Reactive Hyperemia Peripheral Arterial Tonometry Index Research Articles

Association between protein arginine N-methyltransferase 1 polymorphism and overt diabetic nephropathy: Role of asymmetric dimethylarginine in vascular tone

Backgroundω-NG,NG-asymmetric dimethylarginine (ADMA) regulates vascular tone and may participate in the pathogenesis of diabetic nephropathy (DN). ObjectiveTo investigate whether single-nucleotide polymorphisms (SNPs) around the protein arginine N-methyltransferase 1 gene (PRMT1) influence ADMA dynamics and DN incidence and severity. MethodsThis study utilized a hospital-based database containing 310 Japanese patients with type 2 diabetes mellitus (T2DM). The association of PRMT1-related tagged SNPs with DN stage distribution was examined using a dominant model of minor alleles. PRMT1 mRNA, serum ADMA, reactive hyperemia-peripheral arterial tonometry index (RHI), and brachial-ankle pulse wave velocity (baPWV) were compared between the genotype-based subgroups of causal SNP, and correlations between these variables were evaluated. ResultsThe composition of DN stages significantly differed between the GG and GA + AA subgroups of rs892151 (p = 0.026). In a propensity-matching cohort of rs892151, the GA + AA subgroup had an increased incidence of overt DN (odds ratio 2.92, 95 % confidence interval 1.12–7.62, p = 0.028), along with higher PRMT1 mRNA, serum ADMA levels, and baPWV than the GG subgroup (p < 0.001, p = 0.023 and 0.047, respectively). There were correlations between PRMT1 mRNA and serum ADMA levels, between serum ADMA levels and RHI, and between baPWV and urinary albumin excretion (r = 0.335, p < 0.001, r = -0.221, p = 0.029, and r = 0.254, p = 0.004, respectively). ConclusionsT2DM patients carrying the PRMT1-related variant rs892151 were susceptible to overt DN. ADMA-mediated endothelial dysfunction and arterial stiffness may be involved in the variant-related pathogenesis of overt DN.

Abstract 14476: A Randomized, Double-blind Comparison Study of Royal Jelly to Improve Endothelial Function in Healthy Volunteers

Backgrounds: Royal jelly is a creamy substance secreted by honeybees. It has been reported that royal jelly has benefits on dyslipidemia and metabolic syndrome. However, the effects of royal jelly on atherogenesis remains unknown. We prospectively evaluated the effects of royal jelly on endothelial function, which can reflect early atherogenesis, in healthy volunteers. Methods: This was a single center, double-blind, 1:1 randomized placebo-controlled study. One-hundred healthy volunteers were randomly assigned to receive royal jelly 690 mg daily (equivalent 2040 mg of fresh royal jelly) or placebo from October 2018 and December 2019. Royal jelly or placebo were administered for 28 days. Endothelial function assessed by reactive hyperemia peripheral arterial tonometry (RH-PAT) and blood chemistries were compared between baseline and 28 days after enrollment. Primary endpoint was the change of RH-PAT index. Secondary endpoint was the change of liver function and lipid profiles. Results: The mean (SD) age of the participants was 35.0 (9.3) and 36.1 (9.1) years, and male was 45% and 50% in the placebo and the royal jelly group, respectively. The relative change of RH-PAT index was significantly higher in the royal jelly group compared with placebo control (21.4 ± 53.1% vs. 0.05 ± 40.9%, P = 0.037). The relative change of alanine aminotransferase and γ-glutamyl transpeptidase were significantly lower in the royal jelly group than the placebo group (alanine aminotransferase: –6.06 ± 22.2% vs. 11.6 ± 46.5%, P = 0.02; γ-glutamyl transpeptidase: -3.45 ± 17.8% vs. 4.62 ± 19.4%, P = 0.045). Lipid profiles were not significantly different between two study groups. Conclusions: Royal jelly improved endothelial function assessed by RH-PAT and liver function in healthy volunteer. It can be expected that royal jelly has anti-atherogenic property through improving endothelial function.

Metoprolol rescues endothelial progenitor cell dysfunction in diabetes.

