Morphological and functional cardiac consequences of rapid hypertension treatment: a cohort study.

BACKGROUND: Left ventricular (LV) hypertrophy (LVH) in uncontrolled hypertension is an independent predictor of mortality, though its regression with treatment improves outcomes. Retrospective data suggest that early control of hypertension provides a prognostic advantage and this strategy is included in the 2018 European guidelines, which recommend treating grade II/III hypertension to target blood pressure (BP) within 3 months. The earliest LVH regression to date was demonstrated by echocardiography at 24 weeks. The effect of a rapid guideline-based treatment protocol on LV remodelling, with very early BP control by 18 weeks remains controversial and previously unreported. We aimed to determine whether such rapid hypertension treatment is associated with improvements in LV structure and function through paired cardiovascular magnetic resonance (CMR) scanning at baseline and 18 weeks, utilising CMR mass and feature tracking analysis. METHODS: We recruited participants with never-treated grade II/III hypertension, initiating a guideline-based treatment protocol which aimed to achieve BP control within 18 weeks. CMR and feature tracking were used to assess myocardial morphology and function immediately before and after treatment. RESULTS: We acquired complete pre- and 18-week post-treatment data for 41 participants. During the interval, LV mass index reduced significantly (43.5 ± 9.8 to 37.6 ± 8.3 g/m2, p < 0.001) following treatment, accompanied by reductions in LV ejection fraction (65.6 ± 6.8 to 63.4 ± 7.1%, p = 0.03), global radial strain (46.1 ± 9.7 to 39.1 ± 10.9, p < 0.001), mid-circumferential strain (- 20.8 ± 4.9 to - 19.1 ± 3.7, p = 0.02), apical circumferential strain (- 26.0 ± 5.3 to - 23.4 ± 4.2, p = 0.003) and apical rotation (9.8 ± 5.0 to 7.5 ± 4.5, p = 0.003). CONCLUSIONS: LVH regresses following just 18 weeks of intensive antihypertensive treatment in subjects with newly-diagnosed grade II/III hypertension. This is accompanied by potentially advantageous functional changes within the myocardium and supports the hypothesis that rapid treatment of hypertension could improve clinical outcomes. TRIAL REGISTRATION: ISRCTN registry number: 57475376 (assigned 25/06/2015).

Weight change and sulfonylurea therapy are related to 3 year change in microvascular function in people with type 2 diabetes.

AIMS/HYPOTHESIS: Although cardiovascular disease is the biggest cause of death in people with diabetes, microvascular complications have a significant impact on quality of life and financial burden of the disease. Little is known about the progression of microvascular dysfunction in the early stages of type 2 diabetes before the occurrence of clinically apparent complications. We aimed to explore the determinants of endothelial-dependent and -independent microvascular function progression over a 3 year period, in people with and without both diabetes and few clinical microvascular complications. METHODS: Demographics were collected in 154 participants with type 2 diabetes and in a further 99 participants without type 2 diabetes. Skin microvascular endothelium-dependent response to iontophoresis of acetylcholine and endothelium-independent responses to sodium nitroprusside were measured using laser Doppler fluximetry. All assessments were repeated 3 years later. RESULTS: People with type 2 diabetes had impaired endothelial-dependent microvascular response compared with those without (AUC 93.9 [95% CI 88.1, 99.4] vs 111.9 [102.3, 121.4] arbitrary units [AU] × min, p < 0.001, for those with vs without diabetes, respectively). Similarly, endothelial-independent responses were attenuated in those with diabetes (63.2 [59.2, 67.2] vs 75.1 [67.8, 82.4] AU × min, respectively, p = 0.002). Mean microvascular function declined over 3 years in both groups to a similar degree (pinteraction 0.74 for response to acetylcholine and 0.69 for response to sodium nitroprusside). In those with diabetes, use of sulfonylurea was associated with greater decline (p = 0.022 after adjustment for co-prescriptions, change in HbA1c and weight), whereas improving glycaemic control was associated with less decline of endothelial-dependent microvascular function (p = 0.03). Otherwise, the determinants of microvascular decline were similar in those with and without diabetes. The principal determinant of change in microvascular function in the whole population was weight change over 3 years, such that those that lost ≥5% weight had very little decline in either endothelial-dependent or -independent function compared with those that were weight stable, whereas those who gained weight had a greater decline in function (change in endothelial-dependent function was 1.2 [95% CI -13.2, 15.7] AU × min in those who lost weight; -15.8 [-10.5, -21.0] AU × min in those with stable weight; and -37.8 [-19.4, -56.2] AU × min in those with weight gain; ptrend < 0.001). This association of weight change with change in endothelial function was driven by people with diabetes; in people without diabetes, the relationship was nonsignificant. CONCLUSIONS/INTERPRETATION: Over 3 years, physiological change in weight was the greatest predictor of change in microvascular function.

