Prospective study of insulin-like growth factor-I, insulin-like growth factor-binding protein 3, genetic variants in the IGF1 and IGFBP3 genes and risk of coronary artery disease.

Although experimental studies have suggested that insulin-like growth factor I (IGF-I) and its binding protein IGFBP-3 might have a role in the aetiology of coronary artery disease (CAD), the relevance of circulating IGFs and their binding proteins in the development of CAD in human populations is unclear. We conducted a nested case-control study, with a mean follow-up of six years, within the EPIC-Norfolk cohort to assess the association between circulating levels of IGF-I and IGFBP-3 and risk of CAD in up to 1,013 cases and 2,055 controls matched for age, sex and study enrolment date. After adjustment for cardiovascular risk factors, we found no association between circulating levels of IGF-I or IGFBP-3 and risk of CAD (odds ratio: 0.98 (95% Cl 0.90-1.06) per 1 SD increase in circulating IGF-I; odds ratio: 1.02 (95% Cl 0.94-1.12) for IGFBP-3). We examined associations between tagging single nucleotide polymorphisms (tSNPs) at the IGF1 and IGFBP3 loci and circulating IGF-I and IGFBP-3 levels in up to 1,133 cases and 2,223 controls and identified three tSNPs (rs1520220, rs3730204, rs2132571) that showed independent association with either circulating IGF-I or IGFBP-3 levels. In an assessment of 31 SNPs spanning the IGF1 or IGFBP3 loci, none were associated with risk of CAD in a meta-analysis that included EPIC-Norfolk and eight additional studies comprising up to 9,319 cases and 19,964 controls. Our results indicate that IGF-I and IGFBP-3 are unlikely to be importantly involved in the aetiology of CAD in human populations.

Delayed contrast-enhanced MRI of the coronary artery wall in takayasu arteritis.

BACKGROUND: Takayasu arteritis (TA) is a rare form of chronic inflammatory granulomatous arteritis of the aorta and its major branches. Late gadolinium enhancement (LGE) with magnetic resonance imaging (MRI) has demonstrated its value for the detection of vessel wall alterations in TA. The aim of this study was to assess LGE of the coronary artery wall in patients with TA compared to patients with stable CAD. METHODS: We enrolled 9 patients (8 female, average age 46±13 years) with proven TA. In the CAD group 9 patients participated (8 male, average age 65±10 years). Studies were performed on a commercial 3T whole-body MR imaging system (Achieva; Philips, Best, The Netherlands) using a 3D inversion prepared navigator gated spoiled gradient-echo sequence, which was repeated 34-45 minutes after low-dose gadolinium administration. RESULTS: No coronary vessel wall enhancement was observed prior to contrast in either group. Post contrast, coronary LGE on IR scans was detected in 28 of 50 segments (56%) seen on T2-Prep scans in TA and in 25 of 57 segments (44%) in CAD patients. LGE quantitative assessment of coronary artery vessel wall CNR post contrast revealed no significant differences between the two groups (CNR in TA: 6.0±2.4 and 7.3±2.5 in CAD; p = 0.474). CONCLUSION: Our findings suggest that LGE of the coronary artery wall seems to be common in patients with TA and similarly pronounced as in CAD patients. The observed coronary LGE seems to be rather unspecific, and differentiation between coronary vessel wall fibrosis and inflammation still remains unclear.

Contribution of genetic background, traditional risk factors, and HIV-related factors to coronary artery disease events in HIV-positive persons.

