Tumor Necrosis Factor-α Mediates Inflammation-induced Early-Stage Left Ventricular Systolic Dysfunction.

ABSTRACT: Elevated systemic inflammation contributes to pathogenesis of heart failure with preserved ejection fraction (HFpEF), but molecular mechanisms are poorly understood. Although left ventricular (LV) diastolic dysfunction is the main cause of HFpEF, subclinical systolic dysfunction also contributes. We have previously shown that rats with collagen-induced arthritis (CIA) have systemic inflammation, LV diastolic dysfunction, and that increased circulating TNF-α contributes to inflammation-induced HFpEF pathogenesis, but does not mediate LV diastolic dysfunction in CIA rats. Contribution of systemic inflammation to dysfunction of the active process of LV diastolic and systolic function are unknown. In the present study, we used the CIA rat model to investigate the effects of systemic inflammation and TNF-α blockade on systolic function, and mRNA expression of genes involved in active diastolic relaxation and of myosin heavy chain (MyHC) isoforms. Collagen inoculation and TNF-α blockade did not affect LV mRNA expression of genes that mediate active LV diastolic function. Collagen-induced inflammation impaired LV global longitudinal strain ( P = 0.03) and velocity ( P = 0.04). This impairment of systolic function was prevented by TNF-α blockade. Collagen inoculation decreased mRNA expression of α-MyHC ( Myh6, P = 0.03) and increased expression of ß-MyHC ( Myh7, P = 0.0002), a marker, which is upregulated in failing hearts. TNF-α blockade prevented this MyHC isoform-switch. These results show that increased circulating TNF-α changes the relative expression of MyHC isoforms, favoring ß-MyHC, which may underlie changes in contractile function that impair systolic function. Our results indicate that TNF-α initiates early-stage LV systolic, rather than LV diastolic dysfunction.

Interleukin-6 Blockers Improve Inflammation-Induced Lipid Metabolism Impairments but Induce Liver Fibrosis in Collagen-Induced Arthritis.

BACKGROUND: Interleukin-6 (IL-6) receptor blockers improve systemic inflammation, however, their inconsistent effects on lipid metabolism and drug-induced liver injuries warrant further investigation. This study aimed to determine the effects of IL-6 receptor blocker therapy on lipid metabolism and liver morphology in collagen-induced arthritis. METHODS: Sixty three Sprague Dawley rats were divided into control (n = 24), inflammation (n = 24), and IL-6 blocker (n = 15) groups. Inflammation was induced in the inflammation and IL-6- blocker groups using Bovine type-II collagen and incomplete Freund's adjuvant. At first signs of arthritis, the IL-6 blocker group received an IL-6 blocker, tocilizumab for six weeks. Serum concentrations of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and ATP-binding cassette transporter-A1 (ABCA1) were measured. Liver fibrosis was determined by histological stains and liver enzymes were measured using the colorimetric-chemistry analyzer. RESULTS: In the inflammation group, HDL-C and ABCA1 were reduced compared to control (p < 0.0001 and p = 0.04, respectively) and IL-6 blocker (p = 0.0003 and p < 0.0001, respectively) groups. LDL-C was increased in the inflammation compared to control (p = 0.02). Markers of liver fibrosis were increased in the IL-6 blocker group compared to control and inflammation groups (picrosirius red collagen area fraction: p < 0.0001 and p = 0.0008, respectively; Masson's trichrome collagen area fraction: p = 0.0002 and p = 0.01, respectively). Alkaline phosphatase concentrations were increased in the IL-6 blocker group compared to the control (p < 0.0001) and inflammation (p = 0.002) groups. CONCLUSION: IL-6 blockers ameliorated inflammation-induced lipid metabolism impairments, however they induced liver fibrosis. Although IL-6 blockers may reduce inflammation-induced metabolic impairments in chronic inflammatory disorders, routine monitoring of liver function is warranted while on treatment.

Increased protein phosphatase 5 expression in inflammation-induced left ventricular dysfunction in rats.