Prognostic imaging biomarkers for diabetic kidney disease (iBEAt): study protocol.

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 ).

Locally delivered GLP-1 analogues liraglutide and exenatide enhance microvascular perfusion in individuals with and without type 2 diabetes.

AIMS/HYPOTHESIS: Glucagon-like peptide-1 (GLP-1) analogues reduce the risk of macrovascular disease in diabetes; however, little is known about their microvascular effects. This research examined the microvascular actions of the GLP-1 analogues liraglutide and exenatide in individuals with and without type 2 diabetes (study 1). It also explored the involvement of the GLP-1 receptor (study 2) and the nitric oxide pathway in mediating the microvascular effects of the analogues. METHODS: Trial design: Studies 1 and 2 had a randomised, controlled, double-blind study design. Study 1 participants, intervention and methods: three participant groups were recruited: individuals with well-controlled type 2 diabetes, and obese and lean individuals without diabetes (21 participants per group). Liraglutide (0.06 mg), exenatide (0.5 µg) and saline (154 mmol/l NaCl; 0.9%) control were microinjected into separate sites in the dermis (forearm) in a randomised order, blinded to operator and participant. Skin microvascular perfusion was assessed by laser Doppler perfusion imaging. Outcomes were stabilised response (mean skin perfusion between 7.5 and 10 min post microinjection) and total response (AUC, normalised for baseline perfusion). Perfusion response to GLP-1 analogues was compared with saline within each group as well as between groups. Study 2 participants, intervention and methods: in healthy individuals (N = 16), liraglutide (0.06 mg) and saline microinjected sites were pretreated with saline or the GLP-1 receptor blocker, exendin-(9,39), in a randomised order, blinded to participant and operator. Outcomes were as above (stabilised response and total perfusion response). Perfusion response to liraglutide was compared between the saline and the exendin-(9,39) pretreated sites. In vitro study: the effects of liraglutide and exenatide on nitrate levels and endothelial nitric oxide synthase phosphorylation (activation) were examined using human microvascular endothelial cells. RESULTS: Study 1 results: both analogues increased skin perfusion (stabilised response and total response) in all groups (n = 21 per group, p < 0.001), with the microvascular responses similar across groups (p ≥ 0.389). Study 2 results: liraglutide response (stabilised response and total response) was not influenced by pretreatment with exendin-(9,39) (70 nmol/l) (N = 15, one dataset excluded) (p ≥ 0.609). Liraglutide and exenatide increased nitrate production and endothelial nitric oxide synthase (eNOS) phosphorylation (p ≤ 0.020). CONCLUSIONS/INTERPRETATION: Liraglutide and exenatide increased skin microvascular perfusion in individuals with and without well-controlled diabetes, potentially mediated, at least in part, by NO. TRIAL REGISTRATION: ClinicalTrials.gov NCT01677104. FUNDING: This work was supported by Diabetes UK (grant numbers: 09/0003955 and 12/0004600 [RW and JM Collins Legacy, Funded Studentship]).

Metformin is the key factor in elevated plasma growth differentiation factor-15 levels in type 2 diabetes: A nested, case-control study.

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.

Red Blood Cell Susceptibility to Pneumolysin: CORRELATION WITH MEMBRANE BIOCHEMICAL AND PHYSICAL PROPERTIES.

