Genome-wide association study identifies pharmacogenomic loci linked with specific antihypertensive drug treatment and new-onset diabetes.

We conducted a discovery genome-wide association study with expression quantitative trait loci (eQTL) annotation of new-onset diabetes (NOD) among European Americans, who were exposed to a calcium channel blocker-based strategy (CCB strategy) or a ß-blocker-based strategy (ß-blocker strategy) in the INternational VErapamil SR Trandolapril STudy. Replication of the top signal from the SNP*treatment interaction analysis was attempted in Hispanic and African Americans, and a joint meta-analysis was performed (total 334 NOD cases and 806 matched controls). PLEKHH2 rs11124945 at 2p21 interacted with antihypertensive exposure for NOD (meta-analysis P=5.3 × 10-8). rs11124945 G allele carriers had lower odds for NOD when exposed to the ß-blocker strategy compared with the CCB strategy (Odds ratio OR=0.38(0.24-0.60), P=4.0 × 10-5), whereas A/A homozygotes exposed to the ß-blocker strategy had increased odds for NOD compared with the CCB strategy (OR=2.02(1.39-2.92), P=2.0 × 10-4). eQTL annotation of the 2p21 locus provides functional support for regulating gene expression.

Phase I and biomarker study of OPB-51602, a novel signal transducer and activator of transcription (STAT) 3 inhibitor, in patients with refractory solid malignancies.

BACKGROUND: The aim of this study was to determine the maximum-tolerated dose (MTD), safety, pharmacokinetics, and pharmacodynamics of OPB-51602, an oral, direct signal transduction activator of transcription 3 (STAT3) inhibitor, in patients with refractory solid tumors. PATIENTS AND METHODS: Three cohorts were studied: cohort A, a sequential dose escalation of OPB-51602 administered intermittently (days 1-14 every 21 days); cohort B, an expansion cohort evaluating the dose lower than the MTD; cohort C, evaluating continuous daily dosing. RESULTS: Fifty-one patients were studied at 2, 4, and 5 mg per day dosing. The MTD was 5 mg; first-cycle dose-limiting toxicities (DLTs) were grade 3 hyponatremia in one patient, and grade 3 dehydration in another. Intermittent dosing of both 2 and 4 mg doses were tolerable, and the recommended phase II dose was 4 mg. Cohort B investigated 4 mg intermittently, whereas cohort C investigated 4 mg continuously. Common toxicities included fatigue, nausea/vomiting, diarrhea, anorexia, and early-onset peripheral neuropathy. Drug-induced pneumonitis occurred in two patients in cohort C. Continuous dosing was associated with a higher incidence of peripheral neuropathy and a lower mean relative dose intensity, compared with intermittent dosing. Steady-state pharmacokinetics was characterized by high oral clearance, mean elimination half-life ranging from 44 to 61 h, and a large terminal-phase volume of distribution. An active metabolite, OPB-51822, accumulated to a greater extent than OPB-51602. Flow cytometry of peripheral blood mononuclear cells demonstrated pSTAT3 (Tyr(705)) inhibition following exposure. Two patients achieved partial responses at 5 mg intermittently and 4 mg continuously; both had epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC) with prior EGFR tyrosine kinase inhibitor exposure. CONCLUSION: OPB-51602 demonstrates promising antitumor activity, particularly in NSCLC. Its long half-life and poorer tolerability of continuous dosing, compared with intermittent dosing, suggest that less frequent dosing should be explored. CLINICALTRIALSGOV IDENTIFIER: NCT01184807.

Targeted next-generation sequencing in the diagnosis of neurodevelopmental disorders.

We developed a next-generation sequencing (NGS) based mutation screening strategy for neurodevelopmental diseases. Using this system, we screened 284 genes in 40 patients. Several novel mutations were discovered. Patient 1 had a novel mutation in ACTB. Her dysmorphic feature was mild for Baraitser-Winter syndrome. Patient 2 had a truncating mutation of DYRK1A. She lacked microcephaly, which was previously assumed to be a constant feature of DYRK1A loss of function. Patient 3 had a novel mutation in GABRD gene. She showed Rett syndrome like features. Patient 4 was diagnosed with Noonan syndrome with PTPN11 mutation. He showed complete agenesis of corpus callosum. We have discussed these novel findings.

Common variant in 6q26-q27 is associated with distal colon cancer in an Asian population.

