Browsing by Subject "Calcification"
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Item 18F-NaF and 18F-FDG as molecular probes in the evaluation of atherosclerosis(Springer Nature, 2018-11) McKenney-Drake, Mikaela L.; Moghbel, Mateen C.; Paydary, Koosha; Alloosh, Mouhamad; Houshmand, Sina; Moe, Sharon; Salavati, Ali; Sturek, Jeffrey M.; Territo, Paul R.; Weaver, Connie; Werner, Thomas J.; Høilund-Carlsen, Poul Flemming; Sturek, Michael; Alavi, Abass; Cellular and Integrative Physiology, School of MedicineThe early detection of atherosclerotic disease is vital to the effective prevention and management of life-threatening cardiovascular events such as myocardial infarctions and cerebrovascular accidents. Given the potential for positron emission tomography (PET) to visualize atherosclerosis earlier in the disease process than anatomic imaging modalities such as computed tomography (CT), this application of PET imaging has been the focus of intense scientific inquiry. Although 18F-FDG has historically been the most widely studied PET radiotracer in this domain, there is a growing body of evidence that 18F-NaF holds significant diagnostic and prognostic value as well. In this article, we review the existing literature on the application of 18F-FDG and 18F-NaF as PET probes in atherosclerosis and present the findings of original animal and human studies that have examined how well 18F-NaF uptake correlates with vascular calcification and cardiovascular risk.Item Atherosclerosis Burdens in Diabetes Mellitus: Assessment by PET Imaging(MDPI, 2022-09-06) Høilund-Carlsen, Poul F.; Piri, Reza; Madsen, Per Lav; Revheim, Mona-Elisabeth; Werner, Thomas J.; Alavi, Abass; Gerke, Oke; Sturek, Michael; Anatomy, Cell Biology and Physiology, School of MedicineArteriosclerosis and its sequelae are the most common cause of death in diabetic patients and one of the reasons why diabetes has entered the top 10 causes of death worldwide, fatalities having doubled since 2000. The literature in the field claims almost unanimously that arteriosclerosis is more frequent or develops more rapidly in diabetic than non-diabetic subjects, and that the disease is caused by arterial inflammation, the control of which should therefore be the goal of therapeutic efforts. These views are mostly based on indirect methodologies, including studies of artery wall thickness or stiffness, or on conventional CT-based imaging used to demonstrate tissue changes occurring late in the disease process. In contrast, imaging with positron emission tomography and computed tomography (PET/CT) applying the tracers 18F-fluorodeoxyglucose (FDG) or 18F-sodium fluoride (NaF) mirrors arterial wall inflammation and microcalcification, respectively, early in the course of the disease, potentially enabling in vivo insight into molecular processes. The present review provides an overview of the literature from the more than 20 and 10 years, respectively, that these two tracers have been used for the study of atherosclerosis, with emphasis on what new information they have provided in relation to diabetes and which questions remain insufficiently elucidated.Item Atherosclerosis imaging with 18F-sodium fluoride PET: state-of-the-art review(Springer Verlag, 2020-06) Høilund-Carlsen, Poul F.; Sturek, Michael; Alavi, Abass; Gerke, Oke; Anatomy and Cell Biology, School of MedicinePurpose: We examined the literature to elucidate the role of 18F-sodium fluoride (NaF)-PET in atherosclerosis. Methods: Following a systematic search of PubMed/MEDLINE, Embase, and Cochrane Library included articles underwent subjective quality assessment with categories low, medium, and high. Of 2811 records, 1780 remained after removal of duplicates. Screening by title and abstract left 41 potentially eligible full-text articles, of which 8 (about the aortic valve (n = 1), PET/MRI feasibility (n = 1), aortic aneurysms (n = 1), or quantification methodology (n = 5)) were dismissed, leaving 33 published 2010-2012 (n = 6), 2013-2015 (n = 11), and 2016-2018 (n = 16) for analysis. Results: They focused on coronary (n = 8), carotid (n = 7), and femoral arteries (n = 1), thoracic aorta (n = 1), and infrarenal aorta (n = 1). The remaining 15 studies examined more than one arterial segment. The literature was heterogeneous: few studies were designed to investigate atherosclerosis, 13 were retrospective, 9 applied both FDG and NaF as tracers, 24 NaF only. Subjective quality was low in one, medium in 13, and high in 19 studies. The literature indicates that NaF is a very specific tracer that mimics active arterial wall microcalcification, which is positively associated with cardiovascular risk. Arterial NaF uptake often presents before CT-calcification, tends to decrease with increasing density of