Transcriptomic dysregulation and autistic-like behaviors in Kmt2c haploinsufficient mice rescued by an LSD1 inhibitor.

Recent studies have consistently demonstrated that the regulation of chromatin and gene transcription plays a pivotal role in the pathogenesis of neurodevelopmental disorders. Among many genes involved in these pathways, KMT2C, encoding one of the six known histone H3 lysine 4 (H3K4) methyltransferases in humans and rodents, was identified as a gene whose heterozygous loss-of-function variants are causally associated with autism spectrum disorder (ASD) and the Kleefstra syndrome phenotypic spectrum. However, little is known about how KMT2C haploinsufficiency causes neurodevelopmental deficits and how these conditions can be treated. To address this, we developed and analyzed genetically engineered mice with a heterozygous frameshift mutation of Kmt2c (Kmt2c+/fs mice) as a disease model with high etiological validity. In a series of behavioral analyses, the mutant mice exhibit autistic-like behaviors such as impairments in sociality, flexibility, and working memory, demonstrating their face validity as an ASD model. To investigate the molecular basis of the observed abnormalities, we performed a transcriptomic analysis of their bulk adult brains and found that ASD risk genes were specifically enriched in the upregulated differentially expressed genes (DEGs), whereas KMT2C peaks detected by ChIP-seq were significantly co-localized with the downregulated genes, suggesting an important role of putative indirect effects of Kmt2c haploinsufficiency. We further performed single-cell RNA sequencing of newborn mouse brains to obtain cell type-resolved insights at an earlier stage. By integrating findings from ASD exome sequencing, genome-wide association, and postmortem brain studies to characterize DEGs in each cell cluster, we found strong ASD-associated transcriptomic changes in radial glia and immature neurons with no obvious bias toward upregulated or downregulated DEGs. On the other hand, there was no significant gross change in the cellular composition. Lastly, we explored potential therapeutic agents and demonstrate that vafidemstat, a lysine-specific histone demethylase 1 (LSD1) inhibitor that was effective in other models of neuropsychiatric/neurodevelopmental disorders, ameliorates impairments in sociality but not working memory in adult Kmt2c+/fs mice. Intriguingly, the administration of vafidemstat was shown to alter the vast majority of DEGs in the direction to normalize the transcriptomic abnormalities in the mutant mice (94.3 and 82.5% of the significant upregulated and downregulated DEGs, respectively, P < 2.2 × 10-16, binomial test), which could be the molecular mechanism underlying the behavioral rescuing. In summary, our study expands the repertoire of ASD models with high etiological and face validity, elucidates the cell-type resolved molecular alterations due to Kmt2c haploinsufficiency, and demonstrates the efficacy of an LSD1 inhibitor that might be generalizable to multiple categories of psychiatric disorders along with a better understanding of its presumed mechanisms of action.

Topologically associating domains define the impact of de novo promoter variants on autism spectrum disorder risk.

Whole-genome sequencing (WGS) studies of autism spectrum disorder (ASD) have demonstrated the roles of rare promoter de novo variants (DNVs). However, most promoter DNVs in ASD are not located immediately upstream of known ASD genes. In this study analyzing WGS data of 5,044 ASD probands, 4,095 unaffected siblings, and their parents, we show that promoter DNVs within topologically associating domains (TADs) containing ASD genes are significantly and specifically associated with ASD. An analysis considering TADs as functional units identified specific TADs enriched for promoter DNVs in ASD and indicated that common variants in these regions also confer ASD heritability. Experimental validation using human induced pluripotent stem cells (iPSCs) showed that likely deleterious promoter DNVs in ASD can influence multiple genes within the same TAD, resulting in overall dysregulation of ASD-associated genes. These results highlight the importance of TADs and gene-regulatory mechanisms in better understanding the genetic architecture of ASD.

Genetics of bipolar disorder: insights into its complex architecture and biology from common and rare variants.

