Huangqi Decoction, a compound Chinese herbal medicine, inhibits the proliferation and activation of hepatic stellate cells by regulating the long noncoding RNA-C18orf26-1/microRNA-663a/transforming growth factor-ß axis.

OBJECTIVE: Huangqi Decoction (HQD), a classical traditional Chinese medicine formula, has been used as a valid treatment for alleviating liver fibrosis; however, the underlying molecular mechanism is still unknown. Although our previous studies showed that microRNA-663a (miR-663a) suppresses the proliferation and activation of hepatic stellate cells (HSCs) and the transforming growth factor-ß/small mothers against decapentaplegic (TGF-ß/Smad) pathway, whether long noncoding RNAs (lncRNAs) are involved in HSC activation via the miR-663a/TGF-ß/Smad signaling pathway has not yet reported. The present study aimed to investigate the roles of lncRNA lnc-C18orf26-1 in the activation of HSCs and the mechanism by which HQD inhibits hepatic fibrosis. METHODS: The expression levels of lnc-C18orf26-1, miR-663a and related genes were measured by quantitative reverse transcription-polymerase chain reaction. HSCs were transfected with the miR-663a mimic or inhibitor and lnc-C18orf26-1 small interfering RNAs. The water-soluble tetrazolium salt-1 assay was used to assess the proliferation rate of HSCs. Changes in lncRNA expression were evaluated in miR-663a-overexpressing HSCs by using microarray to identify miR-663a-regulated lncRNAs. RNA hybrid was used to predict the potential miR-663a binding sites on lncRNAs. Luciferase reporter assays further confirmed the interaction between miR-663a and the lncRNA. The expression levels of collagen α-2(I) chain (COL1A2), α-smooth muscle actin (α-SMA) and TGF-ß/Smad signaling pathway-related proteins were determined using Western blotting. RESULTS: Lnc-C18orf26-1 was upregulated in TGF-ß1-activated HSCs and competitively bound to miR-663a. Knockdown of lnc-C18orf26-1 inhibited HSC proliferation and activation, downregulated TGF-ß1-stimulated α-SMA and COL1A2 expression, and inhibited the TGF-ß1/Smad signaling pathway. HQD suppressed the proliferation and activation of HSCs. HQD increased miR-663a expression and decreased lnc-C18orf26-1 expression in HSCs. Further studies showed that HQD inhibited the expression of COL1A2, α-SMA, TGF-ß1, TGF-ß type I receptor (TGF-ßRI) and phosphorylated Smad2 (p-Smad2) in HSCs, and these effects were reversed by miR-663a inhibitor treatment. CONCLUSION: Our study identified lnc-C18orf26-1 and miR-663a as promising therapeutic targets for hepatic fibrosis. HQD inhibits HSC proliferation and activation at least partially by regulating the lnc-C18orf26-1/miR-663a/TGF-ß1/TGF-ßRI/p-Smad2 axis.

Huangqi Decoction, a compound Chinese herbal medicine, inhibits the proliferation and activation of hepatic stellate cells by regulating the long noncoding RNA-C18orf26-1/microRNA-663a/transforming growth factor-β axis / 中西医结合学报

