Perspectives of the International Society for Cell & Gene Therapy Gastrointestinal Scientific Committee on the Intravenous Use of Mesenchymal Stromal Cells in Inflammatory Bowel Disease (PeMeGi).

Inflammatory bowel disease (IBD), namely, Crohn's disease and ulcerative colitis, remains a grievous and recalcitrant problem incurring significant human and health care costs, even in consideration of the growing incidence. Initial goals of care aimed to achieve the induction and maintenance of clinical remission. The advent of novel treat-to-target approaches using patient stratification, early introduction of immunosuppressants and rapid escalation to biologics or early use of combination therapy has refocused the goals of care toward the achievement of mucosal healing. This is in an attempt to preserve intestinal function, decrease hospitalization and surgery rates and improve the quality of life of affected patients. Cellular therapeutics for the treatment of IBD offers an unprecedented opportunity to change the current paradigm from single-targeted to systems-targeted therapy, trying to dampen the whole inflammatory cascade instead of a only molecule. Therefore, as we move forward, the importance of designing informative and possibly adaptive trial designs, standardizing methodologies, harmonizing goals of therapy and evaluating methods cannot be underemphasized. In this article, we review the current literature on the application of mesenchymal stromal cells for the treatment of IBD in an effort to establish a consensus on designing efficient and consistent clinical trials for the intravenous use of this cellular therapy in IBD.

[Fundamentals of the microbiome]. / Grundlagen des Mikrobioms.

Until the middle of the 20th century, clinical microbiology was limited to bacterial cultures enabling the detection of pathogenic microorganisms. Knowledge about the mutual relationship between humans and microorganisms has increased slowly. With the introduction of culture-independent analysis methods, comprehensive cataloging of the human microbiome was possible for the first time. Since then, compositional changes in relation to diseases have been studied. The goals of the Human Microbiome Project and MetaHIT include comparative studies of healthy and diseased individuals. Numerous libraries on time- and location-dependent changes of the microbiota composition in human diseases have been created. However, a mathematical correlation does not equal biological or medical relevance. Future research needs to validate the hypotheses generated in these studies in functional experiments and evaluate their true impact on clinical practice.

Aberrant plasmacytoid dendritic cell distribution and function in patients with Crohn's disease and ulcerative colitis.

Dendritic cell (DC) function is believed to be of critical importance for the pathogenesis of inflammatory bowel disease (IBD). To date, most research in animal models and the few human data available is restricted to myeloid DC, while plasmacytoid DC (pDC) capable of controlling both innate and adaptive immune responses have not yet been investigated systematically in human Crohn's disease (CD) or ulcerative colitis (UC). CD11c(-) , CD303(+) /CD304(+) and CD123(+) pDC from peripheral blood (n = 90), mucosal tissue (n = 28) or mesenteric lymph nodes (n = 40) (MLNs) of patients with UC and CD or controls were purified and cultured. Thereafter, pDC were enumerated, phenotyped and cytokine secretion measured by flow cytometry (FACS), immunohistochemistry and/or cytometric bead array, respectively. Interferon (IFN)-α secretion following cytosine phosphatidyl guanine (CpG) A oligodeoxynucleotide (ODN) 2216 (5'-GGGGGACGATCGTCGGGGGG-3') stimulation was assessed by enzyme-linked immunosorbent assay (ELISA). We found a significantly higher frequency of pDC in the inflamed colonic mucosa and MLN of IBD patients. Moreover, the fraction of CD40 and CD86 expressing cultured peripheral blood pDC was significantly higher in flaring UC and CD patients and their secretion of tumour necrosis factor (TNF)-α, interleukin (IL)-6 and IL-8 were increased significantly compared with controls. In contrast, the IFN-α secretion of peripheral blood pDC isolated from flaring IBD, particularly in UC patients, was reduced significantly compared with controls. Our data suggest an aberrant distribution and function of pDC in IBD, contrary to their generally implicated role as inducers of tolerance. We speculate that the impaired IFN-α secretion may relate to the hypothesized defect in innate immunity in IBD and could also impact upon the generation of regulatory T cells (T(reg) ).

