Search

Belgrade Fairground, built in the 1930s, was the first urban complex designed according to modern principles and the first physical structure built in Belgrade on the left bank of the Sava. During its existence, the complex has undergone radical changes - from a fairground, through a concentration camp during World War II, an art colony in the post-war period, to its current state as a marginalized urban segment inhabited by the homeless, with uncontrolled commercial development . These transformations over time have resulted in the creation of numerous layers of identity, which, from a contemporary point of view, the space itself should testify to. The paper examines the transformations that have taken place in the space, and refers to the mutually opposed events that to some extent have hindered the recovery and development of the former Belgrade Fairground. The paper, in the form of a case study, analyzes the space by exploring the application of dissonance in preserving and revitalizing the architectural heritage, since the concept of dissonance is important for articulating opposing meanings and emphasizing the plurality of values. In order to shed light upon all the characteristic phases of the complex's existence, its morphological transformations and then its functional transformations were analyzed, followed by a presentation of how its social relationship with the Belgrade Fairground has been transformed. Accordingly, the ultimate goal was to find a way to manifest the diversity of the fairground's value and its re-perception as belonging to the urban space.

Pulse wave velocity (PWV), a direct marker of arterial stiffness, is an independent cardiovascular risk factor. Although the angiotensin II type 1 receptor blockade belongs to major antihypertensive and cardioprotective therapies, less is known about the effects of long-term stimulation of the angiotensin II type 2 receptor. Previously, compound 21, a selective nonpeptide angiotensin II type 2 receptor agonist improved the outcome of myocardial infarction in rats along with anti-inflammatory properties. We investigated whether compound 21 alone or in combination with angiotensin II type 1 receptor blockade by olmesartan medoxomil could prevent PWV increase and aortic remodeling in N(ω)-nitro-L-arginine-methyl ester (L-NAME)-induced hypertension. Male adult Wistar rats (n=65) were randomly assigned to control, L-NAME, L-NAME+compound-21, L-NAME+olmesartan, and L-NAME+olmesartan+compound-21 groups and treated for 6 weeks. We observed that L-NAME hypertension was accompanied by enhanced PWV, increased wall thickness, and stiffness of the aorta, along with elevated hydroxyproline concentration. Olmesartan completely prevented hypertension, PWV and wall thickness increase, and the increase of aortic stiffness and partly prevented hydroxyproline accumulation. Compound 21 partly prevented all of these alterations, yet without concomitant prevention of blood pressure rise. Although the combination therapy with olmesartan and compound 21 led to blood pressure levels, PWV, and wall thickness comparable to olmesartan-alone-treated rats, only in the combination group was complete prevention of increased hydroxyproline deposition achieved, resulting in even more pronounced stiffness reduction. We conclude that chronic angiotensin II type 2 receptor stimulation prevented aortic stiffening and collagen accumulation without preventing hypertension in rats with inhibited NO synthase. These effects were additive to angiotensin II type 1 receptor blockade, yet without additional blood pressure-lowering effect, and they seem to be NO and blood pressure independent. [ABSTRACT FROM AUTHOR]