OBJECTIVE@#Huangqi Decoction (HQD), a classical traditional Chinese medicine formula, has been used as a valid treatment for alleviating liver fibrosis; however, the underlying molecular mechanism is still unknown. Although our previous studies showed that microRNA-663a (miR-663a) suppresses the proliferation and activation of hepatic stellate cells (HSCs) and the transforming growth factor-β/small mothers against decapentaplegic (TGF-β/Smad) pathway, whether long noncoding RNAs (lncRNAs) are involved in HSC activation via the miR-663a/TGF-β/Smad signaling pathway has not yet reported. The present study aimed to investigate the roles of lncRNA lnc-C18orf26-1 in the activation of HSCs and the mechanism by which HQD inhibits hepatic fibrosis.@*METHODS@#The expression levels of lnc-C18orf26-1, miR-663a and related genes were measured by quantitative reverse transcription-polymerase chain reaction. HSCs were transfected with the miR-663a mimic or inhibitor and lnc-C18orf26-1 small interfering RNAs. The water-soluble tetrazolium salt-1 assay was used to assess the proliferation rate of HSCs. Changes in lncRNA expression were evaluated in miR-663a-overexpressing HSCs by using microarray to identify miR-663a-regulated lncRNAs. RNA hybrid was used to predict the potential miR-663a binding sites on lncRNAs. Luciferase reporter assays further confirmed the interaction between miR-663a and the lncRNA. The expression levels of collagen α-2(I) chain (COL1A2), α-smooth muscle actin (α-SMA) and TGF-β/Smad signaling pathway-related proteins were determined using Western blotting.@*RESULTS@#Lnc-C18orf26-1 was upregulated in TGF-β1-activated HSCs and competitively bound to miR-663a. Knockdown of lnc-C18orf26-1 inhibited HSC proliferation and activation, downregulated TGF-β1-stimulated α-SMA and COL1A2 expression, and inhibited the TGF-β1/Smad signaling pathway. HQD suppressed the proliferation and activation of HSCs. HQD increased miR-663a expression and decreased lnc-C18orf26-1 expression in HSCs. Further studies showed that HQD inhibited the expression of COL1A2, α-SMA, TGF-β1, TGF-β type I receptor (TGF-βRI) and phosphorylated Smad2 (p-Smad2) in HSCs, and these effects were reversed by miR-663a inhibitor treatment.@*CONCLUSION@#Our study identified lnc-C18orf26-1 and miR-663a as promising therapeutic targets for hepatic fibrosis. HQD inhibits HSC proliferation and activation at least partially by regulating the lnc-C18orf26-1/miR-663a/TGF-β1/TGF-βRI/p-Smad2 axis.

Assessing potential liver injury induced by Polygonum multiflorum using potential biomarkers via targeted sphingolipidomics.

CONTEXT: Polygonum multiflorum Thunb. (Polygonaceae) (PM) can cause potential liver injury which is typical in traditional Chinese medicines (TCMs)-induced hepatotoxicity. The mechanism involved are unclear and there are no sensitive evaluation indicators. OBJECTIVE: To assess PM-induced liver injury, identify sensitive assessment indicators, and screen for new biomarkers using sphingolipidomics. MATERIALS AND METHODS: Male Sprague-Dawley (SD) rats were randomly divided into four groups (control, model with low-, middle- and high-dose groups, n = 6 each). Rats in the three model groups were given different doses of PM (i.g., low/middle/high dose, 2.7/8.1/16.2 g/kg) for four months. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in the plasma and liver were quantitatively analyzed. Fixed liver tissue sections were stained with haematoxylin and eosin and examined under a light microscope. The targeted sphingolipidomic analysis of plasma was performed using high-performance liquid chromatography tandem mass spectrometry. RESULTS: The maximal tolerable dose (MTD) of PM administered intragastrically to mice was 51 g/kg. Sphingolipid profiling of normal and PM-induced liver injury SD rats revealed three potential biomarkers: ceramide (Cer) (d18:1/24:1), dihydroceramide (d18:1/18:0)-1-phosphate (dhCer (d18:1/18:0)-1P) and Cer (d18:1/26:1), at 867.3-1349, 383.4-1527, and 540.5-658.7 ng/mL, respectively. A criterion for the ratio of Cer (d18:1/24:1) and Cer (d18:1/26:1) was suggested and verified, with a normal range of 1.343-2.368 (with 95% confidence interval) in plasma. CONCLUSIONS: Three potential biomarkers and one criterion for potential liver injury caused by PM that may be more sensitive than ALT and AST were found.

Genome wide noninvasive prenatal testing detects microduplication of the distal end of chromosome 15 in a fetus: a case report.