BACKGROUND: Persons infected with human immunodeficiency virus (HIV) have increased rates of coronary artery disease (CAD). The relative contribution of genetic background, HIV-related factors, antiretroviral medications, and traditional risk factors to CAD has not been fully evaluated in the setting of HIV infection. METHODS: In the general population, 23 common single-nucleotide polymorphisms (SNPs) were shown to be associated with CAD through genome-wide association analysis. Using the Metabochip, we genotyped 1875 HIV-positive, white individuals enrolled in 24 HIV observational studies, including 571 participants with a first CAD event during the 9-year study period and 1304 controls matched on sex and cohort. RESULTS: A genetic risk score built from 23 CAD-associated SNPs contributed significantly to CAD (P = 2.9 × 10(-4)). In the final multivariable model, participants with an unfavorable genetic background (top genetic score quartile) had a CAD odds ratio (OR) of 1.47 (95% confidence interval [CI], 1.05-2.04). This effect was similar to hypertension (OR = 1.36; 95% CI, 1.06-1.73), hypercholesterolemia (OR = 1.51; 95% CI, 1.16-1.96), diabetes (OR = 1.66; 95% CI, 1.10-2.49), ≥ 1 year lopinavir exposure (OR = 1.36; 95% CI, 1.06-1.73), and current abacavir treatment (OR = 1.56; 95% CI, 1.17-2.07). The effect of the genetic risk score was additive to the effect of nongenetic CAD risk factors, and did not change after adjustment for family history of CAD. CONCLUSIONS: In the setting of HIV infection, the effect of an unfavorable genetic background was similar to traditional CAD risk factors and certain adverse antiretroviral exposures. Genetic testing may provide prognostic information complementary to family history of CAD.

The Atherosclerosis Burden Score (ABS): a Convenient Ultrasound-Based Score of Peripheral Atherosclerosis for Coronary Artery Disease Prediction.

Ultrasonographic detection of subclinical atherosclerosis improves cardiovascular risk stratification, but uncertainty persists about the most discriminative method to apply. In this study, we found that the "atherosclerosis burden score (ABS)", a novel straightforward ultrasonographic score that sums the number of carotid and femoral arterial bifurcations with plaques, significantly outperformed common carotid intima-media thickness, carotid mean/maximal thickness, and carotid/femoral plaque scores for the detection of coronary artery disease (CAD) (receiver operating characteristic (ROC) curve area under the curve (AUC) = 0.79; P = 0.027 to <0.001 with the other five US endpoints) in 203 patients undergoing coronary angiography. ABS was also more correlated with CAD extension (R = 0.55; P < 0.001). Furthermore, in a second group of 1128 patients without cardiovascular disease, ABS was weakly correlated with the European Society of Cardiology chart risk categories (R (2) = 0.21), indicating that ABS provided information beyond usual cardiovascular risk factor-based risk stratification. Pending prospective studies on hard cardiovascular endpoints, ABS appears as a promising tool in primary prevention.

Business model design: an evaluation of paper-based and computer-aided canvases

In recent years, Business Model Canvas design has evolved from being a paper-based activity to one that involves the use of dedicated computer-aided business model design tools. We propose a set of guidelines to help design more coherent business models. When combined with functionalities offered by CAD tools, they show great potential to improve business model design as an ongoing activity. However, in order to create complex solutions, it is necessary to compare basic business model design tasks, using a CAD system over its paper-based counterpart. To this end, we carried out an experiment to measure user perceptions of both solutions. Performance was evaluated by applying our guidelines to both solutions and then carrying out a comparison of business model designs. Although CAD did not outperform paper-based design, the results are very encouraging for the future of computer-aided business model design.

Coronary vasomotor responses to isometric handgrip exercise are primarily mediated by nitric oxide: a noninvasive MRI test of coronary endothelial function.