Bipolar disorder (BD) is a common mental disorder characterized by recurrent mood episodes, which causes major socioeconomic burdens globally. Though its disease pathogenesis is largely unknown, the high heritability of BD indicates strong contributions from genetic factors. In this review, we summarize the recent achievements in the genetics of BD, particularly those from genome-wide association study (GWAS) of common variants and next-generation sequencing analysis of rare variants. These include the identification of dozens of robust disease-associated loci, deepening of our understanding of the biology of BD, objective description of correlations with other psychiatric disorders and behavioral traits, formulation of methods for predicting disease risk and drug response, and the discovery of a single gene associated with bipolar disorder and schizophrenia spectrum with a large effect size. On the other hand, the findings to date have not yet made a clear contribution to the improvement of clinical psychiatry of BD. We overview the remaining challenges as well as possible paths to resolve them, referring to studies of other major neuropsychiatric disorders.

Glyoxalase I disruption and external carbonyl stress impair mitochondrial function in human induced pluripotent stem cells and derived neurons.

Carbonyl stress, a specific form of oxidative stress, is reported to be involved in the pathophysiology of schizophrenia; however, little is known regarding the underlying mechanism. Here, we found that disruption of GLO1, the gene encoding a major catabolic enzyme scavenging the carbonyl group, increases vulnerability to external carbonyl stress, leading to abnormal phenotypes in human induced pluripotent stem cells (hiPSCs). The viability of GLO1 knockout (KO)-hiPSCs decreased and activity of caspase-3 was increased upon addition of methylglyoxal (MGO), a reactive carbonyl compound. In the GLO1 KO-hiPSC-derived neurons, MGO administration impaired neurite extension and cell migration. Further, accumulation of methylglyoxal-derived hydroimidazolone (MG-H1; a derivative of MGO)-modified proteins was detected in isolated mitochondria. Mitochondrial dysfunction, including diminished membrane potential and dampened respiratory function, was observed in the GLO1 KO-hiPSCs and derived neurons after addition of MGO and hence might be the mechanism underlying the effects of carbonyl stress. The susceptibility to MGO was partially rescued by the administration of pyridoxamine, a carbonyl scavenger. Our observations can be used for designing an intervention strategy for diseases, particularly those induced by enhanced carbonyl stress or oxidative stress.

Role of an Atypical Cadherin Gene, Cdh23 in Prepulse Inhibition, and Implication of CDH23 in Schizophrenia.

We previously identified quantitative trait loci (QTL) for prepulse inhibition (PPI), an endophenotype of schizophrenia, on mouse chromosome 10 and reported Fabp7 as a candidate gene from an analysis of F2 mice from inbred strains with high (C57BL/6N; B6) and low (C3H/HeN; C3H) PPI levels. Here, we reanalyzed the previously reported QTLs with increased marker density. The highest logarithm of odds score (26.66) peaked at a synonymous coding and splice-site variant, c.753G>A (rs257098870), in the Cdh23 gene on chromosome 10; the c.753G (C3H) allele showed a PPI-lowering effect. Bayesian multiple QTL mapping also supported the same variant with a posterior probability of 1. Thus, we engineered the c.753G (C3H) allele into the B6 genetic background, which led to dampened PPI. We also revealed an e-QTL (expression QTL) effect imparted by the c.753G>A variant for the Cdh23 expression in the brain. In a human study, a homologous variant (c.753G>A; rs769896655) in CDH23 showed a nominally significant enrichment in individuals with schizophrenia. We also identified multiple potentially deleterious CDH23 variants in individuals with schizophrenia. Collectively, the present study reveals a PPI-regulating Cdh23 variant and a possible contribution of CDH23 to schizophrenia susceptibility.

Fatty Acid Binding Protein 7 is Involved in the Proliferation of Reactive Astrocytes, but not in Cell Migration and Polarity.

