Large meta-analysis of genome-wide association studies identifies five loci for lean body mass

Lean body mass, consisting mostly of skeletal muscle, is important for healthy aging. We performed a genome-wide association study for whole body (20 cohorts of European ancestry with n = 38,292) and appendicular (arms and legs) lean body mass (n = 28,330) measured using dual energy X-ray absorptiometry or bioelectrical impedance analysis, adjusted for sex, age, height, and fat mass. Twenty-one single-nucleotide polymorphisms were significantly associated with lean body mass either genome wide (p < 5 x 10(-8)) or suggestively genome wide (p < 2.3 x 10(-6)). Replication in 63,475 (47,227 of European ancestry) individuals from 33 cohorts for whole body lean body mass and in 45,090 (42,360 of European ancestry) subjects from 25 cohorts for appendicular lean body mass was successful for five single-nucleotide polymorphisms in/ near HSD17B11, VCAN, ADAMTSL3, IRS1, and FTO for total lean body mass and for three single-nucleotide polymorphisms in/ near VCAN, ADAMTSL3, and IRS1 for appendicular lean body mass. Our findings provide new insight into the genetics of lean body mass

Influence of anaphylatoxin C3a and in-vitro Cell-Injury-System on tenocytes referring to healing perspectives of tendon ruptures