BACKGROUND: Noninvasive prenatal testing (NIPT) is the most recent modality widely used in prenatal diagnostics. Commercially available NIPT has high sensitivity and specificity for the common fetal chromosomal aneuploidies. As future advancements in NIPT sequencing technology are becoming promising and more reliable, the ability to detect beyond aneuploidies and to expand detection of submicroscopic genomic alterations, as well as single-gene disorders might become possible. CASE PRESENTATION: Here we present a case of a 34-year-old pregnant woman, G2P1, who had NIPT screening which detected a terminal microduplication of 10.34 Mb on the long arm of chromosome 15 (15q26.1q26.3). Subsequent prenatal diagnostic testing including karyotype, microarray and fluorescence in situ hybridization (FISH) analyses were performed. Microarray testing confirmed and particularized a copy number gain of 10.66 Mb of the distal end of the long arm of chromosome 15. The G-banding cytogenetic studies yielded results consistent with unbalanced translocation between chromosome 15 and 18. To further characterize the abnormality involving the long arm of chromosome 18 and to map the genomic location of the duplicated 15q more precisely, FISH analysis using specific sub-telomeric probes was performed. FISH analysis confirmed that the extra duplicated segment of chromosome 15 is translocated onto the distal end of the long arm of chromosome 18 at band 18q23. Parental karyotype and FISH studies were performed to see if this unbalanced rearrangement was inherited from a healthy balanced translocation carrier versus being a de novo finding. Parental chromosomal analysis provided no evidence of a rearrangement between chromosome 15 and chromosome 18. The final fetal karyotype was reported as 46,XX,der(18)t(15;18)(q26.2;q23)dn. CONCLUSIONS: In this case study, the microduplication of fetal chromosome 15q26.1q26.3 was accurately detected using NIPT. Our results suggest that further refinements in NIPT have the potential to evolve to a powerful and efficient screening method, which might be used to detect a broad range of chromosomal imbalances. Since microduplications and microdeletions are a potential reportable result with NIPT, this must be included in pre-test counseling. Prenatal diagnostic testing of such findings is strongly recommended.

Hexacosenoyl-CoA is the most abundant very long-chain acyl-CoA in ATP binding cassette transporter D1-deficient cells.

X-linked adrenoleukodystrophy (X-ALD) is an inherited disorder caused by deleterious mutations in the ABCD1 gene. The ABCD1 protein transports very long-chain FAs (VLCFAs) from the cytosol into the peroxisome where the VLCFAs are degraded through ß-oxidation. ABCD1 dysfunction leads to VLCFA accumulation in individuals with X-ALD. FAs are activated by esterification to CoA before metabolic utilization. However, the intracellular pools and metabolic profiles of individual acyl-CoA esters have not been fully analyzed. In this study, we profiled the acyl-CoA species in fibroblasts from X-ALD patients and in ABCD1-deficient HeLa cells. We found that hexacosenoyl (26:1)-CoA, but not hexacosanoyl (26:0)-CoA, was the most abundantly concentrated among the VLCFA-CoA species in these cells. We also show that 26:1-CoA is mainly synthesized from oleoyl-CoA, and the metabolic turnover rate of 26:1-CoA was almost identical to that of oleoyl-CoA in both WT and ABCD1-deficient HeLa cells. The findings of our study provide precise quantitative and metabolic information of each acyl-CoA species in living cells. Our results suggest that VLCFA is endogenously synthesized as VLCFA-CoA through a FA elongation pathway and is then efficiently converted to other metabolites, such as phospholipids, in the absence of ABCD1.

A TRAV26-1-encoded recognition motif focuses the biased T cell response in celiac disease.

The semi-public T-cell response towards the gluten epitope DQ2.5-glia-α2 uses a prototypic TCR encoded by the germline segments TRAV26-1 and TRBV7-2. Through mutagenesis experiments, we show that a TRAV26-1encoded recognition motif contacts the MHC ß-chain and the TCR CDR3ß loop underpinning this conserved T-cell response restricted to the prototypic TCRs.

Identification of the Ovine Keratin-Associated Protein 26-1 Gene and Its Association with Variation in Wool Traits.

Keratin-associated proteins (KAPs) are structural components of wool and hair fibres, and are believed to play a role in defining the physico-mechanical properties of the wool fibre. In this study, the putative ovine homologue of the human KAP26-1 gene (KRTAP26-1) was sequenced and four variants (named A-D) were identified. The sequences shared some identity with each other and with other KRTAPs, but they had the greatest similarity with the human KRTAP26-1 sequence. This suggests they represent different variants of ovine KRTAP26-1. The association of these KRTAP26-1 variants with wool traits was investigated in the 383 Merino-Southdown cross sheep. The presence of B was associated (p < 0.05) with an increase in mean fibre diameter (MFD), mean fibre curvature, and prickle factor (PF). The presence of C was found to be associated (p < 0.05) with an increase in wool yield (Yield) and mean staple length (MSL), and a decrease in MFD, fibre diameter standard deviation (FDSD), and PF. The results suggest that sheep with C have, on average, higher wool quality. These results may be useful in the future development of breeding programs based on decreasing wool MFD and FDSD, or on increasing wool MSL.