Purpose: We investigated spatial resolution loss away from isocenter for a prototype deep silicon photon-counting detector (PCD) CT scanner and compare with a clinical energy-integrating detector (EID) CT scanner., Materials and Methods: We performed three scans on a wire phantom at four positions (isocenter, 6.7, 11.8, and 17.1 cm off isocenter). The acquisition modes were 120 kV EID CT, 120 kV high-definition (HD) EID CT, and 120 kV PCD CT. HD mode used double the projection view angles per rotation as the "regular" EID scan mode. The diameter of the wire was calculated by taking the full width of half max (FWHM) of a profile drawn over the radial and azimuthal directions of the wire. Change in wire diameter appearance was assessed by calculating the ratio of the radial and azimuthal diameter relative to isocenter. t tests were used to make pairwise comparisons of the wire diameter ratio with each acquisition and mean ratios' difference from unity., Results: Deep silicon PCD CT had statistically smaller ( P <0.05) changes in diameter ratio for both radial and azimuthal directions compared with both regular and HD EID modes and was not statistically different from unity ( P <0.05). Maximum increases in FWMH relative to isocenter were 36%, 12%, and 1% for regular EID, HD EID, and deep silicon PCD, respectively., Conclusion: Deep silicon PCD CT exhibits less change in spatial resolution in both the radial and azimuthal directions compared with EID CT., Competing Interests: J.P.K. received compensation from Parexel International for consulting. M.G.L. has previous grant funding from Philips and Ethicon, Spouse, and is a consultant to Farcast Biosciences. T.P.S. receives research support from Canon Medical Systems and GE HealthCare, consulting fees from Alara Imaging, Imalogix, Aidoc, and Asto CT/Leo Cancer Care; royalties from Medical Physics Publishing and royalties related to intellectual property from Qaelum; founder of RadUnity. Z.Y., and S.S. are employees of GE HealthCare. The remaining authors declare no conflict of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Study Objective: We aimed to assess and compare the analgesic efficacy and adverse effects of intravenous subdissociative-dose ketamine to nebulized ketamine in emergency department (ED) patients with acute painful conditions., Methods: We conducted a prospective, randomized, double-blind, double-dummy clinical trial in adult patients (ages 18 and older) with a numerical rating scale pain score of ≥5. We randomized subjects to receive either a single dose of 0.3 mg/kg of intravenous (IV) ketamine or 0.75 mg/kg of nebulized ketamine through a breath-actuated nebulizer. Primary outcome was the difference in pain scores on the numerical rating scale between groups at 30 minutes postmedication administration. The secondary outcomes included the need for rescue analgesia, occurrences of adverse events in each group, and the difference in pain scores at 15, 30, 60, 90, and 120 minutes. We calculated a 95% confidence interval (CI) for a mean difference at 30 minutes, with a minimum clinically important difference set at 1.3 points., Results: We enrolled 150 subjects (75 per group). Mean pain scores through numerical rating scale were 8.2 for both groups at baseline, which decreased to 3.6 and 3.8 at 30 minutes, yielding a mean difference of 0.23 (95% CI -1.32 to 0.857). We observed no clinically concerning changes in vital signs. No serious adverse events occurred in any of the groups throughout the study period., Conclusion: We found no difference between the administration of IV and nebulized ketamine for the short-term treatment of moderate to severe acute pain in the ED, with both treatments providing a clinically meaningful reduction in pain scores at 30 minutes., (Copyright © 2024 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.)

BACKGROUND. Variable beam hardening based on patient size causes variation in CT numbers for energy-integrating detector (EID) CT. Photon-counting detector (PCD) CT more accurately determines effective beam energy, potentially improving CT number reliability. OBJECTIVE. The purpose of the present study was to compare EID CT and deep silicon PCD CT in terms of both the effect of changes in object size on CT number and the overall accuracy of CT numbers. METHODS. A phantom with polyethylene rings of varying sizes (mimicking patient sizes) as well as inserts of different materials was scanned on an EID CT scanner in single-energy (SE) mode (120-kV images) and in rapid-kilovoltage-switching dual-energy (DE) mode (70-keV images) and on a prototype deep silicon PCD CT scanner (70-keV images). ROIs were placed to measure the CT numbers of the materials. Slopes of CT number as a function of object size were computed. Materials' ideal CT number at 70 keV was computed using the National Institute of Standards and Technology XCOM Photon Cross Sections Database. The root mean square error (RMSE) between measured and ideal numbers was calculated across object sizes. RESULTS. Slope (expressed as Hounsfield units per centimeter) was significantly closer to zero (i.e., less variation in CT number as a function of size) for PCD CT than for SE EID CT for air (1.2 vs 2.4 HU/cm), water (-0.3 vs -1.0 HU/cm), iodine (-1.1 vs -4.5 HU/cm), and bone (-2.5 vs -10.1 HU/cm) and for PCD CT than for DE EID CT for air (1.2 vs 2.8 HU/cm), water (-0.3 vs -1.0 HU/cm), polystyrene (-0.2 vs -0.9 HU/cm), iodine (-1.1 vs -1.9 HU/cm), and bone (-2.5 vs -6.2 HU/cm) ( p < .05). For all tested materials, PCD CT had the smallest RMSE, indicating CT numbers closest to ideal numbers; specifically, RMSE (expressed as Hounsfield units) for SE EID CT, DE EID CT, and PCD CT was 32, 44, and 17 HU for air; 7, 8, and 3 HU for water; 9, 10, and 4 HU for polystyrene; 31, 37, and 13 HU for iodine; and 69, 81, and 20 HU for bone, respectively. CONCLUSION. For numerous materials, deep silicon PCD CT, in comparison with SE EID CT and DE EID CT, showed lower CT number variability as a function of size and CT numbers closer to ideal numbers. CLINICAL IMPACT. Greater reliability of CT numbers for PCD CT is important given the dependence of diagnostic pathways on CT numbers.

