TGFß1 signaling protects chondrocytes against oxidative stress via FOXO1-autophagy axis.

OBJECTIVE: The forkhead box O1 (FOXO1) transcription factor is a key regulator of autophagy. In chondrocytes, reduced FOXO1 expression with aging causes osteoarthritis due to dysfunction of autophagy, but the mechanisms underlying regulation of FOXO1 expression and the reduction in expression with aging remain unclear. We investigated the mechanism by which transforming growth factor ß1 (TGFß1) signaling regulates the FOXO1-autophagy axis. METHODS: Expression of FOXO1 was measured in chondrocytes after TGFß1 treatment. Immunohistochemistry was performed to estimate the levels of activin receptor-like kinase 5 (ALK5) and FOXO1 in the knee joints of young, middle-aged and old mice. The effects of the ALK5 inhibitor and SMAD3 or SMAD2 knockdown on FOXO1 expression were evaluated. The role of TGFß1 in autophagy after hydrogen peroxide (H2O2) treatment was analyzed. The protective effect of TGFß1 against H2O2 treatment was assessed by cell viability assay and TUNEL assay. RESULTS: TGFß1 promoted the expression of FOXO1 mRNA and protein. Both ALK5 and FOXO1 expression decreased with aging. ALK5 inhibition and SMAD3 knockdown suppressed induction of FOXO1 expression by TGFß1, whereas SMAD2 knockdown increased it. TGFß1 promoted the expression of microtubule-associated proteins 1A/1B light chain 3B (LC3)-I protein via the SMAD3-FOXO1 pathway. Furthermore, under H2O2 treatment, TGFß1 promoted expression of LC3-II. TGFß1 pretreatment suppressed cell death of chondrocytes following H2O2 treatment, but this protective effect was abolished by FOXO1 knockdown. CONCLUSIONS: TGFß1 protects chondrocytes against oxidative stress via the FOXO1-autophagy axis, and a reduction in ALK5 expression might cause reduced FOXO1 expression with aging.

Smectic Liquid-Crystalline Structure of Skyrmions in Chiral Magnet Co_{8.5}Zn_{7.5}Mn_{4}(110) Thin Film.

The organizing of magnetic skyrmions shows several forms similar to atomic arrays of solid states. Using Lorentz transmission electron microscopy, we report the first direct observation of a stable liquid-crystalline structure of skyrmions in chiral magnet Co_{8.5}Zn_{7.5}Mn_{4}(110) thin film, caused by magnetic anisotropy and chiral surface twist. Elongated skyrmions are oriented and periodically arranged only in the ⟨110⟩ directions, whereas they exhibit short-range order along the ⟨001⟩ directions, indicating a smectic skyrmion state. In addition, skyrmions possess anisotropic interaction with an opposite sign depending on the crystal orientation, in contrast to existing isotropic interaction.

Treatment of acute bleeding in acquired haemophilia A with recombinant activated factor VII: analysis of 10-year Japanese postmarketing surveillance data.

INTRODUCTION: Patients with acquired haemophilia A (AHA) have autoantibodies against factor VIII (FVIII), and may develop spontaneous bleeding that requires treatment with FVIII inhibitor bypassing agents such as recombinant activated FVII (rFVIIa, NovoSeven® ). However, data regarding the use of rFVIIa are limited. AIM: To investigate the use, efficacy and safety of rFVIIa for the treatment of AHA by analysis of 10-year multicentre Japanese postmarketing surveillance data. METHODS: Treatment regimens, haemostatic efficacy and adverse events were recorded for rFVIIa therapy of AHA patients with bleeding episodes. Treatment was evaluated as markedly effective, effective, moderate or ineffective. RESULTS: Data were collected for 371 bleeding episodes in 132 patients. Bleeding improved after rFVIIa therapy in 92% of episodes (markedly effective in 41%, effective in 10%, moderate in 41%). The response rate was significantly better in patients who received an initial dose of ≥90 µg kg-1 than in those who received an initial dose of <90 µg kg-1 . The response rate was also significantly better when rFVIIa was administered earlier after the onset of bleeding. Twelve serious adverse events were recorded in six patients, including five serious thromboembolic events in three patients who were all elderly with significant comorbidities. CONCLUSION: This is the largest, single-country study of rFVIIa therapy in AHA patients reported to date. The Japanese surveillance data show comparable efficacy and safety to prior multinational studies. Doses of 90-120 µg kg-1 and prompt initiation of treatment may be important to achieve good bleeding control.

