Hyperemia Peripheral Arterial Tonometry Research Articles

Potential Benefits on Impairment of Endothelial Function after a High‐Fat Meal of 4 Weeks of Flavonoid Supplementation

Studies with foods high in flavonoids have demonstrated improvement in endothelial function. We investigated whether 4 weeks of flavonoid supplementation would prevent an adverse impact on endothelial function of a high-fat meal. Endothelial function was measured by reactive hyperemia peripheral arterial tonometry (RH-PAT). The RH-PAT index was measured both before and 3 h after a high-fat meal, in 23 healthy volunteers. Subjects were randomized in a double-blind, cross-over design to 4 weeks of daily supplementation with OPC-3, or a matching placebo. RH-PAT index before and after the high-fat meal was measured at the beginning and end of each 4-week treatment phase. The high-fat meal caused a decline in endothelial function at baseline in the placebo (-10.71%, P = .006) and flavonoid [-9.97% (P = .077)] groups, and there was no difference in decline between arms (P = .906). The high-fat meal produced a decline after 4 weeks of placebo [-12.37% (P = .005)], but no decline after 4 weeks of flavonoid supplement [-3.16% (P = .663)], and the difference between the two responses was highly significant (P < .0001). Within-group comparisons revealed no difference in endothelial function decline in the placebo arm between baseline and 4 weeks [-10.71% versus -12.37% (P = .758)]. In the flavonoid supplement arm, the difference in endothelial function decline between baseline and 4 weeks was -9.97% versus -3.16%, but did not reach statistical significance (P = .451). These results suggest that the flavonoid supplement used in this study mitigates the impairment of endothelial function caused by a high-fat meal. Whether certain subpopulations derive greater or lesser benefit remains unclear.

Effect of brief secondhand smoke exposure on endothelial function and circulating markers of inflammation

ObjectiveIn contrast to the well defined detrimental consequences of long-term secondhand smoke (SHS) exposure, little is known about the acute effects of passive smoking on endothelial function and inflammation. The aim of the present study was to assess the acute effects of short-term SHS exposure on endothelial function and circulating markers of inflammation. MethodsPeripheral microvascular endothelial function assessed by reactive hyperemia peripheral arterial tonometry (RH-PAT) index, circulating markers of endothelial function (von Willebrand factor antigen, Thrombomodulin, E-selectin) and circulating inflammatory markers (high sensitivity C-reactive protein (hsCRP), Interleukin-6 (IL-6)) were measured in eighteen male, non-smoking volunteers before and 12h after a 1-h SHS exposure. ResultsTwelve hours after passive smoking, average RH-PAT index was significantly lower than before SHS exposure (1.54±0.49 vs 2.01±0.55 (mean±SD), p=0.01) indicating deterioration of peripheral microvascular endothelial function. von Willebrand factor antigen as a marker of endothelial activation was significantly increased after SHS exposure (93.0±25.5% vs 78.4±17.9%, p=0.03). Levels of Thrombomodulin, E-selectin, hsCRP, and IL-6 were unaffected by SHS exposure. ConclusionShort-term SHS exposure leads to a measurable disturbance of endothelial function. However, 1h of passive smoking appears to be too short to elicit a significant inflammatory response.

Effects of lycopene supplementation on oxidative stress and markers of endothelial function in healthy men

ObjectiveThe objective was to determine the effects of lycopene supplementation on endothelial function assessed by reactive hyperemia peripheral arterial tonometry (RH-PAT) and oxidative stress. MethodsHealthy men (n=126) were randomized to receive placebo (n=38), 6mg (n=41), or 15mg (n=37) lycopene daily for 8-week. ResultsSerum lycopene increased in a dose-dependent manner after 8-week supplementation (P<0.001). The 15mg/day group had greater increase in plasma SOD activity (P=0.014) and reduction in lymphocyte DNA comet tail length (P=0.042) than the placebo group. Intragroup comparison revealed a 23% increase in RH-PAT index from baseline (1.45±0.09 vs. 1.79±0.12; P=0.032) in the 15mg/day group after 8-week. hs-CRP, systolic blood pressure, sICAM-1 and sVCAM-1 significantly decreased, and β-carotene and LDL-particle size significantly increased only in the 15mg/day group. Interestingly, the beneficial effect of lycopene supplementation on endothelial function (i.e., RH-PAT and sVCAM-1) were remarkable in subjects with relatively impaired endothelial cell function at initial level. Changes in RH-PAT index correlated with SOD activity (r=0.234, P=0.017) especially in the 15mg lycopene/day group (r=0.485, P=0.003), lymphocyte DNA comet tail moment (r=−0.318, P=0.001), and hs-CRP (r=−0.238, P=0.011). In addition, changes in lycopene correlated with hs-CRP (r=−0.230, P=0.016) and SOD activity (r=0.205, P=0.037). ConclusionAn increase in serum lycopene after supplementation can reduce oxidative stress which may play a role in endothelial function.