Saccharomyces boulardii inhibits lipopolysaccharide-induced activation of human dendritic cells and T cell proliferation.

Saccharomyces boulardii (Sb) is a probiotic yeast preparation that has demonstrated efficacy in inflammatory and infectious disorders of the gastrointestinal tract in controlled clinical trials. Although patients clearly benefit from treatment with Sb, little is known on how Sb unfolds its anti-inflammatory properties in humans. Dendritic cells (DC) balance tolerance and immunity and are involved critically in the control of T cell activation. Thus, they are believed to have a pivotal role in the initiation and perpetuation of chronic inflammatory disorders, not only in the gut. We therefore decided to investigate if Sb modulates DC function. Culture of primary (native, non-monocyte-derived) human myeloid CD1c+CD11c+CD123(-) DC (mDC) in the presence of Sb culture supernatant (active component molecular weight < 3 kDa, as evaluated by membrane partition chromatography) reduced significantly expression of the co-stimulatory molecules CD40 and CD80 (P < 0.01) and the DC mobilization marker CC-chemokine receptor CCR7 (CD197) (P < 0.001) induced by the prototypical microbial antigen lipopolysaccharide (LPS). Moreover, secretion of key proinflammatory cytokines such as tumour necrosis factor-alpha and interleukin (IL)-6 were notably reduced, while the secretion of anti-inflammatory IL-10 increased. Finally, Sb supernatant inhibited the proliferation of naive T cells in a mixed lymphocyte reaction with mDC. In summary, our data suggest that Sb may exhibit part of its anti-inflammatory potential through modulation of DC phenotype, function and migration by inhibition of their immune response to bacterial microbial surrogate antigens such as LPS.

Exaggerated inflammatory response of primary human myeloid dendritic cells to lipopolysaccharide in patients with inflammatory bowel disease.

Inflammatory bowel disease (IBD) results from a breakdown of tolerance towards the indigenous flora in genetically susceptible hosts. Failure of dendritic cells (DC) to interpret molecular microbial patterns appropriately when directing innate and adaptive immune responses is conceivable. Primary (conventional, non-monocyte generated) CD1c(+)CD11c(+)CD14(-)CD16(-)CD19(-) myeloid blood or mucosal dendritic cells (mDC) from 76 patients with Crohn's disease (CD) or ulcerative colitis (UC) in remission, during flare-ups (FU) and 76 healthy or non-IBD controls were analysed by fluorescence activated cell sorter (FACS) flow cytometry and real-time polymerase chain reaction. Cytokine secretion of freshly isolated, cultured and lipopolysaccharide (LPS)-stimulated highly purified mDC (purity >95%) was assessed using cytometric bead arrays (CBA). More cultured and stimulated circulating mDC express CD40 in IBD patients. Stimulated circulating mDC from IBD patients secrete significantly more tumour necrosis factor (TNF)-alpha and interleukin (IL)-8. Toll-like receptor (TLR)-4 expression by mDC was higher in remission and increased significantly in flaring UC and CD patients compared with remission (P < 0.05) and controls (P < 0.001). Fluorochrome-labelled LPS uptake by mDC was evaluated at different time-points over 24 h by measuring mean fluorescence intensity (MFI). Circulating mDC from IBD patients take up more LPS and the uptake begins earlier compared with controls (P < 0.05 in CD-FU and UC-FU at 24 h). The frequency of mucosal mDC (P < 0.05) and the number of CD40 expressing mucosal mDC is significantly greater in UC and CD compared with non-IBD controls (P < 0.001 versus P < 0.01, respectively). Our data suggest an aberrant LPS response of mDC in IBD patients, resulting in an inflammatory phenotype and possibly intestinal homing in acute flares.

Heterozygosity for IL23R p.Arg381Gln confers a protective effect not only against Crohn's disease but also ulcerative colitis.