This study investigated the effect of the biochemical and biophysical properties of the plasma membrane as well as membrane morphology on the susceptibility of human red blood cells to the cholesterol-dependent cytolysin pneumolysin, a key virulence factor of Streptococcus pneumoniae, using single cell studies. We show a correlation between the physical properties of the membrane (bending rigidity and surface and dipole electrostatic potentials) and the susceptibility of red blood cells to pneumolysin-induced hemolysis. We demonstrate that biochemical modifications of the membrane induced by oxidative stress, lipid scrambling, and artificial cell aging modulate the cell response to the toxin. We provide evidence that the diversity of response to pneumolysin in diabetic red blood cells correlates with levels of glycated hemoglobin and that the mechanical properties of the red blood cell plasma membrane are altered in diabetes. Finally, we show that diabetic red blood cells are more resistant to pneumolysin and the related toxin perfringolysin O relative to healthy red blood cells. Taken together, these studies indicate that the diversity of cell response to pneumolysin within a population of human red blood cells is influenced by the biophysical and biochemical status of the plasma membrane and the chemical and/or oxidative stress pre-history of the cell.

GLP-1 analogue-induced weight loss does not improve obesity-induced AT dysfunction.

Glucagon-like peptide-1 (GLP-1) analogues aid weight loss that improves obesity-associated adipose tissue (AT) dysfunction. GLP-1 treatment may however also directly influence AT that expresses the GLP-1 receptor (GLP-1R). The present study aimed to assess the impact of GLP-1 analogue treatment on subcutaneous AT (SCAT) inflammatory and fibrotic responses, compared with weight loss by calorie reduction (control). Among the 39 participants with Type 2 diabetes recruited, 30 age-matched participants were randomized to 4 months treatment with Liraglutide (n=22) or calorie restriction based on dietetic counselling (n=8). Assessments included clinical characteristics and repeated subcutaneous abdominal AT biopsies. Liraglutide resulted in weight loss in most participants (-3.12±1.72 kg, P=0.007) and significant reduction in visceral AT (VAT). It was more effective in lowering fasting glucose, in comparison with weight loss by dieting. However, tumour necrosis factor-α (TNFA) AT-expression (P=0.0005), macrophage chemoattractant protein-1 (MCP-1) expression (P=0.027) and its serum levels (P=0.048) increased with Liraglutide, suggestive of an inflammatory response unlike in the diet arm in which a trend of lower cluster of differentiation 14 (CD14) expression (P=0.09) was found. Liraglutide treatment also increased expression of factors involved in extracellular matrix (ECM) deposition, transforming growth factor-ß (TGFB) and collagen type 1 alpha 1 chain (COL1A1) (TGFB1: before 0.73±0.09 arbitrary units (AU), after 1.00±0.13 AU, P=0.006; COL1A1: 0.84±0.09 AU compared with 1.49±0.26 AU, P=0.026). Liraglutide thus appears to induce an inflammatory response in AT and influences ECM remodelling. Despite its superior effect on glycaemia, Liraglutide does not improve obesity-associated AT dysfunction in subcutaneous tissue. It is yet unclear whether this limits AT storage capacity for lipids. This may be of importance in patients being re-exposed to positive energy balance such as post GLP-1 discontinuation.

Elevated Plasma Levels of MMP-12 Are Associated With Atherosclerotic Burden and Symptomatic Cardiovascular Disease in Subjects With Type 2 Diabetes.

OBJECTIVE: 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. APPROACH AND RESULTS: Plasma levels of MMP-1, -3, -7, -10, and -12 were analyzed by the Proximity Extension Assay technology in 1500 subjects participating in the SUMMIT (surrogate markers for micro- and macrovascular hard end points for innovative diabetes tools) study, 384 incident coronary cases, and 409 matched controls in the Malmö Diet and Cancer study and in 205 carotid endarterectomy patients. Plasma MMP-7 and -12 were higher in subjects with type 2 diabetes mellitus, increased with age and impaired renal function, and was independently associated with prevalent cardiovascular disease, atherosclerotic burden (as assessed by carotid intima-media thickness and ankle-brachial pressure index), arterial stiffness, and plaque inflammation. Baseline MMP-7 and -12 levels were increased in Malmö Diet and Cancer subjects who had a coronary event during follow-up. CONCLUSIONS: The plasma level of MMP-7 and -12 are elevated in type 2 diabetes mellitus, associated with more severe atherosclerosis and an increased incidence of coronary events. These observations provide clinical support to previous experimental studies, demonstrating a role for these MMPs in plaque development, and suggest that they are potential biomarkers of atherosclerosis burden and cardiovascular disease risk.