Reactive gliosis is a defense mechanism to minimize and repair the initial damage after CNS injuries that is characterized by increases in astrocytic reactivity and proliferation, with enhanced expression of glial fibrillary acidic protein (GFAP) and cellular hypertrophy. Fatty acid binding protein 7 (FABP7) is abundantly expressed in several types of glial cells, such as astrocytes and oligodendrocyte precursor cells, during brain development and FABP7-positive astrocytes have been shown to be significantly increased in the mouse cortex after a stab injury. However, the functional significance of FABP7 in gliosis remains unclear. In the present study, we examined the mechanism of FABP7-mediated regulation of gliosis using an in vitro scratch-injury model using primary cultured astrocytes. Western blotting showed that FABP7 expression was increased significantly in scratch wounded astrocytes at the edge of the injury compared with intact astrocytes. Through monitoring the occupancy of the injured area, FAB7-KO astrocytes showed a slower proliferation rate compared with WT astrocytes after 48 hr, which was confirmed by BrdU immunostaining. There were no differences in cell migration and polarity of reactive astrocytes between FABP-KO and WT. Conclusively, our data suggest that FABP7 is important in the proliferation of reactive astrocytes in the context of CNS injury.

Excess hydrogen sulfide and polysulfides production underlies a schizophrenia pathophysiology.

Mice with the C3H background show greater behavioral propensity for schizophrenia, including lower prepulse inhibition (PPI), than C57BL/6 (B6) mice. To characterize as-yet-unknown pathophysiologies of schizophrenia, we undertook proteomics analysis of the brain in these strains, and detected elevated levels of Mpst, a hydrogen sulfide (H2 S)/polysulfide-producing enzyme, and greater sulfide deposition in C3H than B6 mice. Mpst-deficient mice exhibited improved PPI with reduced storage sulfide levels, while Mpst-transgenic (Tg) mice showed deteriorated PPI, suggesting that "sulfide stress" may be linked to PPI impairment. Analysis of human samples demonstrated that the H2 S/polysulfides production system is upregulated in schizophrenia. Mechanistically, the Mpst-Tg brain revealed dampened energy metabolism, while maternal immune activation model mice showed upregulation of genes for H2 S/polysulfides production along with typical antioxidative genes, partly via epigenetic modifications. These results suggest that inflammatory/oxidative insults in early brain development result in upregulated H2 S/polysulfides production as an antioxidative response, which in turn cause deficits in bioenergetic processes. Collectively, this study presents a novel aspect of the neurodevelopmental theory for schizophrenia, unraveling a role of excess H2 S/polysulfides production.

[Long-Term Survival of a Patient with Mediastinal Lymph Node Metastasis Treated with Chemo-Radiotherapy after Surgery for Cecal Cancer].

In June 1997, the patient underwent an operation for cecal colon cancer pStage II .I n May 1999, a liver metastasis at S6 was detected and the patient received a partial liver resection.In April 2004, a liver metastasis in S4 was detected and another partial liver resection was performed.In November 2008, he complained of hemoptysis and cough.The chest CT examination showed lymph node metastases in the mediastinum that invaded the left main bronchus.We performed chemo-radiotherapy for local control from January 2009. Because the lymph nodes were reduced remarkably and clinical complaints disappeared, we administrated a mFOLFOX6 regimen from June.We recognized the effect of treatment to be a complete response.In February 2014, we detected a lymph nodes recurrence around a right pulmonary artery.We performed chemo-radiotherapy again because the patient declined surgery.However, lymph node metastases did not completely respond.We then performed chemotherapy 30 times using a FOLFIRI plus panitumumab regimen.On PET-CT, the recurrent lesion did not show a hot spot.We experienced a case that responded to chemo-radiotherapy for long-term control of lymph node recurrence.

Differential expression and regulatory roles of FABP5 and FABP7 in oligodendrocyte lineage cells.

