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- Aizawa, Kunihiko, et al.
(author)
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Reservoir Pressure Integral Is Independently Associated With the Reduction in Renal Function in Older Adults
- 2022
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In: Hypertension. - 0194-911X. ; 79:10, s. 2364-2372
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Journal article (peer-reviewed)abstract
- Background: Arterial hemodynamic parameters derived from reservoir-excess pressure analysis exhibit prognostic utility. Reservoir-excess pressure analysis may provide useful information about an influence of altered hemodynamics on target organ such as the kidneys. We determined whether the parameters derived from the reservoir-excess pressure analysis were associated with the reduction in estimated glomerular filtration rate in 542 older adults (69.4±7.9 years, 194 females) at baseline and after 3 years. Methods: Reservoir-excess pressure parameters, including reservoir pressure integral, excess pressure integral, systolic, and diastolic rate constants, were obtained by radial artery tonometry. Results: After 3 years, and in a group of 94 individuals (72.4±7.6 years, 26 females), there was an estimated glomerular filtration rate reduction of >5% per year (median reduction of 20.5% over 3 years). A multivariable logistic regression analysis revealed that higher baseline reservoir pressure integral was independently associated with a smaller reduction in estimated glomerular filtration rate after accounting for conventional cardiovascular risk factors and study centers (odds ratio: 0.660 [95% CIs, 0.494-0.883]; P=0.005). The association remained unchanged after further adjustments for potential confounders and baseline renal function (odds ratio: 0.528 [95% CIs, 0.351-0.794]; P=0.002). No other reservoir-excess pressure parameters exhibited associations with the reduction in renal function. Conclusions: This study demonstrates that baseline reservoir pressure integral was associated with the decline in renal function in older adults at 3-year follow-up, independently of conventional cardiovascular risk factors. This suggests that reservoir pressure integral may play a role in the functional decline of the kidneys.
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- Aizawa, Kunihiko, et al.
(author)
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Type 2 diabetes exacerbates changes in blood pressure-independent arterial stiffness : cross-sectional and longitudinal evidence from the SUMMIT study
- 2024
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In: Journal of Applied Physiology. - 8750-7587. ; 136:1, s. 13-22
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Journal article (peer-reviewed)abstract
- Greater central artery stiffness is observed in people with type 2 diabetes (T2DM). Elevated blood pressure (BP) and altered arterial wall structure/composition in T2DM are generally considered as main drivers for this alteration. However, because conventional arterial stiffness measures are BP-dependent and as such an influence of BP remains in a measure, it is unclear if greater central artery stiffness is a function of greater BP, or due to changes in the structure and composition of the arterial wall. We aimed to measure BP-independent arterial stiffness (b0) cross-sectionally and longitudinally in T2DM. We studied 753 adults with T2DM (DM þ) and 436 adults without (DM-) at baseline (Phase 1), and 310 DM þ and 210 DM- adults at 3-yr follow-up (Phase 2). We measured carotid-femoral pulse wave velocity and used it to calculate b0. In Phase 1, b0 was significantly greater in DM þ than DM- after adjusting for age and sex [27.5 (26.6–28.3) vs. 23.6 (22.4–24.8) au, P < 0.001]. Partial correlation analyses after controlling for age and sex showed that b0 was significantly associated with hemoglobin A1c (r ¼ 0.15 P < 0.001) and heart rate [(HR): r ¼ 0.23 P < 0.001)] in DM þ . In Phase 2, percentage-change in b0 was significantly greater in DM þ than DM-[19.5 (14.9–24.0) vs. 5.0 (-0.6 to 10.6) %, P < 0.001] after adjusting for age, sex, and baseline b0. b0 was greater in DM þ than DM- and increased much more in DM þ than in DM- over 3 yr. This suggests that T2DM exacerbates BP-independent arterial stiffness and may have a complemental utility to existing arterial stiffness indices. NEW & NOTEWORTHY We demonstrate in this study a greater BP-independent arterial stiffness b0 in people with type 2 diabetes (T2DM) compared to those without, and also a greater change in b0 over 3 yr in people with T2DM than those without. These findings suggest that the intrinsic properties of the arterial wall may change in a different and more detrimental way in people with T2DM and likely represents accumulation of cardiovascular risk.
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- Dwivedi, Om Prakash, et al.