Sorafenib induced alteration of protein glycosylation in hepatocellular carcinoma cells.

Sorafenib is a multikinase inhibitor and is effective in treating hepatocellular carcinoma (HCC). However, it remains unknown whether sorafenib induces the alteration of protein glycosylation. The present study treated HCC MHCC97L and MHCC97H cells with a 50% inhibitory concentration of sorafenib. Following this treatment, alteration of protein glycosylation was detected using a lectin microarray. Compared with the controls, the binding capacity of glycoproteins extracted from sorafenib-treated HCC cells to the lectins Bauhinia purpurea lectin, Dolichos biflorus agglutinin, Euonymus europaeus lectin, Helix aspersa lectin, Helix pomatia lectin, Jacalin, Maclura pomifera lectin and Vicia villosa lectin were enhanced; while, the binding capacities to the lectins Caragana arborescens lectin, Lycopersicon esculentum lectin, Limulus polyphemus lectin, Maackia amurensis lecin I, Phaseolus vulgaris leucoagglutinin, Ricinus communis agglutinin 60, Sambucus nigra lectin and Solanum tuberosum lectin were reduced (spot intensity median/background intensity median ≥2, P<0.05). This difference in glycoprotein binding capacity indicates that cells treated with sorafenib could increase α-1,3GalNAc/Gal, ß-1,3 Gal, GalNAcα-Ser/Thr(Tn) and α-GalNAc structures and decrease GlcNAc, sialic acid, tetra-antennary complex-type N-glycan and ß-1,4Gal structures. These results were additionally confirmed by lectin blotting. Expression levels of signaling molecules including erythroblastosis 26-1 (Ets-1), extracellular signal-related kinases (ERK) and phosphorylated-ERK were measured by western blotting. There was a reduction in the expression of Ets-1 and ERK phosphorylation in sorafenib or 1,4-Diamino-2,3-dicyano-1,4-bis (2-aminophenylthio) butadiene treated cells suggesting that sorafenib may reduce the expression levels of Ets-1 by blocking the Ras/Raf/mitogen activated protein kinase signaling pathway. In the present study, it was clear that sorafenib could inhibit the proliferation of HCC cells and alter protein glycosylation. The findings of this study may lead to providing a novel way of designing new anti-HCC drugs.

Xq26.1-26.3 duplication including MOSPD1 and GPC3 identified in boy with short stature and double outlet right ventricle.

Xq25q26 duplication syndrome has been reported in individuals with clinical features such as short stature, intellectual disability, syndromic facial appearance, small hands and feet, and genital abnormalities. The symptoms are related to critical chromosome regions including Xq26.1-26.3. In this particular syndrome, no patient with congenital heart disease was previously reported. Here, we report a 6-year-old boy with typical symptoms of Xq25q26 duplication syndrome and double outlet right ventricle (DORV) with pulmonary atresia (PA). He had the common duplicated region of Xq25q26 duplication syndrome extending to the distal region including the MOSPD1 locus. MOSPD1 regulates transforming growth factor beta (TGFß) 2,3 and may be responsible for cardiac development including DORV. In the patient's lymphocytes, mRNA expression of TGFß2 was lower than control, and might cause DORV as it does in TGFß2-deficient mice. Therefore, MOSPD1 is a possible candidate gene for DORV, probably in combination with GPC3. Further studies of the combined functions of MOSPD1 and GPC3 are needed, and identification of additional patients with MOSPD1 and GPC3 duplication should be pursued.

Recurrent fetal syndromic spina bifida associated with 3q26.1-qter duplication and 5p13.33-pter deletion due to familial balanced rearrangement.