Ten-year experience of recombinant activated factor VII use in surgical patients with congenital haemophilia with inhibitors or acquired haemophilia in Japan.

Patients with congenital haemophilia with inhibitors or acquired haemophilia are at risk of bleeding complications during surgery. In these patients, replacement therapy for the missing coagulation factor is ineffective, and a bypassing agent such as recombinant activated factor VII (rFVIIa) is required to manage bleeding. To evaluate the safety and haemostatic efficacy of rFVIIa treatment in Japanese patients with congenital haemophilia with inhibitors to FVIII/FIX or acquired haemophilia undergoing surgery. Postmarketing surveillance data from May 2000 to March 2010 were analysed to assess the haemostatic efficacy of 38 procedures in 22 patients with congenital haemophilia A, 13 procedures in seven patients with congenital haemophilia B, and five procedures in five patients with acquired haemophilia. Postoperative bleeding control was judged to be effective (bleeding was stopped completely or reduced considerably) for 34/38 procedures (89%) in patients with congenital haemophilia A, 10/13 procedures (77%) in patients with congenital haemophilia B, and 4/5 procedures (80%) in patients with acquired haemophilia. Tranexamic acid was used concomitantly for 36/56 procedures (64%). Safety was analysed for 66 procedures in 37 patients. Adverse effects potentially related to rFVIIa treatment included mild superficial thrombophlebitis, mild decrease in platelet count, and mild elevation of the serum alanine transaminase level in one patient each. All adverse effects resolved without treatment. Administration of rFVIIa provided adequate haemostasis without serious adverse effects in the majority of cases. The efficacy and safety data in Japanese patients were similar to previously published data from other countries.

A high efficient protocol for soybean root transformation by Agrobacterium rhizogenes and most stable reference genes for RT-qPCR analysis.

KEY MESSAGE: A 55% transformation efficiency was obtained by our optimized protocol; and we showed that GmELF1 - ß and GmELF1 - α are the most stable reference genes for expression analyses under this specific condition. Gene functional analyses are essential to the validation of results obtained from in silico and/or gene-prospecting studies. Genetic transformation methods that yield tissues of transient expression quickly have been of considerable interest to researchers. Agrobacterium rhizogenes-mediated transformation methods, which are employed to generate plants with transformed roots, have proven useful for the study of stress caused by root phytopathogens via gene overexpression and/or silencing. While some protocols have been adapted to soybean plants, transformation efficiencies remain limited; thus, few viable plants are available for performing bioassays. Furthermore, mRNA analyses that employ reverse transcription quantitative polymerase chain reactions (RT-qPCR) require the use of reference genes with stable expression levels across different organs, development steps and treatments. In the present study, an A. rhizogenes-mediated soybean root transformation approach was optimized. The method delivers significantly higher transformation efficiency levels and rates of transformed plant recovery, thus enhancing studies of soybean abiotic conditions or interactions between phytopathogens, such as nematodes. A 55% transformation efficiency was obtained following the addition of an acclimation step that involves hydroponics and different selection processes. The present study also validated the reference genes GmELF1-ß and GmELF1-α as the most stable to be used in RT-qPCR analysis in composite plants, mainly under nematode infection.

Diffuse dermal angiomatosis.

