loop of neurotoxin, model peptide II or a similar peptide.     

Developmental Toxicology Studies of Vancomycin Hydrochloride Administered Intravenously to Rats and Rabbits

Pregnant CD rats were given vancomycin intravenously in dosesof 0, 40, 120, or 200 mg/kg on Gestation Days (GD) 6–15;pregnant New Zealand white rabbits were given 0, 40, 80, or120 mg/kg intravenously on GD 6–18. Cesarean sectionswere performed on rats and rabbits on GD 20 and 28, respectively.In rats, maternal toxicity was indicated in the 120- and 200-mg/kgtreatment groups by cortical tubular nephrosis. Maternal bodyweight gain and food consumption and fetal viability, weight,and morphology were not adversely affected by vancomycin. Maternaland developmental no observed adverse effect levels (NOAELs)in the rat were 40 and 200 mg/kg, respectively. In rabbits,maternal toxicity was indicated by cortical tubular nephrosisin the 80- and 120-mg/kg treatment groups; a single death anddepression of body weight gain and food consumption occurredin the 120-mg/kg treatment group. Developmental toxicity wasindicated by depression of fetal weight in the 120-mg/kg treatmentgroup; fetal viability and morphology were not adversely affectedby vancomycin. Maternal and developmental NOAELs in the rabbitwere 40 and 80 mg/kg, respectively. Based on these data, vancomycindid not exhibit selective toxicity toward the developing rator rabbit conceptus.     

Developmental Toxicity Study of Clarified Slurry Oil (CSO) in the Rat

Pregnant CD rats were exposed dermally to 0.05, 1, 10, 50, and250 mg/kg/day of Clarified Slurry Oil (CSO) on Days 0–19of gestation to determine its potential developmental toxicity.Untreated and vehicle controls were included in the study. Day20 of gestation Caesarean-derived fetuses were examined forgross, external, and visceral or skeletal alterations. Dosagesof 1 mg/kg/day and higher significantly decreased maternal bodyweight, body weight gain, feed consumption, gravid uterine weight,and live litter size and significantly increased resorptionrate. These dosages also significantly reduced fetal weightsand retarded development of the brain, kidney, thoracic andcaudal vertebrae, metacarpals, and hindpaw phalanges in dosagegroups with live fetuses (high dosage group dams resorbed allconceptuses). The 50- and 250-mg/kg/day dosage group dams hadonly placentas and/or dark red viscous fluid in the uterus orvagina and significant body weight loss (associated with resorption).The highest dosage also caused emaciation, slight dehydration,and swollen dark anogenital areas. These results indicate thatCSO produces adverse developmental effects at maternally toxicdosages. The maternal and developmental NOAELs (no observedadverse effect levels) were 0.05 mg/kg/day. In a second study,groups of 10 mated female rats were exposed to "pulse" exposuresand dosages of 1, 50, or 250 mg/kg/day of CSO applied dermallyfor 2- or 3-day intervals that spanned the gestation period.All dosages reduced maternal feed consumption and body weightgain during the treatment period. Dosages of 50 and 250 mg/kg/dayalso produced early resorptions when administered on Days 6through 8 and 9 through 11 of gestation. However, no increasein fetal alterations occurred, indicating that the effects onembryo–fetal development were due to early death and notto the death of malformed conceptuses.     

Stability of subtilisins and related proteinases (subtilases)

The stability towards thermal and chemical (guanidine hydrochloride, GnHCl) denaturation of six inhibited subtilases (mesentericopeptidase, subtilisins BPN′, Carlsberg and DY, proteinase K and thermitase) has been investigated by kinetic and equilibrium studies. The unfolding processes were monitored by circular dichroic and fluorescence spectroscopy. Experiments in the absence and presence of extraneous calcium in the concentration range 2×10^?3-10^?1 M were performed. The presence of calcium in the weak calcium binding site changes the denaturation drastically. The heat- (or GnHCl-) induced unfolding curves obtained using CD spectroscopy show two independent transitions which seem not to have been resolved before. The presence of Ca²⁺ in the second (third in the case of thermitase) binding site increases the T_m, values by 11-21 °C and the δG_D(H₂O) values obtained from denaturation experiments in GnHCl by 6.7-7.2 kcal/mol when an extraneous Ca²⁺ concentration of 2 × 10^?2 M was used. One interpretation is that the initial step of denaturation in the presence of added calcium is the formation of a partially unfolded intermediate form, retaining a highly ordered structure with 60-85% of the a-helix structure of the native enzyme. This intermediate then unfolds at a temperature considerably higher than that of the same proteinases in the absence of added Ca²⁺. The free energy of stabilization of the intermediates is increased by 1.8-2.8 times in comparison with that for the unfolding reactions of the subtilases with empty Ca2/Ca3 binding sites. A second interpretation is that the two steps in the unfolding curves correspond to enzyme without and with calcium in the weak binding site. Fluorescence experiments confirm the mechanism involving the formation of intermediate states. The results are discussed in relation to the X-ray models of the six subtilases.