BACKGROUND AND AIM: Colorectal cancer (CRC) is a multifactorial disease with both environmental and genetic factors contributing to its development. The incidence of CRC is increasing year by year in Japan. Patients with CRC in advanced stages have a poor prognosis, but detection of CRC at earlier stages can improve clinical outcome. Therefore, identification of epidemiologial factors that influence development of CRC would facilitate the prevention or early detection of disease. METHODS: To identify loci associated with CRC risk, we performed a genome-wide association study (GWAS) for CRC and sub-analyses by tumour location using 1583 Japanese CRC cases and 1898 controls. Subsequently, we conducted replication analyses using a total of 4809 CRC cases and 2973 controls including 225 Korean subjects with distal colon cancer and 377 controls. RESULTS: We identified a novel locus on 6q26-q27 region (rs7758229 in SLC22A3, p = 7.92 × 10⁻9, OR of 1.28) that was significantly associated with distal colon cancer. We also replicated the association between CRC and SNPs on 8q24 (rs6983267 and rs7837328, p = 1.51 × 10⁻8 and 7.44 × 10⁻8, ORs of 1.18 and 1.17, respectively). Moreover, we found cumulative effects of three genetic factors (rs7758229, rs6983267, and rs4939827 in SMAD7) and one environmental factor (alcohol drinking) which appear to increase CRC risk approximately twofold. CONCLUSIONS: We found a novel susceptible locus in SLC22A3 that contributes to the risk of distal colon cancer in an Asian population. These findings would further extend our understanding of the role of common genetic variants in the aetiology of CRC.

Verification of the Usefulness of an Assessment and Risk Control Sheet that Promotes Management of Cancer Drug Therapy.

Background: Proper management of adverse events is crucial for the safe and effective implementation of anticancer drug treatment. Showa University Hospital uses our interview sheet (assessment and risk control [ARC] sheet) for the accurate evaluation of adverse events. On the day of anticancer drug treatment, a nurse conducts a face-to-face interview. As a feature of the ARC sheet, by separately describing the symptoms the day before treatment and the day of treatment and sharing the information on the medical record, it is possible to clearly determine the status of adverse events. In this study, we hypothesized that the usefulness and points for improvement of the ARC sheet would be clarified by using and evaluating a patient questionnaire. Methods: This study included 174 patients (144 at Showa University Hospital (Hatanodai Hospital) and 30 at Showa University Koto Toyosu Hospital (Toyosu Hospital) who underwent pre-examination interviews by nurses and received cancer chemotherapy at the outpatient center of Hatanodai and Toyosu Hospital. In the questionnaire survey, the ARC sheet's content and quality, respondents' satisfaction, structural strengths, and points for improvement were evaluated on a five-point scale. Results: The patient questionnaire received responses from 160 participants, including the ARC sheet use group (132 people) and the non-use group (28 people). Unlike the ARC sheet non-use group, the ARC sheet use group recognized that the sheet was useful to understand the adverse events of aphthous ulcers (p = 0.017) and dysgeusia (p = 0.006). In the satisfaction survey questionnaire, there was a high sense of security in the pre-examination interviews by nurses using the ARC sheet. Conclusions: The ARC sheet is considered an effective tool for comprehensively evaluating adverse events. Pre-examination interviews by nurses using ARC sheets accurately determined the adverse events experienced by patients with anxiety and tension due to confrontation with physicians.

Identification of HLA-A2-restricted CTL epitopes of a novel tumour-associated antigen, KIF20A, overexpressed in pancreatic cancer.

BACKGROUND: Identification of tumour-associated antigens (TAAs) that induce cytotoxic T lymphocytes (CTLs) specific to cancer cells is critical for the development of anticancer immunotherapy. In this study, we aimed at identifying a novel TAA of pancreatic cancer for immunotherapy. METHODS: On the basis of the genome-wide cDNA microarray analysis, we focused on KIF20A (also known as RAB6KIFL/MKlp2) as a candidate TAA in pancreatic cancer cells. The HLA-A2 (A*02:01)-restricted CTL epitopes of KIF20A were identified using HLA-A2 transgenic mice (Tgm) and the peptides were examined to check whether they could generate human CTLs exhibiting cytotoxic responses against KIF20A(+), HLA-A2(+) tumour cells in vitro. RESULTS: KIF20A was overexpressed in pancreatic cancer and in some other malignancies, but not in their non-cancerous counterparts and many normal adult tissues. We found that KIF20A-2 (p12-20, LLSDDDVVV), KIF20A-8 (p809-817, CIAEQYHTV), and KIF20A-28 (p284-293, AQPDTAPLPV) peptides could induce HLA-A2-restricted CTLs in HLA-A2 Tgm without causing autoimmunity. Peptide-reactive human CTLs were generated from peripheral blood mononuclear cells of HLA-A2(+) healthy donors by in vitro stimulation with the three peptides, and those CTLs successfully exhibited cytotoxic responses to cancer cells expressing both KIF20A and HLA-A2. CONCLUSION: KIF20A is a novel promising candidate for anticancer immunotherapeutic target for pancreatic cancers.