Background: Recent improvements in CT detector technology have led to smaller detector pixels resolving frequencies beyond 20 lp/cm and enabled ultra-high-resolution CT. Silicon-based photon-counting detector (PCD) CT is one such technology that promises improved spatial and spectral resolution. However, when the detector pixel sizes are reduced, the impact of cardiac motion on CT images becomes more pronounced. Here, we investigated the effects cardiac motion on the image quality of a clinical prototype Si-PCD scanner in a dynamic heart phantom., Methods: A series of 3D-printed vessels were created to simulate coronary arteries with diameter in the 1-3.5 ​mm range. Four coronary stents were set inside the d ​= ​3.5 ​mm vessels and all vessels were filled with contrast agents and were placed inside a dynamic cardiac phantom. The phantom was scanned in motion (60 bpm) and at rest on a prototype clinical Si-PCD CT scanner in 8-bin spectral UHR mode. Virtual monoenergetic images (VMI) were generated at 70 ​keV and CT number accuracy and effective spatial resolution (blooming) of rest and motion VMIs were compared., Results: Linear regression analysis of CT numbers showed excellent agreement (r ​> ​0.99) between rest and motion. We did not observe a significant difference (p ​> ​0.48) in estimating free lumen diameters. Differences in in-stent lumen diameter and stent strut thickness were non-significant with maximum mean difference of approximately 70 ​μm., Conclusion: We found no significant degradation in CT number accuracy or spatial resolution due to cardiac motion. The results demonstrate the potential of spectral UHR coronary CT angiography enabled by Si-PCD., (Copyright © 2023 Society of Cardiovascular Computed Tomography. Published by Elsevier Inc. All rights reserved.)

Background: All photon counting detectors have a characteristic count rate over which their performance degrades. Degradation in the clinical setting takes the form of increased noise, reduced material quantification accuracy, and image artifacts. Count rate is a function of patient attenuation, beam filtration, scanner geometry, and X-ray technique., Purpose: To guide protocol and technology development in the photon counting space, knowledge of clinical count rates spanning the complete range of clinical indications and patient sizes is needed. In this paper, we use clinical data to characterize the range of computed tomography (CT) count rates., Methods: We retrospectively gathered 1980 patient exams spanning the entire body (head/neck/chest/abdomen/extremity) and sampled 36 951 axial image slices. We assigned the tissue labels air/lung/fat/soft tissue/bone to each voxel for each slice using CT number thresholds. We then modeled four different bowtie filters, 70/80/100/120/140 kV spectra, and a range of mA values. We forward-projected each slice to obtain detector-incident count rates, using the geometry of a GE Revolution Apex scanner. Our analysis divided the detector into thirds: the central one-third, one-third of the detector split into two equal regions adjacent to the central third, and the final one-third divided equally between the outer detector edges. We report the 99th percentile of counts to mimic the upper limits of count rates making passing through a patient as a function of patient water equivalent diameter. We also report the percentage of patient scans, by body region, over different count rate thresholds for all combinations of bowtie and beam energy., Results: For routine exam types, we recorded count rates of approximately 3.5 × 10 8  counts/mm 2 /s in the torso, extremities, and brain. For neck scans, we observed count rates near 6 × 10 8  counts/mm 2 /s. Our simulations of 1000 mA, appropriately mimicking the mA needs for fast pediatric, fast thoracic, and cardiac scanning, resulted in count rates of over 10 × 10 8  counts/mm 2 /s for the torso, extremities, and brain. At 1000 mA, for the neck region, we observed count rates close to 2 × 10 9  counts/mm 2 /s. Importantly, we saw only a small change in maximum count rate needs over patient size, which we attribute to patient mis-positioning with respect to the bowtie filters. As expected, combinations of kV and bowtie filter with higher beam energies and wider/less attenuating bowtie fluence profiles lead to higher count rates relative to lower energies. The 99th-50th percentile count rate changed the most for the torso region, with a maximum variation of 3.9 × 10 8 to 1.2 × 10 7  counts/mm 2 /s. The head/neck/extremity regions had less than a 50% change in count rate from the 99th to 50th percentiles., Conclusions: Our results are the first to use a large patient cohort spanning all body regions to characterize count rates in CT. Our results should be useful in helping researchers understand count rates as a function of body region and mA for various combinations of bowtie filter designs and beam energies. Our results indicate clinical rates >1 × 10 9  counts/mm 2 /s, but they do not predict the image quality impact of using a detector with lower characteristic count rates., (© 2022 The Authors. Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