Endothelial Function as a Functional Expression of Cardiovascular Risk Factors

Traditional cardiovascular risk (CV) factors based on the Framingham study have been used to estimate the risk of CV events and determine target cholesterol levels for primary prevention. Recently published systematic reviews have, however, demonstrated that the Framingham risk score is limited in certain cohorts and requires adjustment. Indeed, traditional CV risk factors fail to predict the development of coronary heart disease in 25-50% of cases. This underscores the complex interplay between traditional CV risk factors, genetic predisposition and other atheroprotective factors present in individuals of different populations in predicting CV events. Endothelial dysfunction, a functional expression of the inherent atherosclerotic risk representing an integrated index of both the overall CV risk-factor burden and the sum of all vasculoprotective factors in an individual, may serve as the missing link between CV risk factors and atherosclerotic disease. Endothelial function measurements may aid in future prediction of CV events and help identify high-risk patients for targeted therapy as well as provide a primary therapeutic end point for clinical follow-up of these patients. Recently introduced reactive hyperemia peripheral arterial tonometry is emerging as a promising tool in endothelial function measurement and CV risk stratification.

Postprandial Vascular Reactivity in Obese and Normal Weight Young Adults

As humans spend a significant amount of time in the postprandial state, we examined whether vascular reactivity (a key indicator of cardiovascular health) was different after a high-fat meal in 11 obese (median BMI 46.4, age 32.1 +/- 6.3 years, 7 men) and 11 normal weight (median BMI 22.6) age- and sex-matched controls. At baseline and 1 and 3 h postmeal, blood pressure (BP), heart rate (HR), reactive hyperemia peripheral artery tonometry (RH-PAT) index, radial augmentation index adjusted for HR (AIx75), brachial pulse wave velocity (PWV(b)), glucose, insulin, total and high-density lipoprotein (HDL) cholesterol, and triglycerides were measured. Brachial flow-mediated dilatation (FMD) and, by venous plethysmography, resting and hyperemic forearm blood flows (FBFs) were measured at baseline and 3 h. At baseline, obese subjects had higher systolic BP, HR, resting FBF, insulin and equivalent FMD, RH-PAT, hyperemic FBF, AIx75, PWV(b), glucose, total cholesterol, triglycerides, and lower HDL cholesterol. In obese and lean subjects, FMD at baseline and 3 h was not significantly different (6.2 +/- 1.7 to 5.8 +/- 4.3% for obese and 4.7 +/- 4.1 to 4.3 +/- 3.9% for normal weight, P = 0.975 for group x time). The meal did not produce significant changes in RH-PAT, hyperemic FBF, and PWV(b) in either group (P > 0.1 for the effect of time and for group x time interactions). In conclusion, the vascular responses to a high-fat meal are similar in obese and normal weight young adults. An exaggerated alteration in postprandial vascular reactivity is thus unlikely to contribute importantly to the increased cardiovascular risk of obesity.