OBJECTIVE: Neural tube defects belong to the second most common group of congenital anomalies, after heart defects, which can be diagnosed by prenatal ultrasonography. Rarely, neural tube defects can be associated with chromosomal abnormalities, including full and partial aneuploidies. We report a familial fetal case with syndromic spina bifida and discuss its association with partial 3q duplication and partial 5p deletion. MATERIALS AND METHODS: Clinical findings of three affected family members in two generations and two carriers of the balanced translocation are described. Conventional cytogenetic and fluorescence in situ hybridization (FISH) analysis of the carrier, as well as subtelomeric multiplex ligation-dependent probe amplification (MLPA) and array comparative genomic hybridization (CGH) analysis on the DNA extracted from affected family members was performed. RESULTS: Subtelomeric FISH analysis of the proposita revealed balanced reciprocal translocation between the long arm of chromosome 3 and short arm of chromosome 5. Subtelomeric MLPA screening of the first child revealed the deletion in 5p15.33 and duplication in 3q29 chromosomal loci, the finding consisting of the unbalanced rearrangement involving the short arm of chromosome 5 and long arm of chromosome 3. Array CGH analysis of the DNA of the second affected child revealed a 31.1Mb duplication of 3q26.1-qter and a 33.6Mb deletion of 5p13.33-pter. CONCLUSION: Our report serves to emphasize the consistency in the prenatal sonographic feature of spina bifida in consecutive pregnancies with fetuses associated with partial trisomy 3q (3q26.1-qter) and partial monosomy 5p (5p13.33-pter). The use of molecular cytogenetic technologies such as array CGH and FISH is important for clarifying any type of unbalanced chromosome rearrangement.

Absence epilepsy and the CHD2 gene: an adolescent male with moderate intellectual disability, short-lasting psychoses, and an interstitial deletion in 15q26.1-q26.2.

Deletions of the 15q26 region encompassing the chromodomain helicase DNA binding domain 2 (CHD2) gene have been associated with intellectual disability, behavioral problems, and several types of epilepsy. Including the cases mentioned in ECARUCA (European cytogeneticists association register of unbalanced chromosome aberrations) and DECIPHER (database of genomic variation and phenotype in humans using ensembl resources), so far, a total of 13 intellectually disabled patients with a genetically proven deletion of the CHD2 gene are described, of whom eleven had a history of severe forms of epilepsy starting from a young age. In this article, a moderately intellectually disabled 15-year-old male with a 15q26.1-q26.2 interstitial deletion is reported, who was referred for analysis of two recent short-lasting psychotic episodes that were nonresponsive to antipsychotic treatment and recurrent disinhibited behaviors since early infancy. Careful interdisciplinary assessment revealed that the psychotic phenomena originated from a previously unrecognized absence epilepsy. Treatment with valproic acid was started which resulted in full remission of psychotic symptoms, and consequently, substantial improvement of behavior. It was concluded that in case of (rare) developmental disorders with genetically proven etiology, a detailed inventory of anamnestic data and description of symptomatology over time may elucidate epilepsy-related psychopathology for which a specific treatment regimen is needed.

Pre- and Postnatal Analysis of Chromosome 15q26.1 and 8p23.1 Deletions in Congenital Diaphragmatic Hernia.

Congenital diaphragmatic hernia (CDH) is defined as a protrusion of abdominal content into the thoracic cavity through an abnormal opening in the diaphragm present at birth. It is a common birth defect with high mortality and morbidity. Submicroscopic deletions of 15q26.1 and 8p23.1 have been reported in several cases of CDH. We studied a total of 17 cases with CDH in pre- and postnatal samples using FISH probes. Deletion 15q26.1 was seen in 1/17 prenatal samples. There was no deletion for 8p23.1 in all the samples analyzed. CDH has a genetic etiology, and deletion 15q26.1 increases the risk of CDH. Deletion 15q26.1 in a fetus with CDH is a predictor of poor prognosis. This deletion is also seen in a phenotype similar to Fryns syndrome. CDH identified pre- or postnatally should be investigated further to exclude a 15q26.1 deletion and enable appropriate parental counseling.

15q26.1 microdeletion encompassing only CHD2 and RGMA in two adults with moderate intellectual disability, epilepsy and truncal obesity.

We report two patients with microdeletions in chromosomal subdomain 15q26.1 encompassing only two genes, CHD2 and RGMA. Both patients present a distinct phenotype with intellectual disability, epilepsy, behavioral issues, truncal obesity, scoliosis and facial dysmorphism. CHD2 haploinsufficiency is known to cause intellectual disability and epilepsy, RGMA haploinsufficiency might explain truncal obesity with onset around puberty observed in our two patients.

