Associations between lipids and subclinical coronary atherosclerosis.

OBJECTIVE: Whether HIV modifies the relationship of serum lipids with coronary atherosclerosis and coronary plaque subtypes is uncertain. We examined the associations between traditional lipids and coronary atherosclerosis among HIV-infected (HIV+) and HIV-uninfected (HIV-) men. DESIGN: The Multicenter AIDS Cohort Study is an observational cohort with a total of 429 HIV+ and 303 HIV- men who had non-contrast cardiac computed tomography performed to measure coronary artery calcium and coronary computed tomography angiography to measure coronary stenosis, coronary plaque presence, and composition. METHODS: We used multivariable adjusted prevalence ratios to examine the relationship between the SD difference in each lipid parameter and coronary atherosclerosis. RESULTS: Total cholesterol (TC)/HDL-cholesterol had the strongest associations with coronary atherosclerosis regardless of HIV status. Overall, lipid parameters were most strongly associated with the presence of mixed plaque, stenosis more than 50%, and coronary artery calcium for both HIV+ and HIV- men. HIV+ men had similar, but weaker associations, between lipid parameters and coronary atherosclerosis compared with HIV- men. The strongest association was between the TC/HDL-cholesterol and stenosis more than 50% for both HIV+ [prevalence ratios 1.25 per SD (95% confidence interval 1.07-1.43)] and HIV- men [prevalence ratios 1.46 per SD (95% confidence interval 1.08-1.85)]. CONCLUSION: The associations between lipids and coronary atherosclerosis tended to be weaker for HIV+ compared with HIV- men, although TC/HDL had the strongest association for both HIV+ and HIV- men. A weaker association between lipid levels and coronary atherosclerosis for HIV+ men may contribute to the decreased discrimination of cardiovascular disease risk observed in HIV+ individuals.

Low-Density Lipoprotein Cholesterol Levels and Statin Treatment by HIV Status Among Multicenter AIDS Cohort Study Men.

Treating cardiovascular disease (CVD) risk factors, including dyslipidemia, is important in HIV care. Low-density lipoprotein cholesterol (LDL-c) target achievement is a readily available benchmark for dyslipidemia control, although use of this target is not uniformly endorsed by professional societies. We examined whether HIV serostatus is associated with not achieving LDL-c target. Among Multicenter AIDS Cohort Study (MACS) participants completing visit 56 (10/1/2011-3/31/2012), we categorized each man as on or off statin therapy and used NCEP ATP III guidelines to determine if each man was at LDL-c target or not at target. We compared proportions of men not at target and determined predictors using multivariate logistic regression. Sixty of 543 (11.1%) HIV-infected men and 87 of 585 (14.9%) HIV-uninfected men not receiving statin therapy were not at target (p=0.07), while 31 of 230 (13.5%) HIV-infected and 29 of 204 (14.2%) HIV-uninfected men receiving statin therapy were not at target (p=0.82). Factors associated with not being at target (among men not receiving statin therapy) included current smoking (OR=2.31, 95% CI 1.31, 4.06) and a diagnosis of hypertension (OR=4.69, 95% CI 2.68, 8.21). Factors associated with not being at target (among men receiving statin therapy) included current smoking (OR=2.72, 95% CI 1.30, 5.67) and diabetes (OR=5.31, 95% CI 2.47, 11.42). HIV-infected and HIV-uninfected men receiving statin therapy demonstrated similar nonachievement of LDL-c targets. Comorbidities (e.g., diabetes) lowered targets and may explain why goals were less likely to be met.

Comparison of racial differences in plaque composition and stenosis between HIV-positive and HIV-negative men from the Multicenter AIDS Cohort Study.