Digital Assessment of Endothelial Function and Ischemic Heart Disease in Women

We investigated the utility of digital reactive hyperemia peripheral arterial tonometry (RH-PAT) in predicting ischemic heart disease (IHD), including obstructive coronary artery disease (CAD) and nonobstructive coronary artery disease (NOCAD), in women. IHD is the leading cause of mortality, and its pathogenesis is diverse in women. Fingertip RH-PAT is a new device that provides noninvasive, automatic, and quantitative evaluation of endothelial dysfunction. RH-PAT was measured using Endo-PAT2000 (Itamar Medical, Caesarea, Israel) before cardiac catheterization in 140 stable women scheduled for hospitalization to examine chest pain. NOCAD was diagnosed by angiography with measurement of coronary blood flow and cardiac lactate production during intracoronary acetylcholine provocation test and cardiac scintigraphy with stress tests. Sixty-eight women (49%) had obstructive CAD and 42 women (30%) had NOCAD. RH-PAT indexes were significantly attenuated in both obstructive CAD and NOCAD as compared with non-IHD (n = 30) (obstructive CAD: median 1.57, interquartile range [IQR] 1.42 to 1.76; NOCAD: median 1.58, IQR 1.41 to 1.78; non-IHD: median 2.15, IQR 1.85 to 2.48, p < 0.001). By multivariate logistic regression analysis, only RH-PAT index was significantly associated with IHD, including obstructive CAD and NOCAD (odds ratio 0.51; 95% confidence interval: 0.38 to 0.68; p < 0.001). In receiver-operating characteristic analysis, RH-PAT index was a significant predictor of IHD (area under the curve 0.86; p < 0.001). Furthermore, only RH-PAT was useful for the prediction of NOCAD after excluding obstructive CAD (area under the curve 0.85; p < 0.001; RH-PAT index of <1.82 had 81% sensitivity and 80% specificity). RH-PAT indexes were significantly attenuated in women with IHD. Digital RH-PAT can predict patients with IHD, especially NOCAD before angiography. RH-PAT is potentially useful for identifying high-risk women for IHD. (Endothelial Dysfunction and Coronary Artery Spasm; NCT00619294).

The diagnostic value of endothelial function as a potential sensor of fatigue in health

Many epidemiological research studies have shown that vital exhaustion and psychosocial factors are associated with the occurrence of cerebrocardiovascular disease (CCVD). Fatigue is thought to induce endothelial dysfunction and may be linked to the occurrence of CCVD; however, no studies have investigated this potential link. We studied to determine the effect of fatigue on endothelial function in healthy subjects with no traditional CCVD risk factors or potential confounding factors to be controlled. Peripheral arterial tonometry (PAT) was used to evaluate endothelial function. The influence of the following parameters on endothelial function was analyzed in 74 office workers without traditional CCVD risk factors at health check-ups: endothelial function before and after work, subjective fatigue, lifestyle factors such as sleeping time, and psychosocial factors such as depression and social support. Twenty-five subjects (33.8%) had low endothelial function; reactive hyperemia (RH)-PAT index <1.67, even though no abnormalities were reported in the health check-ups. There was no significant difference in endothelial function before versus after labor. Of note, endothelial function was associated with the individual's level of subjective fatigue (t = 2.98, P = 0.008) and showed a daily fluctuation, sometimes to a pathological degree (<1.67). We showed that, even in healthy people, endothelial function fluctuates diurnally, with an interaction between the individual's cognitive fatigue and the environment, sometimes to a pathological degree. Based on these findings, we suggest that endothelial function is an objective assessment tool of fatigue in healthy individuals.

Endothelial Function and Stress Response After Simulated Dives to 18 msw Breathing Air or Oxygen

Decompression sickness is caused by gas bubbles released upon decompression. These bubbles have the potential to occlude blood vessels and damage the vascular endothelium. The aim of this study was to quantify damage to the vascular endothelium resulting from decompression by measuring endothelial microparticles (MP) and endothelial function. Five healthy male volunteers undertook a simulated (hyperbaric chamber) air dive and 1 wk later a second dive breathing 100% oxygen at 283 kPa (18 msw) for 60 min bottom time, decompressed with 5-min stops at 161 kPa (6 msw) and 131 kPa (3 msw). Endothelial function was tested pre- and postdive by reactive hyperemia peripheral artery tonometry (RH-PAT) and CD105 (Endoglin) positive MP were quantified by flow cytometry. Plasma E- and P-selectin, interleukin-6, and serum cortisol were also quantified. RH-PAT showed a significantly decreased endothelial function post-decompression after breathing air when compared to oxygen (-0.33 +/- 0.27 vs. +0.18 +/- 0.14). CD105 MP pre- and postdive showed no change on the oxygen dive (460 +/- 370 to 360 +/- 163), however, they increased after breathing air (440 +/- 70 to 1306 +/- 359). There was no change in expression of CD105 on MP. Furthermore no changes were observed in plasma E- or P-selectin, IL-6, or serum cortisol. From the data, at least in the time frame involved, there appears to be no detectable physiological/stress response to decompression, rather decompression from breathing air probably caused mechanical damage to the endothelium, resulting in both MP release and a reduction in endothelial function.

