Fibromuscular dysplasia (FMD) is a nonatherosclerotic vascular disease leading to stenosis, dissection and aneurysm affecting mainly the renal and cerebrovascular arteries. FMD is often an ...underdiagnosed cause of hypertension and stroke, has higher prevalence in females (~80%) but its pathophysiology is unclear. We analyzed ~26K common variants (MAF>0.05) generated by exome-chip arrays in 249 FMD patients and 689 controls. We replicated 13 loci (P<10-4) in 402 cases and 2,537 controls and confirmed an association between FMD and a variant in the phosphatase and actin regulator 1 gene (PHACTR1). Three additional case control cohorts including 512 cases and 669 replicated this result and overall reached the genomic level of significance (OR = 1.39, P = 7.4×10-10, 1,154 cases and 3,895 controls). The top variant, rs9349379, is intronic to PHACTR1, a risk locus for coronary artery disease, migraine, and cervical artery dissection. The analyses of geometrical parameters of carotids from ~2,500 healthy volunteers indicate higher intima media thickness (P = 1.97×10-4) and wall to lumen ratio (P = 0.002) in rs9349379-A carriers, suggesting indices of carotid hypertrophy previously described in carotids of FMD patients. Immunohistochemistry detected PHACTR1 in endothelium and smooth muscle cells of FMD and normal human carotids. The expression of PHACTR1 by genotypes in primary human fibroblasts showed higher expression in rs9349379-A carriers (N = 86, P = 0.003). Phactr1 knockdown in zebrafish resulted in dilated vessels indicating subtle impaired vascular development. We report the first susceptibility locus for FMD and provide evidence for a complex genetic pattern of inheritance and indices of shared pathophysiology between FMD and other cardiovascular and neurovascular diseases.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Organ-specific functions of tissue-resident macrophages in the steady-state heart are unknown. Here, we show that cardiac macrophages facilitate electrical conduction through the distal ...atrioventricular node, where conducting cells densely intersperse with elongated macrophages expressing connexin 43. When coupled to spontaneously beating cardiomyocytes via connexin-43-containing gap junctions, cardiac macrophages have a negative resting membrane potential and depolarize in synchrony with cardiomyocytes. Conversely, macrophages render the resting membrane potential of cardiomyocytes more positive and, according to computational modeling, accelerate their repolarization. Photostimulation of channelrhodopsin-2-expressing macrophages improves atrioventricular conduction, whereas conditional deletion of connexin 43 in macrophages and congenital lack of macrophages delay atrioventricular conduction. In the Cd11bDTR mouse, macrophage ablation induces progressive atrioventricular block. These observations implicate macrophages in normal and aberrant cardiac conduction.
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•Tissue-resident macrophages abound in the mouse and human AV nodes•Connexin 43 connects macrophages with cardiomyocytes•Macrophages modulate the electrical activity of cardiomyocytes•Macrophages assist normal AV nodal conduction
Heart-resident macrophages directly modulate the electrical properties of cardiomyocytes.
In this paper, we present a brief history of silicon photonics from the early research papers in the late 1980s and early 1990s, to the potentially revolutionary technology that exists today. Given ...that other papers in this special issue give detailed reviews of key aspects of the technology, this paper will concentrate on the key technological milestones that were crucial in demonstrating the capability of silicon photonics as both a successful technical platform, as well as indicating the potential for commercial success. The paper encompasses discussion of the key technology areas of passive devices, modulators, detectors, light sources, and system integration. In so doing, the paper will also serve as an introduction to the other papers within this special issue.
RATIONALE:More than 25 million individuals have heart failure worldwide, with ≈4000 patients currently awaiting heart transplantation in the United States. Donor organ shortage and allograft ...rejection remain major limitations with only ≈2500 hearts transplanted each year. As a theoretical alternative to allotransplantation, patient-derived bioartificial myocardium could provide functional support and ultimately impact the treatment of heart failure.
OBJECTIVE:The objective of this study is to translate previous work to human scale and clinically relevant cells for the bioengineering of functional myocardial tissue based on the combination of human cardiac matrix and human induced pluripotent stem cell–derived cardiomyocytes.
METHODS AND RESULTS:To provide a clinically relevant tissue scaffold, we translated perfusion-decellularization to human scale and obtained biocompatible human acellular cardiac scaffolds with preserved extracellular matrix composition, architecture, and perfusable coronary vasculature. We then repopulated this native human cardiac matrix with cardiomyocytes derived from nontransgenic human induced pluripotent stem cells and generated tissues of increasing 3-dimensional complexity. We maintained such cardiac tissue constructs in culture for 120 days to demonstrate definitive sarcomeric structure, cell and matrix deformation, contractile force, and electrical conduction. To show that functional myocardial tissue of human scale can be built on this platform, we then partially recellularized human whole-heart scaffolds with human induced pluripotent stem cell–derived cardiomyocytes. Under biomimetic culture, the seeded constructs developed force-generating human myocardial tissue and showed electrical conductivity, left ventricular pressure development, and metabolic function.
