Factors associated with change in arterial stiffness in patients with rheumatoid arthritis: the JointHeart study.

BACKGROUND: Rheumatoid arthritis (RA) predominantly affects women and is associated with hypertension and arterial stiffness. We explored factors associated with change in arterial stiffness in patients with RA treated with disease-modifying antirheumatic drug (DMARD) therapy. METHODS: Seventy-seven outpatients with RA (age 55 ± 11, 69% women), with indication for treatment with biological or targeted synthetic DMARDs, were included. Pulse wave velocity (PWV), augmentation pressure (AP), augmentation index (AIx) and Disease Activity Score in 28 joints (DAS28) were measured at baseline and after a mean of 22 months of follow-up. RESULTS: At follow-up, 83% used DMARDs and 73% had achieved remission or low disease activity. DAS28 decreased from 3.8 ± 1.3 to 2.8 ± 1.2 (p < 0.001). Mean PWV increased from 7.8 ± 1.6 m/s at baseline to 8.5 ± 1.8 m/s at follow-up (p < 0.001), while AP and AIx were stable. Increase in PWV during follow-up was associated with increase in systolic blood pressure (BP), diabetes, higher DAS28 and body mass index (BMI) at baseline, independent of achieved remission/low disease activity and use of DMARDs at follow-up. In multivariable analyses at follow-up, female sex was associated with higher AP and AIx, but with lower PWV, after adjusting for possible confounders. CONCLUSION: In patients with RA, higher disease activity, BMI and diabetes at baseline, together with increase in office systolic BP were associated with an increase in arterial stiffness during follow-up, despite DMARD therapy. This highlights the need for management of cardiovascular risk factors in addition to reducing the inflammatory load in patients with RA to preserve arterial function.

Rheumatoid arthritis (RA) affects women more often than men and leads to chronic inflammation and faster stiffening of the arteries. In this study, we identified factors that were associated with increase in arterial stiffness during 22 months of follow-up in patients with RA treated with modern antirheumatic medication.This study included 77 patients with RA (69% women), that were in need of change in their disease-modifying antirheumatic medication.We measured arterial stiffness at baseline and repeated it after 22 months of follow-up.At follow-up, arterial stiffness had increased while the disease activity had improved. The rise in arterial stiffness was associated with having diabetes, higher body mass index and higher disease activity at the start of the study and with experiencing an increase in blood pressure during follow-up.This study highlights the need for maintaining a healthy lifestyle and treating cardiovascular risk factors like blood pressure and obesity in patients with RA beyond using modern antirheumatic medication to avoid stiffening of the arteries.

The effect of SGLT2 inhibitors and GLP1 receptor agonists on arterial stiffness: A meta-analysis of randomized controlled trials.

BACKGROUND: Pulse wave velocity (PWV) and augmentation index (AIx) are indices used to assess arterial stiffness. We evaluated the effect of sodium glucose co-transporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP1-RA) on arterial stiffness indices. METHODS: We searched PubMed (up to January 2024) for RCTs assessing the effect of SGLT2i or GLP1-RA on arterial stiffness with reporting outcomes PWV and AIx. Effect sizes of the included studies were expressed as weighted mean difference (WMD) and 95 % confidence interval. Subgroup analyses were performed based on comparator (placebo vs. active comparator), design (RCT vs. crossover), population (diabetic vs. all) and blindness (yes vs. no). RESULTS: A total of 19 studies (SGLT2i, 12 studies; GLP1-RA, 5 studies; SGLT2i/GLP1-RA combination, 2 studies) assessing 1212 participants were included. We did not find any statistically significant association between GLP1-RA or SGLT2i and PWV or AIx. None of the subgroup analyses showed any statistically significant result. CONCLUSION: No evidence of a favorable change in arterial stiffness indices (PWV, AIx) was found following the administration of SGLT2i or GLP1-RA.

Lipoprotein glomerulopathy with markedly increased arterial stiffness successfully treated with a combination of fenofibrate and losartan: a case report.