Anger, depression and anxiety associated with endothelial function in childhood and adolescence

ObjectivePsychosocial adversity is a risk factor for cardiovascular disease (CVD) in adults. The authors assessed associations of reactive hyperaemia peripheral arterial tonometry (RH-PAT), a measure of endothelial function predictive of...

Endothelial Dysfunction and Specific Inflammation in Obesity Hypoventilation Syndrome

BackgroundObesity hypoventilation syndrome (OHS) is associated with increased cardiovascular morbidity. What moderate chronic hypoventilation adds to obesity on systemic inflammation and endothelial dysfunction remains unknown.QuestionTo compare inflammatory status and endothelial function in OHS versus eucapnic obese patients.Methodology14 OHS and 39 eucapnic obese patients matched for BMI and age were compared. Diurnal blood gazes, overnight polysomnography and endothelial function, measured by reactive hyperemia peripheral arterial tonometry (RH-PAT), were assessed. Inflammatory (Leptin, RANTES, MCP-1, IL-6, IL-8, TNFα, Resistin) and anti-inflammatory (adiponectin, IL-1Ra) cytokines were measured by multiplex beads immunoassays.Principal FindingsOHS exhibited a higher PaCO2, a lower forced vital capacity (FVC) and tended to have a lower PaO2 than eucapnic obese patients. HS-CRP, RANTES levels and glycated haemoglobin (HbA1c) were significantly increased in OHS (respectively 11.1±10.9 vs. 5.7±5.5 mg.l−1 for HS-CRP, 55.9±55.3 vs 23.3±15.8 ng/ml for RANTES and 7.3±4.3 vs 6.1±1.7 for HbA1c). Serum adiponectin was reduced in OHS (7606±2977 vs 13660±7854 ng/ml). Endothelial function was significantly more impaired in OHS (RH-PAT index: 0.22±0.06 vs 0.51±0.11).ConclusionsCompared to eucapnic obesity, OHS is associated with a specific increase in the pro-atherosclerotic RANTES chemokine, a decrease in the anti-inflammatory adipokine adiponectin and impaired endothelial function. These three conditions are known to be strongly associated with an increased cardiovascular risk. Trial Registration ClinicalTrials.gov NCT00603096

Ranolazine improves endothelial function in patients with stable coronary artery disease

We investigated the effect of ranolazine on endothelial-dependent vasodilatation (EDV), serum markers of endothelial dysfunction, and inflammation. Endothelial dysfunction has been shown to be independently associated with the occurrence of cardiovascular events. We sought to investigate whether ranolazine, a novel antianginal medication with no effect on heart rate or blood pressure, improves endothelial function in patients with stable coronary artery disease (CAD). Twenty-seven patients with stable CAD were randomly assigned to either 1000 mg twice daily of ranolazine or to matching placebo for 6 weeks and then crossed over for an additional 6 weeks in a double-blind design. EDV was assessed using reactive hyperemia peripheral arterial tonometry (RH-PAT) at baseline, 6, and 12 weeks. Markers of endothelial dysfunction and inflammation were also evaluated. After 6 weeks, treatment with ranolazine significantly increased the EDV RH-PAT index as compared with baseline (1.85+/-0.42 vs. 2.08+/-0.57, P = 0.037). EDV RH-PAT did not change while on placebo (1.69+/-0.35 vs. 1.78+/-0.41, P = 0.29). In addition, there was a significant drop in asymmetric dimethylarginine levels with ranolazine treatment (0.66+/-0.12 vs. 0.60+/-0.11 micromol/l, P = 0.02) and a near significant decrease in C-reactive protein levels (0.40+/-0.80 vs. 0.30+/-0.61 mg/dl, P = 0.05). Ranolazine improves endothelial function, asymmetric dimethylarginine, and C-reactive protein levels in a group of patients with stable CAD. Our results suggest a novel mechanism of action of ranolazine.