Shape relatedness between geographic populations of Culex tritaeniorhynchus, the primary vector of Japanese encephalitis virus: A landmark study.

BACKGROUND: Japanese encephalitis is a severe disease of acute encephalitis, with children and the elderly primarily affected, and with mortality rates reaching over 25%. The virus is transmitted mainly by species of the Culex (Culex) vishnui subgroup, primarily the widely spread Cx. tritaeniorhynchus Giles. The latter is known as a highly migratory mosquito which moves with airflow over large distances. We explored the geometric variation of the wing venation among distant areas of its geographic distribution. Our working hypothesis was that shape variation across geography could reveal known past and present migratory routes. MATERIALS METHODS: We compared the wing venation geometry of 236 female Culex tritaeniorhynchus from different locations in the Madagascan (La Reunion), Oriental (Thailand, Vietnam) and Paleartic (Japan) regions. To ascertain the taxonomic signal of the wing venation we also used two species as relative outgroups, Cx. whitmorei and Cx. brevipalpis. RESULTS: In spite of an increasing morphometric variation as expected with larger geographic dispersion, our Cx. tritaeniorhynchus samples were clustered as a single species when considered relative to other Culex species. The relationships between geographic sites of Cx. tritaeniorhynchus globally conformed with an isolation by distance model. The shape homogeneity of our Palearctic samples (Japan) contrasted with some heterogeneity observed in the Oriental region (Thailand, Vietnam), and could be related to the different regimes of wind trajectories in these regions. CONCLUSION: The average shape variation of Culex tritaeniorhynchus disclosed a separation between Madagascan, Oriental and Palearctic regions in accordance with geography. The wing venation not only could reflect geography, it also contained a clear taxonomic signal separating three Culex species. Within Cx. tritaeniorhynchus, a contrasting pattern of shape variation between the Palearctic and the Oriental regions is tentatively explained by the influence of wind trajectories.

Influence of aggregation and relative humidity on longevity of unfed bush tick, Haemaphysalis longicornis Neumann (Acari: Ixodidae).

The survival of all stages of Haemaphysalis longicornis was investigated at different densities and at 3 levels of relative humidity. Larvae survived longer when the density was higher, or the size of a cluster was larger, or both. However, in nymphs and adults, there was no significant relationship between the density and the survival period. Moreover, in nymphs and adults, there was no positive relationship between the size of the aggregation and tick longevity, except for 2 nymphs/vial in high humidity. These results suggest that the advantage gained from a higher density, or from taking part in a cluster, or both, differed between stages. Furthermore, the fact that the survival period of larvae and nymphs was influenced by cohort suggests that a maternal effect, as well as aggregation, influences the survival of immature ticks.

Up-regulation of the ectodermal-neural cortex 1 (ENC1) gene, a downstream target of the beta-catenin/T-cell factor complex, in colorectal carcinomas.

To clarify the molecular mechanisms of human carcinogenesis associated with abnormal Wnt/wingless signaling, we searched for genes the expression of which was significantly altered by introduction of wild-type AXIN1 into LoVo colon cancer cells. By means of a cDNA microarray, we compared expression profiles of LoVo cells infected with either adenoviruses expressing wild-type AXIN1 (Ad-Axin) or those expressing a control gene (Ad-LacZ). Among the genes showing altered expression, the ectodermal-neural cortex 1 (ENC1) gene was down-regulated in response to Ad-Axin. The promoter activity of ENC1 was elevated approximately 3-fold by transfection of an activated form of beta-catenin together with wild-type T-cell factor (Tcf)4 in HeLa cells. Semiquantitative reverse transcription-PCR experiments revealed that expression of ENC1 was increased in more than two-thirds of 24 primary colon cancer tissues that we examined compared with corresponding noncancerous mucosae. Introduction of exogenous ENC1 increased the growth rate of HCT116 colon cancer cells in serum-depleted medium. In other experiments, overexpression of ENC1 in HT-29 colon cancer cells suppressed the usual increase of two differentiation markers, in response to treatment with sodium butyrate, a differentiation-inducible agent. These data suggest that ENC1 is regulated by the beta-catenin/Tcf pathway and that its altered expression may contribute to colorectal carcinogenesis by suppressing differentiation of colonic cells.