Previous studies demonstrated that blacks have less coronary artery calcification (CAC) than whites. We evaluated racial differences in plaque composition and stenosis in the Multicenter AIDS Cohort Study. HIV-positive and HIV-negative men underwent noncontrast cardiac computed tomography (CT) if they were aged 40 to 70 years, weighed <136 kg, and had no history of cardiac surgery or revascularization and, if eligible, coronary CT angiography (CTA). There were 1,001 men who underwent CT scans and 759 men CTA. We measured CAC on noncontrast CT and identified total plaque, noncalcified plaque, calcified plaque, mixed plaque, and coronary stenosis >50% on CTA. The association of presence and extent of plaque with race was determined after adjustment for HIV serostatus, cardiovascular risk factors, and measures of socioeconomic status. The prevalences of any plaque on CTA and noncalcified plaque were not different between black and white men; however, black men had lower prevalences of CAC (prevalence ratio [PR] 0.79, p = 0.01), calcified plaque (PR 0.69, p = 0.002), and stenosis >50% (PR 0.59, p = 0.009). There were no associations between black race and extent of plaque in fully adjusted models. Using log-linear regression, black race was associated with a lower extent of any plaque on CTA in HIV-positive men (estimate = -0.24, p = 0.051) but not in HIV-negative men (0.12, p = 0.50, HIV interaction p = 0.005). In conclusion, a lower prevalence of CAC in black compared with white men appears to reflect less calcification of plaque and stenosis rather than a lower overall prevalence of plaque.

Comprehensive desmosome mutation analysis in north americans with arrhythmogenic right ventricular dysplasia/cardiomyopathy.

BACKGROUND: Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is an inherited disorder typically caused by mutations in components of the cardiac desmosome. The prevalence and significance of desmosome mutations among patients with ARVD/C in North America have not been described previously. We report comprehensive desmosome genetic analysis for 100 North Americans with clinically confirmed or suspected ARVD/C. METHODS AND RESULTS: In 82 individuals with ARVD/C and 18 people with suspected ARVD/C, DNA sequence analysis was performed on PKP2, DSG2, DSP, DSC2, and JUP. In those with ARVD/C, 52% harbored a desmosome mutation. A majority of these mutations occurred in PKP2. Notably, 3 of the individuals studied have a mutation in more than 1 gene. Patients with a desmosome mutation were more likely to have experienced ventricular tachycardia (73% versus 44%), and they presented at a younger age (33 versus 41 years) compared with those without a desmosome mutation. Men with ARVD/C were more likely than women to carry a desmosome mutation (63% versus 38%). A mutation was identified in 5 of 18 patients (28%) with suspected ARVD. In this smaller subgroup, there were no significant phenotypic differences identified between individuals with a desmosome mutation compared with those without a mutation. CONCLUSIONS: Our study shows that in 52% of North Americans with ARVD/C a mutation in one of the cardiac desmosome genes can be identified. Compared with those without a desmosome gene mutation, individuals with a desmosome gene mutation had earlier-onset ARVD/C and were more likely to have ventricular tachycardia.

MicroRNAs are differentially expressed in ulcerative colitis and alter expression of macrophage inflammatory peptide-2 alpha.

BACKGROUND & AIMS: Chronic inflammatory bowel diseases such as ulcerative colitis (UC) are associated with differential expression of genes involved in inflammation and tissue remodeling. MicroRNAs (miRNAs), which direct mRNA degradation and translational inhibition, influence a number of disease processes. We examined whether miRNAs are differentially expressed in UC tissues and are associated with expression of genes that regulate inflammation. METHODS: miRNA expression was assessed in patients with active UC, inactive UC, Crohn's disease, irritable bowel syndrome, infectious colitis, and microscopic colitis, as well as in healthy subjects by microarray, quantitative reverse transcription-polymerase chain reaction and in situ hybridization analyses. Colonic epithelial cell (HT29) expression of miRNAs was assessed. Regulation of gene expression by miRNAs was assessed by luciferase reporter construct assays and transfection of specific miRNA mimics. RESULTS: Active UC was associated with the differential expression of 11 miRNAs; 3 were significantly decreased and 8 were significantly increased in UC tissues. In situ hybridization analysis indicated that miR-192, an miRNA with decreased expression in active UC, was predominantly localized to colonic epithelial cells. Macrophage inflammatory peptide (MIP)-2 alpha, a chemokine expressed by epithelial cells, was identified as a target of miR-192. In colon epithelial cells, induction of MIP-2 alpha expression by tumor necrosis factor-alpha was accompanied by a concomitant reduction in miR-192 expression and miR-192 was observed to regulate the expression of MIP-2 alpha. CONCLUSIONS: These findings expand the known roles of miRNAs, indicating that tissues from patients with UC, and possibly other chronic inflammatory diseases, have altered miRNA expression patterns. These findings also demonstrate that miRNAs regulate colonic epithelial cell-derived chemokine expression.

