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.

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.

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.

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.

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.

Effects of Different Types of Carbohydrates on Arterial Stiffness: A Comparison of Isomaltulose and Sucrose.

Increased arterial stiffness during acute hyperglycemia is a risk factor for cardiovascular disease, but the type of carbohydrate that inhibits it is unknown. The purpose of this study was to determine the efficacy of low-glycemic-index isomaltulose on arterial stiffness during hyperglycemia in middle-aged and older adults. Ten healthy middle-aged and older adult subjects orally ingested a solution containing 25 g of isomaltulose (ISI trial) and sucrose (SSI trial) in a crossover study. In the SSI trial, the brachial-ankle (ba) pulse wave velocity (PWV) increased 30, 60, and 90 min after ingestion compared with that before ingestion (p < 0.01); however, in the ISI trial, the baPWV did not change after ingestion compared with that before ingestion. Blood glucose levels 30 min after intake were lower in the ISI trial than in the SSI trial (p < 0.01). The baPWV and systolic blood pressure were positively correlated 90 min after isomaltulose and sucrose ingestion (r = 0.640, p < 0.05). These results indicate that isomaltulose intake inhibits an acute increase in arterial stiffness. The results of the present study may have significant clinical implications on the implementation of dietary programs for middle-aged and elderly patients.

Endothelial Dysfunction in Fabry Disease Is Related to Glycocalyx Degradation.

Fabry disease (FD) is an X-linked multisystemic lysosomal storage disease due to a deficiency of α-galactosidase A (GLA/AGAL). Progressive cellular accumulation of the AGAL substrate globotriaosylceramide (Gb3) leads to endothelial dysfunction. Here, we analyzed endothelial function in vivo and in vitro in an AGAL-deficient genetic background to identify the processes underlying this small vessel disease. Arterial stiffness and endothelial function was prospectively measured in five males carrying GLA variants (control) and 22 FD patients under therapy. AGAL-deficient endothelial cells (EA.hy926) and monocytes (THP1) were used to analyze endothelial glycocalyx structure, function, and underlying inflammatory signals. Glycocalyx thickness and small vessel function improved significantly over time (p<0.05) in patients treated with enzyme replacement therapy (ERT, n=16) and chaperones (n=6). AGAL-deficient endothelial cells showed reduced glycocalyx and increased monocyte adhesion (p<0.05). In addition, increased expression of angiopoietin-2, heparanase and NF-κB was detected (all p<0.05). Incubation of wild-type endothelial cells with pathological globotriaosylsphingosine concentrations resulted in comparable findings. Treatment of AGAL-deficient cells with recombinant AGAL (p<0.01), heparin (p<0.01), anti-inflammatory (p<0.001) and antioxidant drugs (p<0.05), and a specific inhibitor (razuprotafib) of angiopoietin-1 receptor (Tie2) (p<0.05) improved glycocalyx structure and endothelial function in vitro. We conclude that chronic inflammation, including the release of heparanases, appears to be responsible for the degradation of the endothelial glycocalyx and may explain the endothelial dysfunction in FD. This process is partially reversible by FD-specific and anti-inflammatory treatment, such as targeted protective Tie2 treatment.

Doxorubicin Impairs Smooth Muscle Cell Contraction: Novel Insights in Vascular Toxicity.

Clinical and animal studies have demonstrated that chemotherapeutic doxorubicin (DOX) increases arterial stiffness, a predictor of cardiovascular risk. Despite consensus about DOX-impaired endothelium-dependent vasodilation as a contributing mechanism, some studies have reported conflicting results on vascular smooth muscle cell (VSMC) function after DOX treatment. The present study aimed to investigate the effects of DOX on VSMC function. To this end, mice received a single injection of 4 mg DOX/kg, or mouse aortic segments were treated ex vivo with 1 µM DOX, followed by vascular reactivity evaluation 16 h later. Phenylephrine (PE)-induced VSMC contraction was decreased after DOX treatment. DOX did not affect the transient PE contraction dependent on Ca2+ release from the sarcoplasmic reticulum (0 mM Ca2+), but it reduced the subsequent tonic phase characterised by Ca2+ influx. These findings were supported by similar angiotensin II and attenuated endothelin-1 contractions. The involvement of voltage-gated Ca2+ channels in DOX-decreased contraction was excluded by using levcromakalim and diltiazem in PE-induced contraction and corroborated by similar K+ and serotonin contractions. Despite the evaluation of multiple blockers of transient receptor potential channels, the exact mechanism for DOX-decreased VSMC contraction remains elusive. Surprisingly, DOX reduced ex vivo but not in vivo arterial stiffness, highlighting the importance of appropriate timing for evaluating arterial stiffness in DOX-treated patients.