BACKGROUND: A recent study reported that a non-synonymous single nucleotide polymorphism (rs11209026, p.Arg381Gln) located in the IL23R gene is a protective marker for inflammatory bowel disease. AIM: To analyse the frequency of p.Arg381Gln in three independent European inflammatory bowel disease cohorts and to evaluate how this variant influences disease behaviour. METHODS: We assessed a European cohort of 919 inflammatory bowel disease patients and compared the IL23R p.Arg381Gln genotype frequency with 845 healthy controls. Inflammatory bowel disease patients originated from Germany [Crohn's disease (CD): n = 318; ulcerative colitis (UC): n = 178], Hungary (CD: n = 148; UC: n = 118) and the Netherlands (CD: n = 157). Ethnically matched controls were included. We performed subtyping analysis in respect to CARD15 alterations and clinical characteristics. RESULTS: The frequency of the glutamine allele of p.Arg381Gln was significantly lower in inflammatory bowel disease patients compared with controls in a pooled analysis of all three cohorts (P < 0.000001) as well as in the individual cohorts (Germany: P = 0.001, Hungary: P = 0.02 and the Netherlands: P = 0.0002). The p.Arg381Gln genotype distribution was similar between CD and UC. We did not observe either statistical interactions between p.Arg381Gln and CARD15 variants or any significant associations between p.Arg381Gln genotype and subphenotypes. CONCLUSIONS: The p.Arg381Gln IL23R variant confers a protective effect against both CD and UC, but does not determine disease phenotype.

G protein beta3 subunit 825T allele and enhanced coronary vasoconstriction on alpha(2)-adrenoceptor activation.

Recently, alpha(2)-adrenoceptor activation was shown to play an important role in the vasoconstriction of normal coronary arteries, whereas in the presence of atherosclerosis, the activation of both alpha(1)- and alpha(2)-adrenoceptors reduces coronary blood flow in humans. alpha(2)-Adrenoceptors activate pertussis toxin (PTX)-sensitive G proteins, whereas alpha(1)-adrenoceptors couple to PTX-insensitive G proteins. Thus, the 825T allele of the beta3 subunit of heterotrimeric G proteins, associated with enhanced PTX-sensitive G protein signaling, was expected to determine the alpha(2)-adrenoceptor-, but not the alpha(1)-adrenoceptor-, mediated reduction in coronary blood flow (CBF). Genotyping was performed on 48 individuals. Twelve of the 48 received the alpha(1)-adrenoceptor agonist methoxamine (MTX; 5 mg IC), and 12 received the alpha(2)-adrenoceptor agonist BHT 933 (BHT; 5 mg IC). Twenty-four additional individuals received both MTX and BHT during the same investigational procedure. CBF was calculated on the basis of coronary angiography and intracoronary Doppler flow velocity measurement. Drug-related ischemia was assessed on the basis of ST-segment changes and angina pectoris. In response to BHT, but not to MTX, CBF was reduced to a significantly greater extent in 825T allele carriers (58+/-4%, n=16) than in individuals homozygous for the C825 allele (28+/-4%, n=19, P=0.001). This finding was independent of cholesterol levels, mean arterial blood pressure, and the presence or absence of coronary artery disease. Ischemic events in response to BHT occurred more frequently in 825T allele carriers than in homozygous 825C allele carriers (P=0.01). alpha(2)-Adrenoceptor coronary vasoconstriction is genetically determined and significantly enhanced in GNB3 825T allele carriers.

Post-interventional homocysteine levels: failure as a predictive biomarker of in-stent restenosis.