BACKGROUND: Titin phosphorylation contributes to left ventricular (LV) diastolic dysfunction. The independent effects of inflammation on the molecular pathways that regulate titin phosphorylation are unclear. METHODS: We investigated the effects of collagen-induced inflammation and subsequent tumor necrosis factor-α (TNF-α) inhibition on mRNA expression of genes involved in regulating titin phosphorylation in 70 Sprague-Dawley rats. LV diastolic function was assessed with echocardiography. Circulating inflammatory markers were quantified by enzyme-linked immunosorbent assay and relative LV gene expression was assessed by Taqman® polymerase chain reaction. Differences in normally distributed variables between the groups were determined by two-way analysis of variance (ANOVA), followed by Tukey post-hoc tests. For non-normally distributed variables, group differences were determined by Kruskal-Wallis tests. RESULTS: Collagen inoculation increased LV relative mRNA expression of vascular cell adhesion molecule 1 (VCAM1), pentraxin 3 (PTX3), and inducible nitric oxide synthase (iNOS) compared to controls, indicating local microvascular inflammation. Collagen inoculation decreased soluble guanylate cyclase alpha-2 (sGCα2) and soluble guanylate cyclase beta-2 (sGCß2) expression, suggesting downregulation of nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate (NO-sGC-cGMP) signaling. Inhibiting TNF-α prevented collagen-induced changes in VCAM1, iNOS, sGCα2 and sGCß2 expression. Collagen inoculation increased protein phosphatase 5 (PP5) expression. Like LV diastolic dysfunction, increased PP5 expression was not prevented by TNF-α inhibition. CONCLUSION: Inflammation-induced LV diastolic dysfunction may be mediated by a TNF-α-independent increase in PP5 expression and dephosphorylation of the N2-Bus stretch element of titin, rather than by TNF-α-induced downregulation of NO-sGC-cGMP pathway-dependent titin phosphorylation. The steady rise in number of patients with inflammation-induced diastolic dysfunction, coupled with low success rates of current therapies warrants a better understanding of the systemic signals and molecular pathways responsible for decreased titin phosphorylation in development of LV diastolic dysfunction. The therapeutic potential of inhibiting PP5 upregulation in LV diastolic dysfunction requires investigation.

The effect of TNF-α inhibitor treatment on microRNAs and endothelial function in collagen induced arthritis.

Chronic inflammation causes dysregulated expression of microRNAs. Aberrant microRNA expression is associated with endothelial dysfunction. In this study we determined whether TNF-α inhibition impacted the expression of miRNA-146a-5p and miRNA-155-5p, and whether changes in the expression of these miRNAs were related to inflammation-induced changes in endothelial function in collagen-induced arthritis (CIA). Sixty-four Sprague-Dawley rats were divided into control (n = 24), CIA (n = 24) and CIA+etanercept (n = 16) groups. CIA and CIA+etanercept groups were immunized with bovine type-II collagen, emulsified in incomplete Freund's adjuvant. Upon signs of arthritis, the CIA+etanercept group received 10mg/kg of etanercept intraperitoneally, every three days. After six weeks of treatment, mesenteric artery vascular reactivity was assessed using wire-myography. Serum concentrations of TNF-α, C-reactive protein, interleukin-6, vascular adhesion molecule-1 (VCAM-1) and pentraxin-3 (PTX-3) were measured by ELISA. Relative expression of circulating miRNA-146a-5p and miRNA-155-5p were determined using RT-qPCR. Compared to controls, circulating miRNA-155-5p, VCAM-1 and PTX-3 concentrations were increased, and vessel relaxation was impaired in the CIA (all p<0.05), but not in the CIA+etanercept (all p<0.05) groups. The CIA group had greater miRNA-146a-5p expression compared to the CIA+etanercept group (p = 0.005). Independent of blood pressure, miRNA-146a-5p expression was associated with increased PTX-3 concentrations (p = 0.03), while miRNA-155-5p expression was associated with impaired vessel relaxation (p = 0.01). In conclusion, blocking circulating TNF-α impacted systemic inflammation-induced increased expression of miRNA-146a-5p and miRNA-155-5p, which were associated with endothelial inflammation and impaired endothelial dependent vasorelaxation, respectively.

TNF-α inhibitors reduce inflammation-induced concentric remodelling, but not diastolic dysfunction in collagen-induced arthritis.

OBJECTIVES: To determine biologic disease-modifying anti-rheumatic drug effects on inflammation-induced cardiac geometry and function changes. METHODS: Male and female Sprague-Dawley rats (n=92) were divided into four groups: control group, collagen-induced arthritis (CIA) group, anti-TNF-α group and anti-IL-6 group. Inflammation was induced by injecting bovine type-II collagen emulsified in incomplete Freund's adjuvant at the base of the tail, in all groups except the control group. Following the onset of arthritis, the anti-TNF-α group received etanercept, and the anti-IL-6 group received tocilizumab, for six weeks. Left ventricular (LV) geometry and function were assessed with echocardiography and circulating inflammatory markers were measured with ELISA. RESULTS: Relative wall thickness in the CIA and anti-IL-6 groups were increased compared to controls (p<0.001 and p=0.02, respectively). TNF-α inhibition protected against inflammation-induced LV concentric remodelling, as relative wall thickness in the anti-TNF-α group was similar to controls (p=0.55). Systolic function variables were not different between the groups. In all groups inoculated with collagen, myocardial relaxation (lateral e') were impaired compared to controls (all p<0.001). LV filling pressures (E/e') were increased in the CIA, anti-TNF-α and anti-IL-6 groups compared to controls (p<0.001, p<0.001 and p=0.05, respectively). Independent of concentric remodelling, circulating CRP concentrations were associated with decreased e' and increased E/e', while TNF-α concentrations were associated with E/A. CONCLUSIONS: TNF-α inhibition protected against inflammation-induced adverse cardiac remodelling, but not diastolic dysfunction. IL-6 receptors blocker effects on inflammation-induced cardiac changes were inconclusive. Systemic inflammation likely impacts LV concentric remodelling and diastolic dysfunction through distinct pathways.