Dexmedetomidine, an α-2a adrenergic agonist, promotes ischemic tolerance in a murine model of spinal cord ischemia-reperfusion.

OBJECTIVE: Dexmedetomidine, an α-2a adrenergic agonist, given pre- and postoperatively was previously shown to attenuate neuronal injury in a murine model of spinal cord ischemia-reperfusion. In the brain, α-2 agonists have been shown to induce the phosphorylation of cyclic AMP response-element binding protein (CREB), a transcription factor necessary for neuron survival. We hypothesized that the α-2a adrenergic agonist given preoperatively increases CREB-mediated neuroprotective proteins, attenuating neuronal injury and cytoarchitectural decay. METHODS: Mice (ie, C57BL/6 mice) underwent 5 minutes of aortic occlusion via median sternotomy. Mice received 25 µg/kg dexmedetomidine or equivalent normal saline at 24 hours, 12 hours, and 30 minutes preoperatively. Functional outcomes were recorded at 6 to 48 hours postoperatively when spinal cords were removed for histologic analysis. Spinal cords were examined for protein kinase B, CREB, B-cell lymphoma 2, and brain-derived neurotrophic factor following treatment alone or ischemia-reperfusion surgery. RESULTS: Following aortic occlusion, mice in the treatment group had preserved neurologic function at all time points (P < .05). Histologic analysis showed preserved cytoarchitecture and decreased neuronal injury in the treatment group when compared with ischemic controls. Additionally, analysis of spinal cord homogenate following surgery and pretreatment revealed a significant (P < .05) increase in B-cell lymphoma 2 and brain-derived neurotrophic factor expression and protein kinase B and CREB phosphorylation with α-2a adrenergic agonist pretreatment. CONCLUSIONS: Pretreatment with the α-2a agonist dexmedetomidine preserved neurologic function and attenuated neuronal injury following thoracic aortic occlusion in mice. This relationship was associated with an increased phosphorylation of protein kinase B and CREB and subsequent up-regulation of antiapoptotic factor B-cell lymphoma 2 and brain-derived neurotrophic factor. Thus, α-2a receptor agonism-induced CREB phosphorylation and contributes to dexmedetomidine's protective mechanism in the spinal cord following ischemia.

Preoperative percutaneous coronary intervention in patients undergoing open thoracoabdominal and descending thoracic aneurysm repair.

OBJECTIVE: Current guidelines have recommended against coronary revascularization before noncardiac surgery in patients with asymptomatic coronary artery disease. However, myocardial infarction after thoracic aneurysm (TA) repair dramatically increases the morbidity and mortality. Revascularization with coronary artery bypass grafting before TA repair minimizes the incidence of perioperative ischemia. However, the recovery can be prolonged, and a percentage of patients will either never return for aneurysm repair or will develop a rupture during convalescence. Percutaneous coronary intervention (PCI) before TA repair might be preferable. Previous studies examining PCI before major vascular surgery included few patients with TAs. We examined the outcomes of patients undergoing PCI before TA repair. METHODS: From 1997 to 2012, 592 patients underwent TA repair. Patients presenting for elective repair underwent cardiac catheterization before surgery. Those with significant single- or double-vessel coronary artery disease underwent PCI. The perioperative outcomes were examined and compared with those of patients undergoing TA repair without revascularization. RESULTS: A total of 44 patients (7.4%) underwent PCI with bare metal stents before surgery. No PCI-related complications occurred. Dual antiplatelet therapy was administered for 4 to 6 weeks. No instances of aneurysm rupture occurred in the interval between PCI and surgery. The incidence of stent thrombosis, myocardial infarction, and mortality for those undergoing PCI was 0. No bleeding complications occurred. CONCLUSIONS: PCI is safe and efficacious in patients undergoing TA repair. Aneurysm rupture did not occur in the interval before surgery. Antiplatelet therapy did not increase the risk of bleeding complications. Stent thrombosis was not seen. We recommend PCI those with significant single- or double-vessel coronary artery disease before elective TA repair.

Incidence and progression of mild aortic regurgitation after Tirone David reimplantation valve-sparing aortic root replacement.