BACKGROUND: Lipoprotein glomerulopathy (LPG) is a apolipoprotein E (ApoE)-related glomerular disease and has been associated with type III hyperlipidemia. Without appropriate treatment, chronic kidney disease (CKD) caused by LPG progresses, and approximately half of the patients develop end-stage kidney disease within 1-27 years of disease onset. However, few studies have highlighted the clinical course of cardiovascular diseases (CVDs) in patients with LPG. Herein, we report the first case of LPG in which the CVD risk was assessed using arterial stiffness. CASE PRESENTATION: A 32-year-old Japanese man was referred to our hospital due to persistent proteinuria. Kidney biopsy showed markedly dilated capillary lumens containing pale-stained thrombi, which stained positively with Oil Red O. Electron microscopy revealed the presence of thrombi in the capillary lumen with low electron density and vacuoles of various sizes in part of the thrombi. Toluidine blue and Sudan IV stains were used to stain the thin sections of Epon-embedded tissue samples for electron microscopy. Sudan IV-positive droplets were observed in the capillary lumens, vascular walls, and cytoplasm of tubular cells. Increased serum ApoE concentration was observed. Liquid chromatography-tandem mass spectrometry of laser-microdissected glomeruli from paraffin sections revealed an increase in ApoE. Direct deoxyribonucleic acid sequencing of ApoE revealed a heterozygous ApoE Sendai mutation (Arg145Pro). The patient was finally diagnosed with LPG with heterozygosity for ApoE-Sendai mutation (Arg145Pro). Notably, at the time of diagnosis, he had markedly increased arterial stiffness for his age. Arterial stiffness was measured using brachial-ankle pulse wave velocity (baPWV), which was equivalent to that of a 56-year-old man. After three months of treatment with fenofibrate and losartan, a significant reduction in proteinuria was achieved along with an improvement in baPWV. Furthermore, these effects were maintained despite the lack of decrease in serum ApoE levels. CONCLUSION: Herein, we report the case of a patient with LPG with markedly increased arterial stiffness at the time of diagnosis, in whom combination therapy with fenofibrate and losartan successfully improved proteinuria and arterial stiffness. To the best of our knowledge, this is the first case report of LPG in which CVD risk was assessed using arterial stiffness.

Long-term exposure to ambient air pollution and measures of central hemodynamics and arterial stiffness among multiethnic Chicago residents.

OBJECTIVES: To examine whether long-term air pollution exposure is associated with central hemodynamic and brachial artery stiffness parameters. METHODS: We assessed central hemodynamic parameters including central blood pressure, cardiac parameters, systemic vascular compliance and resistance, and brachial artery stiffness measures [including brachial artery distensibility (BAD), compliance (BAC), and resistance (BAR)] using waveform analysis of the arterial pressure signals obtained from a standard cuff sphygmomanometer (DynaPulse2000A, San Diego, CA). The long-term exposures to particles with an aerodynamic diameter < 2.5 µm (PM2.5) and nitrogen dioxide (NO2) for the 3-year periods prior to enrollment were estimated at residential addresses using fine-scale intra-urban spatiotemporal models. Linear mixed models adjusted for potential confounders were used to examine associations between air pollution exposures and health outcomes. RESULTS: The cross-sectional study included 2,387 Chicago residents (76% African Americans) enrolled in the ChicagO Multiethnic Prevention And Surveillance Study (COMPASS) during 2013-2018 with validated address information, PM2.5 or NO2, key covariates, and hemodynamics measurements. We observed long-term concentrations of PM2.5 and NO2 to be positively associated with central systolic, pulse pressure and BAR, and negatively associated with BAD, and BAC after adjusting for relevant covariates. A 1-µg/m3 increment in preceding 3-year exposures to PM2.5 was associated with 1.8 mmHg higher central systolic (95% CI: 0.98, 4.16), 1.0 mmHg higher central pulse pressure (95% CI: 0.42, 2.87), a 0.56%mmHg lower BAD (95% CI: -0.81, -0.30), and a 0.009 mL/mmHg lower BAC (95% CI: -0.01, -0.01). CONCLUSION: This population-based study provides evidence that long-term exposures to PM2.5 and NO2 is related to central BP and arterial stiffness parameters, especially among African Americans.

Mechanistic insights into cardiovascular effects of ultrafine particle exposure: A longitudinal panel study.

