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PubMed2004

Impact of liver transplantation on HRQOL in children less than 5 years old.

Our primary goal was to assess health related quality of life (HRQOL) at transplantation and 1 yr after transplantation in pediatric liver transplant patients aged less than 5 years. We conducted a prospective longitudinal study of HRQOL in pediatric liver transplant recipients, aged less than 5 years to define the impact of liver transplantation on HRQOL and identify factors that predict HRQOL after transplantation. The infant toddler health status questionnaire (ITHQ) was completed at the time of listing for liver transplantation and at 6 and 12 months after liver transplantation. The primary outcome measures were the subscale scores that comprise ITHQ. The mean age (+/-s.e.m.) of the enrolled patients (n = 45) at transplantation was 1.4 (+/-1.2) yr. Thirty-eight (84%) of the enrolled patients completed the study. The highest mean baseline scores of 78.6 (+/-3.3) were for global mental health (GlobalMH). ITHQ subscale scores increased steadily after transplantation. The greatest increase was in the first 6 months after transplant. At 1 yr after transplantation, there were significant increases in all of the ITHQ subscale scores except for GlobalMH. ITHQ subscales were similar for patients who received LDLT compared with those who received cadaver donor liver transplantation (CDLT) at baseline and a year after transplant. Time elapsed as transplantation was a significant predictor of functional health in all of the models generated. Scores for general health (GH), global health (GGH), parental time-impact (PT) and parental time-emotion (PE) were higher for male children. Family cohesion (FC) improved with time elapsed since transplant and increased number of inpatient days. HRQOL improves after transplantation in all of our patients irrespective of the donor type. Functional health scores were higher in patients with normal serum bilirubin at 1 yr post-transplant. Assessment of HRQOL should be an integral part of care for liver transplant patients and their caregivers.

Bilirubin↗
PubMed1986

Five-year performance of the Medtronic 6971 polyurethane endocardial electrode.

There is a considerable debate over the long-term performance of polyurethane electrodes. Observation to date has demonstrated surface cracking and some clinical failures in patients. Since 1978 we have implanted about 82 6971 Unipolar Medtronic electrodes in the ventricle. In 33 patients, lead integrity was assessed by chronic thresholds determined by decreasing pulse width and pulse amplitude. Sensing functions were assessed by electrocardiographic rhythm analysis. At a follow-up between 7 and 67 months, chronic thresholds at 2.50 volts were 0.08 +/- 0.04 milliseconds in 26 patients with Medtronic Pulse generators (Models 8423, 5985, and 7000). In two patients with similar units, no loss of capture was seen even at 0.05 milliseconds. Three patients, one with Cordis Unit (233F) showed loss of capture at 0.20 milliseconds at 2.00 MA, the other with a Pacesetter unit (255-6) showed loss of capture at 0.20 milliseconds, at 2.50 volts. One patient with Intermedics unit (283) lost capture at 0.07 milliseconds at 2.70 volts. Insulation breaks seen in two patients were demonstrated by pectoral stimulation and pacemaker oversensing. In addition, 24-hour long-term electrocardiographic monitoring was performed in 22 patients between 23 to 70 months. Appropriate pacemaker function was seen except in one patient who demonstrated oversensing. Interruption in insulation was demonstrated at the ligature site at exploration. Thus, in this series of patients who were paced in the ventricle by the 6971 Medtronic electrode, only two patients have demonstrated insulation failure. The incidence of insulation break in this polyurethane unipolar electrode is uncommon and occurs at further stress points.

Electrodes, Implanted↗
PubMed1991

The influence of elevated 50 Hz electric and magnetic fields on implanted cardiac pacemakers: the role of the lead configuration and programming of the sensitivity.

The influence of the electromagnetic interference (EMI) on performance of 15 implanted cardiac pacemakers (12 generator models) was tested during exposure at a high voltage substation. All patients had an adequate spontaneous heart rate during the study. Tests were performed in the ventricular inhibited mode with unipolar sensing in all pacemakers and repeated with bipolar sensing in four pacemakers. The sensitivity was set to a regular, functionally proper level and then to the highest available level. Exposure was done to moderate (1.2-1.7 kV/m) and strong (7.0-8.0 kV/m) electric fields, which correspond to the immediate vicinity of 110 and 400 kV power lines, respectively. In moderate electric fields the output was inhibited in one pacemaker at regular sensitivity (1.7-3.0 mV) and in five pacemakers at the highest sensitivity (0.5-1.25 mV). In strong electric fields the output was inhibited in five pacemakers at regular sensitivity and several pacemakers converted to noise reversion mode at the highest sensitivity. In bipolar mode only one of four pacemakers at high sensitivity (0.5-1.0 mV) was inhibited in the strongest electric field, whereas all four did so in the unipolar mode. One pacemaker with unipolar sensitivity at 0.5 mV was interfered by 63 microT magnetic field. The results confirm that the programmed sensitivity level and the lead configuration markedly influence pacemakers' vulnerability to EMI. Bipolar sensing mode is rather safe in the presence of EMI, which is encountered in public environments. The programmable features of today's pacemakers permit individualized, less stringent safety measures to avoid electromagnetic hazards.