Involvement of deregulated epiregulin expression in tumorigenesis in vivo through activated Ki-Ras signaling pathway in human colon cancer cells.

To identify the genes located downstream of the activated Ki-Ras signaling pathways in human colon cancer cells, a PCR-based cDNA subtraction library was constructed between HCT116 cells and HCT116-derived activated Ki-ras-disrupted cells (HKe3). One of the genes in HCT116 that was evidently up-regulated was epiregulin, a member of the epidermal growth factor family that is expressed in many kinds of human cancer cells. HKe3-stable transfectants expressing activated Ki-Ras regained over-expression of epiregulin. To further elucidate the biochemical structure and significance of epiregulin expression in tumorigenesis, HKe3-stable transfectants expressing epiregulin (e3-pSE cells) were established. Epiregulin existed as highly glycosylated membrane-bound forms, and TPA rapidly induced ectodomain shedding of epiregulin. Furthermore, the conditioned medium of e3-pSE cells showed more DNA synthesis for 32D cells expressing epidermal growth factor receptor (DER) cells than that of HKe3. Although anchorage-independent growth in soft agar was not observed for e3-pSE cells, tumorigenicity in nude mice was observed evidently, and their growth rate was correlated with each amount of exogenous epiregulin expression. These results suggested that activated Ki-Ras will be one of the factors contributing to the overexpression of epiregulin in human colon cancer cells, and that epiregulin will play a critical role in human tumorigenesis in vivo.

Identification by cDNA microarray of genes involved in ovarian carcinogenesis.

To identify genes involved in the development or progression of ovarian cancer, we analyzed gene expression profiles of nine ovarian tumors using a DNA microarray consisting of 9121 genes. Comparison of expression patterns between carcinomas and the corresponding normal ovarian tissues enabled us to identify 55 genes that were commonly up-regulated and 48 genes that were down-regulated in the cancer specimens. When the five serous adenocarcinomas were analyzed separately from the four mucinous adenocarcinomas, we identified 115 genes that were expressed differently between the two types of tumor. Investigation of these genes should help to disclose the molecular mechanism(s) of ovarian carcinogenesis and define molecular separation of the two most common histological types of ovarian cancer.

Genome-wide analysis of gene expression in human hepatocellular carcinomas using cDNA microarray: identification of genes involved in viral carcinogenesis and tumor progression.

To disclose detailed genetic mechanisms in hepatocellular carcinoma (HCC) with a view toward development of novel therapeutic targets, we analyzed expression profiles of 20 primary HCCs and their corresponding noncancerous tissues by means of cDNA microarrays consisting of 23,040 genes. Up-regulation of mitosis-promoting genes was observed in the majority of the tumors examined. Some genes showed expression patterns in hepatitis B virus-positive HCCs that were different from those in hepatitis C virus-positive HCCs; most of them encoded enzymes that metabolize carcinogens and/or anticancer agents. Furthermore, we identified a number of genes associated with malignant histological type or invasive phenotype. Accumulation of such data will make it possible to define the nature of individual tumors, to provide clues for identifying new therapeutic targets, and ultimately to optimize treatment of each patient.

Identification of AF17 as a downstream gene of the beta-catenin/T-cell factor pathway and its involvement in colorectal carcinogenesis.

To elucidate the molecular mechanism of colorectal carcinogenesis, we have been attempting to isolate genes involved in the beta-catenin/T-cell factor pathway. In the experiments reported here, analysis by cDNA microarray indicated that AF17, a fusion partner of the MLL gene in acute leukemias with t(11;17)(q23;q21), was transactivated according to accumulation of beta-catenin. Expression of AF17 was significantly enhanced in 8 of the 12 colorectal cancer tissues examined. Introduction of a plasmid designed to express AF17 stimulated growth of NIH3T3 cells, and fluorescence-activated cell sorter analysis indicated that the AF17 regulation of cell-cycle progression was occurring mainly at the G(2)-M transition. Our results suggest that the AF17 gene product is likely to be involved in the beta-catenin-T-cell factor/lymphoid enhancer factor signaling pathway and to function as a growth-promoting, oncogenic protein. These findings should aid development of new strategies for diagnosis, treatment, and prevention of colon cancers and acute leukemias by clarifying the pathogenesis of these conditions.