BACKGROUND: Ultrafine particle (UFP) has been linked with higher risks of cardiovascular diseases; however, the biological mechanisms remain to be fully elucidated. OBJECTIVES: This study aims to investigate the cardiovascular responses to short-term UFP exposure and the biological pathways involved. METHODS: A longitudinal panel study was conducted among 32 healthy, non-smoking young adults in Shanghai, China, who were engaged in five rounds of follow-ups between December 2020 and November 2021. Individual exposures were calculated based on the indoor and outdoor real-time measurements. Blood pressure, arterial stiffness, targeted biomarkers, and untargeted proteomics and metabolomics were examined during each follow-up. Linear mixed-effect models were applied to analyze the exposure and health data. The differential proteins and metabolites were used for pathway enrichment analyses. RESULTS: Short-term UFP exposure was associated with significant increases in blood pressure and arterial stiffness. For example, systolic blood pressure increased by 2.10 % (95 % confidence interval: 0.63 %, 3.59 %) corresponding to each interquartile increase in UFP concentrations at lag 0-3 h, while pulse wave velocity increased by 2.26 % (95 % confidence interval: 0.52 %, 4.04 %) at lag 7-12 h. In addition, dozens of molecular biomarkers altered significantly. These effects were generally present within 24 h after UFP exposure, and were robust to the adjustment of co-pollutants. Molecular changes detected in proteomics and metabolomics analyses were mainly involved in systemic inflammation, oxidative stress, endothelial dysfunction, coagulation, and disturbance in lipid transport and metabolism. DISCUSSION: This study provides novel and compelling evidence on the detrimental subclinical cardiovascular effects in response to short-term UFP exposure. The multi-omics profiling further offers holistic insights into the underlying biological pathways.

Is GFR decline induced by SGLT2 inhibitor of clinical importance?

BACKGROUND: Use of sodium-glucose-cotransporter-2 (SGLT2) inhibitors often causes an initial decline in glomerular filtration rate (GFR). This study addresses the question whether the initial decline of renal function with SGLT2 inhibitor treatment is related to vascular changes in the systemic circulation. METHODS: We measured GFR (mGFR) and estimated GFR (eGFR) in 65 patients with type 2 diabetes (T2D) at baseline and after 12 weeks of treatment randomized either to a combination of empagliflozin and linagliptin (SGLT2 inhibitor based treatment group) (n = 34) or metformin and insulin (non-SGLT2 inhibitor based treatment group) (n = 31). mGFR was measured using the gold standard clearance technique by constant infusion of inulin. In addition to blood pressure (BP), we measured pulse wave velocity (PWV) under standardized conditions reflecting vascular compliance of large arteries, as PWV is considered to be one of the most reliable vascular parameter of cardiovascular (CV) prognosis. RESULTS: Both mGFR and eGFR decreased significantly after initiating treatment, but no correlation was found between change in mGFR and change in eGFR in either treatment group (SGLT2 inhibitor based treatment group: r=-0.148, p = 0.404; non-SGLT2 inhibitor based treatment group: r = 0.138, p = 0.460). Noticeably, change in mGFR correlated with change in PWV (r = 0.476, p = 0.005) in the SGLT2 inhibitor based treatment group only and remained significant after adjustment for the change in systolic BP and the change in heart rate (r = 0.422, p = 0.018). No such correlation was observed between the change in eGFR and the change in PWV in either treatment group. CONCLUSIONS: Our main finding is that after initiating a SGLT2 inhibitor based therapy an exaggerated decline in mGFR was related with improved vascular compliance of large arteries reflecting the pharmacologic effects of SGLT2 inhibitor in the renal and systemic vascular bed. Second, in a single patient with T2D, eGFR may not be an appropriate parameter to assess the true change of renal function after receiving SGLT2 inhibitor based therapy. TRIAL REGISTRATION: clinicaltrials.gov (NCT02752113).

Polycyclic aromatic hydrocarbons exposure and arterial stiffness-related plasma miRNAs: A panel study.

The underlying mechanisms between polycyclic aromatic hydrocarbons (PAHs) exposure and arterial stiffness are poorly understood. We carried out a panel study involving three repeated surveys to examine the associations of individual and mixture of PAHs exposure with arterial stiffness-related miRNAs among 123 community adults. In linear mixed-effect (LME) models, we found that urinary 9-hydroxyfluorene (9-OHFlu), 2-hydroxyphenanthrene (2-OHPh), 9-hydroxyphenanthrene (9-OHPh) at lag 0 day were positively linked to miR-146a and/or miR-222. The Bayesian kernel machine regression (BKMR) analyses revealed positive overall associations of PAHs mixture at lag 0 day with miR-146a and miR-222, and urinary 9-OHFlu contributed the most. In addition, an inter-quartile range (IQR) increase in urinary 9-OHFlu at lag 0 day was associated with elevated miR-146a and miR-222 by 0.16 (95% CI: 0.02, 0.30) to 0.34 (95% CI: 0.13, 0.54). Accordingly, exposure to PAHs, especially 9-OHFlu at lag 0 day, was related to elevated arterial stiffness-related plasma miRNAs.

Benefits of Puerarin on Metabolic Syndrome and Its Associated Cardiovascular Diseases in Rats Fed a High-Fat/High-Sucrose Diet.

