Possible role for mast cell-derived cathepsin G in the adverse remodelling of stenotic aortic valves

Aims Aortic stenosis (AS) is characterized by extensive remodellingof the valves, including infiltration of inflammatory cells,extracellular matrix degradation, and fibrosis. The molecularmechanisms behind this adverse remodelling have remained obscure.In this article, we study whether cathepsin G, an angiotensinII (Ang II)-forming elastolytic enzyme, contributes to progressionof AS. Methods and results Stenotic aortic valves (n=86) and controlvalves (n=17) were analysed for cathepsin G, transforming growthfactor-ß1 (TGF-ß1), and collagens I andIII with RT–PCR and immunohistochemistry. Valvular collagen/elastinratio was quantified by histochemistry. In stenotic valves,cathepsin G was present in mast cells and showed increased expression(P<0.001), which correlated positively (P<0.001) withthe expression levels of TGF-ß1 and collagens I andIII. TGF-ß1 was also present in mast cell-rich areasand cathepsin G induced losartan-sensitive TGF-ß1expression in cultured fibroblasts. Collagen/elastin ratio wasincreased in stenotic valves (P<0.001) and correlated positivelywith smoking (P=0.02). Nicotine in cigarette smoke activatedmast cells and induced TGF-ß1 expression in culturedfibroblasts. Fragmented elastin was observed in stenotic valvescontaining activated cathepsin G-secreting mast cells and innormal valves treated with cathepsin G. Conclusion In stenotic aortic valves, mast cell-derived cathepsinG may cause adverse valve remodelling and AS progression.     

Carotid artery intima-media thickness in Finnish families with familial combined hyperlipidemia

BACKGROUND: Familial combined hyperlipidemia (FCHL) is the most common hereditary lipid disorder that predisposes the patients to premature coronary heart disease. Members of FCHL families are categorised as affected or unaffected according to serum lipid levels. This study is aimed to evaluate whether there is a difference in carotid artery wall thickness between asymptomatic FCHL family members who are affected and those who are unaffected according to the currently used lipid criteria. METHODS AND RESULTS: Carotid artery ultrasonography with intima-media thickness (IMT) measurements was performed for 148 members of 39 Finnish FCHL families. Study subjects who had no history of coronary heart disease or stroke were divided into two groups according to their serum total cholesterol and/or triglyceride levels. The average carotid IMT of the affected subjects (0.75+/-0.15 mm) was not significantly different from that of their unaffected relatives (0.73+/-0.13 mm), P=0.90. In multivariate analysis, age, gender, and pulse pressure, but no lipid variables, contributed significantly to the variation of carotid IMT. CONCLUSIONS: The IMT findings in FCHL family members indicate that the current lipid criteria alone are of limited value in predicting long-term risk of cardiovascular disease in asymptomatic members of FCHL families.     

Proinflammatory HLA-DRB1*01-haplotype predisposes to ST-elevation myocardial infarction

BackgroundMajor histocompatibility complex (MHC) gene region harbours haplotypes that associate with coronary artery disease (CAD). Their role in ST-elevation infarction (STEMI) or on the inflammatory level is not known.MethodsFour candidate MHC markers were analyzed by real-time quantitative PCR and constructed into haplotypes from patients with STEMI (n = 162), matched controls with no CAD (n = 319) and general population sample (n = 149). High sensitivity C-reactive protein (hsCRP) was assessed in a follow-up visit from patients (n = 86) and at inclusion from other study subjects.ResultsThe haplotype with one copy of HLA-DRB1*01, C4A, C4B but no HLA-B*35 doubled the risk of STEMI (OR = 2.15, 95%CI = 1.11–4.15, p = 0.020 for patients vs. controls, and OR = 2.26, 95%CI = 0.97–5.24, p = 0.052 for patients vs. population sample). The association between patients and controls persisted in multivariate analyses. The frequency of the haplotype was 5.86% (n = 19/324) in patients, 2.82% (n = 18/638) in controls and 2.68% (n = 8/298) in population sample. None of the individual MHC markers alone showed significant association with STEMI.In multivariate analyses, the haplotype carriers had higher hsCRP levels in patients (median 3.37 mg/L in carriers vs. 1.14 mg/L in non-carriers, p = 0.019) and in controls (median 2.90 mg/L vs. 1.21 mg/L, p = 0.009, respectively).ConclusionThe MHC haplotype associates with STEMI and elevated baseline hsCRP levels. The results are in concordance with previous data on non-STEMI patients, implying that a HLA-DRB1*01 – related haplotype increases the risk of CAD, possibly though increased inflammation.     