OBJECTIVE: The study objective was to determine whether recurrent or residual mild aortic regurgitation, which occurs after valve-sparing aortic root replacement, progresses over time. METHODS: Between 2003 and 2008, 154 patients underwent Tirone David-V valve-sparing aortic root replacement; 96 patients (62%) had both 1-year (median, 12 ± 4 months) and mid-term (62 ± 22 months) transthoracic echocardiograms available for analysis. Age of patients averaged 38 ± 13 years, 71% were male, 31% had a bicuspid aortic valve, 41% had Marfan syndrome, and 51% underwent aortic valve repair, predominantly cusp free margin shortening. RESULTS: Forty-one patients (43%) had mild aortic regurgitation on 1-year echocardiogram. In 85% of patients (n = 35), mild aortic regurgitation remained stable on the most recent echocardiogram (median, 57 ± 20 months); progression to moderate aortic regurgitation occurred in 5 patients (12%) at a median of 28 ± 18 months and remained stable thereafter; severe aortic regurgitation developed in 1 patient, eventually requiring reoperation. Five patients (5%) had moderate aortic regurgitation at 1 year, which did not progress subsequently. Two patients (2%) had more than moderate aortic regurgitation at 1 year, and both ultimately required reoperation. CONCLUSIONS: Although mild aortic regurgitation occurs frequently after valve-sparing aortic root replacement, it is unlikely to progress over the next 5 years and should not be interpreted as failure of the valve-preservation concept. Further, we suggest that mild aortic regurgitation should not be considered nonstructural valve dysfunction, as the 2008 valve reporting guidelines would indicate. We need 10- to 15-year follow-up to learn the long-term clinical consequences of mild aortic regurgitation early after valve-sparing aortic root replacement.

Unilateral versus bilateral antegrade cerebral protection during circulatory arrest in aortic surgery: a meta-analysis of 5100 patients.

OBJECTIVE: Our objective was to determine whether the use of unilateral (u-ACP) or bilateral antegrade cerebral perfusion (b-ACP) results in different mortality and neurologic outcomes after complex aortic surgery. METHODS: PubMed, Embase, and the Cochrane Library were searched for studies reporting on postoperative mortality and permanent (PND) and temporary neurologic dysfunction (TND) in complex aortic surgery requiring circulatory arrest with antegrade cerebral protection. Analysis of heterogeneity was performed with the Cochrane Q statistic. RESULTS: Twenty-eight studies were analyzed for a total of 1894 patients receiving u-ACP versus 3206 receiving b-ACP. Pooled analysis showed similar rates of 30-day mortality (8.6% vs 9.2% for u-ACP and b-ACP, respectively; P = .78), PND (6.1% vs 6.5%; P = .80), and TND (7.1% vs 8.8%; P = .46). Age, sex, and cardiopulmonary bypass time did not influence effect size estimates. Higher rates of postoperative mortality and PND were among nonelective operations and for highest temperatures and duration of the circulatory arrest. The Egger test excluded publication bias for the outcomes investigated. CONCLUSIONS: This meta-analysis shows that b-ACP and u-ACP have similar postoperative mortality and both PND and TND rates after circulatory arrest for complex aortic surgery.

Prognostic value of sustained elevated C-reactive protein levels in patients with acute aortic intramural hematoma.

OBJECTIVES: The appropriate management of aortic intramural hematoma is still controversial, because a variety of aortic events can arise during follow-up in some patients. However, simplified identification of these patients remains challenging. The present study aimed to determine the prognostic significance of serial C-reactive protein measurements for the prediction of adverse events in patients with acute aortic intramural hematoma. METHODS: A total of 180 patients with aortic intramural hematoma were retrospectively reviewed. The C-reactive protein data were obtained at admission and 2 days, 1 week, and 2 weeks from the onset, and the maximum value was obtained during the acute phase. Adverse aorta-related events were defined by a composite of aortic rupture, aortic aneurysm, and surgical or endovascular aortic repair. RESULTS: The C-reactive protein value was 3.0 ± 4.6, 8.7 ± 5.9, 9.0 ± 5.5, and 5.7 ± 4.5 mg/dL on admission and 2 days, 1 week, and 2 weeks from the onset, respectively. The maximal value of C-reactive protein was 12.4 ± 6.3 mg/dL at a mean of 4 days from the onset. Patients with elevated C-reactive protein levels (≥7.2 mg/dL) at 2 weeks had significantly greater rates of aorta-related events (P < .001). On multivariate analysis, an elevated C-reactive protein level at 2 weeks (hazard ratio, 3.16; P < .001) and the development of an ulcer-like projection (hazard ratio, 2.68; P = .002) were independent predictors of adverse aorta-related events. In addition, an elevated C-reactive protein level at 2 weeks had incremental value compared with the development of an ulcer-like projection (chi-square, 16.94 for ulcer-like projection only vs 34.32 with the addition of C-reactive protein at 2 weeks, P < .001). CONCLUSIONS: C-reactive protein was a simple and useful marker providing incremental prognostic information compared with the development of an ulcer-like projection in patients with aortic intramural hematoma.