Added risk portended by diabetes in addition to hypertension has been related to an amplification of endothelial dysfunction. β-blockers are widely used for cardiovascular diseases and improve the endothelial function compared with a placebo. However, the effect of β-blockers on the endothelial progenitor cells (EPCs) function in diabetes is still unknown. Five β-blockers (metoprolol, atenolol, propranolol, bisoprolol, and nebivolol) were tested in EPC functional screening. Metoprolol improved EPC function significantly among the five β-blockers and was chosen for the in vivo tests in STZ induced diabetic mice. Reactive hyperemia peripheral arterial tonometry (RH-PAT) measurements were performed using the Endo-PAT2000 device in diabetic patients. Metoprolol, but not other β-blockers, improved EPC function in both tube formation and migration assay. EPC function was significantly decreased in diabetic mice, and metoprolol treatment restored damaged EPC migration capabilities and circulation EPC number. Metoprolol treatment promoted wound healing and stimulated angiogenesis in diabetic mice. Furthermore, metoprolol significantly enhanced eNOS phosphorylation and decreased O2− levels in EPCs of diabetic mice. In clinical trials, the RH-PAT index was significantly higher in metoprolol-treated versus bisoprolol-treated diabetics. Metoprolol could accelerate wound healing in diabetic mice and improve endothelial function in diabetic subjects, which may be mediated in part by improving impaired EPC function.

Elevated plasma homocysteine levels are associated with impaired peripheral microvascular vasomotor response

BackgroundHyperhomocysteinemia (HHcy) has been proposed as an important cardiovascular risk factor (cRF). However, little is known about the association between plasma homocysteine levels and peripheral microvascular endothelial dysfunction (PMED), which is an integrated index of vascular health. MethodsThis cross-sectional and retrospective cohort study included patients who underwent non-invasive PMED assessment using reactive hyperemia peripheral arterial tonometry (RH-PAT). The association between HHcy and PMED, and its impact on MACE (all-cause mortality and atherosclerotic cardiovascular events) was investigated. ResultsA total of 257 patients were enrolled (HHcy > 10.0 µmol/L, N = 51; lower levels of homocysteine [LHcy] ≤ 10 µmol/L, N = 206). Patients with HHcy were older, predominantly males, and with more comorbidities than patients with LHcy (p < 0.05 for all). RH-PAT index was lower in patients with HHcy versus LHcy (p = 0.01). A significant association between HHcy and PMED was observed in older (≥60 years), obese (≥30 kg/m2), present/past smokers and hypertensive patients. HHcy was significantly associated with PMED even after adjusting for other cRF and B-vitamins supplementation. HHcy was associated with an increased risk of MACE with a hazard ratio of 3.65 (95% CI 1.41–9.48, p = 0.01) and an adjusted hazard ratio of 2.44 (95% CI 0.91–6.51, p = 0.08) after adjustment for age (≥60 years). ConclusionHHcy was independently associated with PMED after adjusting for cRF and B-vitamins supplementation. Thus, the link between homocysteine and MACE could be mediated by endothelial dysfunction, and will require further clarification with future studies.

Endothelial function as predictor in patients with coronary syndrome treated by percutaneous coronary intervention.

We aimed at identifying the predictive role of endothelial function assessed by the RH-PAT index (RHI) for future major cardiovascular events (MACEs) in acute coronary syndrome (ACS) patients treated with percutaneous coronary intervention (PCI). We measured RHI in 308 subjects with ACS, and they were divided into the normal endothelial function (NEF) group and the endothelial dysfunction (DEF) group according to the RHI. The subjects were followed up for a mean of 16 months (interquartile range [IQR]: 14–20 months) after PCI treatment, and their MACEs were also recorded. Cumulative incidence curves were constructed for time-to-event variables with Kaplan–Meier estimates and compared using the log-rank test. The overall incidence of MACEs was 25.39% in the DEF group and 15.96% in the NEF group (P<0.05). Kaplan–Meier analysis also demonstrated a significantly higher probability of MACEs in the DEF group than in the NEF group (log-rank test: P<0.05). Multivariate Cox hazard analysis identified RHI (Model 2, adjusted by blood pressure, hazard ratio [HR]: 0.425; 95% confidence interval [CI]: 0.198–0.914; P=0.029) and SYNTAX score (HR: 1.043; 95% CI: 1.019–1.067; P<0.001) as independent predictors of future MACEs after PCI treatment in ACS patients. Endothelial function measured by reactive hyperemia-peripheral arterial tonometry (RH-PAT) is impaired in ACS subjects treated with PCI. The RHI was an independent predictor of MACEs, suggesting that RHI may be useful as a candidate biomarker in the risk stratification of patients with ACS after PCI treatment.