Association between renin and atherosclerotic burden in subjects with and without type 2 diabetes.

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.

Blood Oxygen Saturation After Ischemia is Altered With Abnormal Microvascular Reperfusion.

OBJECTIVE: We have previously described a distinct abnormality in the cutaneous microcirculation that is characterized by an abnormal reperfusion response following an ischemic stimulus. We investigated the physiological significance of this abnormality; by measuring microvascular perfusion and blood oxygen saturation in groups stratified by three distinct reperfusion responses. METHODS: Cutaneous microvascular reperfusion after four minutes of arterial occlusion above the ankle was measured on the foot using laser Doppler fluximetry and optical reflectance spectroscopy in almost 400 adults. Individuals were stratified into three groups according to the microvascular reperfusion response: normal and two abnormal patterns (DEP and NDEP). RESULTS: Our main findings were that abnormal microvascular reperfusion responses (DEP and NDEP) had a higher baseline oxygen saturation (p = 0.005), a lower plateau in oxygen saturation (p < 0.0001 and <0.0001, respectively), lower oxygen saturation area under the curve (p < 0.0001 and <0.0001), a longer time to reach oxygen saturation plateau (p = 0.002 and 0.001), and a longer time to initiate an increase in oxygen saturation (p = 0.007 and 0.001) compared to normal. Differences remained after adjustment for confounding variables. CONCLUSIONS: Individuals with abnormal microvascular reperfusion had a markedly altered pattern of oxygen increase during reperfusion. We propose that this may represent dysfunctional microvascular autoregulation that is clinically important in the etiopathology of target organ damage.

Are the cardiovascular properties of GLP-1 receptor agonists differentially modulated by sulfonylureas? Insights from post-hoc analysis of EXSCEL.

AIMS: To examine whether the cardiovascular effects of glucagon-like peptide-1 (GLP-1) receptor agonists are attenuated by concurrent sulfonylurea (SU) therapy in a post-hoc analysis of the Exenatide Study of Cardiovascular Event Lowering (EXSCEL). METHODS: We investigated whether SUs, as a class or by specific type, modulated the effects of once-weekly exenatide (EQW) on EXSCEL cardiovascular outcomes in intent-to-treat analyses of all trial participants, categorized as SU users or nonusers. Marginal structural models were used to evaluate whether there were differential EQW effects by SU category on major adverse cardiovascular events (MACE), depending on duration of SU use (6, 12, and 18 months). EQW-by-SU type interaction p-values and hazard ratios (95 % CIs) for EQW versus placebo for each baseline SU type (glibenclamide, gliclazide, glimepiride, other SUs) were calculated. RESULTS: Neither SU use nor baseline SU type modified the effect of EQW on time to MACE (pinteraction = 0.88 and 0.78, respectively), nor did individual SU types, including glibenclamide (a systemically wide-acting SU). CONCLUSIONS: SUs did not modulate the effect of EQW on cardiovascular outcomes, suggesting that SU treatment choices need not be altered to optimize the cardiovascular effects of GLP-1 receptor agonists in people with type 2 diabetes.

Type 2 diabetes exacerbates changes in blood pressure-independent arterial stiffness: cross-sectional and longitudinal evidence from the SUMMIT study.

