Two-year experience with rate-modulated pacing controlled by mixed venous oxygen saturation

Mixed venous oxy-hemoglobin saturation (MVO2) is a physiological variable with several features that might be desirable as a control parameter for rate adaptive pacing. Despite these desirable characteristics, the long-term reliability of the MVO2 sensor in vivo is uncertain. We, therefore, designed a study to prospectively evaluate the long-term performance of a permanently implanted MVO2 saturation sensor in patients requiring VVIR pacing. Under an FDA approved feasibility study, eight patients were implanted with a VVIR pulse generator and a right ventricular pacing lead incorporating an MVO2 sensor. In order to accurately assess long-term stability of the sensor, patients underwent submaximal treadmill exercise using the Chronotropic Assessment Exercise Protocol (CAEP) at 2 weeks, 6 weeks, and 3, 6, 9, 12, 18, and 24 months following pacemaker implantation. Paired maximal exercise testing using the CAEP was also performed with the pacing system programmed to the VVI and VVIR modes in randomized sequence with measurement of expired gas exchange after 6 weeks and 12 months of follow-up. During maximal treadmill exercise the peak exercise heart rate (132 +/- 9 vs 71.5 +/- 5 beats/min, P < 0.00001) and maximal rate of oxygen consumption (1,704 +/- 633 vs 1382 +/- 407 mL/min, P = 0.01) were significantly greater in the VVIR than in the VVI pacing mode. Similarly, the duration of exercise was greater in the VVIR than the VVI pacing mode (8.9 +/- 3.6 min vs 7.6 +/- 3.7 min, P = 0.04). The resting MVO2 and the MVO2 at peak exercise were similar in the VVI and VVIR pacing modes (P = NS). However, the MVO2 at each comparable treadmill exercise stage was significantly higher in the VVIR mode than in the VVI mode (CAEP stage 1 (P = 0.005), stage 2 (P = 0.04), stage 3 (P = 0.008), and stage 4 (P = 0.04). The correlation between MVO2 and oxygen consumption (VO2) was excellent (r = -0.93). Telemetry of the reflectance of red and infrared light and MVO2 in the right ventricle during identical exercise workloads revealed no significant change over the first 12 months of follow-up (ANOVA, P = NS). The chronotropic response to exercise remained proportional to VO2 in all patients over the first 12 months of follow-up. The time course of change in MVO2 during maximal exercise was significantly faster than for VO2. At the 18- and 24-month follow-up exercise tests, a significant deterioration of the sensor signal with attenuation of chronotropic response was noted for 4 of the 8 subjects with replacement of the pacing system required in one patient because of lack of appropriate rate modulation. Rate modulated VVIR pacing controlled by right ventricular MVO2 provides a chronotropic response that is highly correlated with VO2. This parameter responds rapidly to changes in workload with kinetics that are more rapid than those of VO2. Appropriate rate modulation provides a higher MVO2 at identical workloads than does VVI pacing. Although the MVO2 sensor remains stable and accurate over the first year following implantation, significant deterioration of the signal occurs by 18-24 months in many patients.     

A prospective randomized trial of Teflon versus polyethylene stents for distal malignant biliary obstruction

BACKGROUND AND STUDY AIMS: Clogging of biliary stents continues to be a major clinical problem. Different polymer materials may have different effects on clogging. In vitro studies have shown a direct relation between the frictional coefficient of a polymer and the amount of encrusted material. Teflon appeared to be the best polymer for biliary stents. Two different types of stents made of Teflon have been tested in clinical practice and showed favourable patency rates. However, a randomized trial has never been performed. We compared the patency of an Amsterdam-type polyethylene stent with a Teflon stent in a prospective randomized trial. PATIENTS AND METHODS: Between September 1995 and November 1996, 42 patients received a Teflon stent and 42 patients a polyethylene stent. All patients had a distal malignant biliary stricture without a previous drainage procedure. Diagnoses included carcinoma of the pancreas (n = 76), papilla (n = 1), bile duct (n = 5) and metastases (n = 2). The internal and external diameter (10 Fr), length (9 cm) and stent design (a straight stent with two side flaps and one side hole at each end) were similar for both stents. RESULTS: A reduction in bilirubin of more than 20% within one week was seen in 91% of the patients. Early complication rates were similar in both groups (10%). The median follow-up was 142 days. Stent dysfunction occurred in 28 Teflon and 29 polyethylene stents. The thirty-day mortality was 14% in both groups. Patient survival did not differ significantly between the groups (median survival: Teflon 165 days, polyethylene 140 days). The median stent patency was 83 days for Teflon and 80 days for polyethylene stents, and was not significantly different either. CONCLUSION: Teflon material did not improve patency in biliary stents with an Amsterdam-type design.     