Einleitung: Humane Sehnen müssen hohen mechanischen Beanspruchungen standhalten und weisen einen hyporegeneratorischen Stoffwechsel auf. Die Regulation von Komplementfaktoren und Zytokinen durch Anaphylatoxine ist im Sehnengewebe bislang unklar, könnte aber auf die Sehnenheilung und Narbenbildung Einfluss nehmen. Ziel dieser Arbeit ist es gewesen, den Einfluss der Aktivierung des Komplementsystems durch die Effekte des Anaphylatoxins C3a und durch eine direkte Verletzung von Tendozyten im in-vitro Sehnenverletzungsmodell (IVM) auf Tendozyten zu untersuchen. Methodik: Für die Analysen wurden primäre humane Tendozyten mit dem Anaphylatoxin C3a und dem in dieser Arbeit entwickelten IVM behandelt. Es wurde eine RTD-PCR-Analyse der Genexpressionsveränderungen der Komplementrezeptoren C3aR (CD88), C5aR, der Matrix-Metalloprotease (MMP)-1, der Komplement regulatorischen Proteine (CRP) CD46, CD55 sowie der proinflammatorischen Zytokine TNFα, IL-1β und IL-6 in mit C3a und IVM stimulierten Tendozyten im Vergleich zu unbehandelten Kontrollen durchgeführt, n=4 für C3a, n=5 für IVM. Immunhistologische Färbungen ermöglichten eine semiquantitative Auswertung der Expression von C5aR, CD55, TNFα und MMP-1. Statistik: students t-test, Signifikanzniveau p<0,05. Ergebnisse: Für den C3aR und C5aR konnte nach C3a-Stimulation eine Genexpressionsinduktion gezeigt werden. Die CRP CD46 und CD55 sowie die MMP-1 waren in ihrer Genexpression supprimiert. Für die proinflammatorischen Zytokine TNFα und IL-1β konnte eine Genexpressionsinduktion nachgewiesen werden. Im IVM zeigte sich für den C3aR eine Induktion, während der C5aR im IVM in seiner Expression gehemmt wurde. Die komplementinhibitorischen Proteine CD46 und CD55 zeigten im IVM eine Expressionssteigerung. Auch konnte nachgewiesen werden, dass die Genexpression der MMP-1 durch die Verletzung induziert wurde. Die Immunfluoreszenzfärbungen konnten für den C5aR eine verminderte und für CD55 eine erhöhte Proteinexpression nach Verletzung nachweisen, während nach C3a-Stimulation die Expression von C5aR und TNFα erhöht und von CD55 supprimiert war. Schlussfolgerungen: Die Induktion der Anaphylatoxinrezeptoren C3aR und C5aR durch C3a, für C3aR auch durch das IVM, spricht für eine erhöhte Sensitivität der Tendozyten gegenüber einer Komplementaktvierung. Die Suppression der beiden komplementinhibitorischen Proteine CD46 und CD55 durch C3a kann einen, die Aktivität des Komplementsystems begünstigenden Effekt ausüben. Ferner deutet die Induktion der beiden proinflammatorischen Zytokine TNFα und IL-1β eine durch C3a ausgelöste proinflammatorische Reaktion der Tendozyten an. Der Anstieg von zytoprotektivem CD46 und CD55 kann bei mechanischen Verletzungen eine Komplementaktivierung sowie die damit einhergehende chemotaktische Anlockung von immunkompetenten Zellen im Sehnengewebe vermindern. Zusammenfassend konnte in der vorliegenden Arbeit eine Regulation des Komplementsystems durch Komplementspaltprodukte sowie durch mechanische Verletzungen nachgewiesen werden. Eine Komplementdysregulation oder -aktivierung könnte als Pathomechanismus bei Sehnenerkrankungen und Narbenbildung relevant sein und muss in zukünftigen Studien weiter erforscht werden.Introduction: Human tendons have to sustain high mechanical stresses and strains and exhibit a typical hyporegenerative metabolism. The regulation of complement factors and cytokines by complement split fragments such as anaphylatoxins is completely unclear in tendons. The aim of this work was to investigate the interplay between the anaphylatoxin C3a, complement regulatory proteins and cytokines, which could be involved in tendon healing and scar formation. Furthermore, the impact of direct mechanical injuries of human tenocytes was characterized using an in-vitro Cell-Injury-System (CIS). Methods: Primary human tenocytes were either treated with recombinant C3a or applied to the developed CIS. RTD-PCR analyses were performed to identify possible changes in gene expression of the anaphylatoxin receptors C3aR, C5aR, the complement regulatory proteins (CRP) CD46, CD55, the matrix metalloprotease MMP-1, the pro-inflammatory cytokines TNFα, IL-1β, and IL-6 of C3a- and CIS-stimulated tenocytes in comparison to untreated controls. Immunohistological staining of tenocytes and paraffin sections of tendons allowed a semiquantitative evaluation of C5aR (CD88), CD55, TNFα and MMP-1. Statistic: students t-test, significance level p<0.05. Results: After stimulation with C3a, the gene expression of the C3aR and C5aR was significantly increased, whereas the expression of CD46, CD55 and MMP-1 was suppressed. For the proinflammatory cytokines TNFα and IL-1β an induction of their gene expression could be observed. In the CIS the C3aR showed an enhanced gene expression, whereas C5aR was inhibited. Interestingly, the CRP CD46 and CD55 as well as MMP-1 displayed an increased gene expression in the CIS. The immunofluorescence staining revealed for the C5aR a reduced and for the CRP CD55 an elevated protein expression after injury in CIS, whereas after C3a stimulation C5aR and TNFα were elevated and CD55 was suppressed. Conclusions: The induction of the anaphylatoxin receptors C3aR and C5aR by C3a, for C3aR also verified in the CIS, suggests an increased sensitivity of the tenocytes towards an activated complement system. Suppression of the complement inhibiting proteins CD46 and CD55 by C3a can probably enhance the complement activity. The elevated gene expression of TNFα and IL-1β could reflect a proinflammatory response of the tenocytes induced by C3a. Induced expression of cytoprotective CD46 and CD55 can possibly reduce an activation of the complement system in injured tendons. In summary, the present work shows a regulation of complement by complement split fragments and in injured cells. Dysregulated or activated complement could be a pathomechanism in tendon scar formation and diseases and needs to be further investigated

Case report: Refractory cardiac arrest supported with veno-arterial-venous extracorporeal membrane oxygenation and left-ventricular Impella CP®–Physiological insights and pitfalls of ECMELLA

Introduction: To the best of our knowledge, this is the first case report which provides insights into patient-specific hemodynamics during veno-arterio-venous-extracorporeal membrane oxygenation (VAV ECMO) combined with a left-ventricular (LV) Impella® micro-axial pump for therapy-refractory cardiac arrest due to acute myocardial infarction, complicated by acute lung injury (ALI). Patient presentation: A 54-year-old male patient presented with ST-segment elevation acute coronary syndrome complicated by out-of-hospital cardiac arrest with ventricular fibrillation upon arrival of the emergency medical service. As cardiac arrest was refractory to advanced cardiac life support, the patient was transferred to the Cardiac Arrest Center for immediate initiation of extracorporeal cardiopulmonary resuscitation (ECPR) with peripheral VA ECMO and emergency percutaneous coronary intervention using drug eluting stents in the right coronary artery. Due to LV distension and persistent asystole after coronary revascularization, an Impella® pump was inserted for LV unloading and additional hemodynamic support (i.e., “ECMELLA”). Despite successful unloading by ECMELLA, post-cardiac arrest treatment was further complicated by sudden differential hypoxemia of the upper body. This so called “Harlequin phenomenon” was explained by a new onset of ALI, necessitating escalation of VA ECMO to VAV ECMO, while maintaining Impella® support. Comprehensive monitoring as derived from the Impella® console allowed to illustrate patient-specific hemodynamics of cardiac unloading. Ultimately, the patient recovered and was discharged from the hospital 28 days after admission. 12 months after the index event the patient was enrolled in the ECPR Outpatient Care Program which revealed good recovery of neurologic functions while physical exercise capacities were impaired. Conclusion: A combined mechanical circulatory support strategy may successfully be deployed in complex cases of severe cardio-circulatory and respiratory failure as occasionally encountered in clinical practice. While appreciating potential clinical benefits, it seems of utmost importance to closely monitor the physiological effects and related complications of such a multimodal approach to reach the most favorable outcome as illustrated in this case