CT-calcification, and appears, rather than FDG-avid foci, to progress to CT-calcification. It is mainly surface localized, increases with age with a wide scatter but without an obvious sex difference. NaF-avid microcalcification can occur in fatty streaks, but the degree of progression to CT-calcification is unknown. It remains unknown whether medical therapy influences microcalcification. The literature held no therapeutic or randomized controlled trials. Conclusion: The literature was heterogeneous and with few clear cut messages. NaF-PET is a new approach to detect and quantify microcalcification in early-stage atherosclerosis. NaF uptake correlates with cardiovascular risk factors and appears to be a good measure of the body's atherosclerotic burden, potentially suited also for assessment of anti-atherosclerotic therapy.Item Calcium as a cardiovascular toxin in CKD-MBD(Elsevier, 2017-07) Moe, Sharon M.; Medicine, School of MedicineDisordered calcium balance and homeostasis are common in patients with chronic kidney disease. Such alterations are commonly associated with abnormal bone remodeling, directly and indirectly. Similarly, positive calcium balance may also be a factor in the pathogenesis of extra skeletal soft tissue and arterial calcification. Calcium may directly affect cardiac structure and function through direct effects to alter cell signaling due to abnormal intracellular calcium homeostasis 2) extra-skeletal deposition of calcium and phosphate in the myocardium and small cardiac arterioles, 3) inducing cardiomyocyte hypertrophy through calcium and hormone activation of NFAT signaling mechanisms, and 4) increased aorta calcification resulting in chronic increased afterload leading to hypertrophy. Similarly, calcium may alter vascular smooth muscle cell function and affect cell signaling which may predispose to a proliferative phenotype important in arteriosclerosis and arterial calcification. Thus, disorders of calcium balance and homeostasis due to CKD-MBD may play a role in the high cardiovascular burden observed in patients with CKD.Item Connexin Mutants Cause Cataracts Through Deposition of Apatite(Frontiers Media, 2022-07-22) Minogue, Peter J.; Sommer, Andre J.; Williams, James C., Jr.; Bledsoe, Sharon B.; Beyer, Eric C.; Berthoud, Viviana M.; Anatomy, Cell Biology and Physiology, School of MedicineCataracts are lens opacities that are among the most common causes of blindness. It is commonly believed that cataracts develop through the accumulation of damage to lens proteins. However, recent evidence suggests that cataracts can result from calcium ion accumulation and the precipitation of calcium-containing salts. To test for the presence of precipitates and to identify their components, we studied the lenses of mice that develop cataracts due to mutations of connexin46 and connexin50. Micro-computed tomography showed the presence of radio-dense mineral in the mutant lenses, but not in wild-type lenses. Three-dimensional reconstructions of the scans showed that the distribution of the radio-dense mineral closely paralleled the location and morphology of the cataracts. The mutant lens homogenates also contained insoluble particles that stained with Alizarin red (a dye that stains Ca2+ deposits). Using attenuated total internal reflection micro–Fourier transform infrared spectroscopy, we identified the mineral as calcium phosphate in the form of apatite. Taken together, these data support the novel paradigm that cataracts are formed through pathological mineralization within the lens.Item Coronary artery disease progression and calcification in metabolic syndrome(2014) McKenney, Mikaela Lee; Sturek, Michael Stephen; Evans-Molina, Carmella; Moe, Sharon M.; Tune, Johnathan D.For years, the leading killer of Americans has been coronary artery disease (CAD), which has a strong correlation to the U.S. obesity epidemic. Obesity, along with the presence of other risk factors including hyperglycemia, hypercholesterolemia, dyslipidemia, and high blood pressure, comprise of the diagnosis of metabolic syndrome (MetS). The presentation of multiple MetS risk factors increases a patients risk for adverse cardiovascular events. CAD is a complex progressive disease. We utilized the superb model of CAD and MetS, the Ossabaw miniature swine, to investigate underlying mechanisms of CAD progression. We studied the influence of coronary epicardial adipose tissue (cEAT) and coronary smooth muscle cell (CSM) intracellular Ca2+ regulation on CAD progression. By surgical excision of cEAT from MetS Ossabaw, we observed an attenuation of CAD progression. This finding provides evidence for a link between local cEAT and CAD progression. Intracellular Ca2+ is a tightly regulated messenger in CSM that initiates