Concept: Cardiovascular system
To determine whether dietary pattern assessed by a simple self-administered food frequency questionnaire is associated with major adverse cardiovascular events (MACE) in high-risk patients with stable coronary artery disease.
Here, we report the existence of meningeal lymphatic vessels in human and nonhuman primates (common marmoset monkeys) and the feasibility of noninvasively imaging and mapping them in vivo with high-resolution, clinical MRI. On T2-FLAIR and T1-weighted black-blood imaging, lymphatic vessels enhance with gadobutrol, a gadolinium-based contrast agent with high propensity to extravasate across a permeable capillary endothelial barrier, but not with gadofosveset, a blood-pool contrast agent. The topography of these vessels, running alongside dural venous sinuses, recapitulates the meningeal lymphatic system of rodents. In primates, meningeal lymphatics display a typical panel of lymphatic endothelial markers by immunohistochemistry. This discovery holds promise for better understanding the normal physiology of lymphatic drainage from the central nervous system and potential aberrations in neurological diseases.
Systemic administration of exosomes released from mesenchymal stromal cells promote functional recovery and neurovascular plasticity after stroke in rats
- Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism
- Published almost 5 years ago
Here, for the first time, we test a novel hypothesis that systemic treatment of stroke with exosomes derived from multipotent mesenchymal stromal cells (MSCs) promote neurovascular remodeling and functional recovery after stroke in rats. Adult male Wistar rats were subjected to 2 hours of middle cerebral artery occlusion (MCAo) followed by tail vein injection of 100 μg protein from MSC exosome precipitates or an equal volume of vehicle phosphate-buffered saline (PBS) (n=6/group) 24 hours later. Animals were killed at 28 days after stroke and histopathology and immunohistochemistry were employed to identify neurite remodeling, neurogenesis, and angiogenesis. Systemic administration of MSC-generated exosomes significantly improved functional recovery in stroke rats compared with PBS-treated controls. Axonal density and synaptophysin-positive areas were significantly increased along the ischemic boundary zone of the cortex and striatum in MCAo rats treated with exosomes compared with PBS control. Exosome treatment significantly increased the number of newly formed doublecortin (a marker of neuroblasts) and von Willebrand factor (a marker of endothelial cells) cells. Our results suggest that intravenous administration of cell-free MSC-generated exosomes post stroke improves functional recovery and enhances neurite remodeling, neurogenesis, and angiogenesis and represents a novel treatment for stroke.Journal of Cerebral Blood Flow & Metabolism advance online publication, 21 August 2013; doi:10.1038/jcbfm.2013.152.
- Journal of cardiovascular magnetic resonance : official journal of the Society for Cardiovascular Magnetic Resonance
- Published almost 6 years ago
Several studies have correlated elevations in cardiac biomarkers of injury post marathon with transient and reversible right ventricular (RV) systolic dysfunction as assessed by both transthoracic echocardiography (TTE) and cardiovascular magnetic resonance (CMR). Whether or not permanent myocardial injury occurs due to repeated marathon running in the aging population remains controversial.
Background Vasodilatory shock that does not respond to high-dose vasopressors is associated with high mortality. We investigated the effectiveness of angiotensin II for the treatment of patients with this condition. Methods We randomly assigned patients with vasodilatory shock who were receiving more than 0.2 μg of norepinephrine per kilogram of body weight per minute or the equivalent dose of another vasopressor to receive infusions of either angiotensin II or placebo. The primary end point was a response with respect to mean arterial pressure at hour 3 after the start of infusion, with response defined as an increase from baseline of at least 10 mm Hg or an increase to at least 75 mm Hg, without an increase in the dose of background vasopressors. Results A total of 344 patients were assigned to one of the two regimens; 321 received a study intervention (163 received angiotensin II, and 158 received placebo) and were included in the analysis. The primary end point was reached by more patients in the angiotensin II group (114 of 163 patients, 69.9%) than in the placebo group (37 of 158 patients, 23.4%) (odds ratio, 7.95; 95% confidence interval [CI], 4.76 to 13.3; P<0.001). At 48 hours, the mean improvement in the cardiovascular Sequential Organ Failure Assessment (SOFA) score (scores range from 0 to 4, with higher scores indicating more severe dysfunction) was greater in the angiotensin II group than in the placebo group (-1.75 vs. -1.28, P=0.01). Serious adverse events were reported in 60.7% of the patients in the angiotensin II group and in 67.1% in the placebo group. Death by day 28 occurred in 75 of 163 patients (46%) in the angiotensin II group and in 85 of 158 patients (54%) in the placebo group (hazard ratio, 0.78; 95% CI, 0.57 to 1.07; P=0.12). Conclusions Angiotensin II effectively increased blood pressure in patients with vasodilatory shock that did not respond to high doses of conventional vasopressors. (Funded by La Jolla Pharmaceutical Company; ATHOS-3 ClinicalTrials.gov number, NCT02338843 .).