Diffuse dermal angiomatosis (DDA) is characterized clinically by painful erythematous lesions with ulcers and histologically by a benign, diffuse, and self-limited proliferation of tiny blood vessels in the superficial layers of the reticular dermis. Here we describe a case of DDA with leg ulcer. Erythematous lesions presented around the ulcer and angiogram revealed an occlusion of the superficial femoral artery. The erythematous lesions disappeared after revascularization. Although DDA is extremely rare, early correction of the ischemia in the peripheral artery should be taken into consideration.

Prenatal withdrawal from opiates interferes with hatching of otherwise viable chick fetuses.

Fetal chicks were made opiate-dependent by injections of N-desmethyl-1-alpha-acetylmethadol into the chorioallantois on day 3 of embryogenesis. The injections had no effect on subsequent hatchability; however, spontaneous fetal motility was significantly depressed. Injection of naloxone caused a significant increase in the motility of the opiate-exposed fetuses but had no effect on control fetuses. That naloxone's effect was an expression of opiate withdrawal and not due to antagonism of depressed motility is also supported by the observation that naloxone significantly reduced the hatchability of opiate-exposed chicks and not of control chicks. Thus the withdrawal of a developing organism from a narcotic may be more deleterious to its survival than continued exposure.

Expression and function of the Delta-1/Notch-2/Hes-1 pathway during experimental acute kidney injury.

The Notch signaling pathway consists of several receptors and their ligands Delta and Jagged and is important for embryogenesis, cellular differentiation and proliferation. Activation of Notch receptors causes their cleavage yielding cytoplastic domains that translocate into the nucleus to induce target proteins such as the basic-loop-helix proteins Hes and Hey. Here we sought to clarify the significance of the Notch signaling pathway in acute kidney injury using a rat ischemia-reperfusion injury model and cultured NRK-52E cells. Analysis of the whole kidney after injury showed increased expression of Delta-1 and Hes-1 mRNA and protein along with processed Notch-2. Confocal microscopy, using specific antibodies, showed that Delta-1, cleaved Notch-2 and Hes-1 colocalized in the same segments of the injured renal proximal tubules. Recombinant Delta-1 significantly stimulated NRK-52E cell proliferation. Our study suggests that the Delta-1/Notch-2/Hes-1 signaling pathway may regulate the regeneration and proliferation of renal tubules during acute kidney injury.

Mineralocorticoids and acidosis regulate H+/HCO3- transport of intercalated cells.

The effects of acidosis and mineralocorticoids on cellular H+/HCO3- transport mechanisms were examined in intercalated cells of the outer stripe of outer medullary collecting duct (OMCDo) from rabbit. Intracellular pH (pHi) of intercalated cells was monitored by fluorescence ratio imaging using 2',7'-bis(carboxyethyl)-5(6)-carboxyfluorescein (BCECF). pHi recovered from an acid load at 2.8 +/- 0.5 x 10(-3) pHU/s in the absence of ambient Na+. This pHi recovery rate was similar in chronic acidosis induced by NH4Cl loading, but it was enhanced (+111%) by treatment with deoxycorticosterone acetate (DOCA). In a DOCA-treated group, luminal 10 microM SCH28080 and 0.1 mM omeprazole, H(+)-K(+)-ATPase inhibitors, did not change the pHi recovery rate, while luminal 0.5 mM N-ethylmaleimide blocked the rate by 68%. DOCA, but not acidosis, increased (approximately 40%) initial pHi response to bath HCO3- or Cl- reduction in Na(+)-free condition. After an acid load in the absence of Na+ and HCO3-, pHi response to basolateral Na+ addition was stimulated (+66%) by acidosis, but not by DOCA. Our results suggest that (a) mineralocorticoids stimulate H+/HCO3- transport mechanisms involved in transepithelial H+ secretion, i.e., a luminal NEM-sensitive H+ pump and basolateral Na(+)-independent Cl(-)-HCO3- exchange; and (b) acidosis enhances the activity of basolateral Na(+)-H+ exchange that may be responsible for pHi regulation.