(author)
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Genome-wide mRNA profiling in urinary extracellular vesicles reveals stress gene signature for diabetic kidney disease
- 2023
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In: iScience. - 2589-0042. ; 26:5
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Journal article (peer-reviewed)abstract
- Urinary extracellular vesicles (uEV) are a largely unexplored source of kidney-derived mRNAs with potential to serve as a liquid kidney biopsy. We assessed ∼200 uEV mRNA samples from clinical studies by genome-wide sequencing to discover mechanisms and candidate biomarkers of diabetic kidney disease (DKD) in Type 1 diabetes (T1D) with replication in Type 1 and 2 diabetes. Sequencing reproducibly showed >10,000 mRNAs with similarity to kidney transcriptome. T1D DKD groups showed 13 upregulated genes prevalently expressed in proximal tubules, correlated with hyperglycemia and involved in cellular/oxidative stress homeostasis. We used six of them (GPX3, NOX4, MSRB, MSRA, HRSP12 and CRYAB) to construct a transcriptional “stress score” that reflected long-term decline of kidney function and could even identify normoalbuminuric individuals showing early decline. We thus provide workflow and web-resource for studying uEV transcriptomes in clinical urine samples and stress-linked DKD markers as potential early non-invasive biomarkers or drug targets.
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- Gonçalves, Isabel, et al.
(author)
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Association between renin and atherosclerotic burden in subjects with and without type 2 diabetes
- 2016
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In: BMC Cardiovascular Disorders. - : Springer Science and Business Media LLC. - 1471-2261. ; 16:1, s. 1-10
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Journal article (peer-reviewed)abstract
- Background: Activation of the renin-angiotensin-aldosterone-system (RAAS) has been proposed to contribute to development of vascular complications in type 2 diabetes (T2D). The aim of the present study was to determine if plasma renin levels are associated with the severity of vascular changes in subjects with and without T2D. Methods: Renin was analyzed by the Proximity Extension Assay in subjects with (n = 985) and without (n = 515) T2D participating in the SUMMIT (SUrrogate markers for Micro- and Macro-vascular hard endpoints for Innovative diabetes Tools) study and in 205 carotid endarterectomy patients. Vascular changes were assessed by determining ankle-brachial pressure index (ABPI), carotid intima-media thickness (IMT), carotid plaque area, pulse wave velocity (PWV) and the reactivity hyperemia index (RHI). Results: Plasma renin was elevated in subjects with T2D and demonstrated risk factor-independent association with prevalent cardiovascular disease both in subjects with and without T2D. Renin levels increased with age, body mass index, HbA1c and correlated inversely with HDL. Subjects with T2D had more severe carotid disease, increased arterial stiffness, and impaired endothelial function. Risk factor-independent associations between renin and APBI, bulb IMT, carotid plaque area were observed in both T2D and non-T2D subjects. These associations were independent of treatment with RAAS inhibitors. Only weak associations existed between plasma renin and the expression of pro-inflammatory and fibrous components in plaques from 205 endarterectomy patients. Conclusions: Our findings provide clinical evidence for associations between systemic RAAS activation and atherosclerotic burden and suggest that this association is of particular importance in T2D.
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- Goncalves, Isabel, et al.
(author)
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Elevated Plasma Levels of MMP-12 Are Associated With Atherosclerotic Burden and Symptomatic Cardiovascular Disease in Subjects With Type 2 Diabetes.
- 2015
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In: Arteriosclerosis, Thrombosis and Vascular Biology. - 1524-4636. ; 35:7, s. 1723-1731
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Journal article (peer-reviewed)abstract
- Matrix metalloproteinases (MMPs) degrade extracellular matrix proteins and play important roles in development and tissue repair. They have also been shown to have both protective and pathogenic effects in atherosclerosis, and experimental studies have suggested that MMP-12 contributes to plaque growth and destabilization. The objective of this study was to investigate the associations between circulating MMPs, atherosclerosis burden, and incidence of cardiovascular disease with a particular focus on type 2 diabetes mellitus.
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- Gooding, Kim, et al.