Metabolic syndrome (MetS) is a cluster of risk factors for cardiovascular diseases (CVDs) that has become a global public health problem. Puerarin (PUE), the principal active compound of Pueraria lobata, has the effects of regulating glucose and lipid metabolism and protecting against cardiovascular damage. This study aimed to investigate whether dietary supplementation with PUE could ameliorate MetS and its associated cardiovascular damage. Rats were randomly divided into three groups: the normal diet group (NC), the high-fat/high-sucrose diet group (HFHS), and the HFHS plus PUE diet group (HFHS-PUE). The results showed that PUE-supplemented rats exhibited enhanced glucose tolerance, improved lipid parameters, and reduced blood pressure compared to those on the HFHS diet alone. Additionally, PUE reversed the HFHS-induced elevations in the atherogenic index (AI) and the activities of serum lactate dehydrogenase (LDH) and creatine kinase (CK). Ultrasonic evaluations indicated that PUE significantly ameliorated cardiac dysfunction and arterial stiffness. Histopathological assessments further confirmed that PUE significantly mitigated cardiac remodeling, arterial remodeling, and neuronal damage in the brain. Moreover, PUE lowered systemic inflammatory indices including C-reactive protein (CRP), neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), and systemic immune-inflammation index (SII). In conclusion, dietary supplementation with PUE effectively moderated metabolic disorders, attenuated systemic inflammation, and minimized cardiovascular damage in rats with MetS induced by an HFHS diet. These results provide novel insights into the potential benefits of dietary PUE supplementation for the prevention and management of MetS and its related CVDs.

Influence of Blood Pressure Reduction on Pulse Wave Velocity in Primary Hypertension: A Meta-Analysis and Comparison With an Acute Modulation of Transmural Pressure.

BACKGROUND: Increased arterial stiffness and pulse wave velocity (PWV) of the aorta and large arteries impose adverse hemodynamic effects on the heart and other organs. Antihypertensive treatment reduces PWV, but it is unknown whether this results from an unloading of stiffer elements in the arterial wall or is due to an alternate functional or structural change that might differ according to class of antihypertensive drug. METHODS: We performed a systematic review and meta-analysis of the effects of different antihypertensive drug classes and duration of treatment on PWV with and without adjustment for change in mean arterial blood pressure (BP; study 1) and compared this to the change in PWV after an acute change in transmural pressure, simulating an acute change in BP (study 2). RESULTS: A total of 83 studies involving 6200 subjects were identified. For all drug classes combined, the reduction of PWV was 0.65 (95% CI, 0.46-0.83) m/s per 10 mm Hg reduction in mean arterial BP, a change similar to that induced by an acute change in transmural pressure in a group of hypertensive subjects. When adjusted for change in mean arterial BP, the reduction in PWV after treatment with beta-blockers or diuretics was less than that after treatment with angiotensin-converting enzyme inhibitors/angiotensin receptor antagonists or calcium channel antagonists. CONCLUSIONS: Reduction in PWV after antihypertensive treatment is largely explained by the reduction in BP, but there are some BP-independent effects. These might increase over time and contribute to better outcomes over the long term, but this remains to be demonstrated in long-term clinical trials.

MFAP4-Deficiency Aggravates Age-Induced Changes in Resistance Artery Structure, While Ameliorating Hypertension.

BACKGROUND: Abnormalities of resistance arteries may play essential roles in the pathophysiology of aging and hypertension. Deficiency of the vascular extracellular matrix protein MFAP4 (microfibrillar-associated protein 4) has previously been observed as protective against aberrant arterial remodeling. We hypothesized that MFAP4-deficiency would reduce age- and hypertension-dependent arterial changes in extracellular matrix composition and stiffening. METHODS: Mesenteric arteries were isolated from old (20-23 months) littermate Mfap4+/+ and Mfap4-/- mice, and 2-photon excitation microscopy imaging was used to quantify elastin and collagen volumes and dimensions in the vascular wall. Ten-week-old littermate Mfap4+/+ and Mfap4-/- mice were subjected to 20 days of continuous Ang II (angiotensin II) infusion and hypertension was monitored using invasive blood pressure measurements. Arterial stiffness, responses to vascular constrictors, and myogenic tone were monitored using wire- or pressure-myography. Collagen contents were assessed by Western blotting. RESULTS: MFAP4-deficiency significantly increased collagen volume and elastin fragmentation in aged mesenteric arteries without affecting arterial stiffness. MFAP4-deficient mice exhibited reduced diastolic pressure in Ang II-induced hypertension. There was no significant effect of MFAP4-deficiency on mesenteric artery structural remodeling or myogenic tone, although collagen content in mesenteric arteries was tendentially increased in hypertensive Mfap4+/+ mice relative to Mfap4-/- mice. Increased efficacy of vasoconstrictors (phenylephrine, thromboxane) and reduced stiffness were observed in Ang II-treated Mfap4-/- mouse mesenteric arteries in ex vivo myography recordings. CONCLUSIONS: MFAP4-deficiency reduces the elastin/collagen ratio in the aging resistance artery without affecting arterial stiffness. In contrast, MFAP4-deficiency reduces the stiffness of resistance arteries and ameliorates Ang II-induced hypertension.