Adult↗
PubMed1997

Right side implant of the unipolar single lead defibrillation system.

The active can defibrillator has been designed for implantation in the left prepectoral region. Whether this system can be successfully implanted on the right side is unknown. We describe six cases in which placement of the unipolar single lead defibrillation system was successfully attempted in the right prepectoral region due to impediments on the left side. The mean age of the patients was 62 +/- 12 years. Five patients had ischemic heart disease and one idiopathic dilated cardiomyopathy. The endocardial defibrillation electrode was placed in the right ventricle through the right subclavian vein and positioned at the apex in two patients and in the septal position in four patients. Defibrillation threshold testing was performed using a step-up/step-down protocol beginning at 12 J with 3-J increments or decrements. Defibrillation threshold was defined as the lowest energy of the first shock able to terminate ventricular fibrillation. The generator models used were the Medtronic 7218C in 1 patient, the Medtronic 7219C in 3 patients, and the Ventritex Cadet 115 AC in 2 patients. The mean defibrillation threshold was 15 +/- 3 J. The defibrillation thresholds were retested at 1, 3, and 6 months, and showed no significant change in five patients but decreased from 15 J to 12 J in one patient. The presence of impediments on the left side should not preclude attempts to place the unipolar active can system in the right prepectoral region.

Aged↗
PubMed1998

Telemetry guided pacemaker programming: impact of output amplitude and the use of low threshold leads on projected pacemaker longevity.

In a prospective study, a low threshold screw-in electrode (Medtronic 5078, group I, n = 9) was compared to a conventional active fixation lead (Biotronik Y60BP, group II, n = 9) to investigate whether lower pacing thresholds really translate into longer projected service life of the pacemaker. The leads were implanted in the atrium and were connected to a dual chamber pacing system which included the same ventricular lead (Medtronic 5024) and the same pulse generator model (Intermedics 294-03) in both groups. Eighteen months after implantation, atrial and ventricular pacing thresholds were measured as the charge delivered per pulse [microC] at 0.5, 1.0, 1.5, 2.0, and 3.5 V, respectively. For chronic output programming in both channels, patients capturing at 0.5 V were set to 1.0 V, those capturing at 1.5 V were permanently programmed to 2.0 V with the double of the charge threshold as the safety margin for pacing ("safety charge"). A combination of atrial and ventricular output settings was optimal, if it resulted in minimum battery current drain (microA] as measured by pacemaker telemetry. In both groups, current consumption [microA] decreased significantly as output amplitude was decreased, exhibiting its lowest value at 1.0 V in either channel. All ventricular leads could be programmed to the optimum output amplitude of 1.0 V in groups 1 and 2. As the 2:1 "safety charge" values were almost identical, the ventricular channel essential contributes the same amount to the battery drain of the pacing system in both groups. In the atrium, all patients of group 1 could be programmed to the optimum output amplitude of 1.0 V with an average pulse duration of 0.42 +/- 0.15 ms. In group 2, however, all patients had to be programmed to 2.0 V with a mean pulse width of 0.52 +/- 0.15 ms. With the atrial and ventricular output being optimized, the average battery drain of the whole pacing system was 12.19 +/- 0.63 microA in group 1 versus 14.42 +/- 0.32 microA in group 2 (P < 0.001). As patients were chronically programmed to these output settings, this difference translates into a clinically relevant gain in projected pacemaker longevity of 17 months or 18.3% (121 +/- 4 vs. 104 +/- 2 months; P < 0.001). Thus, programming a 2:1 safety margin in terms of charge and optimizing the output parameters by real-time telemetry of the battery current is a useful approach to reduce battery current drain. Making the most of modern lead technology with a different performance in only one channel of an otherwise identical DDD pacing system translates into a significant prolongation of projected pacemaker service life which is of great importance with the increasing awareness of health care expenditures. The gain in projected longevity is mainly due to the option of reducing the output amplitude which is still significantly beneficial well below the nominal voltage of the power source.