CONCLUSIONS:Native cardiac extracellular matrix scaffolds maintain matrix components and structure to support the seeding and engraftment of human induced pluripotent stem cell–derived cardiomyocytes and enable the bioengineering of functional human myocardial-like tissue of multiple complexities.
In July 2007 an intense summer storm resulted in significant activation of the sediment system in the Thinhope Burn, UK. Catchment- and reach-scale morphodynamic modelling is used to investigate the ...geomorphic work undertaken by Thinhope Burn; comparing this with the more subdued responses shown by its neighbours. Total sediment efflux for Thinhope Burn over the 10 yr period 1998-2007 was 18, 801 m3 four times that of the larger Knar Burn catchment and fifty-four times that of the smaller Glendue Burn catchment. For a discharge of 60 m3s-1, equivalent to the July 2007 Thinhope flood, sediment efflux was 575 m3, 76 m3, and 67 m3 for Thinhope, Glendue and Knar Burns respectively. It is clear that Thinhope Burn undertook significantly more geomorphic work compared to its neighbours. Analysis of the population of shear stress for reach-scale simulations on Thinhope Burn highlighted that the final three simulations (flood peaks of 60, 90, 236 m3s-1) all produced very similar distributions, with no marked increase in the modal shear stress (∼250 Nm-2). This possibly suggests that flows >60 m3s-1 are not able to exert significantly greater energy on the channel boundary, indicating that flows in the region of 60 m3s-1 attain ‘peak’ geomorphic work. It is argued that factors such as strength resistance of the key sediment sources (e.g. paleoberms perched on terraces), structural resistance to flood waves imposed by valley form resistance, location sensitivity and transmission resistance, may all offer explanations for increased geomorphic effectiveness compared with its neighbours. With the expectation of greater rainfall totals in the winter and more extreme summer events in upland areas of the UK, it is clear that attention needs to focus upon the implications of this upon the morphological stability of these areas not least to aid future sustainable flood risk management.
Ibrutinib is a Bruton tyrosine kinase inhibitor with remarkable efficacy against B-cell cancers. Ibrutinib also increases the risk of atrial fibrillation (AF), which remains poorly understood.
We ...performed electrophysiology studies on mice treated with ibrutinib to assess inducibility of AF. Chemoproteomic analysis of cardiac lysates identified candidate ibrutinib targets, which were further evaluated in genetic mouse models and additional pharmacological experiments. The pharmacovigilance database, VigiBase, was queried to determine whether drug inhibition of an identified candidate kinase was associated with increased reporting of AF.
We demonstrate that treatment of mice with ibrutinib for 4 weeks results in inducible AF, left atrial enlargement, myocardial fibrosis, and inflammation. This effect was reproduced in mice lacking Bruton tyrosine kinase, but not in mice treated with 4 weeks of acalabrutinib, a more specific Bruton tyrosine kinase inhibitor, demonstrating that AF is an off-target side effect. Chemoproteomic profiling identified a short list of candidate kinases that was narrowed by additional experimentation leaving CSK (C-terminal Src kinase) as the strongest candidate for ibrutinib-induced AF. Cardiac-specific Csk knockout in mice led to increased AF, left atrial enlargement, fibrosis, and inflammation, phenocopying ibrutinib treatment. Disproportionality analyses in VigiBase confirmed increased reporting of AF associated with kinase inhibitors blocking Csk versus non-Csk inhibitors, with a reporting odds ratio of 8.0 (95% CI, 7.3-8.7;
<0.0001).
These data identify Csk inhibition as the mechanism through which ibrutinib leads to AF. Registration: URL: https://ww.clinicaltrials.gov; Unique identifier: NCT03530215.
RATIONALE:Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) are a readily available, robustly reproducible, and physiologically appropriate human cell source for cardiac disease modeling, ...drug discovery, and toxicity screenings in vitro. However, unlike adult myocardial cells in vivo, hPSC-CMs cultured in vitro maintain an immature metabolic phenotype, where majority of ATP is produced through aerobic glycolysis instead of oxidative phosphorylation in the mitochondria. Little is known about the underlying signaling pathways controlling hPSC-CMs’ metabolic and functional maturation.