Ovariectomy-Induced Arterial Stiffening Differs From Vascular Aging and Is Reversed by GPER Activation.

BACKGROUND: Arterial stiffness is a cardiovascular risk factor and dramatically increases as women transition through menopause. The current study assessed whether a mouse model of menopause increases arterial stiffness in a similar manner to aging and whether activation of the G-protein-coupled estrogen receptor could reverse stiffness. METHODS: Female C57Bl/6J mice were ovariectomized at 10 weeks of age or aged to 52 weeks, and some mice were treated with G-protein-coupled estrogen receptor agonists. RESULTS: Ovariectomy and aging increased pulse wave velocity to a similar extent independent of changes in blood pressure. Aging increased carotid wall thickness, while ovariectomy increased material stiffness without altering vascular geometry. RNA-sequencing analysis revealed that ovariectomy downregulated smooth muscle contractile genes. The enantiomerically pure G-protein-coupled estrogen receptor agonist, LNS8801, reversed stiffness in ovariectomy mice to a greater degree than the racemic agonist G-1. In summary, ovariectomy and aging induced arterial stiffening via potentially different mechanisms. Aging was associated with inward remodeling, while ovariectomy-induced material stiffness independent of geometry and a loss of the contractile phenotype. CONCLUSIONS: This study enhances our understanding of the impact of estrogen loss on vascular health in a murine model and warrants further studies to examine the ability of LNS8801 to improve vascular health in menopausal women.

Could the association between ozone and arterial stiffness be modified by fish oil supplementation?

BACKGROUND: Arterial stiffness (AS) is an important predicting factor for cardiovascular disease. However, no epidemiological studies have ever explored the mediating role of biomarkers in the association between ozone and AS, nor weather fish oil modified such association. METHODS: Study participants were drawn from the UK biobank, and a total of 95,699 middle-aged and older adults were included in this study. Ozone was obtained from Community Multiscale Air Quality (CMAQ) model matched to residential addresses, fish oil from self-reported intake, and arterial stiffness was based on device measurements. First, we applied a double robust approach to explore the association between ozone or fish oil intake and arterial stiffness, adjusting for potential confounders at the individual and regional levels. Then, how triglycerides, apolipoprotein B (Apo B)/apolipoprotein A (ApoA) and non-high-density lipoprotein cholesterol (Non-HDL-C) mediate the relationship between ozone and AS. Last, the modifying role of fish oil was further explored by stratified analysis. RESULTS: The mean age of participants was 55 years; annual average ozone exposure was associated with ASI (beta:0.189 [95%CI: 0.146 to 0.233], P < 0.001), and compared to participants who did not consume fish oil, fish oil users had a lower ASI (beta: 0.061 [95%CI: -0.111 to -0.010], P = 0.016). The relationship between ozone exposure and AS was mediated by triglycerides, ApoB/ApoA, and Non-HDL-C with mediation proportions ranging from 10.90% to 18.30%. Stratified analysis showed lower estimates on the ozone-AS relationship in fish oil users (P = 0.011). CONCLUSION: Ozone exposure was associated with higher levels of arterial stiffness, in contrast to fish oil consumption, which showed a protective association. The association between ozone exposure and arterial stiffness was partially mediated by some biomarkers. In the general population, fish oil consumption might provide protection against ozone-related AS.

Effect of TNF inhibitors on arterial stiffness and intima media thickness in rheumatoid arthritis: a systematic review and meta-analysis.