Transcellular water flow modulates water channel exocytosis and endocytosis in kidney collecting tubule.

The regulation of osmotic water permeability (Pf) by vasopressin (VP) in kidney collecting tubule involves the exocytic-endocytic trafficking of vesicles containing water channels between an intracellular compartment and apical plasma membrane. To examine effects of transcellular water flow on vesicle movement, Pf was measured with 1-s time resolution in the isolated perfused rabbit cortical collecting tubule in response to addition and removal of VP (250 microU/ml) in the presence of bath greater than lumen (B greater than L), lumen greater than bath (L greater than B), and lumen = bath (L = B) osmolalities. With VP addition, Pf increased from 12 to 240-270 x 10(-4) cm/s (37 degrees C) in 10 min. At 1 min, Pf was approximately 70 x 10(-4) cm/s for B greater than L, L greater than B, and L = B conditions. At later times, Pf increased fastest for L greater than B and slowest for B greater than L osmolalities; at 5 min, Pf was 250 x 10(-4) cm/s (L greater than B) and 158 x 10(-4) cm/s (B greater than L). With VP removal, Pf returned to pre-VP levels at the fastest rate for B greater than L and the slowest rate for L greater than B osmolalities; at 30 min, Pf was 65 x 10(-4) cm/s (B greater than L) and 183 x 10(-4) cm/s (L greater than B). For a series of osmotic gradients of different magnitudes and directions, the rates of Pf increase and decrease were dependent upon the magnitude of transcellular volume flow; control studies showed that paracellular water flux, asymmetric transcellular water pathways, or changes in cell volume could not account for the data. VP-dependent endocytosis was measured by apical uptake of rhodamine-dextran; in paired studies where the same tubule was used for + and - gradients, B greater than L and L greater than B osmolalities gave 168% and 82% of uptake measured with no gradient. In contrast, endocytosis in proximal tubule was not dependent on gradient direction. These data provide evidence that transcellular volume flow modulates the vasopressin-dependent cycling of vesicles containing water channels, suggesting a novel driving mechanism to aid or oppose the targeted, hormonally directed movement of subcellular membranes.

Cloning, characterization, and chromosomal mapping of human aquaporin of collecting duct.

We recently cloned a cDNA of the collecting duct apical membrane water channel of rat kidney, which is important for the formation of concentrated urine (Fushima, K., S. Uchida, Y. Hara, Y. Hirata, F. Marumo, and S. Sasaki. 1993. Nature [Lond.]. 361:549-552). Since urine concentrating ability varies among mammalian species, we examined whether an homologous protein is present in human kidney. By screening a human kidney cDNA library, we isolated a cDNA clone, designated human aquaporin of collecting duct (hAQP-CD), that encodes a 271-amino acid protein with 91% identity to rat AQP-CD. mRNA expression of hAQP-CD was predominant in the kidney medulla compared with the cortex, immunohistochemical staining of hAQP-CD was observed only in the collecting duct cells, and the staining was dominant in the apical domain. Functional expression study in Xenopus oocytes confirmed that hAQP-CD worked as a water channel. Western blot analysis of human kidney medulla indicated that the molecular mass of hAQP-CD is 29 kD, which is the same mass expected from the amino acid sequence. Chromosomal mapping of the hAQP-CD gene assigned its location to chromosome 12q13. These results could be important for future studies of the pathophysiology of human urinary concentration mechanisms in normal and abnormal states.

Bromide removal by hydrotalcite-like compounds in a continuous system.

Bromide ion removal from a real water matrix by hydrortalcite-like compounds (HTCs) was attempted in a column reactor to control the formation of brominated disinfection by-products in drinking water treatment process. The performance of HTCs was found to be comparable to a commercially available ion exchange resin for relatively low alkalinity water. Also, it was deduced that HTCs are better than ion exchange resins for high sulfate water because of their unique ion selectivity. In addition, the ion exchange reactions by HTCs were faster than a commercially available resin. Thus, HTCs are expected to provide similar performance to organic resins without the concern about secondary contamination (i.e., elution of organic compounds from resins).

