Assessment of Left Ventricular Enlargement at Multidetector Computed Tomography.

PURPOSE: Because left ventricular (LV) enlargement (LVE) is indicative of an array of cardiac pathologies, including cardiomyopathic, ischemic, and valvular heart diseases, it is important to recognize it early in the course of these diseases. The recognition of LVE on nongated contrast-enhanced computed tomography (CT) scans should be facilitated by the availability of a dimensional index. To our knowledge, no CT index of LVE has been proposed. Therefore, the study aimed to define whether the maximum LV diameter (LVd) measured on nongated multidetector computed tomography can identify LVE when referencing echocardiography as the diagnostic standard. MATERIALS AND METHODS: The patient population consisted of 438 consecutive patients who had a contrast-enhanced, nongated 16- or 64-detector CT of the chest for evaluation of pulmonary embolism or aortic dissection between January 2006 and March 2008. One hundred fifty-five patients in this group also had an echocardiogram within 2 months of the CT study. The maximum LV cavity size, septal to lateral wall dimension, was measured perpendicularly to the long axis of the left ventricle on the axial CT scans by 2 observers blinded to the echocardiography data.An receiver operating characteristic analysis was performed to identify a highly specific cutoff for the diagnosis of LVE on CT, using echocardiogram as the standard of reference. Interobserver agreement was assessed using Bland-Altman analysis. RESULTS: A total of 84 females and 71 males were evaluated (female to male ratio of 1.09). The mean age for the 155 patients was 58 years. Six percent of these patients had a diagnosis of LVE on 2-dimensional echocardiography. The mean (SEM) LV internal diameter at nongated multidetector computed tomography between the group with normal LV and the group with LVE by echocardiography was 4.4 (0.7) cm for the normal LV and 5.9 (1.2) cm for the dilated LVs (P < 0.0001). With the use of threshold value of LVd of 5.6 cm, a sensitivity of 78%, specificity of 100%, positive likelihood ratio of 113.5, and negative likelihood ratio of 0.22 were calculated. The LVd measurements had an excellent agreement between observers on the Bland-Altman analysis. CONCLUSIONS: Left ventricular enlargement can be reliably identified on nongated contrast-enhanced multidetector CT when the maximum luminal diameter of the LV is greater than 5.6 cm. Nongated contrast-enhanced CT scan can be used to recognize LVE.

Surgical Modulation of Pulmonary Artery Shear Stress: A Patient-Specific CFD Analysis of the Norwood Procedure.

PURPOSR: This study created 3D CFD models of the Norwood procedure for hypoplastic left heart syndrome (HLHS) using standard angiography and echocardiogram data to investigate the impact of shunt characteristics on pulmonary artery (PA) hemodynamics. Leveraging routine clinical data offers advantages such as availability and cost-effectiveness without subjecting patients to additional invasive procedures. METHODS: Patient-specific geometries of the intrathoracic arteries of two Norwood patients were generated from biplane cineangiograms. "Virtual surgery" was then performed to simulate the hemodynamics of alternative PA shunt configurations, including shunt type (modified Blalock-Thomas-Taussig shunt (mBTTS) vs. right ventricle-to-pulmonary artery shunt (RVPAS)), shunt diameter, and pulmonary artery anastomosis angle. Left-right pulmonary flow differential, Qp/Qs, time-averaged wall shear stress (TAWSS), and oscillatory shear index (OSI) were evaluated. RESULTS: There was strong agreement between clinically measured data and CFD model output throughout the patient-specific models. Geometries with a RVPAS tended toward more balanced left-right pulmonary flow, lower Qp/Qs, and greater TAWSS and OSI than models with a mBTTS. For both shunt types, larger shunts resulted in a higher Qp/Qs and higher TAWSS, with minimal effect on OSI. Low TAWSS areas correlated with regions of low flow and changing the PA-shunt anastomosis angle to face toward low TAWSS regions increased TAWSS. CONCLUSION: Excellent correlation between clinically measured and CFD model data shows that 3D CFD models of HLHS Norwood can be developed using standard angiography and echocardiographic data. The CFD analysis also revealed consistent changes in PA TAWSS, flow differential, and OSI as a function of shunt characteristics.

Short-chain fatty acid inhibitors of histone deacetylases: promising anticancer therapeutics?