Controlling inflammation with tumor necrosis factor (TNF) inhibitors in rheumatoid arthritis (RA) patients is hypothesized to reduce their cardiovascular risk. We performed a systematic review and meta-analysis on the effects of TNF inhibitors on arterial stiffness and carotid intima media thickness (IMT) in RA. MEDLINE, EMBASE, clinicaltrials.gov , and WHO Clinical Trials Registry were searched up to September 2021 for randomized controlled trials, prospective cohort studies, and nonrandomized clinical trials evaluating the effects of TNF inhibitors on pulse wave velocity (PWV), augmentation index (AIx), and IMT in RA. A meta-analysis was performed to assess changes of these measures after therapy during different follow-up periods. Risk of bias assessment was performed using an adjusted Downs and Black checklist (INPLASY: 2022-1-0131). Thirty studies were identified from 1436 records, of which 23 were included in the meta-analysis. PWV and AIx showed a decrease after treatment (PWV: mean difference (MD) -0.51 m/s (95% CI: -0.96, -0.06), p=0.027; AIx: MD -0.57% (95% CI: -2.11, 0.96), p=0.463, sensitivity analysis AIx: MD -1.21% (95% CI: -2.60, 0.19), p=0.089). For IMT, there was a slight increase in the first months of follow-up, but this disappeared on the long-term (overall timepoints MD -0.01 mm (95% CI: -0.04, 0.02), p=0.615). Heterogeneity was high in the overall analyses and subgroups with long follow-up periods (≥12 months). The included studies showed mixed results of the effects of TNF inhibitors on the surrogate markers. The pooled results suggest that PWV and AIx decrease over time, while IMT remains stable. This indicates a favorable effect of TNF inhibitors on the cardiovascular disease risk, all the more since these markers also increase with age.

Metformin improves skeletal muscle microvascular insulin resistance in metabolic syndrome.

Microvascular insulin resistance is present in metabolic syndrome and may contribute to increased cardiovascular disease risk and the impaired metabolic response to insulin observed. Metformin improves metabolic insulin resistance in humans. Its effects on macro and microvascular insulin resistance have not been defined. Eleven subjects with nondiabetic metabolic syndrome were studied four times (before and after 12 wk of treatment with placebo or metformin) using a crossover design, with an 8-wk washout interval between treatments. On each occasion, we measured three indices of large artery function [pulse wave velocity (PWV), radial pulse wave separation analysis (PWSA), brachial artery endothelial function (flow-mediated dilation-FMD)] as well as muscle microvascular perfusion [contrast-enhanced ultrasound (CEU)] before and at 120 min into a 150 min, 1 mU/min/kg euglycemic insulin clamp. Metformin decreased body mass index (BMI), fat weight, and % body fat (P < 0.05, each), however, placebo had no effect. Metformin (not placebo) improved metabolic insulin sensitivity, (clamp glucose infusion rate, P < 0.01), PWV, and FMD after insulin were unaffected by metformin treatment. PWSA improved with insulin only after metformin P < 0.01). Insulin decreased muscle microvascular blood volume measured by contrast ultrasound both before and after placebo and before metformin (P < 0.02 for each) but not after metformin. Short-term metformin treatment improves both metabolic and muscle microvascular response to insulin. Metformin's effect on microvascular insulin responsiveness may contribute to its beneficial metabolic effects. Metformin did not improve aortic stiffness or brachial artery endothelial function, but enhanced radial pulse wave properties consistent with relaxation of smaller arterioles.NEW & NOTEWORTHY Metformin, a first-line treatment for type 2 diabetes, is often used in patients with insulin resistance and metabolic syndrome. Here, we provide the first evidence for metformin improving muscle microvascular insulin sensitivity in insulin-resistant humans. Simultaneously, metformin improved muscle glucose disposal, supporting a close relationship between insulin's microvascular and its metabolic actions in muscle. Whether enhanced microvascular insulin sensitivity contributes to metformin's ability to decrease microvascular complications in diabetes remains to be resolved.

Cystamine reduces vascular stiffness in Western diet-fed female mice.