The effects of estrogen deficiency and aging on myocardial deformation and motion in normotensive female rats.

OBJECTIVE: Estrogen deficiency is associated with left ventricular (LV) dysfunction in postmenopausal women and ovariectomized rats. Whether the relationship between estrogen deficiency and LV dysfunction is independent of cardiovascular disease (CVD) risk factors remains uncertain. This study assessed the effects of short-term and long-term estrogen deficiency on cardiac structure and function using conventional and speckle tracking echocardiography, independent of traditional CVD risk factors. METHODS: Female Sprague-Dawley rats were divided into short-term (6 wks) ovariectomized (n = 9), short-term sham-operated (n = 10), long-term (6 mo) ovariectomized (n = 8), and long-term sham-operated (n = 9) groups. Cardiac geometry, systolic and diastolic function, and myocardial deformation and motion were measured using echocardiography. RESULTS: Ovariectomy had no effect on conventional echocardiography measures of cardiac structure or function. Compared with short-term, long-term groups had reduced LV internal diameter (false discovery rate [FDR] adjusted P = 0.05) and impaired relaxation (e'; FDR adjusted P = 0.0005) independent of body mass and blood pressure (BP). Global longitudinal strain was impaired in ovariectomized compared with sham-operated rats (FDR adjusted P = 0.05), but not after adjusting for body mass and BP (FDR adjusted P = 0.16). Global longitudinal strain (FDR adjusted P = 0.05), strain rate (FDR adjusted P = 0.002), and velocity (FDR adjusted P = 0.04) were impaired in long-term compared with short-term groups. Global longitudinal strain rate remained impaired after adjustments for body mass and BP (FDR adjusted P = 0.02). CONCLUSIONS: Estrogen deficiency does not independently cause cardiac remodeling, LV dysfunction, or impaired myocardial deformation. Traditional CVD risk factors accompanying estrogen deficiency may account for cardiac remodeling and dysfunction observed in postmenopausal women.

Inflammation-induced left ventricular fibrosis is partially mediated by tumor necrosis factor-α.

OBJECTIVE: To determine the mechanisms of inflammation-induced left ventricular (LV) remodeling and effects of blocking circulating tumor necrosis factor alpha (TNF-α) in a model of systemic inflammation. METHODS: Seventy Sprague-Dawley rats were divided into three groups: the control group, the collagen-induced arthritis (CIA) group, and the anti-TNF-α group. Inflammation was induced in the CIA and anti-TNF-α groups. Following the onset of arthritis, the anti-TNF-α group received the TNF-α inhibitor, etanercept, for 6 weeks. LV geometry and function were assessed with echocardiography. Circulating inflammatory markers were measured by ELISA and LV gene expression was assessed by comparative TaqMan® polymerase chain reaction. RESULTS: The LV relative gene expression of pro-fibrotic genes, transforming growth factor ß (TGFß) (p = 0.03), collagen I (Col1) (p < 0.0001), and lysyl oxidase (LOX) (p = 0.002), was increased in the CIA group compared with controls, consistent with increased relative wall thickness (p = 0.0009). Col1 and LOX expression in the anti-TNF-α group were similar to controls (both, p > 0.05) and tended to be lower compared to the CIA group (p = 0.06 and p = 0.08, respectively), and may, in part, contribute to the decreased relative wall thickness in the anti-TNF-α group compared to the CIA group (p = 0.03). In the CIA group, the relative gene expression of matrix metalloproteinase 2 (MMP2) and MMP9 was increased compared to control (p = 0.04) and anti-TNF-α (p < 0.0001) groups, respectively. CONCLUSION: Chronic systemic inflammation induces fibrosis and dysregulated LV extracellular matrix remodeling by increasing local cardiac pro-fibrotic gene expression, which is partially mediated by TNF-α. Inflammation-induced LV diastolic dysfunction is likely independent of myocardial fibrosis.