Cancer is a disease in which cellular growth regulatory networks are disrupted. Lesions in well-characterized oncogenes and tumor suppressors often contribute to the dysregulation, but recent work has also uncovered the fundamental importance of enzymes that modulate the acetylation status of chromatin to the initiation or progression of cancer. Histone acetyltransferases (HATs) and histone deacetylases (HDACs) are known to be involved in physiological cellular processes, such as transcription, cell cycle progression, gene silencing, differentiation, DNA replication, and genotoxic responses, but they are also increasingly being implicated in tumorigenesis. Butyrate is a short-chain fatty acid (SCFA) that acts as a HDAC inhibitor and is being clinically evaluated as an anti-neoplastic therapeutic, primarily because of its ability to impose cell cycle arrest, differentiation, and/or apoptosis in many tumor cell types, and its favorable safety profile in humans. Additionally, HDAC inhibitors could be used in combination with certain established antitumor therapeutics, such as those that target transcription, to augment clinical efficacy, and/or reduce toxicity. The molecular pathways of butyrate and related next-generation synthetic SCFAs in mediating these effects have not been fully elucidated, but HDAC inhibition is associated with regulation of critical cell cycle regulators, such as cyclin D, p21(CIP1/WAF1), and p27(KIP1). It is anticipated that a better understanding of this critical intersection between SCFAs, HDACs, and cell cycle control will lead to the design of novel treatment strategies for neoplasias. This review will summarize some of the recent research in these arenas of HDAC-directed cancer therapy and discuss the potential application of these agents in synergy with current chemotherapeutics.

Computational hemodynamics of an implanted coronary stent based on three-dimensional cine angiography reconstruction.

Coronary stents are supportive wire meshes that keep narrow coronary arteries patent, reducing the risk of restenosis. Despite the common use of coronary stents, approximately 20-35% of them fail due to restenosis. Flow phenomena adjacent to the stent may contribute to restenosis. Three-dimensional computational fluid dynamics (CFD) and reconstruction based on biplane cine angiography were used to assess coronary geometry and volumetric blood flows. A patient-specific left anterior descending (LAD) artery was reconstructed from single-plane x-ray imaging. With corresponding electrocardiographic signals, images from the same time phase were selected from the angiograms for dynamic three-dimensional reconstruction. The resultant three-dimensional LAD artery at end-diastole was adopted for detailed analysis. Both the geometries and flow fields, based on a computational model from CAE software (ANSYS and CATIA) and full three-dimensional Navier-Stroke equations in the CFD-ACE+ software, respectively, changed dramatically after stent placement. Flow fields showed a complex three-dimensional spiral motion due to arterial tortuosity. The corresponding wall shear stresses, pressure gradient, and flow field all varied significantly after stent placement. Combined angiography and CFD techniques allow more detailed investigation of flow patterns in various segments. The implanted stent(s) may be quantitatively studied from the proposed hemodynamic modeling approach.

Histone deacetylase inhibition-mediated post-translational elevation of p27KIP1 protein levels is required for G1 arrest in fibroblasts.

Butyrate, a non-toxic short-chain fatty acid (SCFA) and inhibitor of histone deacetylase (HDAC), has potential as an anti-tumor agent because it imposes a reversible G1 block in normal cells yet induces apoptosis in tumor lines. As a potent reactivator of fetal globin transcription, butyrate is used clinically in the treatment of hemoglobinopathies. The anti-proliferative effect of butyrate and its derivatives on in vivo erythroid cell maturation, however, has limited their utility. The molecular mechanisms underlying the G1 arrest induced by butyrate and related SCFAs remain unclear. One model, drawing on tumor cell data, proposes that HDAC inhibition and subsequent transcriptional induction of cyclin-dependent kinase inhibitor (CKI) p21CIP are required. However, because of potentially confounding genetic mutations present in tumor models, we examined SCFA effects on CKIs in a non-transformed growth control model. Using murine 3T3 fibroblasts, we find p27KIP1 is also strongly induced. Unlike previously described effects of butyrate and HDAC inhibition on p21CIP, p27KIP1 induction did not occur at the transcriptional level; instead, the stability of the p27KIP1 protein increased. Other structurally unrelated HDAC inhibitors, including trichostatin A (TSA), induced p27KIP1 similarly. p27KIP1 was found in cyclin E/Cdk2 complexes, concomitant with suppression of cdk2 activity. Elevation of p27KIP1 is required for the observed G1 blockade, as p27KIP1-deficient fibroblasts were resistant to HDAC inhibition-induced arrest. These data suggest a novel activity for HDAC inhibitors and demonstrate a critical role for p27KIP1 in mediating G1 arrest in response to these drugs.

Concordance of second-order portal venous and biliary tract anatomies on MDCT angiography and MDCT cholangiography.