Consumption of diets high in fat, sugar, and salt (Western diet, WD) is associated with accelerated arterial stiffening, a major independent risk factor for cardiovascular disease (CVD). Women with obesity are more prone to develop arterial stiffening leading to more frequent and severe CVD compared with men. As tissue transglutaminase (TG2) has been implicated in vascular stiffening, our goal herein was to determine the efficacy of cystamine, a nonspecific TG2 inhibitor, at reducing vascular stiffness in female mice chronically fed a WD. Three experimental groups of female mice were created. One was fed regular chow diet (CD) for 43 wk starting at 4 wk of age. The second was fed a WD for the same 43 wk, whereas a third cohort was fed WD, but also received cystamine (216 mg/kg/day) in the drinking water during the last 8 wk on the diet (WD + C). All vascular stiffness parameters assessed, including aortic pulse wave velocity and the incremental modulus of elasticity of isolated femoral and mesenteric arteries, were significantly increased in WD- versus CD-fed mice, and reduced in WD + C versus WD-fed mice. These changes coincided with respectively augmented and diminished vascular wall collagen and F-actin content, with no associated effect in blood pressure. In cultured human vascular smooth muscle cells, cystamine reduced TG2 activity, F-actin:G-actin ratio, collagen compaction capacity, and cellular stiffness. We conclude that cystamine treatment represents an effective approach to reduce vascular stiffness in female mice in the setting of WD consumption, likely because of its TG2 inhibitory capacity.NEW & NOTEWORTHY This study evaluates the novel role of transglutaminase 2 (TG2) inhibition to directly treat vascular stiffness. Our data demonstrate that cystamine, a nonspecific TG2 inhibitor, improves vascular stiffness induced by a diet rich in fat, fructose, and salt. This research suggests that TG2 inhibition might bear therapeutic potential to reduce the disproportionate burden of cardiovascular disease in females in conditions of chronic overnutrition.

Curcumin Therapy to Treat Vascular Dysfunction in Children and Young Adults with ADPKD: A Randomized Controlled Trial.

BACKGROUND AND OBJECTIVES: Clinical manifestations of autosomal dominant polycystic kidney disease (ADPKD), including evidence of vascular dysfunction, can begin in childhood. Curcumin is a polyphenol found in turmeric that reduces vascular dysfunction in rodent models and humans without ADPKD. It also slows kidney cystic progression in a murine model of ADPKD. We hypothesized that oral curcumin therapy would reduce vascular endothelial dysfunction and arterial stiffness in children/young adults with ADPKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In a randomized, placebo-controlled, double-blind trial, 68 children/young adults 6-25 years of age with ADPKD and eGFR>80 ml/min per 1.73 m2 were randomized to either curcumin supplementation (25 mg/kg body weight per day) or placebo administered in powder form for 12 months. The coprimary outcomes were brachial artery flow-mediated dilation and aortic pulse-wave velocity. We also assessed change in circulating/urine biomarkers of oxidative stress/inflammation and kidney growth (height-adjusted total kidney volume) by magnetic resonance imaging. In a subgroup of participants ≥18 years, vascular oxidative stress was measured as the change in brachial artery flow-mediated dilation following an acute infusion of ascorbic acid. RESULTS: Enrolled participants were 18±5 (mean ± SD) years, 54% were girls, baseline brachial artery flow-mediated dilation was 9.3±4.1% change, and baseline aortic pulse-wave velocity was 512±94 cm/s. Fifty-seven participants completed the trial. Neither coprimary end point changed with curcumin (estimated change [95% confidence interval] for brachial artery flow-mediated dilation [percentage change]: curcumin: 1.14; 95% confidence interval, -0.84 to 3.13; placebo: 0.33; 95% confidence interval, -1.34 to 2.00; estimated difference for change: 0.81; 95% confidence interval, -1.21 to 2.84; P=0.48; aortic pulse-wave velocity [centimeters per second]: curcumin: 0.6; 95% confidence interval, -25.7 to 26.9; placebo: 6.5; 95% confidence interval, -20.4 to 33.5; estimated difference for change: -5.9; 95% confidence interval, -35.8 to 24.0; P=0.67; intent to treat). There was no curcumin-specific reduction in vascular oxidative stress or changes in mechanistic biomarkers. Height-adjusted total kidney volume also did not change as compared with placebo. CONCLUSIONS: Curcumin supplementation does not improve vascular function or slow kidney growth in children/young adults with ADPKD. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Curcumin Therapy to Treat Vascular Dysfunction in Children and Young Adults with ADPKD, NCT02494141. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2022_02_07_CJN08950621.mp3.

Blueberry anthocyanin intake attenuates the postprandial cardiometabolic effect of an energy-dense food challenge: Results from a double blind, randomized controlled trial in metabolic syndrome participants.