Mountain Bike Racing Stimulates Osteogenic Bone Signaling and Ingesting Carbohydrate-Protein Compared With Carbohydrate-Only Prevents Acute Recovery Bone Resorption Dominance.

ABSTRACT: Oosthuyse, T, Bosch, AN, Kariem, N, and Millen, AME. Mountain bike racing stimulates osteogenic bone signaling and ingesting carbohydrate-protein compared with carbohydrate-only prevents acute recovery bone resorption dominance. J Strength Cond Res 35(2): 292-299, 2021-Mountain biking, unlike road cycling, includes vibrational accelerations but whether it stimulates osteogenic signaling remains unknown. Furthermore, exercise nutrition influences bone turnover, and the effect of ingesting protein during multiday racing was investigated. We measured plasma bone turnover markers, C-terminal telopeptide of type1-collagen (ß-CTX) and N-terminal propeptides of type1-procollagen (P1NP), and osteocyte mechanosensory signaling factor, sclerostin (SOST), corrected for plasma volume change, before (pre-day 1) and 20-60 minutes after (post-day 3) a multiday mountain bike race in 18 male cyclists randomly assigned to ingest carbohydrate-only (CHO-only) or carbohydrate-with-casein protein hydrolysate (CHO-PRO) during racing. Fourteen cyclists (n = 7 per group) completed the race, and data were analyzed with p < 0.05 accepted as significant. Plasma SOST decreased similarly in both groups (mean ± SD, CHO-only: 877 ± 451 to 628 ± 473 pg·ml-1, p = 0.004; CHO-PRO: 888 ± 411 to 650 ± 443 pg·ml-1, p = 0.003), suggesting that osteocytes sense mountain biking as mechanical loading. However, the bone formation marker, P1NP, remained unchanged in both groups, whereas the bone resorption marker, ß-CTX, increased in CHO-only (0.19 ± 0.034 to 0.31 ± 0.074 ng·ml-1, p = 0.0036) but remained unchanged in CHO-PRO (0.25 ± 0.079 to 0.26 ± 0.074 ng·ml-1, p = 0.95). Mountain bike racing does stimulate osteogenic bone signaling but bone formation is not increased acutely after multiday mountain biking; investigation for a delayed effect is warranted. The acute recovery increase in bone resorption with CHO-only is prevented by ingesting CHO-PRO during racing.

Associations of inflammatory markers with impaired left ventricular diastolic and systolic function in collagen-induced arthritis.

BACKGROUND: High-grade inflammation may play a pivotal role in the pathogenesis of left ventricular (LV) dysfunction. Evidence to support a role of systemic inflammation in mediating impaired LV function in experimental models of rheumatoid arthritis (RA) remains limited. The aim of the present study was to determine the effects of high-grade systemic inflammation on LV diastolic and systolic function in collagen-induced arthritis (CIA). METHODS: To induce CIA, bovine type-II collagen emulsified in incomplete Freund's adjuvant was injected at the base of the tail into 21 three-month old Sprague Dawley rats. Nine-weeks after the first immunisation, LV function was assessed by pulsed Doppler, tissue Doppler imaging and Speckle tracking echocardiography. Cardiac collagen content was determined by picrosirius red staining; circulating inflammatory markers were measured using ELISA. RESULTS: Compared to controls (n = 12), CIA rats had reduced myocardial relaxation as indexed by lateral e' (early diastolic mitral annular velocity) and e'/a' (early-to-late diastolic mitral annular velocity) and increased filling pressures as indexed by E/e'. No differences in ejection fraction and LV endocardial fractional shortening between the groups were recorded. LV global radial and circumferential strain and strain rate were reduced in CIA rats compared to controls. Higher concentrations of circulating inflammatory markers were associated with reduced lateral e', e'/a', radial and circumferential strain and strain rate. Greater collagen content was associated with increased concentrations of circulating inflammatory markers and E/e'. CONCLUSION: High-grade inflammation is associated with impaired LV diastolic function and greater myocardial deformation independent of haemodynamic load in CIA rats.

Associations of inflammatory markers and vascular cell adhesion molecule-1 with endothelial dysfunction in collagen-induced arthritis.