1H NMR investigation of distal mutant deoxy myoglobins. Interpretation of proximal His contact shifts in terms of a localized distal water molecule

1H NMR spectra of a series of distal point mutants of human and sperm whale deoxy myoglobin have been recorded and their spectral parameters compared with those of wild type. The substitutions investigated include His64(E7)-->Gly, Ala, Val, Leu, Ile, and Gln and Val68(E11)-->Ala, Ile. The three resonances from the proximal His F8 imidazole ring, as well as two heme methyl signals, are identified in each of the proteins. Significant perturbations of the NMR spectra of mutant deoxy myoglobins (Mbs) occurred only upon substitution of His64(E7) by any non-polar residue, with only minor variation in parameters throughout the range of side chains. These spectral changes are attributed to the elimination of a non-coordinated ordered water molecule in the distal pocket found hydrogen bonded to His64(E7) in crystals of wild-type deoxy Mb, but abolished in the His64(E7)-->Leu mutant deoxy Mb crystal (Quillin, M. L., Arduini, R. M., Olson, J. S., and Philips, G. N., Jr. (1993) J. Mol. Biol. 234, 140-155). The observed spectral changes, increased His F8 ring spin delocalization, and decreased heme in-plane asymmetry, can be directly attributed to the weakening of the effective axial field and a decrease in the asymmetry in the rhombic ligand field resulting from removal of the water molecule. The hyperfine shift patterns for the mutants His64(E7)-->Gln and Val68(E11)-->Ile deoxy Mbs are minimally perturbed from that of wild type and are interpreted to reflect a conserved distal water-binding site. In the point mutant Val68(E11)-->Ala, the decreased covalency to the axial His F8 is interpreted as reflecting a conserved distal water molecule that can interact more strongly with the iron due to the reduced steric bulk of the E11 side chain. The differential 1H NMR spectral parameters for the His F8 resonances in the two subunits of T state deoxy Hb A are shown to be similarly consistent with the known occupation of the distal water binding site in the alpha-, but not beta-subunit.     

In vitro cleavage of internally quenched fluorogenic human proparathyroid hormone and proparathyroid-related peptide substrates by furin. Generation of a potent inhibitor

The cleavage of parathyroid hormone (PTH) from its precursor proparathyroid hormone (pro-PTH) is accomplished efficiently by the proprotein convertase furin (Hendy, G. N., Bennett, H. P. J., Gibbs, B. F., Lazure, C., Day, R., and Seidah, N. G. (1995) J. Biol. Chem. 270, 9517-9525). We also showed that a synthetic peptide comprising the -6 to +7 sequence of human pro-PTH is appropriately cleaved by purified furin in vitro. The human pro-PTH processing site Lys-Ser-Val-Lys-Lys-Arg differs from the consensus furin site Arg-Xaa-(Lys/Arg)-Arg that is represented by Arg-Arg-Leu-Lys-Arg in the cleavage site of pro-PTH-related peptide (pro-PTHrP). An earlier study demonstrated that an internally quenched fluorogenic substrate bearing an O-aminobenzoyl fluorescent donor at the NH2 terminus and an acceptor 3-nitrotyrosine near the COOH terminus was appropriately cleaved by the convertases furin and PC1 (Jean, F., Basak, A., DiMaio, J., Seidah, N. G., and Lazure, C. (1995) Biochem. J. 307, 689-695). Here, we have synthesized a series of internally quenched fluorogenic substrates based upon the pro-PTH and pro-PTHrP sequences to determine which residues are important for furin cleavage. Purified recombinant furin and PC1 cleaved the human pro-PTH internally quenched substrate at the appropriate site in an identical manner to that observed with the nonfluorescent peptide. Several substitutions in the P6-P3 sequence were well tolerated; however, replacement of the Lys at the P6 position with Gly and replacement of the P3 Lys by an acidic residue led to markedly compromised cleavage by furin. Furin activity was very sensitive to substitution in P' positions. Replacement of Ser at P1' with Gly and Val at P2' with Ala generated substrates that were less well cleaved. Substitution at the P1' position of Val for Ser in conjunction with Ala for Val at P2', as well as a single substitution of Lys for Val at P2', generated specific inhibitors of furin cleavage. The findings of this study open the way to the rational design of inhibitors of furin with therapeutic potential.     