(author)
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Prognostic imaging biomarkers for diabetic kidney disease (iBEAt): study protocol
- 2020
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In: BMC Nephrology. - : Springer Science and Business Media LLC. - 1471-2369. ; 21:1
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Journal article (peer-reviewed)abstract
- BACKGROUND: Diabetic kidney disease (DKD) remains one of the leading causes of premature death in diabetes. DKD is classified on albuminuria and reduced kidney function (estimated glomerular filtration rate (eGFR)) but these have modest value for predicting future renal status. There is an unmet need for biomarkers that can be used in clinical settings which also improve prediction of renal decline on top of routinely available data, particularly in the early stages. The iBEAt study of the BEAt-DKD project aims to determine whether renal imaging biomarkers (magnetic resonance imaging (MRI) and ultrasound (US)) provide insight into the pathogenesis and heterogeneity of DKD (primary aim) and whether they have potential as prognostic biomarkers in DKD (secondary aim). METHODS: iBEAt is a prospective multi-centre observational cohort study recruiting 500 patients with type 2 diabetes (T2D) and eGFR ≥30 ml/min/1.73m2. At baseline, blood and urine will be collected, clinical examinations will be performed, and medical history will be obtained. These assessments will be repeated annually for 3 years. At baseline each participant will also undergo quantitative renal MRI and US with central processing of MRI images. Biological samples will be stored in a central laboratory for biomarker and validation studies, and data in a central data depository. Data analysis will explore the potential associations between imaging biomarkers and renal function, and whether the imaging biomarkers improve the prediction of DKD progression. Ancillary substudies will: (1) validate imaging biomarkers against renal histopathology; (2) validate MRI based renal blood flow measurements against H2O15 positron-emission tomography (PET); (3) validate methods for (semi-)automated processing of renal MRI; (4) examine longitudinal changes in imaging biomarkers; (5) examine whether glycocalyx and microvascular measures are associated with imaging biomarkers and eGFR decline; (6) explore whether the findings in T2D can be extrapolated to type 1 diabetes. DISCUSSION: iBEAt is the largest DKD imaging study to date and will provide valuable insights into the progression and heterogeneity of DKD. The results may contribute to a more personalised approach to DKD management in patients with T2D. TRIAL REGISTRATION: Clinicaltrials.gov ( NCT03716401 ).
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| 9. |
- Khan, Faisel, et al.
(author)
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Plaque characteristics and biomarkers predicting regression and progression of carotid atherosclerosis
- 2022
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In: Cell Reports Medicine. - : Elsevier BV. - 2666-3791. ; 3:7
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Journal article (peer-reviewed)abstract
- The factors that influence the atherosclerotic disease process in high-risk individuals remain poorly understood. Here, we used a combination of vascular imaging, risk factor assessment, and biomarkers to identify factors associated with 3-year change in carotid disease severity in a cohort of high-risk subjects treated with preventive therapy (n = 865). The results show that changes in intima-media thickness (IMT) are most pronounced in the carotid bulb. Progression of bulb IMT demonstrates independent associations with baseline bulb IMT, the plaque gray scale median (GSM), and the plasma level of platelet-derived growth factor (PDGF) (standardized β-coefficients and 95% confidence interval [CI] −0.14 [−0.06 to −0.02] p = 0.001, 0.15 [0.02–0.07] p = 0.001, and 0.20 [0.03–0.07] p < 0.001, respectively). Plasma PDGF correlates with the plaque GSM (0.23 [0.15–0.29] p < 0.001). These observations provide insight into the atherosclerotic process in high-risk subjects by showing that progression primarily occurs in fibrotic plaques and is associated with increased levels of PDGF.
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| 10. |
- Natali, Andrea, et al.
(author)
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Metformin is the key factor in elevated plasma growth differentiation factor-15 levels in type 2 diabetes : A nested, case–control study
- 2019
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In: Diabetes, Obesity and Metabolism. - : Wiley. - 1462-8902. ; 21:2, s. 412-416
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Journal article (peer-reviewed)abstract
- Produced as a tissue defence response to hypoxia and inflammation, growth differentiation factor-15 (GDF-15) is elevated in people receiving metformin treatment. To gain insight into the relationship of GDF-15 with metformin and major cardiovascular risk factors, we analysed the data from the SUMMIT cohort (n = 1438), a four-centre, nested, case–control study aimed at verifying whether biomarkers of atherosclerosis differ according to the presence of type 2 diabetes and cardiovascular disease. While in univariate analysis, major cardiovascular risk factors, with the exception of gender and cholesterol, increased similarly and linearly across GDF-15 quartiles, the independent variables associated with GDF-15, both in participants with and without diabetes, were age, plasma creatinine, N-terminal pro-brain natriuretic peptide, diuretic use, smoking exposure and glycated haemoglobin. In participants with diabetes, metformin treatment was associated with a 40% rise in GDF-15 level, which was independent of the other major factors, and largely explained their elevated GDF-15 levels. The relatively high GDF-15 bioavailability might partly explain the protective cardiovascular effects of metformin.
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