We determined the role of high-grade inflammation on endothelial function and its association with biomarkers of endothelial dysfunction in collagen-induced arthritis. Sprague-Dawley rats were divided into a control (n = 12) or collagen-induced arthritis (CIA; n = 21) group. To induce arthritis, Bovine-type-II collagen emulsified in incomplete Freund's adjuvant was injected at the base of the tail. Nine-weeks after the primary immunisation, vascular reactivity in mesenteric and saphenous arteries was assessed using a wire-myograph. Serum concentrations of inflammatory markers (tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), interleukin 1ß (IL-1ß), C-reactive protein (CRP)) and biomarkers of endothelial dysfunction (vascular cell adhesion molecule-1 (VCAM-1) and asymmetric dimethylarginine (ADMA)) were measured by ELISA. Acetylcholine-induced relaxation in mesenteric and saphenous arteries was impaired in CIA compared to controls (P < 0.05). Responses to sodium nitroprusside were similar between controls and CIA in mesenteric arteries and marginally impaired in saphenous arteries of CIA rats. Compared to controls, TNF-α, IL-6, IL-1ß, CRP (all P < 0.00001) and VCAM-1 (P = 0.02) were elevated in CIA. TNF-α (std ß(SE) = 0.39(0.16); P = 0.03), IL-6 (std ß(SE) = 0.37(0.17); P = 0.03), IL-1ß (std ß(SE) = 0.41(0.16); P = 0.02) and CRP (std ß(SE) = 0.36(0.17); P = 0.04) were associated with VCAM-1. Associations between inflammatory markers and the maximal relaxation (Emax) to acetylcholine in mesenteric arteries were no longer significant after adjusting for VCAM-1 (except for IL-1ß). VCAM-1 was inversely associated with the Emax to acetylcholine in mesenteric (std ß(SE) = -0.49(0.16); P = 0.01) but not in saphenous arteries (std ß(SE) = -0.06(0.18); P = 0.76). In conclusion, exposure to high-grade inflammation impairs endothelial-dependent relaxation. The inflammation-induced increase in VCAM-1 concentrations may contribute to the impaired endothelium-dependent relaxation in mesenteric arteries of CIA rats.

Increased systolic blood pressure associated with hypertriglyceridemia in female Sprague-Dawley rats.

The effect of hyperlipidemia on the cardiovascular system is uncertain in females. The aim of the present study was to determine whether administration of a lipogenic diet alters cardiovascular parameters in female rats. Fifty female Sprague-Dawley rats were assigned into 2 groups of rats receiving a standard or a high-fat, high-sucrose diet (HFHS) for 6 weeks (n = 25 per group). Body mass, blood lipids concentrations, triglycerides clearance, blood pressures (BPs), systolic and diastolic functions, as well as vascular reactivity were assessed at the end of the diet intervention. At termination, body mass was similar between the 2 groups. Fasting blood triglycerides concentration (BTG) was greater in the HFHS group. Triglycerides clearance was impaired in the HFHS group. High-density lipoprotein (HDL) cholesterol concentration was lower in the HFHS group. The early-to-late diastolic filling velocity ratio (E/A) was lower in the HFHS group and negatively associated with BTG. The sensitivity (EC50) of mesenteric arteries to phenylephrine was greater in HFHS and was negatively associated with BTG, but not HDL. Systolic BP was higher in the HFHS group and was positively associated with BTG and HDL. The association between systolic BP and BTG was independent of other lipids measured. In conclusion, hypertriglyceridemia may have increased resistance arteries responsiveness to alpha-agonist and systolic BP in female rats.

Early Wave Reflection and Pulse Wave Velocity Are Associated with Diastolic Dysfunction in Rheumatoid Arthritis.

Rheumatoid arthritis (RA) impacts arterial and diastolic function. This study examined whether arterial properties can determine diastolic function in RA. In 173 RA patients, arterial function measures including carotid femoral pulse wave velocity (PWV), central systolic and pulse pressure, pulse pressure amplification, and the magnitude and timing of the forward and reflected waves were measured using applanation tonometry. Diastolic function parameters including the ratio of early-to-late transmitral velocity (E/A) and ratio of E to the mean of the lateral and septal wall myocardial tissue lengthening (e') were measured using echocardiography. The timing of the reflected wave was associated with E/A; PWV was related to E/e'. The timing of the reflected wave, forward wave magnitude, and pulse pressure amplification were associated with impaired relaxation; PWV was related to increased left ventricular (LV) filling pressure. Early wave reflection and PWV are associated with LV-impaired relaxation and increased filling pressure, respectively, in RA.

Effect of ingesting carbohydrate only or carbohydrate plus casein protein hydrolysate during a multiday cycling race on left ventricular function, plasma volume expansion and cardiac biomarkers.