OBJECTIVES: Purpose of our study was to determine if homocysteine plasma levels are related to the risk of in-stent restenosis after percutaneous coronary stent implantation in de novo lesions. BACKGROUND: The putative role of homocysteine as a predictive cardiovascular biomarker of coronary artery disease is well established. The impact of homocysteine levels in the development of in-stent restenosis, however, is controversially discussed. METHODS: A total of 177 patients with stable angina pectoris undergoing stent implantation in coronary de novo lesions were included. Laboratory determination comprised blood sample evaluation for homocysteine and other conventional risk factors before baseline coronary intervention and prior to six months control catheterization. Binary restenosis, late lumen loss, and late loss index after six months were assessed by quantitative coronary angiography. Endpoints included target lesion and target vessel failure, homocysteine levels as well as major adverse cardiac events. RESULTS: There was a significant correlation between the length of the implanted stent (p<0.006), the percentage of stenosis (p<0.003) and the pre-interventional luminal diameter (p<0.0001) with late loss index. Linear regression analysis demonstrated no significant impact of the initial or six months homocysteine levels on angiographic restenosis, late lumen loss, or late loss index. CONCLUSIONS: In contrast to homocysteine levels, luminal diameter, stent length and percentage of stenosis correlated with the appearance of restenosis. Taking our data into consideration, we hypothesise that homocysteine may not serve as a safe and independent biomarker of in-stent restenosis after a six months period following percutaneous coronary stenting.

Nephrotoxicity of iso-osmolar versus low-osmolar contrast media is equal in low risk patients.

BACKGROUND: Contrast media-induced nephropathy (CIN) is an increasing cause of hospital-acquired acute kidney injury and leads to a significant increase in mortality. There is uncertainty whether the use of iso-osmolar contrast media as opposed to the use of low-osmolar contrast media would be associated with a lower incidence of CIN. Therefore, we compared the nephrotoxicity of isoosmotic contrast media iodixanol with the low-osmotic contrast media iopromid in patients receiving contrast media during coronary angiography. METHODS: In this prospective double-blind study we examined 221 patients with normal renal function who received up to 1,000 ml of contrast media during coronary angiography, and compared the effect of iodixanol and iopromid on inducing contrast media nephropathy. Patients received 800 ml fluid orally before contrast media administration and 1,000 ml saline i.v. thereafter. Creatinine clearance, serum creatinine and urine-N-acetyl-beta-D-glucosaminidase (NAG) concentration was obtained 24 h before and 48 h after contrast media administration. Decrease of 20% of the creatinine clearance, increase of 25% of serum creatinine and increase of 20% of the urine concentration of NAG was defined as CIN. RESULTS: Incidence of CIN assessed by decreased creatinine clearance was 22.2% in the iopromid group and 19.7% in the iodixanol group. CIN defined by increased serum creatinine was 6.9% in the iopromid group and 8.6% in the iodixanol group. The difference between these two groups was not significant. Subgroup analysis of the diabetic patients or the patients that received high dose of contrast media revealed no significant difference in the incidence of CIN between the two contrast media. CONCLUSION: The iso-osmolar and the low-osmolar contrast media exhibited the same incidence of CIN in our study population. If fluid administration is sufficient, the selection of either iopromid or iodixanol has no impact on the risk of developing CIN in patients with normal renal function, even when they are diabetic or receive a high dose of more than 500 ml contrast media.

Vedolizumab induction therapy for inflammatory bowel disease in clinical practice--a nationwide consecutive German cohort study.

BACKGROUND: Vedolizumab (VDZ) is a humanised monoclonal IgG1 antibody targeting α4 ß7 integrin. AIM: To investigate the real-world efficacy of vedolizumab for the treatment of Crohn's disease (CD) and ulcerative colitis (UC). METHODS: A consecutive cohort of 212 adult IBD patients with active disease (HBI >7/partial Mayo >4) newly receiving VDZ was prospectively recruited from 7 academic and 17 community centres. The primary endpoint was clinical remission (CRM) (CD HBI ≤4, UC pMayo ≤1) in week 14. Secondary endpoints included steroid-free remission (SFCRM), clinical response (CRS) (HBI/pMayo score drop ≥3), vedolizumab impact on CRP, calprotectin and haemoglobin. RESULTS: Data of 97 CD (71.1% female, HBI 11) and 115 UC (42.6% female, pMayo 6) patients were analysed. Only 5.2% CD and 24.3% UC were anti-TNFα naïve. Most had extensive mucosal involvement (Montreal L3 69.1%/E3 53.9%). At week 14, 23.7% vs. 23.5% of CD vs. UC patients achieved CRM, 19.6% vs. 19.1% SFCRM and 60.8% vs. 57.4% CRS, respectively (all based on NRI). Week 14 CRM in CD was significantly associated with no history of extraintestinal manifestations (P = 0.019), no prior adalimumab use (P = 0.011), no hospitalisation in the past 12 months (P = 0.015) and low HBI score (P = 0.02) and in UC with active or previous smoking (P = 0.044/0.028) and no anti-TNFα (P = 0.023) use. Low HBI (P = 0.019) and no hospitalisation in the past 12 months (P = 0.01) predict CD CRM. The three most common AE were joint pain, acne and nasopharyngitis. CONCLUSION: Vedolizumab is effective in routine use.