Differences in aortic cusp coaptation between the reimplantation and the remodeling techniques of aortic valve-sparing surgery: an in vitro porcine model study.

OBJECTIVES: We sought to evaluate the effects of the reimplantation type versus the remodeling type of aortic valve-sparing technique on the geometry of the same aortic root. METHODS: Fifteen fresh isolated porcine hearts with normal aortic valves and a standard aortoventricular junction size of 23 mm were processed. An aortic valve-sparing replacement was performed by reimplanting the native aortic root inside a 28-mm Valsalva graft (Vascutek Ltd, Renfrewshire, UK). Hearts were subsequently implanted with instruments in a test circuit, and the aortic roots were pressurized at a fixed pressure of 100 mm Hg. Diameters of the aortoventricular junction, of the sinuses, and of the sinotubular junction, as well as effective height and coaptation height of aortic valve leaflets, were measured by echography. Transition from the reimplantation to the remodeling configuration was then achieved by longitudinally cutting the skirt of the graft from the annulus to the top of each commissure. The same measurements were then repeated. RESULTS: After transition from the reimplantation to the remodeling configuration, significant increases in the sizes of the aortoventricular junction and of the sinuses were observed. Effective height and coaptation height significantly decreased, and the rounded cross-sectional profile of the aortic valve leaflets flattened. CONCLUSIONS: In the same aortic root, transition from the reimplantation to the remodeling configuration of aortic valve-sparing surgery results in a significant increase in aortic root sizes and in a significant reduction of effective height and coaptation height, suggesting a less satisfactory result.

Long-term prognosis of ascending aortic aneurysm after aortic valve replacement for bicuspid versus tricuspid aortic valve stenosis.

OBJECTIVE: The bicuspid aorta is thought to have a higher risk of progressive dilation after aortic valve replacement with a subsequently increased risk of adverse aortic events. Our aim was to compare the risk of late aortic events after isolated aortic valve replacement surgery for bicuspid versus tricuspid aortic valve stenosis with concomitant mild to moderate dilatation of the proximal aorta. METHODS: A total of 325 consecutive patients (60% males; mean age, 59.5 ± 10 years) with aortic valve stenosis and concomitant ascending aortic dilatation of 40 to 50 mm underwent isolated aortic valve replacement from 1995 through 2000. A total of 153 patients (47%) were diagnosed with bicuspid aortic valve stenosis (bicuspid aortic valve group), whereas the remaining 172 patients (53%) had tricuspid aortic valve stenosis (tricuspid aortic valve group). Follow-up (3566 patient-years) was 100% complete. Adverse aortic events were defined as the need for proximal aortic surgery or the occurrence of aortic dissection/rupture or sudden death during follow-up. RESULTS: Overall survival was 78 ± 4% in the bicuspid aortic valve group versus 55 ± 6% in the tricuspid aortic valve group (P = .006) at 15 years postoperatively, but age-adjusted survival was not significantly different between groups (P = .4). A total of 5 patients (3%) in the bicuspid aortic valve group versus 9 patients (5%) in the tricuspid aortic valve group underwent proximal aortic surgery during follow-up. Aortic dissection occurred in 3 patients in the tricuspid aortic valve group and in no bicuspid aortic valve patients. Fifteen-year freedom from adverse aortic events was 93 ± 3% in the bicuspid aortic valve group versus 82 ± 6% in the tricuspid aortic valve group (P = .2). CONCLUSIONS: Patients with bicuspid and tricuspid aortic valve stenosis with concomitant mild to moderate ascending aortic dilatation are at comparably low risk of adverse aortic events 15 years after isolated aortic valve replacement.