Fatty-acid-binding proteins (FABPs) are key intracellular molecules involved in the uptake, transportation and storage of fatty acids and in the mediation of signal transduction and gene transcription. However, little is known regarding their expression and function in the oligodendrocyte lineage. We evaluate the in vivo and in vitro expression of FABP5 and FABP7 in oligodendrocyte lineage cells in the cortex and corpus callosum of adult mice, mixed cortical culture and oligosphere culture by immunofluorescent counter-staining with major oligodendrocyte lineage markers. In all settings, FABP7 expression was detected in NG2(+)/PDGFRα(+) oligodendrocyte progenitor cells (OPCs) that did not express FABP5. FABP5 was detected in mature CC1(+)/MBP(+) oligodendrocytes that did not express FABP7. Analysis of cultured OPCs showed a significant decrease in the population of FABP7-knockout (KO) OPCs and their BrdU uptake compared with wild-type (WT) OPCs. Upon incubation of OPCs in oligodendrocyte differentiation medium, a significantly lower percentage of FABP7-KO OPCs differentiated into O4(+) oligodendrocytes. The percentage of mature MBP(+) oligodendrocytes relative to whole O4(+)/MBP(+) oligodendrocytes was significantly lower in FABP7-KO and FABP5-KO than in WT cell populations. The percentage of terminally mature oligodendrocytes with membrane sheet morphology was significantly lower in FABP5-KO compared with WT cell populations. Thus, FABP7 and FABP5 are differentially expressed in oligodendrocyte lineage cells and regulate their proliferation and/or differentiation. Our findings suggest the involvement of FABP7 and FABP5 in the pathophysiology of demyelinating disorders, neuropsychiatric disorder and glioma, conditions in which OPCs/oligodendrocytes play central roles.

Prediction of the no-reflow phenomenon during percutaneous coronary intervention using coronary computed tomography angiography.

Coronary computed tomography angiography (CTA) can assess plaque characteristics and plaque size noninvasively. The purpose of this study was to investigate whether coronary CTA before percutaneous coronary intervention (PCI) can predict the no-reflow phenomenon during PCI. Seventy-eight patients [acute coronary syndrome (ACS) = 43, stable angina pectoris (SAP) = 35, male/female = 72/6, age: 65 ± 10 years] who underwent 16- or 64-slice CTA in the 4 weeks before PCI were enrolled. The low attenuation plaque size on CTA was compared between patients with (NR+) and without the no-reflow phenomenon (NR-). No-reflow phenomenon was observed in 11 patients, including 10 patients with ACS and 1 patient with SAP. Low attenuation plaque was detected in 9 (82%) NR(+) lesions and 35 (52%) NR(-) lesions. The length of low attenuation plaque was significantly longer in NR(+) than in NR(-) patients (9.0 ± 6.5 vs. 1.6 ± 2.7 mm, p < 0.0001). On step-wise regression analysis, ACS (p = 0.036, 95% CI = 0.009-0.258) and the presence of low attenuation plaque with a length >4.7 mm (p < 0.001, 95% CI = 0.447-0.778) were significant independent predictors of NR(-) no-reflow phenomenon. Low attenuation plaque with lesion length of >4.7 mm on coronary CTA and ACS were the significant predictors for the no-reflow phenomenon during PCI. Coronary CTA assessment before PCI would be useful to predict coronary events during PCI in advance.

Carcinosarcoma of the Sigmoid Colon: Report of a Case.