PURPOSE: Multiday racing causes mild left ventricular (LV) dysfunction from day 1 that persists on successive days. We evaluated ingesting casein protein hydrolysate-carbohydrate (PRO) compared with carbohydrate-only (CHO) during a 3-day mountain bike race. METHODS: Eighteen male cyclists were randomly assigned to ingest 6.7% carbohydrate without (CHO) or with 1.3% casein hydrolysate (PRO) during racing (~ 4-5 h/day; 68/71/71 km). Conventional LV echocardiography, plasma albumin content, plasma volume (PV) and blood biomarkers were measured before day 1 and post race on day 3. RESULTS: Fourteen cyclists (n = 7 per group) completed the race. PV increased in CHO (mean increase (95% CI), 10.2% (0.1 to 20.2)%, p = 0.045) but not in PRO (0.4% (- 6.1 to 6.9)%). Early diastolic transmitral blood flow (E) was unchanged but deceleration time from peak E increased post race (CHO: 46.7 (11.8 to 81.6) ms, p = 0.019; PRO: 24.2 (- 0.5 to 48.9) ms, p = 0.054), suggesting impaired LV relaxation. Tissue Doppler mitral annular velocity was unchanged in CHO, but in PRO septal early-to-late diastolic ratio decreased (p = 0.016) and was compensated by increased lateral early (p = 0.034) and late (p = 0.012) velocities. Systolic function was preserved in both groups; with increased systolic lateral wall velocity in PRO (p = 0.002). Effect size increase in serum creatine kinase (CK) activity, CK-MB and C-reactive protein concentrations was less in PRO than CHO (Cohen's d mean ± SD, PRO: 2.91 ± 2.07; CHO: 7.56 ± 4.81, p = 0.046). CONCLUSION: Ingesting casein hydrolysate with carbohydrate during a 3-day race prevented secondary hypervolemia and failed to curb impaired LV relaxation despite reducing tissue damage and inflammatory biomarkers. Without PV expansion, systolic function was preserved by lateral wall compensating for septal wall dysfunction.

Effects of High Salt-Low Potassium Diet on Blood Pressure and Vascular Reactivity in Male Sprague Dawley Rats.

Sodium (Na) intake increases vascular reactivity. Whether low potassium (K) intake affects vascular reactivity-associated blood pressure (BP) changes is uncertain. This study aimed to determine whether Na-induced increases in BP and vascular reactivity are altered by low K intake. Male Sprague Dawley rats were assigned to 3 dietary groups for 6 weeks: a standard Na-K diet (control, n = 12), a high Na-normal K diet (HS-NormK, n = 12), and a high Na-low K diet (HS-LowK, n = 12). BP was measured at baseline and after the dietary intervention. Na and K excretions and vascular reactivity were measured after the dietary intervention. The Na/K ratio was significantly higher in the HS-LowK compared with the other groups. Systolic and diastolic BPs increased significantly in the HS-NormK and HS-LowK groups. In mesenteric arteries, the dose-response curves for phenylephrine-induced contractions shifted to the left and the EC50 (mean ± SD) was significantly lower in the HS-NormK (0.51 ± 0.17 µM, P = 0.003) and HS-LowK (0.69 ± 0.14 µM, P = 0.005) groups compared with the control (3.24 ± 0.79 µM). Systolic (r = -0.58 P = 0.002) and diastolic (r = -0.61 P = 0.001) BPs were associated with the EC50 of phenylephrine-induced contraction in mesenteric arteries. High Na intake induces increased alpha-1 receptor responsiveness in mesenteric arteries, which may be responsible for the increase in BP and is not affected by low dietary K intake.

Disease severity impacts the relationship of apelin with arterial function in patients with rheumatoid arthritis.

Apelin can improve arterial function by enhancing the expression of endothelial nitric oxide synthase but this effect depends markedly on endothelial integrity. We hypothesized that inflammation influences the potential impact of apelin on arterial function in rheumatoid arthritis (RA). We assessed the associations of apelin concentrations with arterial stiffness (pulse wave velocity), wave reflection (augmentation index, reflected wave pressure, and reflection magnitude), and pressure pulsatility (central systolic pressure (CSP), central pulse pressure (CPP), peripheral pulse pressure (PPP), pulse pressure amplification (PPamp), and forward wave pressure (Pf)) among 170 RA patients without cardiovascular disease. In multivariable regression models, apelin concentrations were not independently associated with arterial function measures (p ≥ 0.15) in all patients. Inflammation markers were not consistently associated with apelin levels but joint deformity counts, Disease Activity Score in 28 joints (DAS28), and erythrocyte sedimentation rate (ESR) impacted apelin-pressure pulsatility relations (interaction p ≤ 0.05). In stratified analysis, apelin was associated with CSP (partial r = - 0.33, p = 0.01), CPP (partial r = - 0.26, p = 0.04), PPamp (partial r = 0.27, p = 0.03), and Pf (partial r = - 0.33, p = 0.01) in patients without but not with joint deformities; apelin was related to CSP (partial r = - 0.24, p = 0.05) in those with a DAS28 joint < 2.8 (median value) (partial r = - 0.24, p = 0.05) but not ≥ 2.8, and to CSP (partial r = - 0.36, p = 0.003) in those with an erythrocyte sedimentation rate < 13 mm/h (median value) but not ≥ 13 mm/h. Apelin is associated with reduced pressure pulsatility in RA patients without but not with a high inflammatory burden. A loss of apelin protective effects on arterial function may contribute to the link between RA severity and cardiovascular risk.