Gastrointestinal carcinoids: the evolution of diagnostic strategies.

Carcinoid tumors are rare, often insidious neoplasms arising from neuroendocrine cells. The majority arise in the gastrointestinal system, and are often incidentally found during investigation, although some may present as an emergency bleed or perforation. The prosaic symptoms of flushing, diarrhea, and sweating are often overlooked; thus, the diagnosis is usually much delayed and the tumor is advanced at presentation. This diagnostic delay renders effective management difficult and adversely affects outcome. This overview provides a current assessment of the evolution of the diagnostic techniques available to establish an accurate biochemical (5-hydroxyindole-3-acetic acid and chromogranin A) and topographic diagnosis (octreoscan, radio-labeled metaidobenzylguanidine, computerized tomography, magnetic resonance imaging, positron emission tomography, enteroclysis, endoscopic ultrasound, enteroscopy, capsule endoscopy, and angiography) of carcinoid tumors. The utility and shortcomings of the respective modalities available are evaluated. Although considerable advances have been made in establishing the diagnosis of carcinoid tumors and in defining the topography of metastatic disease, the major limitation is the inability to establish an early and timely diagnosis before the advent of metastatic disease.

Genetic differentiation of appendiceal tumor malignancy: a guide for the perplexed.

OBJECTIVE: To use differential gene expression of candidate markers to discriminate benign appendiceal carcinoids (APCs) from malignant and mixed cell APCs. SUMMARY BACKGROUND DATA: Controversy exists in regard to the appropriate surgical management of APCs since it is sometimes difficult to predict tumor behavior using traditional pathologic criteria. We have identified 5 differentially expressed genes (a mitosis-regulatory gene NAP1L1, an adhesin MAGE-D2, an estrogen-antagonist, the metastasis marker MTA1, the apoptotic marker NALP, and chromogranin A) that define gut neuroendocrine cell behavior. METHODS: Total RNA was isolated using TRIzol reagent from 42 appendiceal samples, including appendiceal carcinoids identified at exploration for appendicitis (no evidence of metastasis; n = 16), appendicitis specimens (n = 11), malignant appendiceal tumors (> 1.5 cm, evidence of metastatic invasion; n = 7), and mixed (goblet) cell appendiceal adenocarcinoids (n = 3), normal appendiceal tissue (n = 5), and 5 colorectal cancers. Gene expression (CgA, NAP1L1, MAGE-D2, MTA1, and NALP1) was examined by Q-RT PCR (Applied Biosystems) and quantified against GAPDH. RESULTS: CgA message was elevated (> 1000-fold, P < 0.05) in all tumor types. NAP1L1 was elevated (> 10-fold, P < 0.03) in both malignant and goblet cell adenocarcinoids compared with normal and incidental lesions (P < 0.006). MAGE-D2 and MTA1 message were significantly elevated (> 10-fold, P < 0.01) in the malignant and goblet cell adenocarcinoid tumors but not in the appendicitis-associated carcinoids or normal mucosa. The apoptotic marker, NALP1, was overexpressed (> 50-fold, P < 0.05) in the appendicitis-associated and malignant appendiceal carcinoids but was significantly decreased (> 10-fold, P < 0.05) in the goblet cell adenocarcinoids. Elevated CgA transcript and protein levels indicative of a carcinoid tumor were identified in one acute appendicitis sample with no histologic evidence of a tumor. CONCLUSIONS: These data demonstrate that malignant APCs and goblet cell adenocarcinoids have elevated expression of NAP1L1, MAGE-D2, and MTA1 compared with appendiceal carcinoids identified at surgery for appendicitis. This and the differences in NALP1 gene expression (decreased in goblet cell adenocarcinoids) provide a series of molecular signatures that differentiate carcinoids of the appendix. CgA identified all appendiceal tumors as well as covert lesions, which may be more prevalent than previously recognized. The molecular delineation of malignant appendiceal tumor potential provides a scientific basis to define the appropriate surgical management as opposed to morphologic assessment alone.