Ischemia and reperfusion events, such as myocardial infarction (MI), are reported to induce remote organ damage severely compromising patient outcomes. Tissue survival and functional restoration relies on the activation of endogenous redox regulatory systems such as the oxidoreductases of the thioredoxin (Trx) family. Trxs and peroxiredoxins (Prxs) are essential for the redox regulation of protein thiol groups and for the reduction of hydrogen peroxide, respectively. Here, we determined whether experimental MI induces changes in Trxs and Prxs in the heart as well as in secondary organs. Levels and localization of Trx1, TrxR1, Trx2, Prx1, and Prx2 were analyzed in the femur, vertebrae, and kidneys of rats following MI or sham surgery. Trx1 levels were significantly increased in the heart (P = 0.0017) and femur (P < 0.0001) of MI animals. In the femur and lumbar vertebrae, Trx1 upregulation was detected in bone-lining cells, osteoblasts, megakaryocytes, and other hematopoietic cells. Serum levels of Trx1 increased significantly 2 days after MI compared to sham animals (P = 0.0085). Differential regulation of Trx1 in the bone was also detected by immunohistochemistry 1 month after MI. N-Acetyl-cysteine treatment over a period of 1 month induced a significant reduction of Trx1 levels in the bone of MI rats compared to sham and to MI vehicle. This study provides first evidence that MI induces remote organ upregulation of the redox protein Trx1 in the bone, as a response to ischemia-reperfusion injury in the heart.

Epidemiological studies have linked vitamin D deficiency to an increased incidence of myocardial infarction and support a role for vitamin D signalling in the pathophysiology of myocardial infarction. Vitamin D deficiency results in the development of secondary hyperparathyroidism, however, the role of secondary hyperparathyroidism in the pathophysiology of myocardial infarction is not known. Here, we aimed to explore further the secondary hyperparathyroidism independent role of vitamin D signalling in the pathophysiology of myocardial infarction by inducing experimental myocardial infarction in 3-month-old, male, wild-type mice and in mice lacking a functioning vitamin D receptor. In order to prevent secondary hyperparathyroidism in vitamin D receptor mutant mice, all mice were maintained on a rescue diet enriched with calcium, phosphorus, and lactose. Surprisingly, survival rate, cardiac function as measured by echocardiography and intra-cardiac catheterisation and cardiomyocyte size were indistinguishable between normocalcaemic vitamin D receptor mutant mice and wild-type controls, 2 and 8 weeks post-myocardial infarction. In addition, the myocardial infarction-induced inflammatory response was similar in vitamin D receptor mutants and wild-type mice, as evidenced by a comparable upregulation in cardiac interleukin-1-β and tumor-necrosis-factor-α mRNA abundance and similar elevations in circulating interleukin-1-β and tumor-necrosis-factor-α. Our data suggest that the lack of vitamin D signalling in normocalcaemic vitamin D receptor mutants has no major detrimental effect on cardiac function and outcome post-myocardial infarction. Our study may have important clinical implications because it suggests that the secondary hyperparathyroidism induced by vitamin D deficiency, rather than the lack of vitamin D signalling per se, may negatively impact cardiac function post-myocardial infarction., Competing Interests: The authors have declared that no competing interests exist.