Insulin Resistance Is Highly Prevalent and Is Associated With Reduced Exercise Tolerance in Nondiabetic Patients With Heart Failure

The purpose of this study was to establish the prevalence of insulin resistance (IR) among nondiabetic chronic heart failure (CHF) patients and to seek factors associated with IR in CHF, including the relationship of IR to functional class, exercise capacity, and disease severity in CHF. Several lines of evidence suggest that CHF is an IR state. The prevalence of IR in CHF and its relation to CHF have not been fully defined. Fasting insulin resistance index (FIRI) was assessed in a cohort of 129 consecutive CHF patients (mean age 69.2 +/- 10.4 years; 76% males; body mass index 27.4 +/- 4.4 kg/m(2)). Patients underwent cardiopulmonary exercise testing and peripheral endothelial function testing by reactive hyperemia peripheral arterial tonometry (RH-PAT). Prevalence of IR as defined by FIRI > or =2.7 was 61% in our cohort of CHF patients. There was a significant correlation between IR and waist circumference (r = 0.37; p < 0.01), serum triglycerides (r = 0.34; p < 0.01), high-density lipoprotein cholesterol (r = -0.22; p = 0.02), and serum leptin (r = 0.39; p = 0.03). Insulin resistance increased significantly with worsening New York Heart Association functional class (p < 0.01). The CHF patients with IR had a significantly lower exercise capacity and peak oxygen consumption than patients with an FIRI <2.7. The RH-PAT ratio was significantly lower in CHF patients with IR compared with CHF patients with an FIRI <2.7 (1.6 +/- 0.3 vs. 2.0 +/- 0.5; p < 0.05). Insulin resistance is highly prevalent among nondiabetic CHF patients and is associated with decreased exercise capacity in patients with CHF. (Insulin Resistance: Heart Failure; NCT00486967).

Post-Challenge Hyperglycemia in Older Adults Is Associated with Increased Cardiovascular Risk Profile

Post-challenge hyperglycemia (PCH) is common in older adults and is associated with increased cardiovascular disease (CVD) risk and total mortality. However, PCH is rarely recognized in clinical settings, and the glycemic exposure and CVD risk profile of elderly individuals with PCH has not been defined. The aim of the study was to characterize metabolic and CVD risk profile of elderly subjects with PCH and to determine the effect of acute postprandial metabolic changes on vascular biomarkers. We conducted a cross-sectional study with a standard meal challenge protocol. Older adults with normal glucose tolerance (n = 30) or PCH (fasting glucose <126 mg/dl and 2-h glucose >or=170 mg/dl; n = 28) participated in the study. We assessed fasting and postprandial levels of glucose, insulin, lipids, high sensitivity C-reactive protein, plasminogen activator inhibitor-1, and adiponectin and endothelial function using reactive hyperemia peripheral arterial tonometry. Normal glucose tolerance and PCH subjects were matched for age, sex, body mass index, and ethnicity. Fasting glucose (102 +/- 3 vs. 93 +/- 2 mg/dl; P < 0.001) and glycosylated hemoglobin (5.7 vs. 5.4%; P = 0.01) were modestly higher in the PCH group, which was also more insulin resistant (homeostasis model assessment for insulin resistance, 7.0 +/- 1.3 vs. 4.1 +/- 0.6; P = 0.03). Fasting high sensitivity C-reactive protein was higher (2.6 +/- 0.5 vs. 1.3 +/- 0.2 mg/dl; P = 0.05), and adiponectin was lower (11.6 +/- 1.6 vs. 14.0 +/- 1.3 microg/ml; P = 0.03) in subjects with PCH. Peak and 6-h postprandial area under the curve glucose, insulin, and lipids were higher in PCH subjects, who also had higher fasting and postprandial levels of plasminogen activator inhibitor-1. Reactive hyperemia peripheral arterial tonometry declined postprandially only in PCH. Older adults with PCH experience significant fasting and postprandial metabolic dysregulation, which is accompanied by a proatherosclerotic and prothrombotic vascular profile.