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 (ß0) cross-sectionally and longitudinally in T2DM. We studied 753 adults with T2DM (DM+) and 436 adults without (DM-) at baseline (Phase 1), and 310 DM+ and 210 DM- adults at 3-yr follow-up (Phase 2). We measured carotid-femoral pulse wave velocity and used it to calculate ß0. In Phase 1, ß0 was significantly greater in DM+ 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 ß0 was significantly associated with hemoglobin A1c (r = 0.15 P < 0.001) and heart rate [(HR): r = 0.23 P < 0.001)] in DM+. In Phase 2, percentage-change in ß0 was significantly greater in DM+ 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 ß0. ß0 was greater in DM+ than DM- and increased much more in DM+ 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 ß0 in people with type 2 diabetes (T2DM) compared to those without, and also a greater change in ß0 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.

Reservoir-excess pressure parameters are independently associated with NT-proBNP in older adults.

AIMS: Parameters derived from reservoir-excess pressure analysis have been demonstrated to predict cardiovascular events. Thus, altered reservoir-excess pressure parameters could have a detrimental effect on highly-perfused organs like the heart. We aimed to cross-sectionally determine whether reservoir-excess pressure parameters were associated with N-terminal pro-brain-type natriuretic peptide (NT-proBNP) in older adults. METHODS: We studied 868 older adults with diverse cardiovascular risk. Reservoir-excess pressure parameters were obtained through radial artery tonometry including reservoir pressure integral, peak reservoir pressure, excess pressure integral (INTXSP), systolic rate constant (SRC) and diastolic rate constant (DRC). Plasma levels of NT-proBNP, as a biomarker of cardiac overload, were analysed by the Proximity Extension Assay technology. RESULTS: Multivariable linear regression analyses revealed that all reservoir-excess pressure parameters studied were associated with NT-proBNP after adjusting for age and sex. After further adjustments for conventional cardiovascular risk factors, INTXSP [ß = 0.191 (95% confidence interval, CI: 0.099, 0.283), P < 0.001], SRC [ß = -0.080 (95% CI: -0.141, -0.019), P = 0.010] and DRC [ß = 0.138 (95% CI: 0.073, 0.202), P < 0.001] remained associated with NT-proBNP. Sensitivity analysis found that there were occasions where the association between SRC and NT-proBNP was attenuated, but both INTXSP and DRC remained consistently associated with NT-proBNP. CONCLUSIONS: The observed associations between reservoir-excess pressure parameters and NT-proBNP suggest that altered reservoir-excess pressure parameters may reflect an increased load inflicted on the left ventricular cardiomyocytes and could have a potential to be utilized in the clinical setting for cardiovascular risk stratification.

Aortic reservoir-excess pressure parameters are associated with worse cognitive function in people with untreated stage II/III hypertension.

OBJECTIVE: Hypertension is a recognized risk factor for the development of cognitive impairment and dementia in older adults. Aortic stiffness and altered haemodynamics could promote the transmission of detrimental high pressure pulsatility into the cerebral circulation, potentially damaging brain microvasculature and leading to cognitive impairment. We determined whether reservoir-excess pressure parameters were associated with cognitive function in people with hypertension (HT) and normotension (NT). METHODS: We studied 35 middle-aged and older treatment-naïve stage II/III HT (office systolic BP 176 ±â€Š17 mmHg) and 35 age-, sex- and body mass index-matched NT (office systolic BP 127 ±â€Š8 mmHg). Parameters derived from reservoir-excess pressure analysis including reservoir pressure integral (INTPR), excess pressure integral (INTXSP), systolic rate constant (SRC), diastolic rate constant (DRC) and pulse wave velocity (PWV) were calculated from an ensemble-averaged aortic pressure waveform derived from radial artery tonometry. Cognitive function was assessed using the Addenbrooke's Cognitive Examination Revised (ACE-R), Trail Making Test Part A (TMT-A) and Part B (TMT-B). RESULTS: All reservoir-excess pressure parameters were greater in HT than NT (all P < 0.05). Greater INTXSP was associated with lower ACE-R score (rs = -0.31), longer TMT-A (r = 0.31) and TMT-B (r = 0.38). Likewise, greater DRC and PWV were also associated with lower ACE-R score (rs = -0.27 and rs = -0.33), longer TMT-A (r = 0.51 and r = 0.40) and TMT-B (r = 0.38 and r = 0.32). Greater INTXSP, DRC and PWV are consistently associated with worse cognitive function in this study. CONCLUSIONS: These observations support a potential mechanistic link between adverse haemodynamics and a heightened risk of cognitive impairment in older adults with hypertension.