Endothelial cell release of nitric oxide (NO) is a defining characteristic of nondiseased arteries, and abnormal endothelial NO release is both a marker of early atherosclerosis and a predictor of its progression and future events. Healthy coronaries respond to endothelial-dependent stressors with vasodilatation and increased coronary blood flow (CBF), but those with endothelial dysfunction respond with paradoxical vasoconstriction and reduced CBF. Recently, coronary MRI and isometric handgrip exercise (IHE) were reported to noninvasively quantify coronary endothelial function (CEF). However, it is not known whether the coronary response to IHE is actually mediated by NO and/or whether it is reproducible over weeks. To determine the contribution of NO, we studied the coronary response to IHE before and during infusion of N(G)-monomethyl-l-arginine (l-NMMA, 0.3 mg·kg(-1)·min(-1)), a NO-synthase inhibitor, in healthy volunteers. For reproducibility, we performed two MRI-IHE studies ∼8 wk apart in healthy subjects and patients with coronary artery disease (CAD). Changes from rest to IHE in coronary cross-sectional area (%CSA) and diastolic CBF (%CBF) were quantified. l-NMMA completely blocked normal coronary vasodilation during IHE [%CSA, 12.9 ± 2.5 (mean ± SE, placebo) vs. -0.3 ± 1.6% (l-NMMA); P < 0.001] and significantly blunted the increase in flow [%CBF, 47.7 ± 6.4 (placebo) vs. 10.6 ± 4.6% (l-NMMA); P < 0.001]. MRI-IHE measures obtained weeks apart strongly correlated for CSA (P < 0.0001) and CBF (P < 0.01). In conclusion, the normal human coronary vasoactive response to IHE is primarily mediated by NO. This noninvasive, reproducible MRI-IHE exam of NO-mediated CEF promises to be useful for studying CAD pathogenesis in low-risk populations and for evaluating translational strategies designed to alter CAD in patients.

Sudden cardiac death among general population and sport related population in forensic experience.

PURPOSE: The goal of the study was to assess the causes and analyze the cases of sudden cardiac death (SCD) victims referred to the department of forensic medicine in Lausanne, with a particular focus on sports-related fatalities including also leisure sporting activities. To date, no such published assessment has been done nor for Switzerland nor for the central Europe. METHODS: This is a retrospective study based on autopsy records of SCD victims, from 10 to 50 years of age, performed at the University Centre of Legal Medicine in Lausanne from 1995 to 2010. The study population was divided into two groups: sport-related (SR) and not sport-related (NSR) SCDs. RESULTS: During the study period, 188 cases of SCD were recorded: 166 (88%) were NSR and 22 (12%) SR. The mean age of the 188 victims was 37.3 ± 10.1 years, with the majority of the cases being male (79%). A cause of death was established in 84%, and the pathology responsible for death varied according to the age of the victims. In the NSR group, the mean age was 38.2 ± 9.2 years and there was 82% of male. Coronary artery disease (CAD) was the main diagnosis in the victims aged 30-50 years. The majority of morphologically normal hearts were observed in the 15-29 year age range. There was no case in the 10-14 year age range. In the SR group, 91% of victims died during leisure sporting activities. In this group the mean age was 30.5 ± 13.5 years, with the majority being male (82%). The main cause of death was CAD, with 6 cases (27%) and a mean age of 40.8 ± 5.5 years. The youngest victim with CAD was 33 years old. A morphologically normal heart was observed in 5 cases (23%), with a mean age of 24.4 ± 14.9 years. The most frequently implicated sporting activities were hiking (26%) and swimming (17%). CONCLUSION: In this study, CAD was the most common cause of death in both groups. Although this pathology most often affects adults over 35 years of age, there were also some victims under 35 years of age in both groups. SCDs during sport are mostly related to leisure sporting activities, for which preventive measures are not yet usually established. This study highlights also the need to inform both athletes and non athletes of the cardiovascular risks during sport activities and the role of a forensic autopsy and registries involving forensic pathologists for SR SCD.

2015 Update on Acute Adverse Reactions to Gadolinium based Contrast Agents in Cardiovascular MR. Large Multi-National and Multi-Ethnical Population Experience With 37788 Patients From the EuroCMR Registry.