Aged↗
PubMed1992

Selection of immunoglobulin variable regions in autoimmunity to DNA.

Results from our analyses of variable region gene usage among spontaneous anti-DNA antibodies in autoimmune mice have indicated that both the early IgM and later-appearing IgG autoantibodies to DNA are generated by clonally selected B cells. The recurrent usage of particular variable region genes among all the anti-DNA hybridomas analyzed and reported to date supports this hypothesis. The preferential expression of particular light and heavy chain variable region genes among selected populations of both IgM and IgG anti-DNA hybridomas likewise supports the hypothesis. Both IgM and IgG antibody-producing B cells are derived from the same clonal precursor population and may be derived from the same B cell clonal precursor within an individual mouse. The selective and recurrent expression of germline and somatically-derived structures that would be expected to promote protein binding to DNA within anti-DNA antibody variable regions, particularly arginines in both light and heavy chain complementarity-determining regions, indicates that DNA or DNA-containing complexes may be the antigen that stimulates anti-DNA antibody in autoimmune mice. The progressive increase in the specificity of spontaneous anti-DNA antibodies for native DNA as the autoimmune response matures from IgM to IgG likewise suggests that DNA may be the antigenic stimulus for spontaneous anti-DNA in autoimmune mice. A hypothetical, computer-generated model of anti-DNA antibody binding to DNA provides an interesting paradigm for the molecular basis of antibody specificity for DNA.

Amino Acid Sequence↗
PubMed2005

Are we frozen in time? Analysis of the utilization and efficacy of pulsatile perfusion in renal transplantation.

Preservation techniques are crucial to deceased donor kidney transplantation (DDTx), but the efficacy of pulsatile perfusion (PP) versus cold storage (CS) remains uncertain. We describe patterns of PP use and explore four fundamental questions. What kidneys are selected for PP? How does PP affect utilization of donated kidneys? What effect does PP have on outcomes? When does PP appear to be most efficacious? We examined rates of PP in DDTx in the United States from 1994 to 2003. We generated models for organ utilization, delayed graft function (DGF) and for the use of PP. We analyzed the long-term effect of PP with multivariate Cox models. The utilization rates for non-expanded criteria donors (ECDs) were similar by storage type, but for ECDs there was a significantly higher utilization rate with PP (70% with PP vs. 59% with CS, p < 0.001). Use of PP was widely variable across transplant centers. DGF rates were significantly lower with PP (27.6% vs. 19.6%). PP was associated with a mild benefit on death censored graft survival (adjusted hazard ratio = 0.88, 95% CI 0.85-0.91). Reduced DGF and significantly lower discard rates of ECDs associated with PP suggest an important utility of PP in renal transplantation. Additional evidence of improvement in graft survival, particularly in more recent years, provides further encouraging evidence for the use of PP.

Cadaver↗
PubMedDate not supplied

Morphometric assessment of the proximal portion of the tibia in dogs with and without cranial cruciate ligament rupture.

Based on the clinical observation that dogs with a steep tibial plateau slope had variable tibial morphology, we hypothesized that these dogs could be further characterized using measurements developed by examining computer generated models of specific proximal tibial malformations. A 3D tibial model was created from a normal canine tibia. The model was manipulated to reproduce two specific proximal tibial anomalies representing deformities originating from the tibial plateau or the proximal tibial shaft. Data from these models were used to create specific measurements that would characterize the shape of these anomalies. These measurements included the diaphyseal tibial axis (DTA)/proximal tibial axis (PTA) angle, which defined the orientation of the proximal portion of the shaft in relation to the tibial mid-shaft. These measurements were then made on radiographs of dogs with and without cranial cruciate ligament (CCL) rupture. Models with tibial plateau and proximal shaft deformities had a steep tibial plateau slope (TPS). Models with proximal shaft deformity had a markedly increased DTA/PTA angle. The model with a 10 degree proximal shaft deformity had a DTA/PTA angle of 11.23 degrees. Six dogs (9.0%) had a DTA/PTA angle larger than 11.23 degrees (range, 11.4-13.9 degrees). Dogs in this group had ruptured CCL and a steep TPS. Dogs with CCL rupture had higher TPS (mean, 31.8 +/- 4.1 degrees) and DTA/PTA angle (mean, 6.0 +/- 3.3 degrees) than dogs without CCL rupture (means, 23.6 +/- 3.4 degrees and 4.1 +/- 2.2 degrees, respectively). Dogs with proximal shaft deformity represented a distinct group, which could not be identified using the magnitude of the TPS alone. Characterizing more precisely the shape of the proximal portion of the tibia in dogs contributes to our understanding of the pathogenesis of steep TPS and may facilitate the optimization of the surgical management of dogs with CCL rupture.