BACKGROUND: Type VI dual left anterior descending artery (LAD) is a rare coronary anomaly, the first case of which has recently been described. This is the first report of type VI dual LAD anomaly in which the patient presented with non-ST-segment elevation myocardial infarction and percutaneous coronary intervention was performed in the anomalously originating LAD. CASE PRESENTATION: A 52-year-old man with diabetes, hypertension and hyperlipidemia presented with chest pain without ST elevation on EKG, although the patient’s troponin I level was elevated. Coronary angiography revealed a short LAD originating from the left main coronary artery and a long LAD originating from the proximal portion of the right coronary artery (RCA). Three-dimensional reconstruction of computed tomography of images revealed that the long LAD originated from the proximal RCA and coursed between the right ventricular outflow tract (RVOT) and the aortic root before entering the mid anterior interventricular groove. The high take-off RCA originated underneath the RVOT, pointing downwards and forming an acute angle with the proximal portion of the long LAD. The anomalous long LAD displayed significant stenosis. We performed successful percutaneous coronary intervention (PCI) in the anomalous artery. CONCLUSION: With accurate understanding of the coronary anatomy and appropriate hardware selection, successful PCI can be performed in the in the long LAD in patients with type VI dual LAD anomaly.
Although drug-eluting stents have dramatically reduced angiographic restenosis and clinical need for repeat revascularization procedures, some adverse effects, such as late stent thrombosis, have been described. We evaluated clinical performance of paclitaxel-eluting stents coated with a new bioactive polymer system (P-5) based on a copolymer of an acrylic derivative of triflusal in patients with coronary artery disease.
During development, endothelial cells (EC) display tissue-specific attributes that are unique to each vascular bed, as well as generic signaling mechanisms that are broadly applied to create a patent circulatory system. We have previously utilized human embryonic stem cells (hESC) to generate tissue-specific EC sub-types (Rafii et al., 2013) and identify pathways that govern growth and trans-differentiation potential of hESC-derived ECs (James et al., 2010). Here, we elucidate a novel Notch-dependent mechanism that induces endothelial to mesenchymal transition (EndMT) in confluent monolayer cultures of hESC-derived ECs. We demonstrate density-dependent induction of EndMT that can be rescued by the Notch signaling inhibitor DAPT and identify a positive feedback signaling mechanism in hESC-ECs whereby trans-activation of Notch by DLL4 ligand induces elevated expression and surface presentation of DLL4. Increased Notch activation in confluent hESC-EC monolayer cultures induces areas of EndMT containing transitional cells that are marked by increased Jagged1 expression and reduced Notch signal integration. Jagged1 loss of function in monolayer hESC-ECs induces accelerated feedback stimulation of Notch signaling, increased expression of cell-autonomous, cis-inhibitory DLL4, and EndMT. These data elucidate a novel interplay of Notch ligands in modulating pathway activation during both expansion and EndMT of hESC-derived ECs.
The recent discovery of bile acid (BA) receptors and a better delineation of the multiple roles of BAs in relevant biological processes have revamped BA research. The vasoactive actions of BAs were recognized more than three decades ago but the underlying mechanisms of the BA-induced vasorelaxation are now being clarified. Recent evidence shows that the BA receptors FXR and TGR5 are expressed in endothelial cells and may have important effects on both systemic and portal circulation. The availability of genetically engineered mice with ablation of BA receptors and the development of BA receptor agonists has allowed to explore the modulation of XR and, in a lesser extent, of TGR5 in the setting of portal hypertension (PHT) with promising results. In this review, we summarize recent data on how BA-dependent pathways influence several processes that impact in PHT and the preclinical data showing that pharmacological modulation of those pathways may hold promise in the treatment of PHT.
Coronary artery disease is one of the most common causes of death and disability, afflicting more than 15 million Americans. Although pharmacological advances and revascularization techniques have decreased mortality, many survivors will eventually succumb to heart failure secondary to the residual microvascular perfusion deficit that remains after revascularization. We present a novel system that rescues the myocardium from acute ischemia, using photosynthesis through intramyocardial delivery of the cyanobacterium Synechococcus elongatus. By using light rather than blood flow as a source of energy, photosynthetic therapy increases tissue oxygenation, maintains myocardial metabolism, and yields durable improvements in cardiac function during and after induction of ischemia. By circumventing blood flow entirely to provide tissue with oxygen and nutrients, this system has the potential to create a paradigm shift in the way ischemic heart disease is treated.