contraction, translation, proliferation and migration. When regulation is lost, CSM dedifferentiate from their mature, contractile phenotype found in the healthy vascular wall to a synthetic, proliferative phenotype. Synthetic CSM are found in intimal plaque of CAD patients. We investigated the changes in intracellular Ca2+ signaling in enzymatically isolated CSM from Ossabaw swine with varying stages of CAD using the fluorescent Ca2+ indicator, fura-2. This time course study revealed heightened Ca2+ signaling in early CAD followed by a significant drop off in late stage calcified plaque. Coronary artery calcification (CAC) is a result of dedifferentiation into an osteogenic CSM that secretes hydroxyapatite in the extracellular matrix. CAC is clinically detected by computed tomography (CT). Microcalcifications have been linked to plaque instability/rupture and cannot be detected by CT. We used 18F-NaF positron emission tomography (PET) to detect CAC in Ossabaw swine with early stage CAD shown by mild neointimal thickening. This study validated 18F-NaF PET as a diagnostic tool for early, molecular CAC at a stage prior to lesions detectable by CT. This is the first report showing non-invasive PET resolution of CAC and CSMC Ca2+ dysfunction at an early stage previously only characterized by invasive cellular Ca2+ imaging.Item Hexasodium fytate for the treatment of calciphylaxis: a randomised, double-blind, phase 3, placebo-controlled trial with an open-label extension(Elsevier, 2024-08-16) Sinha, Smeeta; Nigwekar, Sagar U.; Brandenburg, Vincent; Gould, Lisa J.; Serena, Thomas E.; Moe, Sharon M.; Aronoff, George R.; Chatoth, Dinesh K.; Hymes, Jeffrey L.; Carroll, Kevin J.; Alperovich, Gabriela; Keller, Laurence H.; Perelló, Joan; Gold, Alex; Chertow, Glenn M.; Medicine, School of MedicineBackground: In the CALCIPHYX trial, we investigated hexasodium fytate, an inhibitor of vascular calcification, for the treatment of calcific uraemic arteriolopathy (calciphylaxis), a rare condition characterised by painful, non-healing skin lesions. Methods: In this international, phase 3, randomised, double-blind, placebo-controlled trial, adults with an ulcerated calciphylaxis lesion and pain visual analogue scale (VAS) score ≥50/100 were randomised 1:1 to hexasodium fytate 7 mg/kg or placebo intravenously during maintenance haemodialysis. Primary efficacy outcomes were an 8-item modification of the Bates-Jensen Wound Assessment Tool (BWAT-CUA) and Pain VAS in the intention-to-treat population. ClinicalTrials.gov number: NCT04195906. Findings: Overall, 34/37 patients randomised to hexasodium fytate and 26/34 patients randomised to placebo completed the 12-week randomised treatment period. At Week 12, both groups (hexasodium fytate versus placebo) showed similar improvements in BWAT-CUA (mean [standard deviation (SD)], -5.3 [5.2] versus -6.0 [6.2]; least squares mean difference, 0.3 [96% confidence interval (CI): -2.5, 3.0]; p = 0.88) and Pain VAS (mean [SD], -19.5 [26.9] versus -32.2 [38.5]; least squares mean difference, 11.5 [96% CI: -4.8, 27.8]; p = 0.15). One patient randomised to placebo briefly received hexasodium fytate in error. Serious adverse events through Week 12 included: calciphylaxis-related events leading to hospitalisation (2/38 [5%] versus 11/33 [33%]) and death (1/38 [3%] versus 5/33 [15%]). During the subsequent 12 weeks of open-label hexasodium fytate and 4 weeks of follow-up, there were no additional calciphylaxis-related events leading to hospitalisation. Over the course of the entire trial, deaths were 2/38 [5%] for the hexasodium fytate group and 7/33 [21%] for the placebo group. Interpretation: In patients with calciphylaxis, BWAT-CUA and Pain VAS improved similarly in hexasodium fytate- and placebo-treated patients; over the course of the entire trial, there were fewer deaths and calciphylaxis-related events leading to hospitalisation in the hexasodium fytate group.Item Human femoral neck has less cellular periosteum, and more mineralized periosteum, than femoral diaphyseal bone(Elsevier, 2005-02) Allen, Matthew R.; Burr, David B.; Department of Anatomy & Cell Biology, IU School of MedicinePeriosteal expansion enhances bone strength and is controlled by osteogenic cells of the periosteum. The extent of cellular periosteum at the human femoral neck, a clinically relevant site, is unclear. This study was designed to histologically evaluate the human femoral neck periosteal surface. Femoral neck samples from 11 male and female cadavers (ages 34–88) were histologically assessed and four periosteal surface classifications (cellular periosteum, mineralizing periosteum, cartilage, and mineralizing cartilage) were quantified. Femoral mid-diaphysis samples from the same cadavers were used as within-specimen