Therapeutic options for gastrointestinal carcinoids.

Although wide surgical resection is the optimal curative therapy for carcinoid tumors, in most patients the presence of metastatic disease at diagnosis usually renders excision a palliative procedure. This nevertheless decreases tumor burden, facilitates symptom control, and prevents complications caused by bleeding, perforation, or bowel obstruction resulting from fibrosis. In the stomach (types I and II) and rectum endoscopic excision may be adequate provided the lesion(s) are local. Long-term therapy is focused on symptom alleviation and improvement of quality of life using somatostatin analogues, particularly in a subcutaneous depot formulation. In some instances interferons may have a role but their usage often is associated with substantial adverse events. Conventional chemotherapy and external radiotherapy either alone or in a variety of permutations are of minimal efficacy and should be balanced against the decrease in quality of life often engendered by such agents. Hepatic metastases may be amenable to surgery, radiofrequency ablation, or embolization either alone or in combination with chemotherapeutic agents or isotopically loaded microspheres. Rarely hepatic transplantation may be of benefit although controversy exists as to its actual use. Peptide-receptor-targeted radiotherapy for advanced disease using radiolabeled octapeptide analogs (111In/90Yt/177Lu-octreotide) appear promising but data are limited and its status remains investigational. A variety of antiangiogenesis and growth factor-targeted agents have been evaluated, but as yet have shown little promise. The keystone of current therapy remains the long-acting somatostatin analogues that alleviate symptomatology and substantially improve quality of life with minimal adverse effects.

Utility of molecular genetic signatures in the delineation of gastric neoplasia.

BACKGROUND: Current techniques to define gastric neoplasia are limited but molecular genetic signatures can categorize tumors and provide biological rationale for predicting clinical behavior. We identified three gene signatures: Chromogranin A (CgA), MAGE-D2 (adhesion), and MTA1 (metastasis) that define gastrointestinal (GI) carcinoids and hypothesize that their expression can delineate gastric neoplasia. This strategy provides a molecular basis to define neuroendocrine gastric carcinoids (GCs), neuronal stromal tumors (GISTs), or epithelial cell (gastric adenocarcinomas [GCAs])-derived tumors. METHODS: Total RNA was isolated from 38 GCs: Type I/II (n = 7), Type III/IV (n = 6), GISTs (n = 12), GCAs (n = 13), and normal mucosa (n = 12). Quantitative reverse transcriptase polymerase chain reaction (Q RT-PCR) gene expression was quantified against glyseraldehyde-3-phosphate dehydrogenase (GAPDH) and CgA and MTA1 protein expression levels were analyzed by immunohistochemical analyses of a gastric neoplasia microarray. RESULTS: CgA was elevated in Type I/II (10-fold; P < .01) and Type III/IV (100-fold, P < .005), decreased in GISTs (100-fold, P < .03), and unchanged in GCAs. MAGE-D2 was 5-10-fold elevated (P < .05) in Type III/IV, GISTs, and GCAs but not in Type I/II tumors. MTA1 (> 5-fold, P < .01) was elevated in GCs (Type III/IV>I/II, P < .05), in GISTs (> 4-fold, P < .05), and GCAs. CgA protein levels were elevated in GCs (P < .005) but not in GISTs and GCAs. MTA1 levels were elevated in all tumors (P < .02) compared with normal, and especially with tumor invasion (P < .05). CONCLUSION: CgA discriminates GCs from other gastric neoplasms; overexpression of MAGE-D2 and MTA1 differentiate Type III/IV from Type I/II GCs. GISTs share similar expression patterns with Type III/IV GCs but have decreased CgA. MTA1 is a marker of tumor invasion.