OBJECTIVES: Specifically we aim to demonstrate that the results of our earlier safety data hold true in this much larger multi-national and multi-ethnical population. BACKGROUND: We sought to re-evaluate the frequency, manifestations, and severity of acute adverse reactions associated with administration of several gadolinium- based contrast agents during routine CMR on a European level. METHODS: Multi-centre, multi-national, and multi-ethnical registry with consecutive enrolment of patients in 57 European centres. RESULTS: During the current observation 37,788 doses of Gadolinium based contrast agent were administered to 37,788 patients. The mean dose was 24.7 ml (range 5-80 ml), which is equivalent to 0.123 mmol/kg (range 0.01 - 0.3 mmol/kg). Forty-five acute adverse reactions due to contrast administration occurred (0.12%). Most reactions were classified as mild (43 of 45) according to the American College of Radiology definition. The most frequent complaints following contrast administration were rashes and hives (15 of 45), followed by nausea (10 of 45) and flushes (10 of 45). The event rate ranged from 0.05% (linear non-ionic agent gadodiamide) to 0.42% (linear ionic agent gadobenate dimeglumine). Interestingly, we also found different event rates between the three main indications for CMR ranging from 0.05% (risk stratification in suspected CAD) to 0.22% (viability in known CAD). CONCLUSIONS: The current data indicate that the results of the earlier safety data hold true in this much larger multi-national and multi-ethnical population. Thus, the "off-label" use of Gadolinium based contrast in cardiovascular MR should be regarded as safe concerning the frequency, manifestation and severity of acute events.

Tabagisme et système digestif: une relation complexe. Partie 2: Microbiote intestinal et tabagisme [Smoking and digestive tract: a complex relationship. Part 2: Intestinal microblota and cigarette smoking].

Le système digestif est colonisé dès la naissance par une population bactérienne, le microbiote, qui influence le développement du système immunitaire. Des modifications dans sa composition sont associées à des pathologies comme l'obésité et les maladies inflammatoires chroniques de l'intestin. Outre les antibiotiques, des facteurs environnementaux comme le tabagisme semblent aussi avoir une influence sur la composition de la flore intestinale, pouvant en partie expliquer la prise de poids à l'arrêt du tabac avec une modification de la composition du microbiote proche de celle observée chez des personnes obèses (profil microbiotique montrant des capacités accrues d'extraction calorique des aliments ingérés). Ces découvertes permettent d'imaginer de nouvelles approches diagnostiques et thérapeutiques via la régulation de ce microbiome. The digestive tract is colonized from birth by a bacterial population called the microbiota which influences the development of the immune system. Modifications in its composition are associated with problems such as obesity or inflammatory bowel diseases. Antibiotics are known to influence the intestinal microbiota but other environmental factors such as cigarette smoking also seem to have an impact on its composition. This influence might partly explain weight gain which is observed after smoking cessation. Indeed there is a modification of the gut microbiota which becomes similar to that of obese people with a microbiotical profile which is more efficient to extract calories from ingested food. These new findings open new fields of diagnostic and therapeutic approaches through the regulation of the microbiota.

On the use of an appropriate TdT-mediated dUTP-biotin nick end labeling assay to identify apoptotic cells.

Apoptosis is an essential cellular mechanism involved in many processes such as embryogenesis, metamorphosis, and tissue homeostasis. DNA fragmentation is one of the key markers of this form of cell death. DNA fragmentation is executed by endogenous endonucleases such as caspase-activated DNase (CAD) in caspase-dependent apoptosis. The TUNEL (TdT-mediated dUTP-biotin nick end labeling) technique is the most widely used method to identify apoptotic cells in a tissue or culture and to assess drug toxicity. It is based on the detection of 3'-OH termini that are labeled with dUTP by the terminal deoxynucleotidyl transferase. Although the test is very reliable and sensitive in caspase-dependent apoptosis, it is completely useless when cell death is mediated by pathways involving DNA degradation that generates 3'-P ends as in the LEI/L-DNase II pathway. Here, we propose a modification in the TUNEL protocol consisting of a dephosphorylation step prior to the TUNEL labeling. This allows the detection of both types of DNA breaks induced during apoptosis caspase-dependent and independent pathways, avoiding underestimating the cell death induced by the treatment of interest.