controls. The femoral neck surface had significantly less (P < 0.05) cellular periosteum (18.4 ± 9.7%) compared to the femoral diaphysis (59.2 ± 13.8%). A significant amount of the femoral neck surface was covered by mineralizing periosteal tissue (20–70%). These data may provide an alternate explanation for the apparent femoral neck periosteal expansion with age and suggest the efficiency of interventions that stimulate periosteal expansion may be reduced, albeit still possible, at the femoral neck of humans.Item Hyperphosphatemic Tumoral Calcinosis With Pemigatinib Use(Elsevier, 2022-07-16) Puar, Akshan; Donegan, Diane; Helft, Paul; Kuhar, Matthew; Webster, Jonathan; Rao, Megana; Econs, Michael; Medicine, School of MedicineBackground/objective: Pemigatinib, a fibroblast growth factor receptor (FGFR) 1-3 inhibitor, is a novel therapeutic approach for treating cholangiocarcinoma when an FGFR fusion or gene rearrangement is identified. Although the most reported side effect of pemigatinib is hyperphosphatemia, tumoral calcinosis with soft tissue calcifications is not widely recognized as a complication. We report a case of patient with hyperphosphatemic tumoral calcinosis on pemigatinib. Case report: A 59-year-old woman with progressive metastatic cholangiocarcinoma, despite receiving treatment with cisplatin and gemcitabine for 7 months, was found to have an FGFR2-BICC1 fusion in the tumor on next-generation sequencing. Pemigatinib was, therefore, initiated. Four months into the therapy, multiple subcutaneous nodules developed over the lower portion of her back, hips, and legs. Punch biopsies revealed deep dermal and subcutaneous calcifications. Investigations revealed elevated serum phosphorus (7.5 mg/dL), normal serum calcium (8.7 mg/dL), and elevated intact fibroblast growth factor-23 (FGF23, 1216 pg/mL; normal value <59 pg/mL) levels. Serum phosphorus levels improved with a low-phosphorus diet and sevelamer. Calcifications regressed with pemigatinib discontinuation. Discussion: Inhibition or deficiency of FGF-23 results in hyperphosphatemia and can lead to ectopic calcification. Pemigatinib, a potent inhibitor of FGFR-1-3, blocks the effect of FGF-23 leading to hyperphosphatemia and tumoral calcinosis as observed in our case. Treatment is aimed primarily at lowering serum phosphate levels through dietary restriction or phosphate binders; however, the regression of tumoral calcinosis can occur with pemigatinib cessation, as seen in this case. Conclusion: As the use of FGFR 1-3 inhibitors becomes more prevalent, we aim to raise attention to the potential side effects of tumoral calcinosis.Item Incidence and Importance of Calcium Deposition in Kidney Biopsy Specimens(Karger, 2022) Gaddy, Anna; Schwantes-An, Tae-Hwi; Moorthi, Ranjani N.; Phillips, Carrie L.; Eadon, Michael T.; Moe, Sharon M.; Medical and Molecular Genetics, School of MedicineIntroduction: Calcification on native kidney biopsy specimens is often noted by pathologists, but the consequence is unknown. Methods: We searched the pathology reports in the Biopsy Biobank Cohort of Indiana for native biopsy specimens with calcification. Results: Of the 4,364 specimens, 416 (9.8%) had calcification. We compared clinical and histopathology findings in those with calcification (n = 429) compared to those without calcification (n = 3,936). Patients with calcification were older, had more comorbidities, lower estimated glomerular filtration rates (eGFR), were more likely to have hyaline arteriosclerosis, interstitial fibrosis/tubular atrophy, and a primary pathologic diagnosis of acute tubular injury or acute tubular necrosis when compared to patients without calcification. Patients with calcium oxalate deposition alone, compared to calcium phosphate or mixed calcifications, had fewer comorbidities but were more likely to have a history of gastric bypass surgery or malabsorption and take vitamin D. In patients with two or more years of follow-up, multivariate analyses showed the presence of calcification (HR 0.59, 0.38-0.92, p = 0.02) and higher eGFR (HR 0.76, 0.73-0.79, p < 0.001), was associated with decreased likelihood of progressing to end-stage renal disease. The presence of calcification was also associated with a reduced slope/decline in eGFR compared to known biopsy and clinical risk factors for decline in kidney function. We hypothesized this was due to more recoverable acute kidney injury (AKI) and found more severe acute kidney injury network stage in patients with kidney calcification but also greater improvement over time. Discussion/conclusion: In summary, we demonstrated that calcification on kidney biopsy specimens was associated with a better prognosis than those without calcification due to the association with recoverable AKI.