Assessment of endothelial function during the loading phase of infliximab in psoriasis: a potential predictor of its drug survival.

Tumor necrosis factor inhibitors decrease the risk of cardiovascular events in moderate to severe psoriasis, but the association between their effects on endothelial function and those on skin lesions has not been well studied. We investigated the association between infliximab effects on endothelial function during the loading phase and those on skin lesions in patients with psoriasis. We evaluated endothelial function with reactive hyperemia-peripheral arterial tonometry index (RHI) in 15 patients with psoriasis before the first and third infusions of infliximab. Patients were stratified into two groups; those who maintained Psoriasis Area and Severity Index (PASI) 75 response for more than 6 months (defined as responders) and the others (defined as nonresponders). Six weeks after the initiation of infliximab (before the third infusion), PASI scores were significantly improved compared with baseline, while RHI values were not altered in the whole patient group. However, when the responders and the nonresponders were analyzed separately, RHI values tended to be decreased before the third infusion compared with baseline in the nonresponders, while being unchanged in the responders. Importantly, the difference in ∆RHI reached a statistical significance between the two groups, and the cutoff value (mean - 2 standard deviation of RHI values in the responders) identified the nonresponders with 67% of sensitivity and 100% of specificity. The decrease in RHI values before the third infusion may serve as a predictor for the long-term unfavorable effect of infliximab on psoriatic skin lesions.

Endothelial Dysfunction Is Associated with Cognitive Impairment of Elderly Cardiovascular Disease Patients.

Cognitive impairment is frequently represented in elderly patients with cardiovascular disease (CVD); yet, the mechanism is uncertain. Recent studies have suggested the association between the vascular endothelial dysfunction and cognitive impairment. The aim of this study was to clarify the association between endothelial dysfunction and cognitive impairment in elderly patients with CVD.A total of 80 elderly patients (> 70 years old) with CVD were included. Patients who had already pharmacologically intervened for cognitive impairment were excluded. The endothelial dysfunction was assessed by the reactive hyperemia-peripheral arterial tonometry (RH-PAT). Cognitive impairment was diagnosed by the Mini-mental state examination.The RH-PAT index was significantly lower in cognitive impairment (median 1.60 [interquartile range (IQR) 1.34 to 1.89], n = 51) as compared with non-cognitive impairment (median 1.75 [IQR 1.55 to 2.30], n = 29, P = 0.005). By a multivariate analysis, the RH-PAT index was independently associated with cognitive impairment (odds ratio: 0.89; 95% confidence interval: 0.81 to 0.97; per 0.1, P = 0.044). In the receiver-operating characteristic analysis, the best cut-off of the RH-PAT index to identify cognitive impairment was 1.65 (area under the curve 0.67; P = 0.011) with limited the sensitivity (63%) and specificity (66%).A lower RH-PAT index was significantly associated with the presence of cognitive impairment in elderly CVD patients. Further studies are required to clarify the mechanism and the causal relationship between the endothelial dysfunction and cognitive impairment in patients with CVD.

The SGLT2 Inhibitor Dapagliflozin Significantly Improves the Peripheral Microvascular Endothelial Function in Patients with Uncontrolled Type 2 Diabetes Mellitus.

Objective Sodium-glucose co-transporter 2 (SGLT2) inhibitors reduce cardiovascular events and decrease the body fat mass in patients with type 2 diabetes mellitus (T2DM). We examined whether or not the SGLT2-inhibitor dapagliflozin can improve the endothelial function associated with a reduction in abdominal fat mass. Methods We prospectively recruited patients with uncontrolled [hemoglobin A1c (HbA1c) >7.0%] T2DM who were not being treated by SGLT2 inhibitors. Patients were treated with add-on dapagliflozin (5 mg/day) or non-SGLT2 inhibitor medicines for 6 months to improve their HbA1c. We measured the peripheral microvascular endothelial function as assessed by reactive hyperemia peripheral arterial tonometry (RH-PAT) and calculated the natural logarithmic transformed value of the RH-PAT index (LnRHI). We then investigated changes in the LnRHI and abdominal fat area using computed tomography (CT). Results The subjects were 54 patients with uncontrolled T2DM (72.2% men) with a mean HbA1c of 8.1%. The HbA1c was significantly decreased in both groups, with no significant difference between the groups. Dapagliflozin treatment, but not non-SGLT2 inhibitor treatment, significantly increased the LnRHI. The changes in the LnRHI were significantly greater in the dapagliflozin group than in the non-SGLT2 inhibitor group. Dapagliflozin treatment, but not non-SGLT2 inhibitor treatment, significantly decreased the abdominal visceral fat area, subcutaneous fat area (SFA), and total fat area (TFA) as assessed by CT and significantly increased the plasma adiponectin levels. The percentage changes in the LnRHI were significantly correlated with changes in the SFA, TFA, systolic blood pressure, and adiponectin. Conclusion Add-on treatment with dapagliflozin significantly improves the glycemic control and endothelial function associated with a reduction in the abdominal fat mass in patients with uncontrolled T2DM.