Colonic methanogenesis in vivo and in vitro and fecal pH after resection of colorectal cancer and in healthy intact colon

Purpose  

We compared colonic methanogenesis in vivo and in vitro as well as fecal pH in healthy subjects and in patients with resected colorectal cancer thus without the possible confounding effects of the tumor.     

Physiological responses to emotional excitement in healthy subjects and patients with coronary artery disease

Emotional excitement may trigger cardiovascular (CV) events, particularly in patients with coronary artery disease (CAD). Our aim was to compare changes in various biomarkers in CAD patients and age-matched healthy male subjects during “real-life” emotional excitement. Enthusiastic male ice hockey spectators (CAD n = 18, healthy subjects n = 16) attended Finnish national ice hockey play-off matches. Heart rate variability, plasma catecholamines, endothelin-1 (ET-1) and interleukin-6 (IL-6) were determined at the baseline and during the match. A significantly more marked increase in both ET-1 and IL-6 was observed in CAD patients compared with healthy subjects during the match (time × group interaction p = 0.009 and p = 0.018 for ET-1 and IL-6, respectively). The high-frequency power of R–R intervals decreased in CAD patients (p < 0.001) but did not change in healthy subjects (p = ns, time × group interaction p < 0.001). Changes in adrenaline and noradrenaline did not differ between the groups. Emotional excitement causes more marked increases of markers of vasoconstriction and acute inflammation and withdrawal of cardiac vagal regulation in patients with CAD.     

Matrix metalloproteinases in the restorative proctocolectomy pouch of pediatric ulcerative colitis

AIM: To investigate matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in pouch mucosa of pediatric onset ulcerative colitis (UC).METHODS: In this cross-sectional study, 28 patients with pediatric onset UC underwent ileal pouch biopsy 13 years (median) after proctocolectomy. Expression of MMPs-3, -7, -8, -9, -12 and -26 and TIMPs-1, -2 and -3 in samples was examined using immunohistochemichal methods, and another biopsy was used to evaluate the grade of histological inflammation. Two investigators independently graded the immunohistochemical specimens in a semiquantitative fashion, using a scale marking staining intensity as follows: 0 = less than 20 positive cells; 1 = 20-50 positive cells; 2 = 50-200 positive cells; 3 = over 20 positive cells. Fecal calprotectin and blood inflammatory markers [serum C-reactive protein (CRP) and erythrocyte sedimentation rate] were determined during a follow-up visit to examine correlations between these markers and the expression of MMPs and TIMPs.RESULTS: Of the 28 patients with pediatric onset UC, nine had not experienced pouchitis, whereas thirteen reported a single episode, and six had recurrent pouchitis (≥ 4 episodes). At the time of the study, six patients required metronidazole. In all of the others, the most recent episode of pouchitis had occurred over one month earlier, and none were on antibiotics. Only four samples depicted no sign of inflammation, and these were all from patients who had not had pouchitis. Two samples were too small to determine the grade of inflammation, but both had suffered pouchitis, the other recurrent. No sample depicted signs of colonic metaplasia. Most pouch samples showed expression of epithelial (e) and stromal (s) MMP-3 (e, n = 22; s, n = 20), MMP-7 (e, n = 28; s, n = 27), MMP-12 (e, n = 20; s, n =24), TIMP-2 (e, n = 23; s, n = 23) and MMP-3 (e, n = 23; s, n = 28) but MMP-8 (e, n = 0; s, n = 1), MMP-9 (e, n = 0; s, n = 9) and MMP-26 (e, n = 0; s, n = 3) and TIMP-1 (n = 0, both) were lacking. In samples with low grade of inflammatory activity, the epithelial MMP-3 and MMP-7 expression was increased (r = -0.614 and r = -0.472, respectively, P < 0.05 in both). MMPs and TIMPs did not correlate with the markers of inflammation, fecal calprotectin, erythrocyte sedimentation rate, or CRP, with the exception of patients with low fecal calprotectin (< 100 μg/g) in whom a higher expression of epithelial MMP-7 was found no differences in MMP- or TIMP-profiles were seen in patients with a history of pouchitis compared to ones with no such episodes. Anastomosis with either straight ileoanal anastomosis or ileoanal anastomosis with J-pouch did depict differences in MMP- or TIMP-expression.CONCLUSION: The expression of MMPs pediatric UC pouch in the long-term shares characteristics with inflammatory bowel disease, but inflammation cannot be classified as a reactivation of the disease.