The RANK (receptor activator of nuclear factor κB)/RANKL (RANK ligand)/OPG (osteoprotegerin) axis is activated after myocardial infarction (MI), but its pathophysiological role is not well understood. Here, we investigated how global and cell compartment-selective inhibition of RANKL affects cardiac function and remodeling after MI in mice. Global RANKL inhibition was achieved by treatment of human RANKL knock-in (huRANKL-KI) mice with the monoclonal antibody AMG161. huRANKL-KI mice express a chimeric RANKL protein wherein part of the RANKL molecule is humanized. AMG161 inhibits human and chimeric but not murine RANKL. To dissect the pathophysiological role of RANKL derived from hematopoietic and mesenchymal cells, we selectively exchanged the hematopoietic cell compartment by lethal irradiation and across-genotype bone marrow transplantation between wild-type and huRANKL-KI mice, exploiting the specificity of AMG161. After permanent coronary artery ligation, mice were injected with AMG161 or an isotype control antibody over 4 weeks post-MI. MI increased RANKL expression mainly in cardiomyocytes and scar-infiltrating cells 4 weeks after MI. Only inhibition of RANKL derived from hematopoietic cellular sources, but not global or mesenchymal RANKL inhibition, improved post-infarct survival and cardiac function. Mechanistically, hematopoietic RANKL inhibition reduced expression of the pro-inflammatory cytokine IL-1ß in the cardiac cellular infiltrate. In conclusion, inhibition of RANKL derived from hematopoietic cellular sources is beneficial to maintain post-ischemic cardiac function by reduction of pro-inflammatory cytokine production. KEY MESSAGES: Experimental myocardial infarction (MI) augments cardiac RANKL expression in mice. RANKL expression is increased in cardiomyocytes and scar-infiltrating cells after MI. Global or mesenchymal cell RANKL inhibition has no influence on cardiac function after MI. Inhibition of RANKL derived from hematopoietic cells improves heart function post-MI. Hematopoietic RANKL inhibition reduces pro-inflammatory cytokines in scar-infiltrating cells.

Left ventricular hypertrophy (LVH) ultimately leads to heart failure in conditions of increased cardiac pre- or afterload. The bone-derived phosphaturic and sodium-conserving hormone fibroblast growth factor-23 (FGF23) and its co-receptor Klotho have been implicated in the development of uremic LVH. Using transverse aortic constriction (TAC) in gene-targeted mouse models, we examine the role of Fgf23 and Klotho in cardiac hypertrophy and dysfunction induced by pressure overload. TAC profoundly increases serum intact Fgf23 due to increased cardiac and bony Fgf23 transcription and downregulation of Fgf23 cleavage. Aldosterone receptor blocker spironolactone normalizes serum intact Fgf23 levels after TAC by reducing bony Fgf23 transcription. Notably, genetic Fgf23 or Klotho deficiency does not influence TAC-induced hypertrophic remodelling, LV functional impairment, or LV fibrosis. Despite the profound, aldosterone-mediated increase in circulating intact Fgf23 after TAC, our data do not support an essential role of Fgf23 or Klotho in the pathophysiology of pressure overload-induced cardiac hypertrophy.

Estrogen is critical for skeletal homeostasis and regulates bone remodeling, in part, by modulating the expression of receptor activator of NF-κB ligand (RANKL), an essential cytokine for bone resorption by osteoclasts. RANKL can be produced by a variety of hematopoietic (e.g. T and B-cell) and mesenchymal (osteoblast lineage, chondrocyte) cell types. The cellular mechanisms by which estrogen acts on bone are still a matter of controversy. By using murine reconstitution models that allow for selective deletion of estrogen receptor-alpha (ERα) or selective inhibition of RANKL in hematopoietic vs. mesenchymal cells, in conjunction with in situ expression profiling in bone cells, we identified bone lining cells as important gatekeepers of estrogen-controlled bone resorption. Our data indicate that the increase in bone resorption observed in states of estrogen deficiency in mice is mainly caused by lack of ERα-mediated suppression of RANKL expression in bone lining cells.

Antiangiogenic therapies, such as sunitinib, have revolutionized renal cell carcinoma (RCC) treatment. However, a precarious understanding of how resistance emerges and a lack of tractable experimental systems hinder progress. We evaluated the potential of primary RCC cultures (derived from tumors and tumor grafts) to signal to endothelial cells (EC) and fibroblasts in vitro and to stimulate angiogenesis ex vivo in chorioallantoic membrane (CAM) assays. From 65 patients, 27 primary cultures, including several from patients with sunitinib-resistant RCC, were established. RCC cells supported EC survival in coculture assays and induced angiogenesis in CAM assays. RCC-induced EC survival was sensitive to sunitinib in half of the tumors and was refractory in tumors from resistant patients. Sunitinib sensitivity correlated with vascular endothelial growth factor (VEGF) production. RCC induced paracrine extracellular signal-regulated kinase (ERK) activation in EC which was inhibited by sunitinib in sensitive but not in resistant tumors. As determined by fibroblast growth factor receptor substrate 2 (FRS2) phosphorylation in fibroblasts, RCC broadly induced low-level fibroblast growth factor receptor (FGFR) signaling. Whereas ERK activation in EC was uniformly inhibited by combined VEGF/platelet-derived growth factor (PDGF)/FGF receptor inhibitors, paracrine ERK activation in fibroblasts was blocked in only a fraction of tumors. Our data show that RCC activates EC through VEGF-dependent and -independent pathways, that sunitinib sensitivity correlates with VEGF-mediated ERK activation, and that combined inhibition of VEGF/PDGF/FGF receptors is sufficient to inhibit mitogenic signaling in EC but not in fibroblasts., (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)

