Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD

The regeneration potential after human and autologous stem cell transplantation in a rat sciatic nerve injury model can be monitored by MRI

Traumatic nerve injuries are a major clinical challenge. Tissue engineering using a combination of nerve conduits and cell-based therapies represents a promising approach to nerve repair. The aim of this study was to examine the regeneration potential of human adipose-derived stem cells (hASCs) after transplantation in a nonautogenous setting and to compare them with autogenous rat ASCs (rASCs) for early peripheral nerve regeneration. Furthermore, the use of MRI to assess the continuous process of nerve regeneration was elaborated. The sciatic nerve injury model in female Sprague-Dawley rats was applied, and a 10-mm gap created by using a fibrin conduit seeded with the following cell types: rASCs, Schwann cell (SC)-like cells from rASC, rat SCs (rSCs), hASCs from the superficial and deep abdominal layer, as well as human stromal vascular fraction (1 × 10(6) cells). As a negative control group, culture medium only was used. After 2 weeks, nerve regeneration was assessed by immunocytochemistry. Furthermore, MRI was performed after 2 and 4 weeks to monitor nerve regeneration. Autogenous ASCs and SC-like cells led to accelerated peripheral nerve regeneration, whereas the human stem cell groups displayed inferior results. Nevertheless, positive trends could be observed for hASCs from the deep abdominal layer. By using a clinical 3T MRI scanner, we were able to visualize the graft as a small black outline and small hyperintensity indicating the regenerating axon front. Furthermore, a strong correlation was found between the length of the regenerating axon front measured by MRI and the length measured by immunocytochemistry (r = 0.74, p = 0.09). We successfully transplanted and compared human and autologous stem cells for peripheral nerve regeneration in a rat sciatic nerve injury model. Furthermore, we were able to implement the clinical 3T MRI scanner to monitor the efficacy of cellular therapy over time

Denervation leads to volume regression in breast cancer

The nervous system plays a key role in controlling the dynamic functions of multicellular complex organisms. Although peripheral nerves are supposed to play a pivotal role in tumor growth and dissemination, little experimental evidence exists to date. We assessed the effect of denervation on breast cancer growth by magnetic resonance imaging (MRI) in rats. Human breast cancer cells were implanted into adipofascial flaps with intact or surgically excised supplying nerve. Tumor volumes were measured 2 and 8 weeks after implantation by in vivo MRI. Results were validated by histology. Postoperative tumor volumes at 2 and 8 weeks were reduced by 76% (95% CI: 22-93%) in the denervated groups. Tumor area as determined histologically was reduced by 70% (95% CI: 60-78%). Thus, peripheral denervation may be an effective surgical approach for the palliative treatment of locally progressing or uncontrollable breast cancer

Peripheral Nerve Repair: Multimodal Comparison of the Long-Term Regenerative Potential of Adipose Tissue-Derived Cells in a Biodegradable Conduit

Tissue engineering is a popular topic in peripheral nerve repair. Combining a nerve conduit with supporting adipose-derived cells could offer an opportunity to prevent time-consuming Schwann cell culture or the use of an autograft with its donor site morbidity and eventually improve clinical outcome. The aim of this study was to provide a broad overview over promising transplantable cells under equal experimental conditions over a long-term period. A 10-mm gap in the sciatic nerve of female Sprague-Dawley rats (7 groups of 7 animals, 8 weeks old) was bridged through a biodegradable fibrin conduit filled with rat adipose-derived stem cells (rASCs), differentiated rASCs (drASCs), human (h)ASCs from the superficial and deep abdominal layer, human stromal vascular fraction (SVF), or rat Schwann cells, respectively. As a control, we resutured a nerve segment as an autograft. Long-term evaluation was carried out after 12 weeks comprising walking track, morphometric, and MRI analyses. The sciatic functional index was calculated. Cross sections of the nerve, proximal, distal, and in between the two sutures, were analyzed for re-/myelination and axon count. Gastrocnemius muscle weights were compared. MRI proved biodegradation of the conduit. Differentiated rat ASCs performed significantly better than undifferentiated rASCs with less muscle atrophy and superior functional results. Superficial hASCs supported regeneration better than deep hASCs, in line with published in vitro data. The best regeneration potential was achieved by the drASC group when compared with other adipose tissue-derived cells. Considering the ease of procedure from harvesting to transplanting, we conclude that comparison of promising cells for nerve regeneration revealed that particularly differentiated ASCs could be a clinically translatable route toward new methods to enhance peripheral nerve repair

Erratum : Genetic loci associated with heart rate variability and their effects on cardiac disease risk

This corrects the article DOI: 10.1038/ncomms15805

Genetic loci associated with heart rate variability and their effects on cardiac disease risk (vol 8, pg 15805, 2017)

status: publishe

Genetic loci associated with heart rate variability and their effects on cardiac disease risk

Reduced cardiac vagal control reflected in low heart rate variability (HRV) is associated with greater risks for cardiac morbidity and mortality. In two-stage meta-analyses of genome-wide association studies for three HRV traits in up to 53,174 individuals of European ancestry, we detect 17 genome-wide significant SNPs in eight loci. HRV SNPs tag non-synonymous SNPs (in NDUFA11 and KIAA1755), expression quantitative trait loci (eQTLs) (influencing GNG11, RGS6 and NEO1), or are located in genes preferentially expressed in the sinoatrial node (GNG11, RGS6 and HCN4). Genetic risk scores account for 0.9 to 2.6% of the HRV variance. Significant genetic correlation is found for HRV with heart rate (-0.74<r g <-0.55) and blood pressure (-0.35<r g <-0.20). These findings provide clinically relevant biological insight into heritable variation in vagal heart rhythm regulation, with a key role for genetic variants (GNG11, RGS6) that influence G-protein heterotrimer action in GIRK-channel induced pacemaker membrane hyperpolarization