Animals↗
PubMed2005

Characterization of the molten globule state of retinol-binding protein using a molecular dynamics simulation approach.

Retinol-binding protein transports retinol, and circulates in the plasma as a macromolecular complex with the protein transthyretin. Under acidic conditions retinol-binding protein undergoes a transition to the molten globule state, and releases the bound retinol ligand. A biased molecular dynamics simulation method has been used to generate models for the ensemble of conformers populated within this molten globule state. Simulation conformers, with a radius of gyration at least 1.1 A greater than that of the native state, contain on average 37%beta-sheet secondary structure. In these conformers the central regions of the two orthogonal beta-sheets that make up the beta-barrel in the native protein are highly persistent. However, there are sizable fluctuations for residues in the outer regions of the beta-sheets, and large variations in side chain packing even in the protein core. Significant conformational changes are seen in the simulation conformers for residues 85-104 (beta-strands E and F and the E-F loop). These changes give an opening of the retinol-binding site. Comparisons with experimental data suggest that the unfolding in this region may provide a mechanism by which the complex of retinol-binding protein and transthyretin dissociates, and retinol is released at the cell surface.

Computer Simulation↗
PubMed1992

Use of LANDSAT MSS imagery and soil type in a geographic information system to assess site-specific risk of fascioliasis on Red River Basin farms in Louisiana.

A geographic information system (GIS) was constructed in an ERDAS environment using maps of soil types from the USDA Soil Conservation Service, LANDSAT satellite multispectral scanner data (MSS), boundaries for 25 study farms, and slope and hydrologic features shown in a two-quadrangle (USGS, 7.5') area in the Red River Basin near Alexandria, Louisiana. Fecal sedimentation examinations were done in the fall of 1989, spring of 1990, and fall and winter of 1990-1991 on 10-16 random samples per herd. Fecal egg shedding rates for F. hepatica ranged from 10-100% prevalence and 0.3-21.7 eggs per two grams of feces (EP2G). For Paramphistomum spp., a rumen fluke also transmitted by F. bulimoides but not affected by flukicides, egg shedding rates ranged from 10-91% prevalence and 0.1-42.8 EP2G. Soil types present ranged from sandy loams to hydric, occasionally flooded clays. Herd Paramphistomum spp. egg shedding rates increased with the proportion of hydric clays present, adjusted for slope and major hydrologic features. F. hepatica infection intensity followed a similar trend, but were complicated by differing treatment practices. Results suggest that earth observation satellite data and soil maps can be used, with an existing climate forecast based on the Thornthwaite water budget, to develop a second generation model that accounts for both regional climate variation and site-specific differences in fascioliasis risk based on soils prone to snail habitat.

Animals↗
PubMed2005

An electrical analysis of slow wave propagation in the guinea-pig gastric antrum.

This paper provides an electrical description of the propagation of slow waves and pacemaker potentials in the guinea-pig gastric antrum in anal and circumferential directions. As electrical conduction between laterally adjacent circular muscle bundles is regularly interrupted, anal conduction of pacemaker potentials was assumed to occur via an electrically interconnected chain of myenteric interstitial cells of Cajal (ICC(MY)). ICC(MY) were also connected resistively to serially connected compartments of longitudinal muscle. Circumferential conduction occurred in a circular smooth muscle bundle that was represented as a chain of electrically connected isopotential compartments: each compartment contained a proportion of intramuscular interstitial cells of Cajal (ICC(IM)) that are responsible for the regenerative component of the slow wave. The circular muscle layer, which contains ICC(IM), and the ICC(MY) network incorporated a mechanism, modelled as a two-stage chemical reaction, which produces an intracellular messenger. The first stage of the reaction is proposed to be activated in a voltage-dependent manner as described by Hodgkin and Huxley; the messenger altered the mean rate of discharge of depolarizing unitary potentials as a function of the concentration of messenger according to a conventional dose-effect relationship. A separate membrane conductance, scaled by the product of an independent voltage-sensitive reaction, was included in the ICC(MY) compartments; this was used to describe the primary component of pacemaker potentials and simulated a delay before the activation of this membrane current. The model generates pacemaker potentials and slow waves with propagation velocities similar to those determined in the physiological experiments described in the accompanying paper.

