Browsing by Subject "Cardiovascular system"

Now showing 1 - 7 of 7
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    Computational Methods and Models in Circulatory and Reproductive Systems
    (Hindawi, 2016) Tian, Fang-Bao; Sui, Yi; Zhu, Luoding; Shu, Chang; Sung, Hyung J.; Department of Mathematical Sciences, School of Science
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    The Emerging Roles of the RNA Binding Protein QKI in Cardiovascular Development and Function
    (Frontiers Media, 2021-06-16) Chen, Xinyun; Yin, Jianwen; Cao, Dayan; Xiao, Deyong; Zhou, Zhongjun; Liu, Ying; Shou, Weinian; Pediatrics, School of Medicine
    RNA binding proteins (RBPs) have a broad biological and physiological function and are critical in regulating pre-mRNA posttranscriptional processing, intracellular migration, and mRNA stability. QKI, also known as Quaking, is a member of the signal transduction and activation of RNA (STAR) family, which also belongs to the heterogeneous nuclear ribonucleoprotein K- (hnRNP K-) homology domain protein family. There are three major alternatively spliced isoforms, QKI-5, QKI-6, and QKI-7, differing in carboxy-terminal domains. They share a common RNA binding property, but each isoform can regulate pre-mRNA splicing, transportation or stability differently in a unique cell type-specific manner. Previously, QKI has been known for its important role in contributing to neurological disorders. A series of recent work has further demonstrated that QKI has important roles in much broader biological systems, such as cardiovascular development, monocyte to macrophage differentiation, bone metabolism, and cancer progression. In this mini-review, we will focus on discussing the emerging roles of QKI in regulating cardiac and vascular development and function and its potential link to cardiovascular pathophysiology.
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    Kidney, Cardiovascular, and Safety Outcomes of Canagliflozin according to Baseline Albuminuria: A CREDENCE Secondary Analysis
    (Wolters Kluwer, 2021) Jardine, Meg; Zhou, Zien; Lambers Heerspink, Hiddo J.; Hockham, Carinna; Li, Qiang; Agarwal, Rajiv; Bakris, George L.; Cannon, Christopher P.; Charytan, David M.; Greene, Tom; Levin, Adeera; Li, Jing-Wei; Neuen, Brendon L.; Neal, Bruce; Oh, Richard; Oshima, Megumi; Pollock, Carol; Wheeler, David C.; de Zeeuw, Dick; Zhang, Hong; Zinman, Bernard; Mahaffey, Kenneth W.; Perkovic, Vlado; Medicine, School of Medicine
    Background and objectives: The kidney protective effects of renin-angiotensin system inhibitors are greater in people with higher levels of albuminuria at treatment initiation. Whether this applies to sodium-glucose cotransporter 2 (SGLT2) inhibitors is uncertain, particularly in patients with a very high urine albumin-to-creatinine ratio (UACR; ≥3000 mg/g). We examined the association between baseline UACR and the effects of the SGLT2 inhibitor, canagliflozin, on efficacy and safety outcomes in the Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) randomized controlled trial. Design, setting, participants, & measurements: The study enrolled 4401 participants with type 2 diabetes, an eGFR of 30 to <90 ml/min per 1.73 m2, and UACR of >300 to 5000 mg/g. Using Cox proportional hazards regression, we examined the relative and absolute effects of canagliflozin on kidney, cardiovascular, and safety outcomes according to a baseline UACR of ≤1000 mg/g (n=2348), >1000 to <3000 mg/g (n=1547), and ≥3000 mg/g (n=506). In addition, we examined the effects of canagliflozin on UACR itself, eGFR slope, and the intermediate outcomes of glycated hemoglobin, body weight, and systolic BP. Results: Overall, higher UACR was associated with higher rates of kidney and cardiovascular events. Canagliflozin reduced efficacy outcomes for all UACR levels, with no evidence that relative benefits varied between levels. For example, canagliflozin reduced the primary composite outcome by 24% (hazard ratio [HR], 0.76; 95% confidence interval [95% CI], 0.56 to 1.04) in the lowest UACR subgroup, 28% (HR, 0.72; 95% CI, 0.56 to 0.93) in the UACR subgroup >1000 to <3000 mg/g, and 37% (HR, 0.63; 95% CI, 0.47 to 0.84) in the highest subgroup (Pheterogeneity=0.55). Absolute risk reductions for kidney outcomes were greater in participants with higher baseline albuminuria; the number of primary composite events prevented across ascending UACR categories were 17 (95% CI, 3 to 38), 45 (95% CI, 9 to 81), and 119 (95% CI, 35 to 202) per 1000 treated participants over 2.6 years (Pheterogeneity=0.02). Rates of kidney-related adverse events were lower with canagliflozin, with a greater relative reduction in higher UACR categories. Conclusions: Canagliflozin safely reduces kidney and cardiovascular events in people with type 2 diabetes and severely increased albuminuria. In this population, the relative kidney benefits were consistent over a range of albuminuria levels, with greatest absolute kidney benefit in those with an UACR ≥3000 mg/g.