Novel Approach for In Vivo Detection of Vulnerable Coronary Plaques using Molecular 3-T CMR Imaging with an Albumin-Binding Probe

Objectives This study sought to investigate the potential of the noninvasive albumin-binding probe gadofosveset-enhanced cardiac magnetic resonance (GE-CMR) for detection of coronary plaques that can cause acute coronary syndromes (ACS). Background ACS are frequently caused by rupture or erosion of coronary plaques that initially do not cause hemodynamically significant stenosis and are therefore not detected by invasive x-ray coronary angiography (XCA). Methods A total of 25 patients with ACS or symptoms of stable coronary artery disease underwent GE-CMR, clinically indicated XCA, and optical coherence tomography (OCT) within 24 h. GE-CMR was performed approximately 24 h following a 1-time application of gadofosveset-trisodium. Contrast-to-noise ratio (CNR) was quantified within coronary segments in comparison with blood signal. Results A total of 207 coronary segments were analyzed on GE-CMR. Segments containing a culprit lesion in ACS patients (n = 11) showed significant higher signal enhancement (CNR) following gadofosveset-trisodium application than segments without culprit lesions (n = 196; 6.1 [3.9 to 16.5] vs. 2.1 [0.5 to 3.5]; p &lt; 0.001). GE-CMR was able to correctly identify culprit coronary lesions in 9 of 11 segments (sensitivity 82%) and correctly excluded culprit coronary lesions in 162 of 195 segments (specificity 83%). Additionally, segmented areas of thin-cap fibroatheroma (n = 22) as seen on OCT demonstrated significantly higher CNR than segments without coronary plaque or segments containing early atherosclerotic lesions (n = 185; 9.2 [3.3 to 13.7] vs. 2.1 [0.5 to 3.4]; p = 0.001). Conclusions In this study, we demonstrated for the first time the noninvasive detection of culprit coronary lesions and thin-cap fibroatheroma of the coronary arteries in vivo by using GE-CMR. This method may represent a novel approach for noninvasive cardiovascular risk prediction

Large meta-analysis of genome-wide association studies identifies five loci for lean body mass.

Lean body mass, consisting mostly of skeletal muscle, is important for healthy aging. We performed a genome-wide association study for whole body (20 cohorts of European ancestry with n = 38,292) and appendicular (arms and legs) lean body mass (n = 28,330) measured using dual energy X-ray absorptiometry or bioelectrical impedance analysis, adjusted for sex, age, height, and fat mass. Twenty-one single-nucleotide polymorphisms were significantly associated with lean body mass either genome wide (p &lt; 5 × 10-8) or suggestively genome wide (p &lt; 2.3 × 10-6). Replication in 63,475 (47,227 of European ancestry) individuals from 33 cohorts for whole body lean body mass and in 45,090 (42,360 of European ancestry) subjects from 25 cohorts for appendicular lean body mass was successful for five single-nucleotide polymorphisms in/near HSD17B11, VCAN, ADAMTSL3, IRS1, and FTO for total lean body mass and for three single-nucleotide polymorphisms in/near VCAN, ADAMTSL3, and IRS1 for appendicular lean body mass. Our findings provide new insight into the genetics of lean body mass.Lean body mass is a highly heritable trait and is associated with various health conditions. Here, Kiel and colleagues perform a meta-analysis of genome-wide association studies for whole body lean body mass and find five novel genetic loci to be significantly associated

Erratum: Large meta-analysis of genome-wide association studies identifies five loci for lean body mass.

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