Comparison of the effects of linagliptin and voglibose on endothelial function in patients with type 2 diabetes and coronary artery disease: a prospective, randomized, pilot study (EFFORT).

Endothelial dysfunction contributes to poor cardiovascular prognosis in patients with type 2 diabetes mellitus (T2DM) and coronary artery disease (CAD). The effect of dipeptidyl peptidase-4 inhibitors on endothelial function remains controversial. We sought to compare the effects of linagliptin and voglibose on endothelial function, as assessed by reactive hyperemia-peripheral arterial tonometry (RH-PAT). Sixteen patients with newly diagnosed T2DM and CAD were randomized 1:1 to linagliptin (5mg, once-daily) or voglibose (0.9mg, thrice-daily). The RH-PAT and laboratory parameters, including 75g oral glucose tolerance test, were measured at baseline and 3months. Linagliptin increased serum levels of active glucagon-like peptide-1 and high-molecular-weight adiponectin. Age-, sex-, and baseline-adjusted changes in logarithmic RH-PAT index (LnRHI) after 3months were significant between groups (linagliptin, 0.135±0.097; voglibose, -0.124±0.091; P=0.047). In the linagliptin group, change in LnRHI was positively correlated with change in high-density lipoprotein cholesterol and negatively correlated with changes in both urine albumin-to-creatinine ratio and high-sensitivity C-reactive protein. Furthermore, linagliptin treatment for 3months reduced serum levels of both glucose and insulin at 2h, relative to voglibose, in the age-, sex-, and baseline-adjusted model. Linagliptin improved endothelial function relative to voglibose, accompanied by amelioration of glycemic, renal, and cardiometabolic parameters, in patients with newly diagnosed T2DM and CAD.Trial registration Unique Trial Number, UMIN 000029169 ( https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000012442 ).

Effect of Aggressive lipid-lowering treatment with Rosuvastatin on vascular endoTHelium function: evaluation of vascular endothelium function (EARTH study).

Vascular endothelial dysfunction plays an important role in the process of atherosclerosis up to the final stage of plaque rupture. Vascular endothelial dysfunction is reversible, and can be recovered by medications and life-style changes. Improvement in endothelial function may reduce cardiovascular events and improve long-term prognosis. A total of 50 patients with stable angina and dyslipidemia were enrolled, including patients who had not received prior treatment with statins and had serum LDL-C levels≥100mg/dL, and patients who had previously received statin treatment. All agreed to register regardless of their LDL-C level. Rosuvastatin was initially administered at a dose of 2.5mg and appropriately titrated up to the maximum dose of 20mg or until LDL-C levels lower than 80mg/dL were achieved, for 24weeks. Endothelial function was assessed by the reactive hyperemia peripheral arterial tonometry (RH-PAT) index in the radial artery by Endo-PAT® 2000 (Endo-PAT®2000, software version 3.0.4, Itamar Medical Ltd., Caesarea, Israel). RH-PAT data were digitally analyzed online by Endo-PAT®2000 at baseline and at 24weeks. LDL-C and MDA-LDL-C decreased from 112.6±23.3 to 85.5±20.2mg/dL and from 135.1±36.4 to 113.9±23.5mg/dL respectively (p<0.0001). However, HDL-C, hs-CRP and TG did not change significantly after treatment. RH-PAT index levels significantly improved, from 1.60±0.31 to 1.77±0.57 (p=0.04) after treatment, and the percent change of the RH-PAT index was 12.8±36.9%. Results of multivariate analysis show that serum LDL-C levels over 24weeks did not act as a predictor of improvement of the RH-PAT index. However, HbA1c at baseline was an independent predictor which influenced the 24-week RH-PAT index level. The RH-PAT index of patients with high HbA1c at baseline did not improve after administration of rosuvastatin but it did improve in patients with low HbA1c at baseline. Aggressive lowering of LDL-C with rosuvastatin significantly improved the RH-PAT index, suggesting that it may improve endothelial function in patients with coronary artery disease.Clinical Trial Registration No: UMIN-CTR, UMIN000010040.