Nitric Oxide-Dependent Blood Flow in Patients with Sickle Cell Disease Is Reflected by the Reactive Hyperemia-Peripheral Arterial Tonometry Index

Background: Decreased nitric oxide (NO) bioavailability is increasingly recognized as an important contributor to endothelial dysfunction and vascular complications of sickle cell disease. Unlike in other states of endothelial dysfunction, where NO production is impaired but response to exogenous NO donors is preserved, the vascular dysfunction observed in sickle cell disease is characterized by a diminished response to NO donors. Our group has previously demonstrated this NO resistance state through invasive strain-gauge venous occlusion plethysmography, the gold standard for evaluating peripheral endothelial function. Reactive hyperemia-peripheral arterial tonometry (RH-PAT) (ENDO-PAT 2000, Itamar Medical) is a relatively new, non-invasive technique for assessing endothelial function that records the reactive hyperemia response by measuring finger pulse wave amplitude after occlusion of the arm. We sought to compare these two techniques and validate peripheral arterial tonometry (PAT) as a tool for assessing vascular function in the sickle cell population.Methods: Thirteen patients with HbSS sickle cell disease have participated in this ongoing study. Subjects were recruited while in steady state and were not receiving chronic transfusions. Following an overnight fast, subjects underwent PAT. According to manufacturer specifications, RH-PAT indices ≤ 1.67 are indicative of endothelial dysfunction and those > 1.67 represent normal endothelial function. The subjects subsequently underwent venous occlusion plethysmography (AI6, D.E. Hokanson, Inc). Infusions of acetylcholine (ACh) and sodium nitroprusside (SNP) were administered to measure endothelium-dependent and endothelium-independent blood flow, respectively. To further characterize the nitric oxide resistance state, plasma samples from the first eight patients were assayed for NO consumption, and nitrite, a NO metabolite.Results: Following intra-arterial infusion of 7.5, 15, and 30 μg/min of ACh, patients with an RH-PAT index ≤ 1.67 had an increase in blood flow over baseline of 196 ± 30%, 287 ± 43%, and 338 ± 53%, respectively. This was not significantly different from the percentage change in blood flow response in patients with RH-PAT index > 1.67 (281 ± 68%, 277 ± 48%, 407 ± 53%, respectively, p = 0.60). In contrast, patients with an RHPAT index ≤ 1.67 demonstrated a significantly blunted response to 0.8, 1.6, and 3.2 μg/min infusions of SNP (28 ± 7%, 45 ± 11%, and 76 ± 17% vs. 85 ± 18%, 142 ± 36%, and 240 ± 48%, respectively, p < 0.001). This blunted response was also observed when comparing absolute forearm flow values (p < 0.01).Lactate dehydrogenase, an established biomarker of the NO resistance state and associated endothelial dysfunction in sickle cell disease, was found to be inversely correlated with plasma nitrite levels (Spearman r = −0.95, p = 0.001). Plasma nitrite levels were also inversely correlated with NO consumption (Pearson r = −0.80, 95% CI = −0.96 to −0.23, p = 0.016). Patients with an RH-PAT ≤ 1.67 demonstrated greater NO consumption than patients with an RH-PAT > 1.67 (3.32 μM ± 0.49, n = 4 vs. 2.06 μM ± 0.18, n = 4, (mean ± SEM), p= 0.029), consistent with a state of decreased NO bioavailability. Plasma nitrite reserve in patients with sickle cell disease has not been clearly established, but these data suggest a potential relationship between decreased nitrite and NO resistance. Interestingly, decreased plasma nitrite levels have been shown to correlate with endothelial dysfunction in other patient populations.Conclusions: In this cohort of sickle cell patients, RH-PAT was closely associated with the NO-mediated component of endothelial function. Lower RH-PAT is associated with blunted response to SNP and increased NO consumption, suggesting that RH-PAT provides a non-invasive method for assessing NO resistance in sickle cell disease. In addition, our results present preliminary support that plasma hemoglobin redirects NO metabolism away from nitrite production.