Myocardial infarction (MI) is a major cause of death worldwide. Epidemiological studies have linked vitamin D deficiency to MI incidence. Because fibroblast growth factor-23 (FGF23) is a master regulator of vitamin D hormone production and has been shown to be associated with cardiac hypertrophy per se, we explored the hypothesis that FGF23 may be a previously unrecognized pathophysiological factor causally linked to progression of cardiac dysfunction post-MI. Here, we show that circulating intact Fgf23 was profoundly elevated, whereas serum vitamin D hormone levels were suppressed, after induction of experimental MI in rat and mouse models, independent of changes in serum soluble Klotho or serum parathyroid hormone. Both skeletal and cardiac expression of Fgf23 was increased after MI. Although the molecular link between the cardiac lesion and circulating Fgf23 concentrations remains to be identified, our study has uncovered a novel heart-bone-kidney axis that may have important clinical implications and may inaugurate the new field of cardio-osteology., (© 2015 American Society for Bone and Mineral Research.)

Myocardial infarction (MI) is a major condition causing heart failure (HF). After MI, the renin angiotensin system (RAS) and its signalling octapeptide angiotensin II (Ang II) interferes with cardiac injury/repair via the AT1 and AT2 receptors (AT1R, AT2R). Our study aimed at deciphering the mechanisms underlying the link between RAS and cellular components of the immune response relying on a rodent model of HF as well as HF patients. Flow cytometric analyses showed an increase in the expression of CD4(+) AT2R(+) cells in the rat heart and spleen post-infarction, but a reduction in the peripheral blood. The latter was also observed in HF patients. The frequency of rat CD4(+) AT2R(+) T cells in circulating blood, post-infarcted heart and spleen represented 3.8 ± 0.4%, 23.2 ± 2.7% and 22.6 ± 2.6% of the CD4(+) cells. CD4(+) AT2R(+) T cells within blood CD4(+) T cells were reduced from 2.6 ± 0.2% in healthy controls to 1.7 ± 0.4% in patients. Moreover, we characterized CD4(+) AT2R(+) T cells which expressed regulatory FoxP3, secreted interleukin-10 and other inflammatory-related cytokines. Furthermore, intramyocardial injection of MI-induced splenic CD4(+) AT2R(+) T cells into recipient rats with MI led to reduced infarct size and improved cardiac performance. We defined CD4(+) AT2R(+) cells as a T cell subset improving heart function post-MI corresponding with reduced infarction size in a rat MI-model. Our results indicate CD4(+) AT2R(+) cells as a promising population for regenerative therapy, via myocardial transplantation, pharmacological AT2R activation or a combination thereof., (© 2015 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Fibroblast growth factor-23 (FGF23) is a bone-derived hormone regulating renal phosphate reabsorption and vitamin D synthesis in renal proximal tubules. Here, we show that FGF23 directly regulates the membrane abundance of the Na(+):Cl(-) co-transporter NCC in distal renal tubules by a signaling mechanism involving the FGF receptor/αKlotho complex, extracellular signal-regulated kinase 1/2 (ERK1/2), serum/glucocorticoid-regulated kinase 1 (SGK1), and with-no lysine kinase-4 (WNK4). Renal sodium (Na(+)) reabsorption and distal tubular membrane expression of NCC are reduced in mouse models of Fgf23 and αKlotho deficiency. Conversely, gain of FGF23 function by injection of wild-type mice with recombinant FGF23 or by elevated circulating levels of endogenous Fgf23 in Hyp mice increases distal tubular Na(+) uptake and membrane abundance of NCC, leading to volume expansion, hypertension, and heart hypertrophy in a αKlotho and dietary Na(+)-dependent fashion. The NCC inhibitor chlorothiazide abrogates FGF23-induced volume expansion and heart hypertrophy. Our findings suggest that FGF23 is a key regulator of renal Na(+) reabsorption and plasma volume, and may explain the association of FGF23 with cardiovascular risk in chronic kidney disease patients., (© 2014 The Authors. Published under the terms of the CC BY 4.0 license.)