BACKGROUND & AIMS: Whilst the cardioprotective effects of blueberry intake have been shown in prospective studies and short-term randomized controlled trials (RCTs), it is unknown whether anthocyanin-rich blueberries can attenuate the postprandial, cardiometabolic dysfunction which follows energy-dense food intakes; especially in at-risk populations. We therefore examined whether adding blueberries to a high-fat/high-sugar meal affected the postprandial cardiometabolic response over 24 h. METHODS: A parallel, double-blind RCT (n = 45; age 63.4 ± 7.4 years; 64% male; BMI 31.4 ± 3.1 kg/m2) was conducted in participants with metabolic syndrome. After baseline assessments, an energy-dense drink (969 Kcals, 64.5 g fat, 84.5 g carbohydrate, 17.9 g protein) was consumed with either 26 g (freeze-dried) blueberries (equivalent to 1 cup/150 g fresh blueberries) or 26 g isocaloric matched placebo. Repeat blood samples (30, 60, 90, 120, 180, 360 min and 24 h), a 24 h urine collection and vascular measures (at 3, 6, and 24 h) were performed. Insulin and glucose, lipoprotein levels, endothelial function (flow mediated dilatation (FMD)), aortic and systemic arterial stiffness (pulse wave velocity (PWV), Augmentation Index (AIx) respectively), blood pressure (BP), and anthocyanin metabolism (serum and 24 h urine) were assessed. RESULTS: Blueberries favorably affected postprandial (0-24 h) concentrations of glucose (p < 0.001), insulin (p < 0.01), total cholesterol (p = 0.04), HDL-C, large HDL particles (L-HDL-P) (both p < 0.01), extra-large HDL particles (XL-HDL-P; p = 0.04) and Apo-A1 (p = 0.01), but not LDL-C, TG, or Apo-B. After a transient higher peak glucose concentration at 1 h after blueberry intake ([8.2 mmol/L, 95%CI: 7.7, 8.8] vs placebo [6.9 mmol/L, 95%CI: 6.4, 7.4]; p = 0.001), blueberries significantly attenuated 3 h glucose ([4.3 mmol/L, 95%CI: 3.8, 4.8] vs placebo [5.1 mmol/L, 95%CI: 4.6, 5.6]; p = 0.03) and insulin concentrations (blueberry: [23.4 pmol/L, 95%CI: 15.4, 31.3] vs placebo [52.9 pmol/L, 95%CI: 41.0, 64.8]; p = 0.0001). Blueberries also improved HDL-C ([1.12 mmol/L, 95%CI: 1.06, 1.19] vs placebo [1.08 mmol/L, 95%CI: 1.02, 1.14]; p = 0.04) at 90 min and XL-HDLP levels ([0.38 × 10-6, 95%CI: 0.35, 0.42] vs placebo [0.35 × 10-6, 95%CI: 0.32, 0.39]; p = 0.02) at 3 h. Likewise, significant improvements were observed 6 h after blueberries for HDL-C ([1.17 mmol/L, 95%CI: 1.11, 1.24] vs placebo [1.10 mmol/L, 95%CI: 1.03, 1.16]; p < 0.001), Apo-A1 ([1.37 mmol/L, 95%CI: 1.32, 1.41] vs placebo [1.31 mmol/L, 95%CI: 1.27, 1.35]; p = 0.003), L-HDLP ([0.70 × 10-6, 95%CI: 0.60, 0.81] vs placebo [0.59 × 10-6, 95%CI: 0.50, 0.68]; p = 0.003) and XL-HDLP ([0.44 × 10-6, 95%CI: 0.40, 0.48] vs placebo [0.40 × 10-6, 95%CI: 0.36, 0.44]; p < 0.001). Similarly, total cholesterol levels were significantly lower 24 h after blueberries ([4.9 mmol/L, 95%CI: 4.6, 5.1] vs placebo [5.0 mmol/L, 95%CI: 4.8, 5.3]; p = 0.04). Conversely, no effects were observed for FMD, PWV, AIx and BP. As anticipated, total anthocyanin-derived phenolic acid metabolite concentrations significantly increased in the 24 h after blueberry intake; especially hippuric acid (6-7-fold serum increase, 10-fold urinary increase). In exploratory analysis, a range of serum/urine metabolites were associated with favorable changes in total cholesterol, HDL-C, XL-HDLP and Apo-A1 (R = 0.43 to 0.50). CONCLUSIONS: For the first time, in an at-risk population, we show that single-exposure to the equivalent of 1 cup blueberries (provided as freeze-dried powder) attenuates the deleterious postprandial effects of consuming an energy-dense high-fat/high-sugar meal over 24 h; reducing insulinaemia and glucose levels, lowering cholesterol, and improving HDL-C, fractions of HDL-P and Apo-A1. Consequently, intake of anthocyanin-rich blueberries may reduce the acute cardiometabolic burden of energy-dense meals. CLINICAL TRIAL REGISTRY: NCT02035592 at www.clinicaltrials.gov.