High-dose atorvastatin versus moderate dose on early vascular protection after ST-elevation myocardial infarction.

Background and aimClinical benefits of early high-dose statin therapy after acute coronary syndromes are widely known; however, there is poor evidence on the specific setting of ST-elevation myocardial infarction (STEMI) and dose-dependent effects of this therapy on endothelial function and inflammatory biomarkers in the most vulnerable phase after acute coronary syndromes: the postdischarge period. In our study, we compared the short-term effects of high (80 mg) vs moderate doses of atorvastatin (20 mg) in patients with STEMI undergoing primary percutaneous coronary intervention on endothelial function and vascular inflammation. The aim of our study was the evaluation of dose-dependent short-term effects.Subjects and methodsWe enrolled 52 patients within 48 hours of a STEMI to atorvastatin 80 mg (n=26) or 20 mg (n=26). Every patient underwent endothelial function evaluation by the reactive hyperemia–peripheral arterial tonometry (RH-PAT) index on the first day and 1 month after the STEMI. At the same time, we measured lipid profile and serum levels of high-sensitivity CRP, IL6, TNFα, and oxidized LDL.ResultsAfter 1 month of therapy, we observed differences in high-sensitivity CRP levels (0.04±0.02 mg/dL vs 0.36±0.3 mg/dL, P=0.001), IL6 (1.12±0.93 pg/mL vs 3.13±2.84 pg/mL, P=0.03), and improvement in RH-PAT index (1.96±0.16 vs 1.72±0.19, P=0.002) in the group treated with high-dose vs moderate-dose atorvastatin. There was no significant difference in levels of TNFα or oxidized LDL with atorvastatin 20 mg, while there was a reduction in these variables in the group treated with atorvastatin 80 mg. We observed a correlation between high-sensitivity polymerase chain reaction and RH-PAT index on the 30th day after STEMI (r=0.5, P=0.001).ConclusionHigher dose statin therapy in patients with STEMI undergoing primary percutaneous coronary intervention showed early greater vascular protective effects that moderate dose.

Differences in endothelial dysfunction induced by paroxysmal and persistent atrial fibrillation: Insights from restoration of sinus rhythm by catheter ablation

BackgroundAtrial fibrillation (AF) is associated with endothelial dysfunction. Studies have shown the incidence of cardiovascular events to be greater in patients with persistent AF (PeAF) than paroxysmal AF (PAF). ObjectiveThe aim of this study was to investigate whether endothelial dysfunction and the impact of catheter ablation on the endothelial function differs between PAF and PeAF. MethodsWe prospectively measured the endothelial function by reactive hyperemia peripheral arterial tonometry (RH-PAT) in 103 PAF, 75 PeAF, and 51 control patients at baseline, with follow-up in the AF patients at 6 and 12months after the catheter ablation. ResultsThe log-transformed RH-PAT index (ln RHI) was the highest in the control group, followed by the PAF and PeAF (0.67±0.23, 0.57±0.29, and 0.45±0.3, respectively, p<0.001) groups. PeAF was determined to be an independent factor of endothelial dysfunction (ln RHI <0.55) even after adjustment for the conventional cardiovascular risk factors. For 12months after the catheter ablation, 102 (99%) PAF and 72 (96%) PeAF patients maintained sinus rhythm. On average, the ln RHI in the PAF group did not change during the follow-up, but it significantly increased in the PeAF group to a level comparable to that of the PAF patients 6months after the catheter ablation (0.53±0.28, p=0.034), and maintained the same level at 12months after the catheter ablation. ConclusionsThe persistent form of AF may independently contribute to endothelial dysfunction. In addition, by catheter ablation, the maintenance of sinus rhythm may protect against exacerbations of endothelial dysfunction.