Our case was a 65-year-old male, with the chief complaints of diarrhea and abdominal distention. Three years earlier, the patient had undergone transcatheter arterial embolization and radiofrequency treatment based on a diagnosis of hepatocellular carcinoma due to hepatitis B by another doctor. In October 2007, the patient developed diarrhea and increased abdominal distention. In December, CT examination conducted by the previous doctor revealed a 20-cm tumor within the pelvis. The patient was diagnosed with sigmoid colon cancer based on barium enema examination using gastrografin, and was introduced to our hospital for treatment. He was diagnosed with low-differentiated carcinoma by biopsy of the colon during endoscopy and underwent sigmoidectomy based on a diagnosis of sigmoid colon cancer. The tumor had infiltrated the bladder, and a tumorectomy was conducted through partially combined resection. The tumor was a huge lesion occupying the inside of the lumen, and histopathological findings revealed that the tumor, the main part of which lay beneath the mucous membrane, had a transitional image composed of both spindle-shaped atypical cells and sarcomatoid shape. The result of immunostaining was CK7(+), CK20(-), AFP(-), and the patient was diagnosed as having carcinosarcoma of the colon. Carcinosarcoma of the colon is a malignant tumor with poor prognosis, and the mean survival period in past reports was approximately 6 months. The patient was treated with FOLFIRI+Bevacizumab therapy according to chemotherapy for colon cancer, but he was refractory to the therapy.

Serial coronary CT angiography-verified changes in plaque characteristics as an end point: evaluation of effect of statin intervention.

OBJECTIVES: This study sought to assess, by serial computed tomography angiography (CTA), the effect of statin treatment on coronary plaque morphology. BACKGROUND: In addition to the assessment of luminal stenosis, CTA also allows characterization of plaque morphology. Large, positively remodeled plaques with large necrotic cores have been reported as indicators of plaque instability. METHODS: CTA was performed in 32 patients (26 men, ages 64.3 +/- 8.5 years). Of these, 24 received fluvastatin after the baseline study; 8 subjects who refused statin treatment were followed as the control subjects. Serial imaging was performed after a median interval of 12 months. All vessels were examined in every subject, and a 10-mm-long segment was identified for comparison before and after intervention. Total plaque volume, low attenuation plaque (LAP) volume, lumen volume, and remodeling index were calculated. RESULTS: In the statin-treated patients, the total plaque volume (92.3 +/- 37.7 vs. 76.4 +/- 26.5 mm(3), p < 0.01) and LAP volume (4.9 +/- 7.8 vs. 1.3 +/- 2.3 mm(3), p = 0.01) were significantly reduced over time; however, there was no change in the lumen volume (63.9 +/- 25.3 vs. 65.2 +/- 26.2 mm(3), p = 0.59). On the other hand, no change was observed in the CTA characteristics in the control subjects, including total plaque volume (94.4 +/- 21.2 vs. 98.4 +/- 28.6 mm(3), p = 0.48), LAP volume (2.1 +/- 3.0 vs. 2.3 +/- 3.6 mm(3), p = 0.91), and lumen volume (80.5 +/- 20.7 vs. 75.0 +/- 16.3 mm(3), p = 0.26). The plaque volume change (-15.9 +/- 22.2 vs. 4.0 +/- 14.0 mm(3), p = 0.01) and LAP volume change (-3.7 +/- 7.0 vs. 0.2 +/- 1.5 mm(3), p < 0.01) were significantly greater in the statin than the control group. The lumen volume (1.3 +/- 15.6 vs. -5.5 +/- 13.1 mm(3), p = 0.24) and remodeling index (-2.4 +/- 6.8% vs. -0.3 +/- 6.5%, p = 0.53) did not show the significant differences between the 2 groups. The decrease in the plaque volume was due to reduction in the LAP volume (R = 0.83, p < 0.01), and was not related to any changes in the lumen volume (R = 0.21, p = 0.24). CONCLUSIONS: This preliminary study suggests that serial CTA evaluation of coronary plaques allows for the assessment of interval change in the plaque morphology. Statin treatment results in decreases in the plaque and necrotic core volume. The features known to be associated with plaque instability.

The washout rate of (123)I-BMIPP and the evolution of left ventricular function in patients with successfully reperfused ST-segment elevation myocardial infarction: comparisons with the echocardiography.