Schizophrenia-like phenotypes in mice with NMDA receptor ablation in intralaminar thalamic nucleus cells and gene therapy-based reversal in adults.

In understanding the mechanism of schizophrenia pathogenesis, a significant finding is that drug abuse of phencyclidine or its analog ketamine causes symptoms similar to schizophrenia. Such drug effects are triggered even by administration at post-adolescent stages. Both drugs are N-methyl-d-aspartate receptor (NMDAR) antagonists, leading to a major hypothesis that glutamate hypofunction underlies schizophrenia pathogenesis. The precise region that depends on NMDAR function, however, is unclear. Here, we developed a mouse strain in which NMDARs in the intralaminar thalamic nuclei (ILN) were selectively disrupted. The mutant mice exhibited various schizophrenia-like phenotypes, including deficits in working memory, long-term spatial memory, and attention, as well as impulsivity, impaired prepulse inhibition, hyperlocomotion and hyperarousal. The electroencephalography analysis revealed that the mutant mice had a significantly reduced power in a wide range of frequencies including the alpha, beta and gamma bands, both during wake and rapid eye movement (REM) sleep, and a modest decrease of gamma power during non-REM sleep. Notably, restoring NMDARs in the adult ILN rescued some of the behavioral abnormalities. These findings suggest that NMDAR dysfunction in the ILN contributes to the pathophysiology of schizophrenia-related disorders. Furthermore, the reversal of inherent schizophrenia-like phenotypes in the adult mutant mice supports that ILN is a potential target site for a therapeutic strategy.

Structures of genomic and complementary DNAs coding for Pleurotus ostreatus manganese (II) peroxidase.

To study the mechanism of regulation and structure/function relationship of the Pleurotus ostreatus manganese (II) peroxidase (MnP), we amplified the full-length genomic and complementary DNAs for the major isozyme of the MnP mainly by the cassette-primer PCR technique and then sequenced them. The cDNA contained an open reading frame of 1083 bp encoding for a polypeptide of 361 amino-acid residues, including the suggested signal peptide of 29 amino-acid residues with a prepro structure. The predicted amino-acid sequence of the protein shared several common characteristics with those of fungal lignin and manganese (II) peroxidases. We could find a suggested metal response element and two heat-shock element-like sequences in the 5'-flanking region of the structural gene. The structural gene contained 15 introns, many of which lie identical to those in lignin peroxidase genes rather than to those in the known MnP genes.

Cloning and characterization of the gene encoding the iron-sulfur protein of succinate dehydrogenase from Pleurotus ostreatus.

Genomic and cDNA fragments encoding the iron-sulfur protein (Ip) subunit of dehydrogenase (EC 1.3.99.1) have been cloned from the edible basidiomycetous fungus, Pleurotus ostreatus. The gene is interrupted by five introns and is predicted to encode a polypeptide of 268 amino acid residues. Sequence comparison with the Ip subunit from other species identified three conserved cysteine-rich clusters. One of these contains a critical histidine residue implicated in carboxin sensitivity in the heterobasidiomycete Ustilago maydis.

Different development of apical and basolateral Na-H exchangers in LLC-PK1 renal epithelial cells: characterization by inhibitors and antisense oligonucleotide.