AT2R stimulation with C21 prevents arterial stiffening and endothelial dysfunction in the abdominal aorta from mice fed a high-fat diet.

The aim of the present study was to evaluate the effect of Compound 21 (C21), a selective AT2R agonist, on the prevention of endothelial dysfunction, extracellular matrix (ECM) remodeling and arterial stiffness associated with diet-induced obesity (DIO). Five-week-old male C57BL/6J mice were fed a standard (Chow) or high-fat diet (HF) for 6 weeks. Half of the animals of each group were simultaneously treated with C21 (1 mg/kg/day, in the drinking water), generating four groups: Chow C, Chow C21, HF C, and HF C21. Vascular function and mechanical properties were determined in the abdominal aorta. To evaluate ECM remodeling, collagen deposition and TGF-ß1 concentrations were determined in the abdominal aorta and the activity of metalloproteinases (MMP) 2 and 9 was analyzed in the plasma. Abdominal aortas from HF C mice showed endothelial dysfunction as well as enhanced contractile but reduced relaxant responses to Ang II. This effect was abrogated with C21 treatment by preserving NO availability. A left-shift in the tension-stretch relationship, paralleled by an augmented ß-index (marker of intrinsic arterial stiffness), and enhanced collagen deposition and MMP-2/-9 activities were also detected in HF mice. However, when treated with C21, HF mice exhibited lower TGF-ß1 levels in abdominal aortas together with reduced MMP activities and collagen deposition compared with HF C mice. In conclusion, these data demonstrate that AT2R stimulation by C21 in obesity preserves NO availability and prevents unhealthy vascular remodeling, thus protecting the abdominal aorta in HF mice against the development of endothelial dysfunction, ECM remodeling and arterial stiffness.

Vitamin K2-a neglected player in cardiovascular health: a narrative review.

Vitamin K2 serves an important role in cardiovascular health through regulation of calcium homeostasis. Its effects on the cardiovascular system are mediated through activation of the anti-calcific protein known as matrix Gla protein. In its inactive form, this protein is associated with various markers of cardiovascular disease including increased arterial stiffness, vascular and valvular calcification, insulin resistance and heart failure indices which ultimately increase cardiovascular mortality. Supplementation of vitamin K2 has been strongly associated with improved cardiovascular outcomes through its modification of systemic calcification and arterial stiffness. Although its direct effects on delaying the progression of vascular and valvular calcification is currently the subject of multiple randomised clinical trials, prior reports suggest potential improved survival among cardiac patients with vitamin K2 supplementation. Strengthened by its affordability and Food and Drug Adminstration (FDA)-proven safety, vitamin K2 supplementation is a viable and promising option to improve cardiovascular outcomes.

Effect of empagliflozin on ketone bodies in patients with stable chronic heart failure.

BACKGROUND: Recent studies indicated that sodium glucose cotransporter (SGLT)2 inhibition increases levels of ketone bodies in the blood in patients with type 1 and 2 diabetes. Other studies suggested that in patients with chronic heart failure (CHF), increased myocardial oxygen demand can be provided by ketone bodies as a fuel substrate. Experimental studies reported that ketone bodies, specifically beta-hydroxybutyrate (ß-OHB) may increase blood pressure (BP) by impairing endothelium-dependant relaxation, thereby leading to increased vascular stiffness. In our study we assessed whether the SGLT 2 inhibition with empagliflozin increases ketone bodies in patients with stable CHF and whether such an increase impairs BP and vascular function. METHODS: In a prospective, double blind, placebo controlled, parallel-group single centre study 75 patients with CHF (left ventricular ejection fraction 39.0 ± 8.2%) were randomised (2:1) to the SGLT-2 inhibitor empagliflozin 10 mg orally once daily or to placebo, 72 patients completed the study. After a run-in phase we evaluated at baseline BP by 24 h ambulatory blood pressure (ABP) monitoring, vascular stiffness parameters by the SphygmoCor system (AtCor Medical, Sydney, NSW, Australia) and fasting metabolic parameters, including ß-OHB by an enzymatic assay (Beckman Coulter DxC 700 AU). The same measurements were repeated 12 weeks after treatment. In 19 of the 72 patients serum levels of ß-OHB were beneath the lower border of our assay (< 0.05 mmol/l) therefore being excluded from the subsequent analysis. RESULTS: In patients with stable CHF, treatment with empagliflozin (n = 36) was followed by an increase of ß-OHB by 33.39% (p = 0.017), reduction in 24 h systolic (p = 0.038) and diastolic (p = 0.085) ABP, weight loss (p = 0.003) and decrease of central systolic BP (p = 0.008) and central pulse pressure (p = 0.008). The increase in ß-OHB was related to an attenuated decrease of empagliflozin-induced 24 h systolic (r = 0.321, p = 0.069) and diastolic (r = 0.516, p = 0.002) ABP and less reduction of central systolic BP (r = 0.470, p = 0.009) and central pulse pressure (r = 0.391, p = 0.033). No significant changes were seen in any of these parameters after 12 weeks of treatment in the placebo group (n = 17). CONCLUSION: In patients with stable CHF ketone bodies as assessed by ß-OHB increased after treatment with empagliflozin. This increase led to an attenuation of the beneficial effects of empagliflozin on BP and vascular parameters. Trial registration The study was registered at http://www.clinicaltrials.gov (NCT03128528).