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    Non-coding cause of congenital heart defects: Abnormal RNA splicing with multiple isoforms as a mechanism for heterotaxy
    (Elsevier, 2024) Wells, John R.; Padua, Maria B.; Haaning, Allison M.; Smith, Amanda M.; Morris, Shaine A.; Tariq, Muhammad; Ware, Stephanie M.; Medical and Molecular Genetics, School of Medicine
    Heterotaxy is a disorder characterized by severe congenital heart defects (CHDs) and abnormal left-right patterning in other thoracic or abdominal organs. Clinical and research-based genetic testing has previously focused on evaluation of coding variants to identify causes of CHDs, leaving non-coding causes of CHDs largely unknown. Variants in the transcription factor zinc finger of the cerebellum 3 (ZIC3) cause X-linked heterotaxy. We identified an X-linked heterotaxy pedigree without a coding variant in ZIC3. Whole-genome sequencing revealed a deep intronic variant (ZIC3 c.1224+3286A>G) predicted to alter RNA splicing. An in vitro minigene splicing assay confirmed the variant acts as a cryptic splice acceptor. CRISPR-Cas9 served to introduce the ZIC3 c.1224+3286A>G variant into human embryonic stem cells demonstrating pseudoexon inclusion caused by the variant. Surprisingly, Sanger sequencing of the resulting ZIC3 c.1224+3286A>G amplicons revealed several isoforms, many of which bypass the normal coding sequence of the third exon of ZIC3, causing a disruption of a DNA-binding domain and a nuclear localization signal. Short- and long-read mRNA sequencing confirmed these initial results and identified additional splicing patterns. Assessment of four isoforms determined abnormal functions in vitro and in vivo while treatment with a splice-blocking morpholino partially rescued ZIC3. These results demonstrate that pseudoexon inclusion in ZIC3 can cause heterotaxy and provide functional validation of non-coding disease causation. Our results suggest the importance of non-coding variants in heterotaxy and the need for improved methods to identify and classify non-coding variation that may contribute to CHDs.
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    SCMR level II/independent practitioner training guidelines for cardiovascular magnetic resonance: integration of a virtual training environment
    (BMC, 2021-12-27) Patel, Amit R.; Kelle, Sebastian; Fontana, Marianna; Jacob, Ron; Stojanovska, Jadranka; Collins, Jeremy; Patel, Hena N.; Francone, Marco; Han, Yuchi; Bandettini, W. Patricia; Bucciarelli‑Ducci, Chiara; Raman, Subha; Weissman, Gaby; Medicine, School of Medicine
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    Simulation of blood flow past distal arteriovenous-graft anastomosis with intimal hyperplasia
    (AIP, 2021-05) Zhu, Luoding (祝罗丁 ); Sakai, Kaoru; Mathematical Sciences, School of Science
    Late-stage kidney disease patients have to rely on hemodialysis for the maintenance of their regular lives. Arteriovenous graft (AVG) is one of the commonly used devices for dialysis. However, this artificially created shunt may get clotted and eventually causes the dialysis to fail. The culprit behind the AVG clotting and failure is the intimal hyperplasia (IH), the gradual thickening of vein-wall in the vicinity of the blood vessel-graft conjunctions. The mechanism of IH is not well understood despite extensive studies. In this work, we investigate the effects of the IH development, including its location and severity on the flow and force fields in the distal AVG anastomosis using computational fluid dynamics. The stenosis due to IH is modeled in the shape of a Gaussian function with two free parameters. The blood is modeled as a viscous incompressible fluid, and the blood flow (pulsatile) is governed by the Navier–Stokes equations which are numerically solved by the lattice Boltzmann model (D3Q19). The fluid-structure interaction is modeled by the immersed boundary framework. Our computational results show that the IH severity has the most significant influences on the wall shear stress, wall-normal stress, and the axial oscillating index. The stenosis location and flow pulsatility do not have pronounced effects on flow and force fields. Our results indicate that the IH progression tends to exacerbate the disease and accelerate the closure of the vein lumen, and hence the dialysis failure.
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    Society for Cardiovascular Magnetic Resonance (SCMR) guidelines for reporting cardiovascular magnetic resonance examinations
    (Elsevier, 2022-04-28) Hundley, W. Gregory; Bluemke, David A.; Bogaert, Jan; Flamm, Scott D.; Fontana, Marianna; Friedrich, Matthias G.; Grosse‑Wortmann, Lars; Karamitsos, Theodoros D.; Kramer, Christopher M.; Kwong, Raymond Y.; McConnell, Michael; Nagel, Eike; Neubauer, Stefan; Nijveldt, Robin; Pennell, Dudley J.; Petersen, Steffen E.; Raman, Subha V.; van Rossum, Albert; Medicine, School of Medicine