Autoimmunity in Crohn's Disease-A Putative Stratification Factor of the Clinical Phenotype.

Inflammation in inflammatory bowel diseases (IBD) has been linked to a loss of tolerance to self-antigens suggesting the existence of autoantibodies in specific disease phenotypes. However, the lack of clearly defined autoantigenic targets has slowed down research. Genome-wide association studies have identified an impressive number of immune-related susceptibility loci for IBD with no clearly discernible pattern among them. Growing evidence supports the hypothesis that innate immune responses to a low-diversity and impaired gut microbiota may be of key importance in initiating and perpetuating chronic inflammation in IBD. Increasing evidence suggests that reduced microbial diversity and microbial-mucosal epithelium interaction (including adhesion and clearance) are critically involved in IBD pathogenesis. Along these lines the discovery of autoantigenic targets in Crohn's disease (CD) has refocused research in IBD on the possible role of autoimmune responses. The identification of the major zymogen granule membrane glycoprotein 2 (GP2) as an autoantigen in CD patients and its proposed role in the sensing of the microbiota lends credence to this trend. Loss of tolerance to GP2 occurs in up to 40% of patients with CD. Corresponding autoantibodies appear to be associated with distinct disease courses (types or phenotypes) in CD. Here, we critically review autoantibodies in CD for their impact on clinical practice and future IBD research. The immunomodulatory role of GP2 in innate and adaptive intestinal immunity is also discussed.

Ferric maltol therapy for iron deficiency anaemia in patients with inflammatory bowel disease: long-term extension data from a Phase 3 study.

BACKGROUND: Ferric maltol was effective and well-tolerated in iron deficiency anaemia patients with inflammatory bowel disease during a 12-week placebo-controlled trial. AIM: To perform a Phase 3 extension study evaluating long-term efficacy and safety with ferric maltol in inflammatory bowel disease patients in whom oral ferrous therapies had failed to correct iron deficiency anaemia. METHODS: After 12 weeks of randomised, double-blind treatment, patients with iron deficiency anaemia and mild-to-moderate ulcerative colitis or Crohn's disease received open-label ferric maltol 30 mg b.d. for 52 weeks. RESULTS: 111 patients completed randomised treatment and 97 entered the open-label ferric maltol extension. In patients randomised to ferric maltol ('continued'; n = 50), mean ± s.d. haemoglobin increased by 3.07 ± 1.46 g/dL between baseline and Week 64. In patients randomised to placebo ('switch'; n = 47), haemoglobin increased by 2.19 ± 1.61 g/dL. Normal haemoglobin was achieved in high proportions of both continued and switch patients (89% and 83% at Week 64, respectively). Serum ferritin increased from 8.9 µg/L (baseline) to 26.0 µg/L (Week 12) in ferric maltol-treated patients, and to 57.4 µg/L amongst all patients at Week 64. In total, 80% of patients reported ≥1 adverse event by Week 64. Adverse events considered related to ferric maltol were recorded in 27/111 (24%) patients: 8/18 discontinuations due to adverse events were treatment-related. One patient was withdrawn due to increased ulcerative colitis activity. CONCLUSIONS: Normal haemoglobin was observed in ≥80% of patients from weeks 20-64 of long-term ferric maltol treatment, with concomitant increases in iron storage parameters. Ferric maltol was well-tolerated throughout this 64-week study.

Long-term Outcomes in Steroid-refractory Ulcerative Colitis Treated with Tacrolimus Alone or in Combination with Purine Analogues.