Nesfatin-1 and visfatin expression is associated with reduced atherosclerotic disease risk in patients with rheumatoid arthritis.

Nesfatin is an anti-inflammatory molecule that reduces atherosclerotic cardiovascular risk. By contrast, visfatin has pro-inflammatory properties and is pro-atherogenic. We examined the potential impact of nesfatin and visfatin on atherosclerotic disease in 232 (113 black and 119 white) consecutive rheumatoid arthritis (RA) patients from 2 centers. Independent relationships of nesfatin and visfatin concentrations with metabolic risk factors, endothelial activation, carotid atherosclerosis and altered plaque stability were determined in multivariable regression models. Rheumatoid factor (RF) positivity was associated with both nesfatin (ß = 0.650, p < 0.0001) and visfatin levels (ß = 0.157, p = 0.03). Visfatin concentrations were related to increased diastolic blood pressure (ß = 4.536, p = 0.01) and diabetes prevalence (ß = 0.092, p = 0.04). Nesfatin levels were associated with reduced carotid intima-media thickness (ß = -0.017, p = 0.008). Nesfatin (ß = 0.116, p = 0.001) and visfatin concentrations (ß = 0.234, p = 0.001) were related to those of matrix metalloproteinase-2 (MMP-2), a plaque stability mediator. Nesfatin and visfatin concentrations were directly correlated (Spearman's rho = 0.516). The nesfatin-MMP-2 and visfatin-MMP-2 relations were both stronger in RF negative compared to RF positive patients (interaction p = 0.01 and p = 0.04, respectively). Nesfatin is associated with reduced atherosclerosis and increased plaque stability mediator levels in RA. Visfatin is related to adverse cardio-metabolic risk in RA. Increased MMP-2 expression in relation to visfatin may represent a compensatory mechanism aimed at reducing cardiovascular risk in RA.

Systemic Angiotensinogen Concentrations Are Independently Associated With Left Ventricular Diastolic Function in a Community Sample.

BACKGROUND: Left ventricular (LV) diastolic dysfunction characterizes heart failure with a preserved ejection fraction. Although it is recognized that the renin-angiotensin-aldosterone system (RAAS) decreases LV diastolic function, whether systemic angiotensinogen (AGT) contributes to these effects is uncertain. Hence, the aim was to determine the relationship between systemic AGT concentrations and LV diastolic function. METHODS: LV diastolic function was determined from the mean of the lateral and septal wall myocardial tissue lengthening at the mitral annulus (average e') and from the ratio of early transmitral blood flow velocity (E) to average e' (E/e') in 445 Black African participants from a community sample. RESULTS: In multivariate regression models with adjustments for age, sex, waist circumference diabetes mellitus, alcohol and tobacco use, hypertension treatment, systolic blood pressure (BP), and relative wall thickness, the square root of serum AGT concentrations was independently associated with E/e' (partial r (95% confidence interval [CI]) = 0.11 (0.02-0.21), P = 0.04), but not with average e' (partial r (95% CI) = -0.06 (-0.15 to 0.04), P = 0.25). There was no association between plasma renin concentrations and markers of diastolic function (all P > 0.05). CONCLUSION: Circulating AGT concentrations are associated with LV diastolic function beyond BP and other confounders in an African population. Hence, through circulating AGT, the systemic RAAS may play an important role in contributing to LV diastolic function in Black Africans.

Arterial wave reflection and subclinical atherosclerosis in rheumatoid arthritis.