Thoracic fat volume is independently associated with coronary vasomotion.

PURPOSE: Thoracic fat has been associated with an increased risk of coronary artery disease (CAD). As endothelium-dependent vasoreactivity is a surrogate of cardiovascular events and is impaired early in atherosclerosis, we aimed at assessing the possible relationship between thoracic fat volume (TFV) and endothelium-dependent coronary vasomotion. METHODS: Fifty healthy volunteers without known CAD or major cardiovascular risk factors (CRFs) prospectively underwent a (82)Rb cardiac PET/CT to quantify myocardial blood flow (MBF) at rest, and MBF response to cold pressor testing (CPT-MBF) and adenosine (i.e., stress-MBF). TFV was measured by a 2D volumetric CT method and common laboratory blood tests (glucose and insulin levels, HOMA-IR, cholesterol, triglyceride, hsCRP) were performed. Relationships between CPT-MBF, TFV and other CRFs were assessed using non-parametric Spearman rank correlation testing and multivariate linear regression analysis. RESULTS: All of the 50 participants (58 ± 10y) had normal stress-MBF (2.7 ± 0.6 mL/min/g; 95 % CI: 2.6-2.9) and myocardial flow reserve (2.8 ± 0.8; 95 % CI: 2.6-3.0) excluding underlying CAD. Univariate analysis revealed a significant inverse relation between absolute CPT-MBF and sex (ρ = -0.47, p = 0.0006), triglyceride (ρ = -0.32, p = 0.024) and insulin levels (ρ = -0.43, p = 0.0024), HOMA-IR (ρ = -0.39, p = 0.007), BMI (ρ = -0.51, p = 0.0002) and TFV (ρ = -0.52, p = 0.0001). MBF response to adenosine was also correlated with TFV (ρ = -0.32, p = 0.026). On multivariate analysis, TFV emerged as the only significant predictor of MBF response to CPT (p = 0.014). CONCLUSIONS: TFV is significantly correlated with endothelium-dependent and -independent coronary vasomotion. High TF burden might negatively influence MBF response to CPT and to adenosine stress, even in persons without CAD, suggesting a link between thoracic fat and future cardiovascular events.

Combining T2-preparation with spectral and spatial selectivity for improved coronary MRA