BACKGROUND AND AIMS: Tacrolimus is recommended for the treatment of steroid-refractory ulcerative colitis (UC). Concomitantly started purine analogues (PAs) are used for the maintenance of remission, though their therapeutic relevance remains uncertain. Here we studied the role of PAs in the long-term outcome of steroid-refractory UC after tacrolimus treatment. METHODS: In five centres, charts of tacrolimus-treated UC patients with a steroid-refractory moderate to severe course were reviewed. Long-term efficacy was determined by colectomy rates and clinical remission in cases of colectomy-free survival for 3 months. RESULTS: We identified 156 patients (median age 34 years) with a median Lichtiger score of 12 (4-17) and pancolitis (E3) in 65% (101). The Kaplan-Meier curve for colectomy-free survival after month 3 showed a benefit in the PA group (p = 0.02). In patients treated with PA clinical remission was achieved in 82% (65/79) vs 67% (39/58) in those not treated with PA (p = 0.02). Time to colectomy was 2 years (median, 0.7-5.8) in the PA group and 0.8 years (0.3-4.7) in the group not treated with PAs (p = 0.02). Time to relapse was 1.2 years (median, 0.3-6.2) in patients with PA treatment and 0.5 years (0.3-3.9) in those without PA treatment (p = 0.05). Overall, clinical remission was achieved in 67% (104/156) of patients. Colectomy was performed in 29% (45/156) 0.5 years (median, 0.04-5.79) after initiation of tacrolimus. Ten (6%) patients had to stop tacrolimus due to adverse events and two (without PA treatment) died. CONCLUSIONS: Our study supports the efficacy of tacrolimus in steroid-refractory UC. Purine analogues appear to be beneficial for the long-term outcome of these patients.

Vedolizumab provides clinical benefit over 1 year in patients with active inflammatory bowel disease - a prospective multicenter observational study.

BACKGROUND: Vedolizumab, a monoclonal antibody targeting the α4ß7-integrin, is effective in inducing and maintaining clinical remission in Crohn's disease and ulcerative colitis according to randomised clinical trials. AIM: To determine the long-term effectiveness of vedolizumab in a real-world clinical setting. METHODS: This observational registry assessed the clinical outcome in patients treated with vedolizumab for clinically active Crohn's disease (n = 67) or ulcerative colitis (n = 60). Primary endpoint was clinical remission (HBI ≤ 4/pMayo ≤ 1) at week 54. Secondary endpoints included clinical response rates (HBI/pMayo score drop ≥3) and steroid-free clinical remission at weeks 30 and 54. RESULTS: Vedolizumab was stopped in 69/127 (56%) patients after a median time of 18 weeks (range 2-49) predominantly owing to lack or loss of response. Using nonresponder imputation analysis, clinical remission and steroid-free remission rates were 21% and 15% in Crohn's disease and 25% and 22% in ulcerative colitis, respectively. Lack of clinical remission was associated with prior treatment with anti-TNF or with steroids for more than 3 months in the last 6 months in ulcerative colitis. At week 14, the absence of remission in Crohn's disease or nonresponse in ulcerative colitis indicated a low likelihood of clinical remission at week 54 [2/31 (7%) in Crohn's disease, 4/41 (10%) in ulcerative colitis]. Accordingly, declining C-reactive protein in inflammatory bowel disease and/or lower faecal calprotectin in ulcerative colitis at week 14 predicted remission at week 54. CONCLUSION: Among patients who started vedolizumab for active inflammatory bowel disease, clinical remission rates are 21-25% after 54 weeks.

alpha-adrenergic coronary vasoconstriction and myocardial ischemia in humans.

The use of quantitative coronary angiography, combined with Doppler and PET, has recently been directed at the study of alpha-adrenergic coronary vasomotion in humans. Confirming prior animal experiments, there is no evidence of alpha-adrenergic coronary constrictor tone at rest. Again confirming prior experiments, responses to alpha-adrenoceptor activation are augmented in the presence of coronary endothelial dysfunction and atherosclerosis, involving both alpha(1)- and alpha(2)-adrenoceptors in epicardial conduit arteries and microvessels. Such augmented alpha-adrenergic coronary constriction is observed during exercise and coronary interventions, and it is powerful enough to induce myocardial ischemia and limit myocardial function. Recent studies indicate a genetic determination of alpha(2)-adrenergic coronary constriction.