The evolution of the oxidative metabolism of (11)C acetate parallels the recovery of left ventricular(LV) contraction following acute myocardial infarction(AMI). This study was designed to unravel, for the first time, the impact of the global washout rate(WR) of (123)I-beta-methyl-p-iodophenylpentadecanoic acid (BMIPP) on the recovery of LV function followingAMI, as evidenced from conventional echocardiography.Twenty consecutive patients (age: 58 +/- 13 years; 16 males and 4 females) with ST-segment elevation myocardial infarction (STEMI) were enrolled and all of them underwent successful percutaneous coronary intervention (PCI). (123)I-BMIPP cardiac scintigraphy was performed at 7 +/- 3 days after admission. The WR was calculated from the polar map and the regional BMIPP defect score was calculated using a 17 segment model. Echocardiography was performed within 24 h of admission and at 3 months to record the ejection fraction (EF), the wall motion score index (WMSI), the ratio of the mitralinflow velocity to the early diastolic velocity (E/E0)and the myocardial performance index (MPI). The mean global WR of the BMIPP was 22.12 +/- 7.22%, and it was significantly correlated with the improvement of the WMSI (r = 0.61, P\0.004). However,the relative changes of the EF, E/E0 and MPI were not correlated with the WR. The BMIPP defect score (18 +/- 10) was significantly correlated with the WMSI on admission (r = 0.74, P = 0.0002), but the defect score was not correlated with the relative changes of any of the echocardiographic parameters. We proved that the WR of the BMIPP is a promising indicator of improvement of the LV wall motion (WMSI) following ST-segment elevation myocardial infarction and successful reperfusion.

Fatty acid metabolism and myocardial perfusion imaging for the evaluation of global left ventricular dysfunction following acute myocardial infarction: comparisons with echocardiography.

BACKGROUND: Myocardial fatty acid metabolic imaging with beta-methyl iodophenyl pentadecanoic acid (BMIPP) and perfusion imaging with tetrofosmin (TF) combined can predict post ischemic salvageable myocardium and persistent left ventricular (LV) dysfunction. This study was designed for the first time to assess systolic, diastolic and global LV dysfunction considering BMIPP and TF mismatched defect score (MMDS), and comparing this approach with the conventional Doppler echocardiography. METHODS: Thirty four patients with first acute myocardial infarction (AMI) were enrolled, and all of them underwent percutaneous coronary intervention (PCI). BMIPP and Tetrofosmin (TF) scans were performed at 7+/-3.5 days of admission. Echocardiography was performed within 24 h of admission, at an interval of 1 and 3 months. MMDS was compared with systolic: ejection fraction (EF), wall motion score index (WMSI), fractional shortening (FS); diastolic: mitral valve deceleration time (MVDT), E/E', left atrial volume index (LAVI); combined systolic and diastolic parameter: left ventricular myocardial performance index (LVMPI). RESULTS: A good correlation was observed between BMIPP and TF defect score (p<0.00001), and in 31 (91%) patients BMIPP defect score was higher than that of TF. The MMDS showed significant correlation with EF (r=-0.64, p=<0.00001), WMSI (r=0.61, p<0.0001), and FS(r=-0.65, p<0.00001), LAVI (r=-0.32, p<0.05), and LVMPI (r=0.37, p<0.02) during follow up echocardiography at 1 month. MVDT and E/E' did not correlate with MMDS. CONCLUSION: Perfusion-metabolism mismatched defect score was well correlated with the evolution of global left ventricular dysfunction following AMI evidenced from conventional Doppler echocardiography.

(123)I-BMIPP and (99m)Tc-TF discordance on myocardial scintigraphy and it's correlation with functional recovery following acute myocardial infarction: role of conventional echocardiography.