Angiopoietin-2 is associated with decreased endothelial nitric oxide and poor clinical outcome in severe falciparum malaria

Adherence of parasitized erythrocytes to activated endothelium causes microvascular obstruction, tissue ischemia, and clinical complications in severe malaria (SM); however, the mechanisms leading to endothelial activation remain unclear. The angiogenic factors, angiopoietin-2 (Ang-2) and vascular endothelial growth factor (VEGF) are modulators of endothelial activation, with Ang-2 release from Weibel-Palade bodies (WPBs) being regulated by endothelial nitric oxide (NO). We explored the relationships between endothelial NO bioavailability, Ang-2, VEGF, tissue perfusion, and clinical outcomes in SM. We measured plasma Ang-2 and VEGF, together with biomarkers of severity from 146 adults with and without SM, in parallel with longitudinal measures of endothelial function by using reactive hyperemia peripheral arterial tonometry (a measure of endothelial NO bioavailability). Regression was used to relate concentrations of Ang-2/VEGF with malaria disease severity, biomarkers of perfusion, endothelial activation, and parasite biomass. The longitudinal relationship between Ang-2 and endothelial function was assessed by using a mixed-effects model. Ang-2 concentrations were elevated in SM and associated with increased venous lactate, plasma intercellular cell adhesion molecule-1 concentrations, parasite biomass, and mortality. In contrast, VEGF concentrations were inversely associated with these biomarkers. Ang-2 concentrations were significantly better predictors of death than venous lactate (P = 0.03). Recovery of endothelial function was associated with falling concentrations of Ang-2. Ang-2 release from endothelial cells with reduced NO bioavailability is likely to contribute to endothelial activation, sequestered parasite biomass, impaired perfusion, and poor outcome in severe falciparum malaria. Agents that improve endothelial NO, reduce WPB exocytosis, and/or antagonize Ang-2 may have therapeutic roles in SM.

Abstract 4508: Endothelial Dysfunction is Associated with Coronary Lesion Complexity in Patients with Coronary Artery Disease

Endothelial dysfunction is an important step in the atherosclerosis progression, and associates with future cardiovascular events. Reactive hyperemia peripheral arterial tonometry (RH-PAT) is a noninvasive, automatic, and objective tool to evaluate endothelial dysfunction. Angiographic complex coronary lesions are involved in plaque vulnerability. We investigated whether finger values of RH-PAT could correlate with angiographic coronary plaque complexity in patients with coronary artery disease (CAD). RH-PAT was measured using Endo-PAT2000 in 171 patients who were referred to Kumamoto University Hospital for cardiac catheterization. We defined the two group as below, Control group; coronary artery stenosis &gt; 25% (n = 36, age 63 ± 11, male 25 %), and CAD group; coronary artery stenosis &gt; 25 % (n = 135, age 68 ± 11, male 74 %). Coronary lesions (single-vessel; n = 29, multi-vessel disease; n = 106) were classified as of simple appearance (n = 43) or complex appearance (n = 92) by coronary angiography. Values of RH-PAT were significantly lower in patients with CAD than Control (1.65 [1.50 – 1.86] versus 1.92 [1.80 – 2.28], P &lt; 0.01), and were significantly lower in CAD patients with complex coronary appearance than patients with simple coronary appearance (1.55 [1.45 – 1.76] versus 1.81 [1.66 – 1.95], P &lt; 0.01). All patients underwent selective coronary angiography, and the extent of coronary stenosis was assessed using the scoring system. RH-PAT was significantly correlated with coronary plaque Extent Score (Rs = −0.33, P &lt; 0.01). Single logistic regression analysis demonstrated that high-density lipoprotein cholesterol, triglycerides, and RH-PAT value significantly associated with the presence of complex coronary lesions, and multivariable analysis including cardiovascular risk factors identified that lower RH-PAT value was the only factor associated with the complex coronary lesions (odds ratio 1.45, 95% confidence interval 1.14 – 1.84; P &lt; 0.01). Endothelial dysfunction was significantly associated with angiographic complex appearance of coronary plaques in patients with CAD. CAD patients with lower RH-PAT values might be vulnerable patients with vulnerable plaques and vulnerable endothelium.