Prediction of sensitivity of esophageal tumors to adjuvant chemotherapy by cDNA microarray analysis of gene-expression profiles.

We applied cDNA microarray analyses of 9216 genes to establish a genetic method for predicting the outcome of adjuvant chemotherapy to esophageal cancers. We analyzed expression profiles of 20 esophageal cancer tissues from patients who were treated with the same adjuvant chemotherapy after removal of tumor by operation, and we attempted to find genes associated with the duration of survival after surgery. By comparing expression profiles of those cancer tissues, we identified by statistical analysis 52 genes that were likely to be correlated with prognosis and possibly with sensitivity/resistance to the anticancer drugs. We also developed a drug response score based on the differential expression of these genes, and we found a significant correlation between the drug response score and individual patients' prognoses. Our results indicated that this scoring system, based on microarray analysis of selected genes, is likely to have great potential for predicting the prognosis of individual cancer patients with the adjuvant chemotherapy.

Alterations of gene expression during colorectal carcinogenesis revealed by cDNA microarrays after laser-capture microdissection of tumor tissues and normal epithelia.

To identify a set of genes involved in the development of colorectal carcinogenesis, we compared expression profiles of colorectal cancer cells from eight tumors with corresponding noncancerous colonic epithelia using a DNA microarray consisting of 9216 human genes. These cell populations had been rendered homogeneous by laser-capture microdissection. Expression change in more than half of the tumors was observed for 235 genes, i.e., 44 up-regulated and 191 down-regulated genes. The differentially expressed genes include those associated with signal transduction, metabolizing enzymes, production of reactive oxygen species, cell cycle, transcription, mitosis, and apoptosis. Subsequent examination of 10 genes (five up-regulated and five down-regulated) by semiquantitative reverse transcription-PCR using the eight tumors together with an additional 12 samples substantiated the reliability of our analysis. The extensive list of genes identified in these experiments provides a large body of potentially valuable information of colorectal carcinogenesis and represents a source of novel targets for cancer therapy.

Growth and gene expression profile analyses of endometrial cancer cells expressing exogenous PTEN.

The PTEN tumor suppressor gene encodes a multifunctional phosphatase that plays an important role in inhibiting the phosphatidylinositol-3-kinase pathway and downstream functions that include activation of Akt/protein kinase B, cell survival, and cell proliferation. Enforced expression of PTEN in various cancer cell lines decreases cell proliferation through arrest of the cell cycle, accompanied in some cases by induction of apoptosis. We used cDNA microarrays containing 4009 cDNAs to examine changes in gene-expression profiles when exogenous PTEN was induced in PTEN-defective cells. The microarrays and subsequent semi-quantitative reverse transcription-PCR analysis revealed transcriptional stimulation of 99 genes and repression of 72 genes. Some of the differentially expressed genes already had been implicated in cell proliferation, differentiation, apoptosis, or cell cycle control, e.g., overexpression of PTEN-induced transactivation of cyclin-dependent inhibitor 1B (p27Kip1) and 2B (p15INK4B), members of the TNF receptor family, tumor necrosis factor-associated genes, and members of the Notch-signaling and Mad families. To our knowledge this is the first report of transactivation of those genes by PTEN. The genes differentially expressed in our experiments also included many whose correlation with cancer development had not been recognized before. Our data should contribute to a greater understanding of the broad spectrum of ways in which PTEN affects intracellular signaling pathways. Analysis of expression profiles with microarrays appears to be a powerful approach for identifying anticancer genes and/or disease-specific targets for cancer therapy.

Identification of AXUD1, a novel human gene induced by AXIN1 and its reduced expression in human carcinomas of the lung, liver, colon and kidney.