LLC-PK1 cells are known to possess respective Na(+)-H+ exchangers (NHE) in apical and basolateral membranes. We examined the developmental difference between these NHEs. LLC-PK1 cells seeded on a filter membrane at a saturation density formed a confluent monolayer after 1 day. Intracellular pH (pHi) was measured 1-6 days after seeding using 2',7'-bis(carboxyethyl)-5(6)-carboxyfluorescein. The activities of apical and basolateral NHEs were estimated separately by the initial pHi responses to Na+ after NH3/NH4+ prepulses in the absence of HCO3- at 37 degrees C. Significant apical and basolateral NHE activities were detected at day 1 (1 day after seeding). Apical NHE activity increased 2.9-fold during days 1-3. By contrast, basolateral NHE activity remained unchanged up to day 6. At day 1, both apical and basolateral NHEs showed sensitivity to inhibition by ethylisopropyl amiloride (EPIA). Apical NHE acquired 4.5-fold resistance to EIPA during days 1-3, whereas the EIPA sensitivity of basolateral NHE was constant. As a result, apical NHE became 29-times more resistant to EPIA than basolateral NHE at day 3 or 4. Treatment with an antisense oligonucleotide targeting NHE-1 (inhibitor-sensitive NHE) mRNA decreased basolateral NHE activity at days 2 and 4, and apical NHE activity at day 2. These results suggest: (1) NHE-1 is distributed over the plasma membrane in early confluent LLC-PK1 monolayers; and (2) then, NHE-2 (inhibitor-resistant NHE) gradually begins to be expressed specifically in the apical membrane, and the distribution of NHE-1 becomes confined to basolateral membrane.

Functional characterization of a water channel of the nematode Caenorhabditis elegans.

A genome project for the species Caenorhabditis elegans has demonstrated the presence of eight cDNAs belonging to the major intrinsic protein (MIP) family. We previously characterized one of these cDNAs known as C01G6.1. C01G6.1 was confirmed to be a water channel and newly designated as AQP-CE1 [Am. J. Physiol. 275 (1998) C1459-C1464]. In this paper, we examined the function of another MIP protein encoded by F40F9.9. This cDNA encodes a 274-amino acid protein showing a high sequence identity with mammalian aquaporin-8 (AQP8) water channel (35%) and d-TIP (34%), an AQP of Arabidopsis. The expression of F40F9.9 in Xenopus oocytes increased the osmotic water permeability (P(f)) 10.4-fold, and the activation energy for P(f) from Arrhenius plot was 4.7 kcal/mol, suggesting that F40F9.9 is a water channel (AQP-CE2). AQP-CE2 was not permeable to glycerol or urea. Oocyte P(f) was reversibly inhibited by 58% after an incubation with 0.3 mM HgCl(2). To identify the mercury-sensitive site, four individual cysteine residues in AQP-CE2 (at positions 47, 132, 149, 259) were altered to serine by site-directed mutagenesis. Of these mutants, only C132S had a P(f) similar to that of the wild-type together with an acquired mercury resistance, suggesting that Cys-132 is the mercury-sensitive site. Similar results were obtained by the mutation of Cys-132 to alanine (C132A). Replacement of Cys-132 with tryptophan decreased P(f) by 64%, but P(f) was still 2.5 times higher than that of the control. Cys-132 is located in the transmembrane helix 3, close to the transition to the extracellular loop C. These results suggest that the transmembrane helix 3, including Cys-132, might participate in the aqueous pore formation, or, alternatively, that Cys-132 might contribute to the construction of the AQP protein.

Three-dimensional analysis of regional myocardial function in response to nitroglycerin in patients with coronary artery disease.