Lenvatinib, an oral multi-kinases inhibitor, -associated hypertension: Potential role of vascular endothelial dysfunction

Background and aimsLenvatinib (Lenvima®), an oral multi-kinase inhibitor, is effective in the treatment of differentiated thyroid carcinomas (DTCs). A severe adverse effect of lenvatinib is hypertension, thus limiting its use as an anti-cancer treatment. Although the pathogenesis of hypertension is generally assumed to involve microvascular bed reduction and an increase in peripheral vascular resistance due to a decrease in nitrogen oxide (NOx) production after vascular endothelial growth factor (VEGF) inhibition, the effects of hypertension on vascular endothelial function in actual patients remain unclear. Here, we examined how lenvatinib affects vascular endothelial function. MethodsTen consecutive DTC patients who did not take any cardiovascular agents were orally administered 24 mg of lenvatinib once daily. Using an EndoPAT2000® system, we used reactive hyperemia-peripheral arterial tonometry (RH-PAT) and evaluated vascular endothelial function on the basis of the RH-PAT index (RHI). We expressed the results as %RHI, which indicates the change compared with pretreatment levels. Additionally, we measured serum NOx and plasma VEGF concentrations pre- and post-treatment. ResultsAll of the patients treated with lenvatinib exhibited significant hypertension; the %RHI levels were significantly decreased the day after treatment with lenvatinib. Furthermore, serum NOx and plasma VEGF concentrations were significantly decreased and increased, respectively, compared with pretreatment levels. These results indicate that hypertension induced by lenvatinib may be caused by a decrease in nitric oxide production, as a result of VEGF inhibition and impaired vascular endothelial function. ConclusionsWe provide the first demonstration that lenvatinib causes hypertension via vascular endothelial dysfunction in human subjects.

Stretching Exercises Improve Vascular Endothelial Dysfunction Through Attenuation of Oxidative Stress in Chronic Heart Failure Patients With an Implantable Cardioverter Defibrillator.

Endurance training improves oxidative stress and vascular endothelial dysfunction in patients with chronic heart failure (CHF). However, patients with CHF and an implantable cardioverter defibrillator (ICD) or cardiac resynchronization therapy-defibrillator (CRT-D) often avoid endurance training for fear of ICD shock. Recent studies have reported that stretching exercises enhance antioxidant activity and improve vascular responses. Therefore, we aimed to assess the effects of 4 weeks of stretching exercises on oxidative stress and vascular endothelial function in patients with CHF with an ICD or CRT-D. Fifty sedentary patients with CHF (78% males; mean age = 70 ± 9 years; left ventricular ejection fraction = 26% ± 8%) with an ICD or CRT-D were randomly divided into a group that performed 4 weeks of stretching exercises (stretching group) and a group that continued a sedentary lifestyle (control group). We compared the reactive hyperemia peripheral arterial tonometry (RH-PAT) index and blood parameters, such as von Willebrand factor (vWF), malondialdehyde-modified low-density lipoprotein cholesterol (MDA-LDL), reactive oxygen species (ROS), high-sensitivity C-reactive protein, pentraxin 3, and fibrinogen between the 2 groups before and after the 4-week study period. In the stretching group, a significant increase in the RH-PAT index and significant decreases in vWF, MDA-LDL, ROS, and fibrinogen concentrations were observed after the study compared with before (all P < .05). No significant changes were observed in the control group. Four weeks of stretching exercises improved vascular endothelial dysfunction through attenuation of oxidative stress in sedentary patients with CHF with an ICD or CRT-D.

Nitric Oxide-Dependent Endothelial Dysfunction and Reduced Arginine Bioavailability in Plasmodium vivax Malaria but No Greater Increase in Intravascular Hemolysis in Severe Disease.

Pathogenesis of severe Plasmodium vivax malaria is poorly understood. Endothelial dysfunction and reduced nitric oxide (NO) bioavailability characterize severe falciparum malaria, but have not been assessed in severe vivax malaria. In patients with severe vivax malaria (n = 9), patients with nonsevere vivax malaria (n = 58), and healthy controls (n = 79), we measured NO-dependent endothelial function by using reactive hyperemia-peripheral arterial tonometry (RH-PAT) and assessed associations with arginine, asymmetric dimethylarginine (ADMA), and hemolysis. The L-arginine level and the L-arginine to ADMA ratio (a measure of L-arginine bioavailability) were reduced in patients with severe vivax malaria and those with nonsevere vivax malaria, compared with healthy controls (median L-arginine level, 65, 66, and 98 µmol/mL, respectively [P = .0001]; median L-arginine to ADMA ratio, 115, 125, and 187, respectively [P = .0001]). Endothelial function was impaired in proportion to disease severity (median RH-PAT index, 1.49, 1.73, and 1.97 in patients with severe vivax malaria, those with nonsevere vivax malaria, and healthy controls, respectively; P = .018) and was associated with the L-arginine to ADMA ratio. While the posttreatment fall in hemoglobin level was greater in severe vivax malaria as compared to nonsevere vivax malaria (2.5 vs 1 g/dL; P = .0001), markers of intravascular hemolysis were not higher in severe disease. Endothelial function is impaired in nonsevere and severe vivax malaria, is associated with reduced L-arginine bioavailability, and may contribute to microvascular pathogenesis. Severe disease appears to be more associated with extravascular hemolysis than with intravascular hemolysis.