OBJECTIVE:To define the molecular pathways controlling cardiomyocytes’ metabolic pathway selections and improve cardiomyocyte metabolic and functional maturation.
METHODS AND RESULTS:We cultured hPSC-CMs in different media compositions including glucose-containing media, glucose-containing media supplemented with fatty acids, and glucose-free media with fatty acids as the primary carbon source. We found that cardiomyocytes cultured in the presence of glucose used primarily aerobic glycolysis and aberrantly upregulated HIF1α (hypoxia-inducible factor 1α) and its downstream target lactate dehydrogenase A. Conversely, glucose deprivation promoted oxidative phosphorylation and repressed HIF1α. Small molecule inhibition of HIF1α or lactate dehydrogenase A resulted in a switch from aerobic glycolysis to oxidative phosphorylation. Likewise, siRNA inhibition of HIF1α stimulated oxidative phosphorylation while inhibiting aerobic glycolysis. This metabolic shift was accompanied by an increase in mitochondrial content and cellular ATP levels. Furthermore, functional gene expressions, sarcomere length, and contractility were improved by HIF1α/lactate dehydrogenase A inhibition.
CONCLUSIONS:We show that under standard culture conditions, the HIF1α-lactate dehydrogenase A axis is aberrantly upregulated in hPSC-CMs, preventing their metabolic maturation. Chemical or siRNA inhibition of this pathway results in an appropriate metabolic shift from aerobic glycolysis to oxidative phosphorylation. This in turn improves metabolic and functional maturation of hPSC-CMs. These findings provide key insight into molecular control of hPSC-CMs’ metabolism and may be used to generate more physiologically mature cardiomyocytes for drug screening, disease modeling, and therapeutic purposes.
Quantitative assessments of the impacts of extreme floods on channel morphology are rare. Real Time Kinematic (RTK) GPS surveys of a 500-m reach of the Thinhope Burn, an upland gravel-bed stream in ...the UK, taken in 2003 and 2004 permitted an assessment of geomorphic work whilst the channel was at steady-state. A large flood that occurred on 17 July 2007 resulted in a catastrophic impact to the Thinhope Burn valley floor. The reach was re-surveyed after the event in 2007, and again in 2008 and in 2011. Digital elevation models were produced from the survey data, which allowed the spatial patterns of erosion and deposition and volumetric changes between surveys to be established. A total of 5202
m
3 of deposition and 2125
m
3 of erosion was recorded in the reach following the flood event. Field walking of the catchment and comparison of aerial photographs for 2003 and 2007 suggested that most of the material mobilised had originated from existing sediment held in terraces and paleoberms on the valley floor. Although slope failures were evident, including peat slides in the headwaters, delivery of sediment from coupling zones to the channel was thought to play a secondary role in the geomorphic response shown by the channel. Similarly, large volumes of erosion and deposition were found after resurveys in 2008 and 2011, suggesting that the system was still in its relaxation phase. The results obtained in this investigation coupled with historical information on the flood history of Thinhope Burn dating back to 1766 suggested that rare large floods are the geomorphically effective flows in the catchment.
Induced pluripotent stem cells (iPSCs) offer an unprece-dented opportunity to study human physiology and disease at the cellular level. They also have the potential to be leveraged in the practice of ...precision medicine, for example, personalized drug testing. This statement comprehensively describes the provenance of iPSC lines, their use for cardiovascular disease modeling, their use for precision medicine, and strategies through which to promote their wider use for biomedical applications. Human iPSCs exhibit properties that render them uniquely qualified as model systems for studying human diseases: they are of human origin, which means they carry human genomes; they are pluripotent, which means that in principle, they can be differentiated into any of the human body's somatic cell types; and they are stem cells, which means they can be expanded from a single cell into millions or even billions of cell progeny. iPSCs offer the opportunity to study cells that are genetically matched to individual patients, and genome-editing tools allow introduction or correction of genetic variants. Initial progress has been made in using iPSCs to better understand cardiomyopathies, rhythm disorders, valvular and vascular disorders, and metabolic risk factors for ischemic heart disease. This promising work is still in its infancy. Similarly, iPSCs are only just starting to be used to identify the optimal medications to be used in patients from whom the cells were derived. This statement is intended to (1) summarize the state of the science with respect to the use of iPSCs for modeling of cardiovascular traits and disorders and for therapeutic screening; (2) identify opportunities and challenges in the use of iPSCs for disease modeling and precision medicine; and (3) outline strategies that will facilitate the use of iPSCs for biomedical applications. This statement is not intended to address the use of stem cells as regenerative therapy, such as transplantation into the body to treat ischemic heart disease or heart failure.
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