Genome-wide mRNA profiling in urinary extracellular vesicles reveals stress gene signature for diabetic kidney disease.

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.

Reservoir Pressure Integral Is Independently Associated With the Reduction in Renal Function in Older Adults.

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.

Carotid-femoral pulse wave velocity acquisition methods and their associations with cardiovascular risk factors and subclinical biomarkers of vascular health.

BACKGROUND: Different methods to measure carotid-femoral pulse wave velocity (CFPWV) may affect the measurements obtained and influence the association between CFPWV, cardiovascular risk factors and biomarkers of subclinical vascular health. The estimation of distance between the carotid and femoral artery measurement sites (the arterial path length) is particularly problematic. METHOD: We determined if CFPWV and equation-based estimates of CFPWV were influenced by arterial path length and if this affected the association of CFPWV with cardiovascular risk factors and subclinical vascular biomarkers. The CFPWV derived from the measurement of surface distance (CFPWV-D), arterial path length formula (CFPWV-F), and estimated CFPWV (ePWV) were obtained from 489 older adults (67.2 ±â€Š8.8 years). Macrovascular [carotid artery: lumen diameter (LD), inter-adventitial diameter (IAD), intima-media thickness (IMT) and total plaque area (TPA)] and microvascular [reactive hyperaemia index and urinary albumin-creatinine ratio (UACR)] biomarkers were also measured. RESULTS: CFPWV-D was significantly greater than CFPWV-F [9.6 (8.0-11.2) vs. 8.9 (7.6-10.5) m/s, P < 0.001], because of estimated path length being longer in CFPWV-D than CFPWV-F (495.4 ±â€Š44.8 vs. 465.3 ±â€Š20.6 mm, P < 0.001). ePWV was significantly greater than both CFPWV-F and CFPWV-D [11.0 (10.0-12.2) m/s, P < 0.001]. The three CFPWV methods were similarly associated with LD, IAD, IMT, TPA and UACR but not with cardiovascular risk factors. CONCLUSION: Different methods to measure CFPWV affect the derived measurement values and the association with cardiovascular risk factors but not the association with subclinical biomarkers of vascular health. These hitherto unreported observations are important considerations in experimental design, data interpretation and of particular importance, comparison between studies where CFPWV is measured.

Plaque characteristics and biomarkers predicting regression and progression of carotid atherosclerosis.

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 ß-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.

Cerebral small vessel disease, systemic vascular characteristics and potential therapeutic targets.

INTRODUCTION: Cerebral small vessel disease (SVD) is prevalent in the elderly population and is associated with increased risk of dementia, stroke and disability. Currently there are no clear targets or strategies for the treatment of cerebral SVD. We set out to identify modifiable vascular treatment targets. PATIENTS AND METHODS: 112 participants with and without a history of CVD underwent macrovascular, microvascular and endothelial function tests and an MRI head scan. RESULTS: Increased carotid intima media thickness and carotid-femoral pulse wave velocity were associated with cerebral WMH (ß=1·1 p=0·001 and ß=1·66, p<0·0001 respectively). Adjusted cerebral resistance index (p=0·03) and brachial flow mediated dilation time to peak (p=0·001) were associated with the severity of cerebral WMH independent of age and sex. Post occlusive reactive hyperaemia time as a measure of microvascular reactivity was associated with WMH after adjustment for age and sex (p=0·03). Ankle Brachial Pressure Index and urinary albumin excretion rate predicted the severity of cerebral WMH (p=0·02 and 0·01 respectively). Age and hypertension were the most important risk factors for WMH severity (p< 0·0001). DISCUSSION: In addition to hypertension, microalbuminuria, arterial stiffness, vascular reactivity and cerebrovascular resistance could be potential treatment targets to halt the development or progression of cerebral SVD.

Reservoir-Excess Pressure Parameters Independently Predict Cardiovascular Events in Individuals With Type 2 Diabetes.

[Figure: see text].