Endothelial function assessment in nutritional research studies: a comparison of two arterial occlusion sites for assessing reactive hyperemia using a peripheral arterial tonometry device

Endothelial function assessment can be an important tool in evaluating artery health in humans, and can be an important phenotyping tool in nutritional research studies as well as an early indicator of cardiovascular disease. We conducted a study of endothelial function in healthy adults using reactive hyperemia peripheral arterial tonometry (RH‐PAT) by the EndoPAT™ device (Itamar Medical Ltd., Caesarea, Israel) in order to compare two arterial occlusion sites. Brachial artery (upper arm) occlusion is the most common occlusion site, yet a forearm occlusion site may be a potentially valid site for endothelial function testing. RH‐PAT testing is an operator independent, non‐invasive technique that measures the arterial pulse wave amplitude using pneumatic fingertip probes during reactive hyperemia allowing a RH‐PAT index (RHI) to be calculated. Reactive hyperemia was achieved by occluding either the upper arm (brachial artery) or the forearm (ulnar and radial arteries) in the individual using a blood pressure cuff inflated to ~200 mmHg for 5 minutes. Twenty healthy adults (14 female, 6 male), age 38 ± 12 years (mean ± SD) and BMI 24 ± 3 kg/m2 participated in the study. RH‐PAT measurements were determined in the morning after a 12 hour fast. Participants were tested approximately 3 days apart using a crossover design with randomization of upper arm and forearm as occlusion sites. The participant's non‐dominant arm was always the occluded arm. Participants were tested in a quiet, temperature‐controlled (21–24°C) room in a supine position for at least 15 minutes prior to the 15 minute test: 5 minute baseline, 5 minute occlusion, and 5 minute post‐occlusion. A self‐reported numeric pain intensity scale (0–10) was used to evaluate pain during the occlusion and post‐occlusion (hyperemic period) portion of the measurement. The RHI is the post‐to‐pre occlusion PAT signal ratio in the occluded arm, relative to the same ratio in the control arm, corrected for baseline vascular tone of the occluded arm. The mean RHI for the two occlusion sites: 2.15 ± 0.78 (upper arm) and 2.36 ± 0.75 (forearm) was not different (p=0.18, paired t‐test). A Pearson correlation of the RHI from both sites (r=0.602, p=0.005) was positive and significant. The mean reported pain intensity for the upper arm was 3.7 ± 1.3 compared to 2.7 ± 1.8 for the forearm; these indices were significantly different (p=0.002, signed‐rank test). In summary, occlusion of the forearm appears to be a potentially valid alternate occlusion site for RH‐PAT measurement and is less painful than using the upper arm as an occlusion site. In addition, the occlusion site should be standardized in the study protocol. Human study approved by the UC Davis Institutional Review Board.Support or Funding InformationUSDA, ARS Projects: 2032‐51000‐022; 203253000‐001

Helicobacter pylori-seropositivity along with pro-inflammatory interleukin-1 polymorphisms correlated with myocardial infarction