(123)I-beta-methyl-iodophenyl pentadecanoic acid (BMIPP) and (99m)Tc-Tetrofosmin (TF) mismatch designated as stunned myocardium having both systolic and diastolic components. The degree of mismatch might reflect subsequent functional improvement, and this study was designed to unravel the impact of mismatched defect score (MMDS) on recovery of both systolic and diastolic function following acute myocardial infarction (AMI). Forty patients with recent AMI were recruited, and all of them underwent emergency percutaneous coronary intervention. Echocardiography and BMIPP and TF cardiac scintigraphy were performed on 7 +/- 3 days of admission. Follow up echocardiography was performed after 3 months. MMDS were compared with the systolic [ejection fraction (EF) and wall motion score index (WMSI)] and diastolic [peak velocity of early diastolic filling of mitral inflow/peak early diastolic velocity of the mitral annulus(E/E') and left atrial volume index(LAVI)] parameters. BMIPP defect score was significantly higher than the TF defect score and there was a strong positive correlation between them (r = 0.90, P < 0.00001). Thirty-two (80%) patients showed mismatched defect and rest 8(20%) showed matched defect. Of 32 patients 24(75%), 22(69%), 19(59%), and 20(62.5%) showed improved EF, WMSI, E/E' and LAVI respectively. Conversely out of 8 only 2(25%), 1(12.5%), and 2(25%) patients showed improvement of EF, WMSI and LAVI, respectively. E/E' was not improved in patients with matched defect. MMDS were significantly correlated with the improvement of EF (r = -0.46, P = 0.002), WMSI (r = 0.41, P = 0.007), E/E' (r = 0.56, P < 0.0002), and LAVI (r = 0.44, P = 0.004). Mismatched defect score could predict the approximate amount of viable dysfunctional myocardium, and the degree of mismatch showed a significant correlation with the improvement of both systolic and diastolic function.

Computed tomographic angiography characteristics of atherosclerotic plaques subsequently resulting in acute coronary syndrome.

OBJECTIVES: In a computed tomographic (CT) angiography study, we identified the characteristics of atherosclerotic lesions that were associated with subsequent development of acute coronary syndrome (ACS). BACKGROUND: The CT characteristics of culprit lesions in ACS include positive vessel remodeling (PR) and low-attenuation plaques (LAP). These 2 features have been observed in the lesions that have already resulted in ACS, but their prospective relation to ACS has not been previously described. METHODS: In 1,059 patients who underwent CT angiography, atherosclerotic lesions were analyzed for the presence of 2 features: PR and LAP. The remodeling index, and plaque and LAP areas and volumes were calculated. The plaque characteristics of lesions resulting in ACS during the follow-up of 27 +/- 10 months were evaluated. RESULTS: Of the 45 patients showing plaques with both PR and LAP (2-feature positive plaques), ACS developed in 10 (22.2%), compared with 1 (3.7%) of the 27 patients with plaques displaying either feature (1-feature positive plaques). In only 4 (0.5%) of the 820 patients with neither PR nor LAP (2-feature negative plaques) did ACS develop. None of the 167 patients with normal angiograms had acute coronary events (p < 0.001). ACS was independently predicted by PR and/or LAP (hazard ratio: 22.8, 95% confidence interval: 6.9 to 75.2, p < 0.001). Among 2- or 1-feature positive segments, those resulting in ACS demonstrated significantly larger remodeling index (126.7 +/- 3.9% vs. 113.4 +/- 1.6%, p = 0.003), plaque volume (134.9 +/- 14.1 mm(3) vs. 57.8 +/- 5.7 mm(3), p < 0.001), LAP volume (20.4 +/- 3.4 mm(3) vs. 1.1 +/- 1.4 mm(3), p < 0.001), and percent LAP/total plaque area (21.4 +/- 3.7 mm(2) vs. 7.7 +/- 1.5 mm(2), p = 0.001) compared with segments not resulting in ACS. CONCLUSIONS: The patients demonstrating positively remodeled coronary segments with low-attenuation plaques on CT angiography were at a higher risk of ACS developing over time when compared with patients having lesions without these characteristics.