Augmented alpha-adrenergic constriction of atherosclerotic human coronary arteries.

BACKGROUND: Although adrenergic activation plays a major role in the initiation of experimental myocardial ischemia, the significance of alpha-adrenergic coronary constriction in humans has been questioned. The present study assessed the impact of selective alpha-adrenergic receptor activation in patients with normal or atherosclerotic coronary arteries. METHODS AND RESULTS: In 39 patients, coronary blood flow (CBF, mL/min) was determined from combined angiography and Doppler measurements. In 8 patients with normal coronary arteries (group 1) and 9 with single coronary artery stenosis (group 2), doses of 1, 2.5, 5, and 10 mg IC of the alpha1-agonist methoxamine (M) were injected. Identical doses of the alpha2-agonist BHT933 (B) were injected in 8 patients with normal coronary arteries (group 3) and 8 with single stenosis (group 4). In 6 additional patients with single stenosis (group 5), aortocoronary sinus lactate differences were measured in response to M and B. CBF remained unchanged in group 1. In contrast, CBF was decreased dose-dependently in group 2, with a maximum at 10 mg M (39.0+/-9.4 versus 15.2+/-7.0). In groups 3 and 4, CBF was also decreased dose-dependently, with a maximum at 10 mg B (63.3+/-24.8 versus 49. 1+/-27.9 and 41.5+/-19.0 versus 12.7+/-8.0, respectively). In group 5, there was more net lactate production with B than with M (-0. 34+/-0.11 versus -0.04+/-0.09 mmol/L). CONCLUSIONS: In normal coronary arteries, alpha1-adrenergic activation does not reduce CBF, whereas alpha2-adrenergic activation reduces CBF by microvascular constriction. Both alpha1- and alpha2-adrenergic epicardial and microvascular constriction are augmented by atherosclerosis and can induce myocardial ischemia.

Intracoronary Doppler- and quantitative coronary angiography-derived predictors of major adverse cardiac events after stent implantation.

BACKGROUND: Distal coronary flow velocity reserve (CVR) is significantly improved after a successful balloon angioplasty (PTCA). Furthermore, a postinterventional CVR >2.5 and a percent diameter stenosis (%DS) 0.88 was the best single predictor of MACE, with an incidence of 6.8%, whereas the combination of a CVR(rel)>0.88 and a %DS

Abnormal coronary flow velocity reserve after coronary intervention is associated with cardiac marker elevation.

BACKGROUND: Residual reduction of relative coronary flow velocity reserve (rCVR) after successful coronary intervention has been related to microvascular impairment. However, the incidence of cardiac enzyme elevation as a surrogate marker of an underlying embolic myocardial injury in these cases has not been studied. METHODS AND RESULTS: A series of 55 consecutive patients with successful coronary stenting, periprocedural intracoronary Doppler analysis, and determination of creatine kinase (CK; upper limit of normal [ULN] for women 70 IU/L, for men 80 IU/L) and cardiac troponin T (cTnT; bedside test, threshold 0.1 ng/mL) before and 6, 12, and 24 hours after intervention were studied. Postprocedural rCVR was the only intracoronary Doppler parameter that independently correlated with cTnT (r=-0.498, P<0.001) and CK outcome (r=-0.406, P=0.002). Receiver operating characteristic analysis identified a postprocedural rCVR of 0.78 as the best discriminating value, with a sensitivity of 83.3% and 69.2% and a specificity of 79.1% and 76.2% for detection of cTnT and CK elevation, respectively. Stratified according to this cutoff value, the incidence of cTnT elevation was 52.6% in patients with (n=19) and 5.6% in patients without (n=36) a postprocedural rCVR <0.78 (P<0.001), associated with a CK elevation >1 times the ULN in 36.8% and 5.6% (P=0.005) of patients, respectively. CONCLUSIONS: Cardiac marker elevation can frequently be found after coronary procedures that are associated with a persistent reduction of rCVR, indicating procedural embolization of atherothrombotic debris with microvascular impairment and myocardial injury as a potential underlying mechanism.