OBJECTIVES: Atherosclerotic cardiovascular disease risk is increased in rheumatoid arthritis (RA). Wave reflection occurs at arterial branching points, which are particularly prone to atherosclerosis. We explored the relationship of wave reflection with atherosclerosis in RA. METHODS: One hundred and sixty three RA patients (110 white, 31 Asian, 17 black and 5 of mixed ancestry) without cardiovascular disease participated. Arterial stiffness, wave reflection, pressure pulsatility, plaque in the extracranial carotid artery tree and the mean of the left and right common carotid arteries intima-thickness were determined. Associations were identified in multivariable regression models. RESULTS: One SD increase in reflected wave pressure (OR (95% CI) = 2.54 (1.41-4.44), p=0.001), reflection magnitude (OR (95% CI) = 1.84 (1.17-2.89), p=0.008), central pulse pressure (OR (95% CI) = 1.89 (1.12-3.22), p=0.02) and peripheral pulse pressure (OR (95% CI) = 2.09 (1.23-3.57), p=0.007) were associated with plaque. The association of wave reflection with plaque was independent of arterial stiffness and pressure pulsatility, and was present in both hypertensive and normotensive RA patients. In receiver operator characteristic curve analysis, the optimal cutoff value for reflected wave pressure in predicting plaque presence was 25 mmHg with a sensitivity, specificity, positive predictive value and negative predictive value of 45.2%, 89.3%, 78.6% and 66.2%, respectively; a reflected wave pressure of >25 mmHg was associated with plaque in univariate and adjusted analysis (p<0.0001 for both). Arterial function was not independently related to carotid intima-media thickness. CONCLUSIONS: Consideration and therapeutic targeting of wave reflection may improve cardiovascular disease prevention in RA.

Cardiovascular Risk Factors and Disease Characteristics Are Consistently Associated with Arterial Function in Rheumatoid Arthritis.

OBJECTIVE: Arterial properties influence cardiovascular disease (CVD) risk. We identified potential determinants of arterial function in patients with rheumatoid arthritis (RA). METHODS: Relationships of traditional cardiovascular risk factors and RA characteristics with arterial stiffness (pulse wave velocity), wave reflection (augmentation index, reflected wave pressure, and reflection magnitude), and pressure pulsatility (central systolic and pulse pressure, peripheral pulse pressure, pulse pressure amplification, and forward wave pressure) were identified in multivariable backward regression models among 177 patients without established CVD (118 white, 32 Asian, 22 black, 5 mixed ancestry). RESULTS: Recorded characteristics explained 37% (pulse wave velocity) to 71% (reflected wave pressure) of the variability in arterial function. These factors were particularly associated with wave reflection and pressure pulsatility: RA duration (p = 0.04), rheumatoid factor status (p = 0.01 to 0.03), leukocyte counts (p = 0.02 to 0.05), and total cholesterol (p < 0.01 to 0.03). Body mass index (p < 0.01 to 0.02) and insulin resistance (p < 0.01 to 0.01) were related to reduced wave reflection and peripheral pulse pressure. Exercise (p = 0.02) and alcohol consumption (p < 0.01) were associated with increased pulse pressure amplification and decreased peripheral pulse pressure, respectively. Tumor necrosis factor-α inhibition (p < 0.01) was related to reduced pulse wave velocity, and tetracycline use (p = 0.02) to decreased peripheral pulse pressure. CONCLUSION: Traditional cardiovascular risk factors and disease characteristics are consistently associated with vascular hemodynamic alterations in RA. The relative effect of arterial stiffness, wave reflection, and pressure pulsatility on CVD risk in RA needs further study.

Omentin concentrations are independently associated with those of matrix metalloproteinase-3 in patients with mild but not severe rheumatoid arthritis.

Omentin is an adipokine that reportedly protects against cardiometabolic risk. We investigated the relationships between omentin concentrations and subclinical cardiovascular disease in rheumatoid arthritis (RA). Omentin concentrations were measured in 213 (104 black; 109 white) RA patients. Relationships of omentin levels with those of endothelial activation markers, ultrasound determined carotid intima-media thickness and plaque, and matrix metalloproteinase (MMP)-2, -3 and -9 that mediate altered plaque stability, were identified in confounder adjusted multivariate regression models. Omentin concentrations were inversely associated with MMP-3 levels [ß = -364 (0.113), p = 0.002]. This relationship was influenced by population origin, RA activity and the erythrocyte sedimentation rate and joint deformity count (interaction p value = 0.009, 0.04, 0.04 and 0.007, respectively). Accordingly, the omentin-MMP-3 concentration relationship was reproduced in white [ß (SE) = -0.450 (0.153), p = 0.0004)] but not black patients [ß (SE) = -0.099 (0.195), p = 0.6)], in participants with disease remission or mild disease activity [ß (SE) = -0.411 (0.139), p = 0.004] but not with moderate or severe RA activity [ß (SE) = -0.286 (0.202), p = 0.2], and in those with a small [ß (SE) = -0.534 (0.161), p = 0.001] but not large erythrocyte sedimentation rate [-0.212 (0.168), p = 0.2] and without [ß (SE) = -0.554 (0.165), p = 0.0001] but not with large joint deformity counts [-0.110 (0.173), p = 0.5]. Omentin levels were unrelated to endothelial activation and atherosclerosis. Among patients with RA, a lack of plaque stabilizing effects by omentin may contribute to the reported link between severe disease and increased cardiovascular risk. The association between concentrations of omentin and MMP-3 is population specific in RA.