Left ventricular (LV) remodeling is the main reason for the development of progressive cardiac dysfunction after myocardial infarction (MI). This study investigated whether stimulation of the angiotensin type 2 receptor is able to ameliorate post-MI cardiac remodeling and what the underlying mechanisms may be. MI was induced in Wistar rats by permanent ligation of the left coronary artery. Treatment with the angiotensin type 2 receptor agonist compound 21 (0.03 mg/kg) was started 6 hours post-MI and continued for 6 weeks. Hemodynamic parameters were measured by echocardiography and intracardiac catheter. Effects on proteolysis were studied in heart tissue and primary cardiac fibroblasts. Compound 21 significantly improved systolic and diastolic functions, resulting in improved ejection fraction (71.2±4.7% versus 53.4±7.0%; P<0.001), fractional shortening (P<0.05), LV internal dimension in systole (P<0.05), LV end-diastolic pressure (16.9±1.2 versus 22.1±1.4 mm Hg; P<0.05), ratio of early (E) to late (A) ventricular filling velocities, and maximum and minimum rate of LV pressure rise (P<0.05). Compound 21 improved arterial stiffness parameters and reduced collagen content in peri-infarct myocardium. Tissue inhibitor of matrix metalloproteinase 1 was strongly upregulated, whereas matrix metalloproteinases 2 and 9 and transforming growth factor β1 were diminished in LV of treated animals. In cardiac fibroblasts, compound 21 initially induced tissue inhibitor of matrix metalloproteinase 1 expression followed by attenuated matrix metalloproteinase 9 and transforming growth factor β1 secretion. In conclusion, angiotensin type 2 receptor stimulation improves cardiac function and prevents cardiac remodeling in the late stage after MI, suggesting that angiotensin type 2 receptor agonists may be considered a future pharmacological approach for the improvement of post-MI cardiac dysfunction.

The vitamin D hormone 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3] is essential for the preservation of serum calcium and phosphate levels but may also be important for the regulation of cardiovascular function. Epidemiological data in humans have shown that vitamin D insufficiency is associated with hypertension, left ventricular hypertrophy, increased arterial stiffness, and endothelial dysfunction in normal subjects and in patients with chronic kidney disease and type 2 diabetes. However, the pathophysiological mechanisms underlying these associations remain largely unexplained. In this study, we aimed to decipher the mechanisms by which 1,25(OH)2D3 may regulate systemic vascular tone and cardiac function, using mice carrying a mutant, functionally inactive vitamin D receptor (VDR). To normalize calcium homeostasis in VDR mutant mice, we fed the mice lifelong with the so-called rescue diet enriched with calcium, phosphate, and lactose. Here, we report that VDR mutant mice are characterized by lower bioavailability of the vasodilator nitric oxide (NO) due to reduced expression of the key NO synthesizing enzyme, endothelial NO synthase, leading to endothelial dysfunction, increased arterial stiffness, increased aortic impedance, structural remodeling of the aorta, and impaired systolic and diastolic heart function at later ages, independent of changes in the renin-angiotensin system. We further demonstrate that 1,25(OH)2D3 is a direct transcriptional regulator of endothelial NO synthase. Our data demonstrate the importance of intact VDR signaling in the preservation of vascular function and may provide a mechanistic explanation for epidemiological data in humans showing that vitamin D insufficiency is associated with hypertension and endothelial dysfunction.