Comparison of electron beam computed tomography with intracoronary ultrasound and coronary angiography for detection of coronary atherosclerosis.

OBJECTIVES: This analysis compared the results of electron beam computed tomography (EBCT) with those of coronary angiography and intracoronary ultrasound (ICUS) for the in vivo detection of coronary atherosclerotic plaques. BACKGROUND: EBCT is a new imaging modality for identification of coronary calcifications. Coronary angiography depicts advanced changes in coronary morphology, whereas ICUS is an established diagnostic tool that detects the early stages of coronary artery disease. METHODS: In 57 patients (54 +/- 9 years old), 267 coronary segments were analyzed with EBCT (3-mm slices, acquisition time 100 ms, threshold definition of coronary calcification at 130 Hounsfield units in an area > or = 1 mm2, Agatston calcium score), coronary angiography and ICUS. The analysis was based on the number and extent of coronary calcifications on EBCT, coronary lumen reduction on coronary angiography and plaque formation with and without ultrasound signs of calcifications on ICUS. RESULTS: Compared with coronary angiography, EBCT yielded a sensitivity of 66%, a specificity of 78%, a positive predictive value of 39% and a negative predictive value of 91%. Compared with ICUS, EBCT yielded an overall sensitivity of 66%, a specificity of 88% and an overall accuracy of 81%. For plaques with and without ultrasound signs of calcifications, the sensitivity of EBCT was 97% and 47%, specificity 80% and 75% and overall accuracy 82% and 69%, respectively. CONCLUSIONS: This in vivo correlation between ICUS and EBCT demonstrates that EBCT is a noninvasive method that helps to visualize the atherosclerotic process by localization and quantification of coronary artery calcifications. EBCT detects calcified plaques with high accuracy. Plaques without ultrasound signs of calcifications can be detected by EBCT but with lower sensitivity but equivalent specificity.

Corrected coronary flow velocity reserve: a new concept for assessing coronary perfusion.

OBJECTIVES: In order to limit the variability of coronary flow velocity reserve (CFVR), we analyzed which factors independently affect CFVR and established a new parameter integrating these factors. BACKGROUND: Coronary flow velocity reserve (CFVR) is a frequently used parameter for evaluating the physiological significance of epicardial stenosis and microvascular function. Since CFVR measurements are done in substantially different hemodynamic and clinical situations, interpretation of CFVR requires correction for major influencing factors. METHODS: In 141 patients with angina-like symptoms and angiographically unobstructed coronary arteries, intracoronary Doppler measurements were performed in at least two coronary vessels. Coronary flow velocity reserve was calculated as the ratio of hyperemic average peak velocity (hAPV), after intracoronary bolus of adenosine, to baseline average peak velocity (bAPV). RESULTS: Analysis of covariance revealed that only bAPV (p < 0.0001) and age (p < 0.0001) were independent factors influencing CFVR. Based on a regression model for estimation of predicted CFVR values, individual CFVR values (CFVRind) obtained at different bAPV and age were transformed in corrected CFVR values (CFVRcorr) by relating them to a mean bAPV of 15 cm/s and a mean age of 55 years. The transformation from CFVRind into CFVRcorr for the left anterior descending artery can be done by using the following equation: CFVRcorr = 2.85*CFVR(ind)*10(0.48*log(bAPV)+(0.0025*age)-1.16). When applying this new parameter to conditions assumed to cause microvascular dysfunction, analysis showed that only patients with diabetes showed a significant decrease of traditional CFVR and CFVRcorr, whereas a history of hypertension and current smoking habit had no influence on CFVRcorr. CONCLUSIONS: The concept of CFVRcorr standardizes CFVR for bAPV and age as the major physiological determinants. Especially in patients with microvascular dysfunction, this approach may help to discriminate between conditions directly affecting vasodilator reserve and conditions primarily affecting bAPV.