The NS gene--a possible determinant of apathogenicity of a cold-adapted donor of attenuation A /Leningrad/134/47/57 and its reassortants

Phenotypical properties of single-gene reassortants of attenuated cold-adapted strain A/Leningrad/135/47/57 (H2N2) and strain A/PR8/34 virulent for laboratory animals were studied. Only the group of reassortants inheriting NS gene from cold-adapted virus was fully attenuated for various animals species, similarly as reassortants with 6/2 genomic formula containing all the 6 internal protein genes from strain A/Leningrad/134/47/57. Reassortant 25A-1 single-gene for NS was temperature-sensitive (ts) on mammalian cells but formed plaques at 40 degrees C on chicken kidney cells. Reassortants with genomic formula 6/2 were temperature-sensitive in all types of cells used. Reassortant 25A-1 could synthesize normal amounts of polypeptides in MDCK cells at 39 degrees C, whereas protein synthesis of reassortants with 6/2 genomic formula was noticeably reduced at this temperature. Hence, a similar level of attenuation of both reassortant groups appears to be due to various molecular mechanisms. Possible role of NS2 gene mutation in attenuation of strain A/Leningrad/134/47/57 and its reassortants is discussed.     

Retrograde coronary venous infusion of ethanol for ablation of canine ventricular myocardium

INTRODUCTION: Permanent cure of reentrant ventricular tachycardia (VT) associated with coronary artery disease is difficult to achieve. Retrograde coronary venous infusion of ethanol for ablation of ventricular myocardium associated with reentrant tachyarrhythmias has several potential advantages, including use of physiologic mapping techniques and production of deeper, wider necrotic zones. METHODS AND RESULTS: Nine anesthetized dogs had baseline hemodynamic measurement, left ventriculography, coronary arteriography, occlusive coronary venography, and programmed electrical stimulation of the right ventricular apex and outflow tract. A balloon-tipped infusion catheter was advanced into a distal coronary venous branch, the balloon slowly inflated, and pure ethanol infused at volumes of 1.5, 3, or 5 cc. Hemodynamic measurements, angiography, ventriculography, and programmed electrical stimulation were repeated immediately and 1 week following ablation. Formalin-perfused hearts were serially sectioned and lesion volumes determined. Histologic examination of ablation beds then was performed. No significant difference was found in any hemodynamic measurement before or after ablation. Coronary arteriograms and left ventriculograms were unchanged after ablation. Nonsustained VT occurred in eight dogs during ethanol infusion; however, VT was not inducible in any dog before or after ablation. Infusion volumes of 3 cc or more were required to produce transmural lesions. CONCLUSION: Retrograde coronary venous infusions of ethanol using a balloon-tipped infusion catheter were effective in ablating ventricular myocardium. Retrograde chemical ablation did not itself result in inducible VT or adversely affect hemodynamic measurements or coronary arteries. Transmural myocardial necrosis, necessary in the ablation of VT associated with coronary artery disease, can be produced by higher infusion volumes.