Action Potentials↗
PubMed1984

A multispeaker analysis of durations in read French paragraphs.

Understanding how the durations of acoustic segments vary in natural language can lead to more intelligible synthetic speech, and to improved automatic recognition. Toward this goal, a 111-word French paragraph was read by 29 native speakers from France. Measured durations of acoustic segments were significantly shorter than those in earlier studies of stressed words in French sentences read from a list. Previously recognized trends (short schwa vowels and function words; long unvoiced fricatives, nasalized vowels, and prepausal syllables) are confirmed and quantitative results are given. Vowels were longer preceding voiced fricatives (but not prior to/r/), and were also longer at sentence-internal pauses than at the end of a sentence. Standard deviations of acoustic segment durations (at fixed positions in the paragraph) across speakers averaged less than 25% in most cases. The exceptional, larger deviations occurred primarily in segments adjacent to pauses. Speaking rate variations could account for only one-sixth of the deviations, the rest being attributable to relatively free variation across speakers. A generative model of French durations, suitable for synthesis-by-rule, is presented, and applications to automatic recognition are discussed.

Female↗
PubMed2000

Maximum a posteriori deconvolution of ultrasonic signals using multiple transducers

A new method for deconvolution of ultrasonic pulse-echo measurements employing multiple-transducer setup is proposed in the paper. An optimal way of estimating the material reflection sequence for a linear signal generation model using maximum a posteriori estimation is proposed. The method combines the measurements from a number of transducers covering different frequency bands yielding an optimal estimate of the reflection sequence. The main idea of this approach is to complement the information unavailable from one transducer in some frequency bands with the information from the other transducers. The method is based on the assumption that the measurements are performed using transducers with identical apertures and apodization, which are located exactly at the same position relative to the test object during the measurement. An error analysis presented in the paper proves that when the above assumptions are fulfilled, the proposed method, by utilizing more data for estimation, consistently yields more accurate reflection sequence estimates than the classical Wiener filter. Experimental evidence is presented using both simulated and real ultrasonic data as a verification of the correctness of the multiple-transducer model and the estimation scheme. An illustration of the advantages of the method is also given using real ultrasonic data.

Journal Article↗
PubMed1989

Transmembrane channels based on tartaric acid-gramicidin A hybrids.

The gramicidin A transmembrane channel is believed to consist of two head-to-head beta helices. Computer-generated models were used to formulate the structure of new single-chain channel molecules based on the gramicidin motif. The chemical synthesis of two tartaric acid-gramicidin A hybrids and single-channel analyses of their conducting properties are reported. These studies illustrate the rational design and synthesis of long-lived channels with tunable conductance properties and provide support for current molecular models of the natural (dimeric) gramicidin channel.

Amino Acid Sequence↗
PubMed1987

Isolation and structure of a covalent cross-link adduct between mitomycin C and DNA.

A DNA cross-link adduct of the antitumor agent mitomycin C (MC) to DNA has been isolated and characterized; the results provide direct proof for bifunctional alkylation of DNA by MC. Exposure of MC to Micrococcus luteus DNA under reductive conditions and subsequent nuclease digestion yielded adducts formed between MC and deoxyguanosine residues. In addition to the two known monoadducts, a bisadduct was obtained. Reductive MC activation with Na2S2O4 (sodium dithionite) leads to exclusive bifunctional alkylation. The structure of the bisadduct was determined by spectroscopic methods that included proton magnetic resonance, differential Fourier transform infrared spectroscopy, and circular dichroism. Formation of the same bisadduct in vivo was demonstrated upon injection of rats with MC. Computer-generated models of the bisadduct that was incorporated into the center of the duplex B-DNA decamer d(CGTACGTACG)2 indicated that the bisadduct fit snugly into the minor groove with minimal distortion of DNA structure. A mechanistic analysis of the factors that govern monofunctional and bifunctional adduct formation is presented.

Chemical Phenomena↗
PubMed2003

Tenofovir resistance and resensitization.