Effects of L-Citrulline Supplementation and Aerobic Training on Vascular Function in Individuals with Obesity across the Lifespan.

Children with obesity are at higher risk for developing cardiometabolic diseases that once were considered health conditions of adults. Obesity is commonly associated with cardiometabolic risk factors such as dyslipidemia, hyperglycemia, hyperinsulinemia and hypertension that contribute to the development of endothelial dysfunction. Endothelial dysfunction, characterized by reduced nitric oxide (NO) production, precedes vascular abnormalities including atherosclerosis and arterial stiffness. Thus, early detection and treatment of cardiometabolic risk factors are necessary to prevent deleterious vascular consequences of obesity at an early age. Non-pharmacological interventions including L-Citrulline (L-Cit) supplementation and aerobic training stimulate endothelial NO mediated vasodilation, leading to improvements in organ perfusion, blood pressure, arterial stiffness, atherosclerosis and metabolic health (glucose control and lipid profile). Few studies suggest that the combination of L-Cit supplementation and exercise training can be an effective strategy to counteract the adverse effects of obesity on vascular function in older adults. Therefore, this review examined the efficacy of L-Cit supplementation and aerobic training interventions on vascular and metabolic parameters in obese individuals.

Fructose plus High-Salt Diet in Early Life Results in Salt-Sensitive Cardiovascular Changes in Mature Male Sprague Dawley Rats.

Fructose and salt intake remain high, particularly in adolescents and young adults. The present studies were designed to evaluate the impact of high fructose and/or salt during pre- and early adolescence on salt sensitivity, blood pressure, arterial compliance, and left ventricular (LV) function in maturity. Male 5-week-old Sprague Dawley rats were studied over three 3-week phases (Phases I, II, and III). Two reference groups received either 20% glucose + 0.4% NaCl (GCS-GCS) or 20% fructose + 4% NaCl (FHS-FHS) throughout this study. The two test groups ingested fructose + 0.4% NaCl (FCS) or FHS during Phase I, then GCS in Phase II, and were then challenged with 20% glucose + 4% NaCl (GHS) in Phase III: FCS-GHS and FHS-GHS, respectively. Compared with GCS-GCS, systolic and mean pressures were significantly higher at the end of Phase III in all groups fed fructose during Phase I. Aortic pulse wave velocity (PWV) was elevated at the end of Phase I in FHS-GHS and FHS-FHS (vs. GCS-GCS). At the end of Phase III, PWV and renal resistive index were higher in FHS-GHS and FHS-FHS vs. GCS-GCS. Diastolic, but not systolic, LV function was impaired in the FHS-GHS and FHS-FHS but not FCS-FHS rats. Consumption of 20% fructose by male rats during adolescence results in salt-sensitive hypertension in maturity. When ingested with a high-salt diet during this early plastic phase, dietary fructose also predisposes to vascular stiffening and LV diastolic dysfunction in later life.

Carbamylation of elastic fibers is a molecular substratum of aortic stiffness.

Because of their long lifespan, matrix proteins of the vascular wall, such as elastin, are subjected to molecular aging characterized by non-enzymatic post-translational modifications, like carbamylation which results from the binding of cyanate (mainly derived from the dissociation of urea) to protein amino groups. While several studies have demonstrated a relationship between increased plasma concentrations of carbamylated proteins and the development of cardiovascular diseases, molecular mechanisms explaining the involvement of protein carbamylation in these pathological contexts remain to be fully elucidated. The aim of this work was to determine whether vascular elastic fibers could be carbamylated, and if so, what impact this phenomenon would have on the mechanical properties of the vascular wall. Our experiments showed that vascular elastin was carbamylated in vivo. Fiber morphology was unchanged after in vitro carbamylation, as well as its sensitivity to elastase degradation. In mice fed with cyanate-supplemented water in order to increase protein carbamylation within the aortic wall, an increased stiffness in elastic fibers was evidenced by atomic force microscopy, whereas no fragmentation of elastic fiber was observed. In addition, this increased stiffness was also associated with an increase in aortic pulse wave velocity in ApoE-/- mice. These results provide evidence for the carbamylation of elastic fibers which results in an increase in their stiffness at the molecular level. These alterations of vessel wall mechanical properties may contribute to aortic stiffness, suggesting a new role for carbamylation in cardiovascular diseases.