OBJECTIVE: We sought to investigate the concordance between second-order portal venous and biliary tract anatomies using MDCT angiography and MDCT cholangiography. MATERIALS AND METHODS: We retrospectively identified 56 living related potential liver donors who underwent both MDCT angiography and MDCT cholangiography. Two reviewers independently rated axial images and 3D reconstructions of MDCT angiograms and cholangiograms as diagnostic or nondiagnostic with respect to depiction of second-order portal venous and biliary tract anatomies. In images rated as diagnostic, second-order portal venous and biliary tract anatomies were categorized as conventional or variant. The concordance between portal venous and biliary tract anatomies was analyzed using McNemar exact chi-square test. RESULTS: All examinations were diagnostic. Second-order portal venous variants were seen in 10 (18%) and biliary branch variants were seen in 23 (41%) of the 56 patients. Patients with variant portal venous anatomy (6/10, 60%) were more likely to have variant biliary tract anatomy than patients with conventional portal venous anatomy (17/46, 37%; p < 0.01). The sensitivity of variant portal venous anatomy as a marker for variant biliary anatomy was 26% (6/23 patients). CONCLUSION: Concordance between second-order portal venous and biliary tract anatomies is statistically significant. However, in our series, a number of patients with conventional portal venous anatomy had variant biliary anatomy; therefore, the finding of conventional portal venous anatomy does not obviate preoperative biliary tract imaging in patients before liver donation.

Characterization of p21Ras-mediated apoptosis induced by protein kinase C inhibition and application to human tumor cell lines.

Suppression of PKC activity can selectively induce apoptosis in cells expressing a constitutively activated p21Ras protein. We demonstrate that continued expression of p21Ras activity is required in PKC-mediated apoptosis because farnesyltransferase inhibitors abrogated the loss of viability in p21Ras-transformed cells occurring following PKC inhibition. Studies utilizing gene transfer or viral vectors demonstrate that transient expression of oncogenic p21Ras activity is sufficient for induction of apoptosis by PKC inhibition, whereas physiologic activation of p21Ras by growth factor is not sufficient to induce apoptosis. Mechanistically, the p21Ras-mediated apoptosis induced by PKC inhibition is dependent upon mitochondrial dysregulation, with a concurrent loss of mitochondrial membrane potential (psim). Cyclosporine A, which prevented the loss of psim, also inhibited HMG-induced DNA fragmentation in cells expressing an activated p21Ras. Induction of apoptosis by PKC inhibition in human tumors with oncogenic p21Ras mutations was demonstrated. Inhibition of PKC caused increased apoptosis in MIA-PaCa-2, a human pancreatic tumor line containing a mutated Ki-ras allele, when compared to HS766T, a human pancreatic tumor line with normal Ki-ras alleles. Furthermore, PKC inhibition induced apoptosis in HCT116, a human colorectal tumor line containing an oncogenic Ki-ras allele but not in a subline (Hke3) in which the mutated Ki-ras allele had been disrupted. The PKC inhibitor 1-O-hexadecyl-2-O-methyl-rac-glycerol (HMG), significantly reduced p21Ras-mediated tumor growth in vivo in a nude mouse MIA-PaCa-2 xenograft model. Collectively these studies suggest the therapeutic feasibility of targeting PKC activity in tumors expressing an activated p21Ras oncoprotein.

Alpha-lipoic acid induces p27Kip-dependent cell cycle arrest in non-transformed cell lines and apoptosis in tumor cell lines.

alpha-Lipoic acid is a naturally-occurring co-factor found in a number of multi-enzyme complexes regulating metabolism. We report here that alpha-lipoic acid induces hyperacetylation of histones in vivo and has differential effects on the growth and viability of normal versus transformed cell lines. The human tumor cell lines FaDu and Jurkat, as well as a Ki-v-Ras-transformed Balb/c-3T3 murine mesenchymal cell line, all initiated apoptosis following exposure to alpha-lipoic acid. In contrast, treatment of non-transformed cell lines with alpha-lipoic acid resulted only in reversible cell cycle arrest in G0/G1. Treatment with butyrate, another short-chain fatty acid, induced a G0/G1 arrest in both transformed and non-transformed cell lines. alpha-Lipoic acid caused a post-translational elevation in the levels of the cyclin-dependent kinase inhibitor p27Kip1. Studies using p27Kip1-deficient MEF cells demonstrated that p27Kip1 was required for the alpha-lipoic acid-mediated cell cycle arrest. The mechanism of apoptosis was independent of Fas-mediated signaling, as alpha-lipoic acid-treated Jurkat cell mutants deficient in Fas or FADD retained sensitivity to apoptosis. The differential selectivity of the pro-apoptotic effects of alpha-lipoic acid for transformed cells supports its potential use in the treatment of neoplastic disorders.