Human immunodeficiency viruses in 321 samples from tenofovir-naïve patients were retrospectively evaluated for resistance to this nucleotide analogue. All virus strains with insertions between amino acids 67 and 70 of the reverse transcriptase (n = 6) were highly resistant. Virus strains with the Q151M mutation were divided into susceptible (n = 12) and highly resistant (n = 8) viruses. This difference was due to the absence or presence of the K65R mutation, which was confirmed by site-directed mutagenesis. Viral clones with various combinations of the mutations M41L, K70R, L210W, and T215F or T215Y were analyzed for cross-resistance induced by thymidine analogue mutations (TAMs). The levels of increased resistance induced by single, double, and triple mutations at the indicated positions could be ranked as follows: for mutants with single mutations, mutations at positions 41 > 215 > 70; for mutants with double mutations, mutations at positions 41 and 215 > 70 and 215 = 210 and 215 > 41 and 70; for mutants with triple mutations, mutations at positions 41, 210, and 215 > 41, 70, and 215. Viral clones with M184V or M184I exhibited slightly increased susceptibilities to tenofovir (0.7-fold). Almost all clones with TAM-induced resistance were resensitized when M184V was present (P < 0.001). Among the viruses in the clinical samples, the rate of tenofovir resistance significantly increased with the number of TAMs both in the samples with 184M and in those with 184V (P = 0.005 and P = 0.003, respectively). A resensitizing effect of M184V was confirmed for all samples exhibiting at least one TAM (P = 0.03). However, accumulation of at least two TAMs resulted in more than 2.0-fold reduced susceptibility to tenofovir, irrespective of the presence of M184V. Decision tree building, a classical machine learning technique, was used to generate models for the interpretation of mutations with respect to tenofovir resistance. The application of previously proposed cutoffs for a reduced response to therapy and treatment failure demonstrated the central roles of positions 215 and 65 for 1.5- and 4.0-fold reduced susceptibilities, respectively. Thus, clinically relevant resistance may be conferred by the accumulation of TAMs, and the resensitizing effect of M184V should be considered only minor.

Adenine↗
PubMed2001

Use of operon fusions in Mannheimia haemolytica to identify environmental and cis-acting regulators of leukotoxin transcription.

The leukotoxin of Mannheimia haemolytica is an important virulence factor that contributes to much of the pathology observed in the lungs of animals with bovine shipping fever pneumonia. We believe that identification of factors that regulate leukotoxin expression may provide insight into M. haemolytica pathogenicity. The DNA sequence upstream of the leukotoxin operon is divergently shared by P(lapT), which transcribes an arginine permease gene. The intergenic region contains several elements that are potential sites for transcriptional modulation of the promoters. We have developed plasmid-borne chloramphenicol acetyltransferase (cat) operon fusions, as well as lktC::cat chromosomal fusions, to study transcription initiation in M. haemolytica. Using these genetic tools, we have identified cis-acting sequences and environmental conditions that modulate transcription of the leukotoxin and lapT promoters. By deletion analysis, promoters were shown to rely on sequences upstream of their -10 and -35 regions for full activity. Direct repeats of the sequence TGT-N(11)-ACA and a static bend region caused by phased adenine tracts were necessary for full activation of P(lkt). A computer-generated model of the promoter's structure shows how DNA bending brings the repeat sequences within close proximity to the P(lkt) RNA polymerase, and we hypothesize that these repeats are a binding site for an activator of leukotoxin transcription. The lktC::cat operon fusion was also used to demonstrate that, like that of other RTX toxins, leukotoxin transcription is environmentally regulated. Roles for iron deprivation and temperature change were identified.

Bacterial Toxins↗
PubMed2002

Type 1 phosphatase, a negative regulator of cardiac function.

Increases in type 1 phosphatase (PP1) activity have been observed in end stage human heart failure, but the role of this enzyme in cardiac function is unknown. To elucidate the functional significance of increased PP1 activity, we generated models with (i) overexpression of the catalytic subunit of PP1 in murine hearts and (ii) ablation of the PP1-specific inhibitor. Overexpression of PP1 (threefold) was associated with depressed cardiac function, dilated cardiomyopathy, and premature mortality, consistent with heart failure. Ablation of the inhibitor was associated with moderate increases in PP1 activity (23%) and impaired beta-adrenergic contractile responses. Extension of these findings to human heart failure indicated that the increased PP1 activity may be partially due to dephosphorylation or inactivation of its inhibitor. Indeed, expression of a constitutively active inhibitor was associated with rescue of beta-adrenergic responsiveness in failing human myocytes. Thus, PP1 is an important regulator of cardiac function, and inhibition of its activity may represent a novel therapeutic target in heart failure.

Adrenergic beta-Agonists↗