SPARTE Study: Normalization of Arterial Stiffness and Cardiovascular Events in Patients With Hypertension at Medium to Very High Risk.

[Figure: see text].

Spironolactone Reduces Aortic Stiffness in Patients With Resistant Hypertension Independent of Blood Pressure Change.

Background Aortic stiffness is an independent predictor of cardiovascular events in patients with arterial hypertension. Resistant hypertension is often linked to hyperaldosteronism and associated with adverse outcomes. Spironolactone, a mineralocorticoid receptor antagonist, has been shown to reduce both the arterial blood pressure (BP) and aortic stiffness in resistant hypertension. However, the mechanism of aortic stiffness reduction by spironolactone is not well understood. We hypothesized that spironolactone reduces aortic stiffness in resistant hypertension independently of BP change. Methods and Results Patients with uncontrolled BP (≥140/90 mm Hg) despite use of ≥3 antihypertensive medications (including diuretics) were prospectively recruited. Participants were started on spironolactone at 25 mg/d, and increased to 50 mg/d at 4 weeks while other antihypertensive medications were withdrawn to maintain constant mean BP. Phase-contrast cardiac magnetic resonance imaging of the ascending aorta was performed in 30 participants at baseline and after 6 months of spironolactone treatment to measure aortic pulsatility, distensibility, and pulse wave velocity. Pulse wave velocity decreased (6.3±2.3 m/s to 4.5±1.8 m/s, P<0.001) and pulsatility and distensibility increased (15.9%±5.3% to 22.1%±7.9%, P<0.001; and 0.28%±0.10%/mm Hg to 0.40%±0.14%/mm Hg, P<0.001, respectively) following 6 months of spironolactone. Conclusions Our results suggest that spironolactone improves aortic properties in resistant hypertension independently of BP, which may support the hypothesis of an effect of aldosterone on the arterial wall. A larger prospective study is needed to confirm our findings.

Effects of Spironolactone and Chlorthalidone on Cardiovascular Structure and Function in Chronic Kidney Disease: A Randomized, Open-Label Trial.

BACKGROUND AND OBJECTIVES: In a randomized double-blind, placebo-controlled trial, treatment with spironolactone in early-stage CKD reduced left ventricular mass and arterial stiffness compared with placebo. It is not known if these effects were due to BP reduction or specific vascular and myocardial effects of spironolactone. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A prospective, randomized, open-label, blinded end point study conducted in four UK centers (Birmingham, Cambridge, Edinburgh, and London) comparing spironolactone 25 mg to chlorthalidone 25 mg once daily for 40 weeks in 154 participants with nondiabetic stage 2 and 3 CKD (eGFR 30-89 ml/min per 1.73 m2). The primary end point was change in left ventricular mass on cardiac magnetic resonance imaging. Participants were on treatment with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker and had controlled BP (target ≤130/80 mm Hg). RESULTS: There was no significant difference in left ventricular mass regression; at week 40, the adjusted mean difference for spironolactone compared with chlorthalidone was -3.8 g (95% confidence interval, -8.1 to 0.5 g, P=0.08). Office and 24-hour ambulatory BPs fell in response to both drugs with no significant differences between treatment. Pulse wave velocity was not significantly different between groups; at week 40, the adjusted mean difference for spironolactone compared with chlorthalidone was 0.04 m/s (-0.4 m/s, 0.5 m/s, P=0.90). Hyperkalemia (defined ≥5.4 mEq/L) occurred more frequently with spironolactone (12 versus two participants, adjusted relative risk was 5.5, 95% confidence interval, 1.4 to 22.1, P=0.02), but there were no patients with severe hyperkalemia (defined ≥6.5 mEq/L). A decline in eGFR >30% occurred in eight participants treated with chlorthalidone compared with two participants with spironolactone (adjusted relative risk was 0.2, 95% confidence interval, 0.05 to 1.1, P=0.07). CONCLUSIONS: Spironolactone was not superior to chlorthalidone in reducing left ventricular mass, BP, or arterial stiffness in nondiabetic CKD.