BackgroundHost genetic factors of interleukin (IL)-1 polymorphisms influence Helicobacter pylori infection pathogenic activity. We examined whether H. pylori-infected patients with IL-1 polymorphisms are associated with myocardial infarction (MI). Materials and methodsWe recruited 594 consecutive coronary artery disease patients and excluded those who met exclusion criteria. After matching age and sex, 82 cases with MI and 82 controls were enrolled. Immunoglobulin G antibodies against H. pylori and IL-1 polymorphisms (IL-1 beta-511 base pairs and IL-1 receptor antagonist) were analyzed. We assessed high sensitivity C-reactive protein (hs-CRP) level and reactive hyperemia-peripheral arterial tonometry (RH-PAT) index (RHI) using the EndoPAT2000 system. ResultsThe simultaneous prevalence of H. pylori-seropositivity and IL-1 polymorphisms was 45.1% and 19.5% in the cases and controls, respectively (P=0.001). H. pylori-positive patients with IL-1 polymorphisms showed significantly higher serum levels of natural logarithm of hs-CRP in the cases and controls (−2.8±1.0 vs. −3.4±0.6, respectively; P=0.003 and −2.8±0.9 vs. −3.2±0.6, respectively; P=0.02) and significantly lower levels of natural logarithm of RHI in the cases and controls (0.51±0.13 vs. 0.61±0.23, respectively; P=0.039 and 0.47±0.13 vs. 0.69±0.23, respectively; P=0.005). H. pylori-seropositivity with IL-1 polymorphisms was significantly associated with MI by logistic regression analysis (odds ratio, 4.83; 95% confidence interval, 1.99–11.7; P<0.001). ConclusionsH. pylori-positive patients with IL-1 polymorphisms showed higher levels of hs-CRP and lower levels of RHI, and were significantly correlated with the MI.

Time Rate of Blood Pressure Variation Is Associated With Endothelial Function in Patients With Metabolic Syndrome.

The time rate of blood pressure (BP) variation indicates the speed of BP fluctuations. Previous studies have demonstrated that the time rate of BP variation was associated with target organ damage. However, the association between time rate of BP variation and endothelial function has not been evaluated.24-hour ambulatory blood pressure monitoring (ABPM) was performed in 61 patients with metabolic syndrome. Time rate of BP variation was calculated from BP recordings of ABPM. Endothelial function was assessed using reactive hyperemia-peripheral arterial tonometry index (RHI) by EndoPat2000. Multiple linear regression models were used to detect the association between time rate of BP variation and RHI.Among all the subjects (n = 61), the multiple linear regression models revealed that the daytime rate of systolic blood pressure (SBP) variation was independently associated with RHI (β = -0.334, P = 0.008). A 0.1 mmHg/minute increase in the daytime rate of SBP variation correlated with a decline of 0.20 in RHI. The same effect was also found in the subjects with eGFR ≥ 60 mL/ (minute*1.73 m(2)). A greater association was found in those who were not taking a statin, β-blocker, ACEI/ARB, or diuretic and those without diabetes compared with those with any antihypertensive medication or with diabetes. Other ambulatory blood pressure parameters and central hemodynamics were not found to be associated with RHI.Our findings have shown that the daytime rate of SBP variation was associated with endothelial function in patients with metabolic syndrome, independent of other BP parameters and central hemodynamics.

A Single Session of Neuromuscular Electrical Stimulation Enhances Vascular Endothelial Function and Peripheral Blood Circulation in Patients With Acute Myocardial Infarction

This study aimed to investigate whether a single session of neuromuscular electrical stimulation (NMES) can enhance vascular endothelial function and peripheral blood circulation in patients with acute myocardial infarction (AMI). Thirty-four male patients with AMI were alternately assigned to 2 groups, and received NMES with muscle contraction (NMES group, n = 17) or without muscle contraction (control group, n = 17) after admission. NMES was performed for quadriceps and gastrocnemius muscles of both legs for 30 minutes. We measured systolic blood pressure as a parameter of cardiovascular responses and the low-frequency component of blood pressure variability as an index of sympathetic activity. Reactive hyperemia peripheral arterial tonometry (RH-PAT) index and transcutaneous oxygen pressure in foot (Foot-tcPO2) were also measured as parameters of vascular endothelial function and peripheral blood circulation, respectively. All patients completed the study without severe adverse events. Systolic blood pressure and the low-frequency component increased significantly during the NMES session in both groups (P < 0.01 and P < 0.05, respectively). However, elevation from systolic blood pressure at rest was < 10 mmHg in both groups. In the NMES group, the RH-PAT index and Foot-tcPO2 increased significantly after NMES (P < 0.05 and P < 0.001, respectively). No significant changes were observed in these parameters throughout the session in the control group. In conclusion, a single session of NMES with muscle contraction enhanced vascular endothelial function, leading to improvement in peripheral blood circulation without inducing excessive cardiovascular and autonomic responses in patients with AMI (UMIN000014196).

Endothelial Function in Diabetic Patients: Estimation by RHI (Reactive Hyperemia Peripheral Arterial Tonometry Index)

Endothelial Function in Diabetic Patients: Estimation by RHI (Reactive Hyperemia Peripheral Arterial Tonometry Index)