The cannabinoid receptors, CB1 and CB2, are expressed in the heart, but their role under pathological conditions remains controversial. This study examined the effect of CB1 receptor blockade on cardiovascular functions after experimental MI and in experimental metabolic syndrome. MI was induced in Wistar rats by permanent ligation of the left coronary artery. Treatment with the CB1 receptor antagonist rimonabant (10 mg/kg i.p. daily) started 7 days before or 6 h after MI and continued for 6 weeks. Haemodynamic parameters were measured via echocardiography and intracardiac Samba catheter. CB1 blockade improved systolic and diastolic heart function, decreased cardiac collagen and hydroxyproline content and down-regulated TGF-β1. Additionally, rimonabant decreased arterial stiffness, normalised QRS complex duration and reduced brain natriuretic peptide levels in serum. In primary cardiac fibroblasts, rimonabant decreased MMP-9 activity and TGF-β1 expression. Furthermore, rimonabant improved depressed systolic function of spontaneously hypertensive obese rats and reduced weight gain. Blocking of CB1 receptor with rimonabant improves cardiac functions in the early and late stages after MI, decreases arterial stiffness and reduces cardiac remodelling. Rimonabant also has cardioprotective actions in rats characterised by the metabolic syndrome. Inhibition of proteolysis and TGF-β1 expression and reduced collagen content by rimonabant may attenuate destruction of the extracellular matrix and decrease fibrosis after MI.

Emerging evidence suggests a cardioprotective role of the angiotensin AT2R, albeit the underlying cellular mechanisms are not well understood. We aimed in this article to elucidate a potential role of cardiac angiotensin AT2R in regulating cellular immune response to ischemic heart injury. Seven days after myocardial infarction in rats, double-immunofluorescence staining showed that AT2R was detected in a fraction of CD8(+) T cells infiltrating in the peri-infarct myocardium. We developed a method that allowed the isolation of myocardial infiltrating CD8(+)AT2R(+) T cells using modified MACS, and further characterization and purification with flow cytometry. Although the CD8(+)AT2R(-) T cells exhibited potent cytotoxicity to both adult and fetal cardiomyocytes (CMs), the CD8(+)AT2R(+) T cells were noncytotoxic to these CMs. The CD8(+)AT2R(+) T cells were characterized by upregulated IL-10 and downregulated IL-2 and INF-γ expression when compared with CD8(+)AT2R(-) T cells. We further showed that IL-10 gene expression was enhanced in CD8(+) T cells on in vitro AT2R stimulation. Importantly, in vivo AT2R activation engendered an increment of CD8(+)AT2R(+) T cells and IL-10 production in the ischemic myocardium. In addition, intramyocardial transplantation of CD8(+)AT2R(+) T cells (versus CD8(+)AT2R(-)) led to reduced ischemic heart injury. Moreover, the CD8(+)AT2R(+) T cell population was also demonstrated in human peripheral blood. Thus, we have defined the cardioprotective CD8(+)AT2R(+) T cell population, which increases during ischemic heart injury and contributes to maintaining CM viability and providing IL-10, hence revealing an AT2R-mediated cellular mechanism in modulating adaptive immune response in the heart.

The expression pattern of angiotensin AT2 receptors with predominance during fetal life and upregulation under pathological conditions during tissue injury/repair process suggests that AT2 receptors may exert an important action in injury/repair adaptive mechanisms. Less is known about AT2 receptors in acute ischemia-induced cardiac injury. We aimed here to elucidate the role of AT2 receptors after acute myocardial infarction. Double immunofluorescence staining showed that cardiac AT2 receptors were mainly detected in clusters of small c-kit+ cells accumulating in peri-infarct zone and c-kit+AT2+ cells increased in response to acute cardiac injury. Further, we isolated cardiac c-kit+AT2+ cell population by modified magnetic activated cell sorting and fluorescence activated cell sorting. These cardiac c-kit+AT2+ cells, represented approximately 0.19% of total cardiac cells in infarcted heart, were characterized by upregulated transcription factors implicated in cardiogenic differentiation (Gata-4, Notch-2, Nkx-2.5) and genes required for self-renewal (Tbx-3, c-Myc, Akt). When adult cardiomyocytes and cardiac c-kit+AT2+ cells isolated from infarcted rat hearts were cocultured, AT2 receptor stimulation in vitro inhibited apoptosis of these cocultured cardiomyocytes. Moreover, in vivo AT2 receptor stimulation led to an increased c-kit+AT2+ cell population in the infarcted myocardium and reduced apoptosis of cardiomyocytes in rats with acute myocardial infarction. These data suggest that cardiac c-kit+AT2+ cell population exists and increases after acute ischemic injury. AT2 receptor activation supports performance of cardiomyocytes, thus contributing to cardioprotection via cardiac c-kit+AT2+ cell population.