Biplane cineventriculography was performed at rest and after sublingual nitroglycerin in 13 patients with coronary artery disease. In six patients (responders), there was a significant increase in ejection fraction [40 +/- 5 to 52 +/- 4% (p less than 0.001)], while in the other seven (nonresponders), there was no alteration in ejection fraction. To evaluate the extent of regional myocardial response to nitroglycerin, the contractile pattern of the regional myocardium over the entire ventricular surface was analyzed using a computer-generated three-dimensional model. The spatial coordinates that define the elliptic ventricular surface on a given horizontal plane cross section of the chamber were determined by four counter values in the two orthogonal silhouettes. Then, 32 points at equal angles around the center of gravity of the end-diastolic cavity were generated to form the border image. Repetition of this process for 16 successive cross sections allowed for reconstruction of the ventricular surface by the sequence of 32 X 16 (512) points. The regional wall motion was expressed as the percent change of the radial length, drawn from the center of gravity to each surface point. There was significant heterogeneity in regional response to nitroglycerin. In the responders, the normally contracting area was significantly increased (from 16.5 +/- 16.0 to 36.2 +/- 14.9% of the total surface area, p less than 0.001), largely mediated by the greater improvement in segmental shortening of each graded contractile pattern relative to its deterioration. In the nonresponders, a lessening of the severe dysfunction of the given area was associated with significant deterioration of segmental shortening of the other normally contracting area (49.1 +/- 19.7% of the area with a contractile pattern of grade 5 had deteriorated, p less than 0.05). Thus, the ratio of the area with respective graded segmental shortening was virtually unchanged. These differences in response of the ischemic ventricle to nitroglycerin appeared to be related to the development of adequate coronary collateral vessels as well as to an interaction of changes in preload and afterload.

Changes in diastolic properties of the regional myocardium during pacing-induced ischemia in human subjects.

Mechanisms related to alterations in the diastolic properties of the left ventricle during angina were studied in seven patients with coronary artery disease. Single plane left ventriculograms were obtained using a high fidelity micromanometer-tipped catheter in both the resting state and immediately after rapid cardiac pacing. In all patients, typical anginal pain developed with pacing stress. After atrial pacing, the left ventricular end-diastolic pressure increased from 10 +/- 3 to 21 +/- 7 mm Hg (+/- standard deviation) (p less than 0.005) regardless of the changes in the end-diastolic volume. The ejection fraction was reduced from 59 +/- 10 to 48 +/- 13% (p less than 0.05). The diastolic pressure-volume curves shifted upward in post-pacing beats in four patients, while in three the curves shifted more to the right. The regional myocardial function was expressed in quantitative terms by a radial coordinate system with the origin at the center of gravity of the end-diastolic silhouette. Two representative radial grids for normal and ischemic segments were selected. In the normal segment, the end-diastolic length was augmented by 15% (p less than 0.005) and was associated with a 24% increase in stroke excursion with pacing stress (p less than 0.05). The increase in diastolic pressure was accompanied by comparable increases in end-diastolic length, and the diastolic pressure-length relation moved up to the higher portion of the single curve. In the ischemic segment, the end-diastolic length remained unchanged in the post-pacing beat, but segment shortening was significantly reduced.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of asynchronous wall motion by regional pressure-length loops in patients with coronary artery disease.

The progression of regional dysfunction during angina pectoris was studied in eight patients with coronary artery disease. Single plane left ventriculograms were obtained using a high fidelity micromanometer-tipped catheter both at rest and immediately after rapid cardiac pacing. Each image of the left ventriculogram was digitized and transferred to a computer. The boundary of the ventricular cavity was automatically determined and sequentially superimposed. Regional shortening was quantified by a radial coordinate system originating at the center of gravity of the end-diastolic silhouette. Thirty-two radial grids were drawn around the center of gravity, and the length of each radial grid was measured to characterize the centripetal motion of a given surface point. Each radial length was then plotted simultaneously and continuously against left ventricular pressure to generate a pressure-length loop. The area of the pressure-length loop provided an index of regional myocardial work. In the ischemic ventricle, the loops exhibited a striking deformity in configuration. Prolonged relaxation of ischemic segments was associated with outward motion of the normal segments. Shortening of the normal segment occurred earlier than that of the ischemic segment associated with its stretch. Thus, the loops of the two areas inclined in opposite directions. Pacing stress increased the magnitude of hypofunction in the potentially ischemic area, the average extent of shortening being reduced by 30% and the segmental work by 25% (p less than 0.005). In the normal area, contrary to the significant increase in segmental shortening (20% above control values [p less than 0.005]), the average segmental work remained at 7% below control values because of an augmented deformation of the loop.(ABSTRACT TRUNCATED AT 250 WORDS)