The molecular genetics of gastroenteropancreatic neuroendocrine tumors.

The pathobiology of neuroendocrine tumors (NETs) is hampered by the lack of scientific tools that define their mechanisms of secretion, proliferation, and metastasis; and, currently, there are no accurate means to assess tumor behavior and disease prognosis. Molecular biologic techniques and genetic analysis may facilitate the delineation of the molecular pathology of NETs and provide novel insights into their cellular mechanisms. The current status and recent advances in assessment of the molecular basis of tumorigenesis of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) were reviewed (1981-2004). The objectives of this retrospective study were to provide a cohesive overview of the current state of knowledge and to develop a molecular understanding of these rare tumor entities to facilitate the establishment of therapeutic targets and rational management strategies. Multiple differences in chromosomal aberration patterns were noted between gastrointestinal (GI) neuroendocrine and pancreatic endocrine tumors (PETs). Divergence in gene expression patterns in the development of GI carcinoids and PETs was identified, whereas examination of the PET and GI carcinoid data demonstrated only few areas of overlap in the accumulation of genetic aberrations. These data suggest that the recent World Health Organization classification of GEP-NETs may require updating. In addition, previous assumptions of tumor similarity (pancreatic vs. GI) may be unfounded when they are examined at a molecular level. On the basis of the evolution of genetic information, enteric neuroendocrine lesions (carcinoids) and PETs may need to be classified as two distinct entities rather than grouped together as the single entity "GEP-NETs."

Current status of gastrointestinal carcinoids.

Gastrointestinal (GI) carcinoids are ill-understood, enigmatic malignancies, which, although slow growing compared with adenocarcinomas, can behave aggressively. Carcinoids are classified based on organ site and cell of origin and occur most frequently in the GI (67%) where they are most common in small intestine (25%), appendix (12%), and rectum (14%). Local manifestations--mass, bleeding, obstruction, or perforation--reflect invasion or tumor-induced fibrosis and often result in incidental detection at emergency surgery. Symptoms are protean (flushing, sweating, diarrhea, bronchospasm), usually misdiagnosed, and reflect secretion of diverse amines and peptides. Biochemical diagnosis is established by elevation of plasma chromogranin A (CgA), serotonin, or urinary 5-hydroxyindoleacetic acid (5-HIAA), while topographic localization is by Octreoscan, computerized axial tomography (CAT) scan, or endoscopy/ultrasound. Histological identification is confirmed by CgA and synaptophysin immunohistochemistry. Primary therapy is surgical excision to avert local manifestations and decrease hormone secretion. Hepatic metastases may be amenable to cytoreduction, radiofrequency ablation, embolization alone, or with cytotoxics. Hepatic transplantation may rarely be beneficial. Chemotherapy and radiotherapy have minimal efficacy and substantially decrease quality of life. Intravenously administered receptor-targeted radiolabeled somatostatin analogs are of use in disseminated disease. Local endoscopic excision for gastric (type I and II) and rectal carcinoids may be adequate. Somatostatin analogues provide the most effective symptomatic therapy, although interferon has some utility. Overall 5-year survival for carcinoids of the appendix is 98%, gastric (types I/II) is 81%, rectum is 87%, small intestinal is 60%, colonic carcinoids is 62%, and gastric type III/IV is 33%.