Axin, an important regulator of beta-catenin, is frequently mutated in human hepatocellular carcinomas (HCCs), and transduction of the wild-type Axin gene (AXIN1) induces apoptosis in HCC cells as well as in colon cancer cells. To investigate the detailed biological function of Axin, we searched on a cDNA microarray for genes whose expression was altered by transfer of wild-type AXIN1 into colon-cancer cell line LoVo. Among the genes showing altered expression, we focused on one, termed AXUD1 (AXIN1 up-regulated), that revealed enhanced expression in response to exogenously expressed AXIN1 but not to LacZ, a control gene. The AXUD1 gene consists of five exons and encodes a transcript with an open reading frame of 1767 bp. A 3.2-kb transcript of AXUD1 was expressed in all human tissues examined, most abundantly in lung, placenta, skeletal muscle, pancreas and leukocyte. By radiation-hybrid mapping we assigned its chromosomal location at 3p22, a region where frequent loss of heterozygosity has been reported in lung, renal, prostate, breast and cervical cancers. AXUD1 was frequently down-regulated in lung, kidney, liver and colon cancers compared with their corresponding normal tissues, suggesting that AXUD1 may have a tumor-suppressor function in those organs.

Tumor necrosis factor-alpha-induced release of plasminogen activator inhibitor-1 from human umbilical vein endothelial cells: involvement of intracellular ceramide signaling event.

We have investigated the biochemical mechanism of tumor necrosis factor (TNF)-alpha-induced release of plasminogen activator inhibitor-1 (PAI-1) from human umbilical vein endothelial cells (HUVEC). Treatment of HUVEC with TNF-alpha for 3 h resulted in a 2. 8-fold increase in the PAI-1 release compared with control. The increase in PAI-1 release was accompanied by a 133% increase in the intracellular acidic sphingomyelinase (SMase) activity. High-performance liquid chromatographic (HPLC) analysis revealed that the intracellular ceramide levels increased to 126% of the control (P<0.05), but the contents of membranous ceramide remained unaltered. We have previously shown that a cell-permeable ceramide analog, N-acetylsphingosine (C2-ceramide) enhances the PAI-1 release from HUVEC. Here, N-acetylsphinganine (C2-dihydroceramide) was found to specifically suppress both C2-ceramide- and TNF-alpha-induced increase in PAI-1 release from HUVEC without affecting the control PAI-1 release. Treatment of HUVEC with staphylococcal SMase that may mimic the activation of the membranous neutral SMase also increased the PAI-1 release. The increase in PAI-1 release by this mechanism was suppressed by a cyclooxygenase inhibitor, aspirin, whereas the inhibitor did not affect TNF-alpha-induced increase in PAI-1 release. Taken together, these findings suggest that TNF-alpha prominently utilizes the lysosomal acidic SMase-ceramide signaling pathway in the induction of PAI-1 release from HUVEC.

Coronary flow velocity immediately after primary coronary stenting as a predictor of ventricular wall motion recovery in acute myocardial infarction.

OBJECTIVES: The purpose of this study was to examine the relationship between the pattern of coronary blood flow velocity immediately after successful primary stenting and the recovery of left ventricular (LV) wall motion in patients with acute myocardial infarction (AMI). BACKGROUND: It is difficult to predict the recovery of LV wall motion immediately after direct angioplasty in AMI. Recent reports indicate that dysfunctional coronary microcirculation is an important determinant of prognosis for AMI patients after successful reperfusion. METHODS: We measured left anterior descending coronary flow velocity variables using a Doppler guide wire immediately after successful primary stenting in 31 patients with their first anterior AMI. The patients were divided into two groups: those with and those without early systolic reverse flow (ESRF). Changes in LV regional wall motion (RWM) and ejection fraction (EF) at admission and at discharge were compared between the two groups. Coronary flow velocity variables immediately after primary stenting were compared with changes in left ventriculographic indexes. RESULTS: The change in RWM was significantly greater in the non-ESRF group than it was in the ESRF group (0.9 +/- 0.7 vs. -0.1 +/- 0.3 standard deviation/chord, respectively, p < 0.001). The change in EF was also significantly greater in the non-ESRF group than it was in the ESRF group (10 +/- 10 vs. 1 +/- 6%, respectively, p < 0.05). In the non-ESRF group (diastolic to systolic velocity ratio [DSVR] <3.0), the DSVR correlated positively with the change in RWM (r = 0.60, p < 0.005, n = 24) and the change in EF (r = 0.52, p < 0.01). CONCLUSIONS: The coronary flow velocity pattern measured immediately after successful primary stenting is predictive of the recovery of regional and global LV function in patients with AMI.