Cardiovascular disease is the leading cause of death worldwide. Within this subset, coronary artery disease (CAD) is the most prevalent. Magnetic resonance angiography (MRA) is an emerging technique that provides a safe, non-invasive way of assessing CAD progression. To generate contrast between tissues, MR images are weighted according to the magnetic properties of those tissues. In cardiac MRI, T2 contrast, which is governed by the rate of transverse signal loss, is often created through the use of a T2-Preparation module. T2-Preparation, or T2-Prep, is a magnetization preparation scheme used to improve blood/myocardium contrast in cardiac MRI. T2-Prep methods generally use a non-selective +90°, 180°, 180°, -90° train of radiofrequency (RF) pulses (or variant thereof), to tip magnetization into the transverse plane, allow it to evolve, and then to restore it to the longitudinal plane. A key feature in this process is the combination of a +90° and -90° RF pulse. By changing either one of these, a mismatch occurs between signal excitation and restoration. This feature can be exploited to provide additional spectral or spatial selectivity. In this work, both of these possibilities are explored. The first - spectral selectivity - has been examined as a method of improving fat saturation in coronary MRA. The second - spatial selectivity - has been examined as a means of reducing imaging time by decreasing the field of view, and as a method of reducing artefacts originating from the tissues surrounding the heart. Two additional applications, parallel imaging and self-navigation, are also presented. This thesis is thus composed of four sections. The first, "A Fat Signal Suppression for Coronary MRA at 3T using a Water-Selective Adiabatic T2-Preparation Technique", was originally published in the journal Magnetic Resonance in Medicine (MRM) with co-authors Ruud B. van Heeswijk and Matthias Stuber. The second, "Combined T2-Preparation and 2D Pencil Beam Inner Volume Selection", again with co-authors Ruud van Heeswijk and Matthias Stuber, was also published in the journal MRM. The third, "A cylindrical, inner volume selecting 2D-T2-Prep improves GRAPPA-accelerated image quality in MRA of the right coronary artery", written with co-authors Jerome Yerly and Matthias Stuber, has been submitted to the "Journal of Cardiovascular Magnetic Resonance", and the fourth, "Combined respiratory self-navigation and 'pencil-beam' 2D-T2 -Prep for free-breathing, whole-heart coronary MRA", with co¬authors Jerome Chaptinel, Giulia Ginami, Gabriele Bonanno, Simone Coppo, Ruud van Heeswijk, Davide Piccini, and Matthias Stuber, is undergoing internal review prior to submission to the journal MRM. -- Les maladies cardiovasculaires sont la cause principale de décès dans le monde : parmi celles-ci, les maladies coronariennes sont les plus répandues. L'angiographie par résonance magnétique (ARM) est une technique émergente qui fournit une manière sûre, non invasive d'évaluer la progression de la coronaropathie. Pour obtenir un contraste entre les tissus, les images d'IRM sont pondérées en fonction des propriétés magnétiques de ces tissus. En IRM cardiaque, le contraste en T2, qui est lié à la décroissance du signal transversal, est souvent créé grâce à l'utilisàtion d'un module de préparation T2. La préparation T2, ou T2-Prep, est un système de préparation de l'aimantation qui est utilisé pour améliorer le contraste entre le sang et le myocarde lors d'une IRM cardiaque. Les méthodes de T2-Prep utilisent généralement une série non-sélective d'impulsions de radiofréquence (RF), typiquement [+ 90°, 180°, 180°, -90°] ou une variante, qui bascule l'aimantation dans le plan transversal, lui permet d'évoluer, puis la restaure dans le plan longitudinal. Un élément clé de ce processus est la combinaison des impulsions RF de +90° et -90°. En changeant l'une ou l'autre des impulsions, un décalage se produit entre l'excitation du signal et de la restauration. Cette fonction peut être exploitée pour fournir une sélectivité spectrale ou spatiale. Dans cette thèse, les deux possibilités sont explorées. La première - la sélectivité spectrale - a été examinée comme une méthode d'améliorer la saturation de la graisse dans l'IRM coronarienne. La deuxième - la sélectivité spatiale - a été étudiée comme un moyen de réduire le temps d'imagerie en diminuant le champ de vue, et comme une méthode de réduction des artefacts provenant des tissus entourant le coeur. Deux applications supplémentaires, l'imagerie parallèle et la self-navigation, sont également présentées. Cette thèse est ainsi composée de quatre sections. La première, "A Fat Signal Suppression for Coronary MRA at 3T using a Water-Selective Adiabatic T2-Preparation Technique", a été publiée dans la revue médicale Magnetic Resonance .in Medicine (MRM) avec les co-auteurs Ruud B. van Heeswijk et Matthias Stuber. La deuxième, Combined T2-Preparation and 2D Pencil Beam Inner Volume Selection", encore une fois avec les co-auteurs Ruud van Heeswijk et Matthias Stuber, a également été publiée dans le journal MRM. La troisième, "A cylindrical, inner volume selecting 2D-T2-Prep improves GRAPPA- accelerated image quality in MRA of the right coronary artery", écrite avec les co-auteurs Jérôme Yerly et Matthias Stuber, a été présentée au "Journal of Cardiovascular Magnetic Resonance", et la quatrième, "Combined respiratory self-navigation and 'pencil-beam' 2D-T2 -Prep for free-breathing, whole-heart coronary MRA", avec les co-auteurs Jérôme Chaptinel, Giulia Ginami, Gabriele Bonanno , Simone Coppo, Ruud van Heeswijk, Davide Piccini, et Matthias Stuber, subit un examen interne avant la soumission à la revue MRM.