Sex differences in vascular and endothelial responses to acute mental stress

Our objective was to assess the differences in systemic vascular and endothelial function in response to acute mental stress between men and women. The endothelium plays a pivotal role in vascular homeostasis and the development of atherosclerotic heart disease. The mechanism and presentation of cardiovascular events show a sex-based difference, although the sex difference in the vascular and endothelial response to mental stress is not known. Male (n = 34) and female (n = 53) subjects participated in a series of three different mental stress tasks during which vascular response was measured non-invasively using peripheral arterial tonometry. Endothelial function was assessed using reactive hyperemia peripheral arterial tonometry. Double product (systolic blood pressure x heart rate) was calculated. Males had a greater double product response (27.2 + 3.6% increase in double product vs. 19.2 + 1.7%; P = 0.01), and a greater vascular reactivity to mental stress. Females demonstrated a reduced response to reactive hyperemia (-0.47 vs. 13.74%; P = 0.01). Furthermore, a subgroup of females who showed the least vaso-reactivity to mental stress showed the greatest decline in endothelial function (-10.5 + 4% vs. 17.4 + 6.3%; P < 0.001). This study demonstrates sex-based differences in the vascular and endothelial responses to mental stress. The mental stress-induced reduction in endothelial function and increased double product seen in the females might manifest clinically as contributing to the pathophysiology of mental stress-mediated cardiovascular events in female patients and provide further information regarding the potential mechanism for sex differences in cardiac events.

Arginine, nitric oxide, carbon monoxide, and endothelial function in severe malaria.

Parasiticidal therapy of severe falciparum malaria improves outcome, but up to 30% of these patients die despite best therapy. Nitric oxide is protective against severe disease, and both nitric oxide and arginine (the substrate for nitric oxide synthase) are low in clinical malaria. Parasitized red blood cell interactions with endothelium are important in the pathophysiology of malaria. This review describes new information regarding nitric oxide, arginine, carbon monoxide, and endothelial function in malaria. Low arginine, low nitric oxide production, and endothelial dysfunction are common in severe malaria. The degree of hypoargininemia and endothelial dysfunction (measured by reactive hyperemia-peripheral artery tonometry) is proportional to parasite burden and severity of illness. Plasma arginase (an enzyme that catabolizes arginine) is elevated in severe malaria. Administering arginine intravenously reverses hypoargininemia and endothelial dysfunction. The cause(s) of hypoargininemia in malaria is unknown. Carbon monoxide (which shares certain functional properties with nitric oxide) protects against cerebral malaria in mice. Replenishment of arginine and restoration of nitric oxide production in clinical malaria should diminish parasitized red blood cells adherence to endothelium and reduce the sequelae of these interactions (e.g. cerebral malaria). Arginine therapy given in addition to conventional antimalaria treatment may prove to be beneficial in severe malaria.

Recovery of Endothelial Function in Severe Falciparum Malaria: Relationship with Improvement in Plasmal‐Arginine and Blood Lactate Concentrations

Severe malaria is characterized by microvascular obstruction, endothelial dysfunction, and reduced levels of L-arginine and nitric oxide (NO). L-Arginine infusion improves endothelial function in moderately severe malaria. Neither the longitudinal course of endothelial dysfunction nor factors associated with recovery have been characterized in severe malaria. Endothelial function was measured longitudinally in adults with severe malaria (n = 49) or moderately severe malaria (n = 48) in Indonesia, using reactive hyperemia peripheral arterial tonometry (RH-PAT). In a mixed-effects model, changes in RH-PAT index values in patients with severe malaria were related to changes in parasitemia, lactate, acidosis, and plasma L-arginine concentrations. Among patients with severe malaria, the proportion with endothelial dysfunction fell from 94% (46/49 patients) to 14% (6/42 patients) before discharge or death (P < .001). In severe malaria, the median time to normal endothelial function was 49 h (interquartile range, 20-70 h) after the start of antimalarial therapy. The mean increase in L-arginine concentrations in patients with severe malaria was 11 micromol/L/24 h (95% confidence interval [CI], 9-13 micromol/L/24 h), from a baseline of 49 micromol/L (95% CI, 37-45 micromol/L). Improvement of endothelial function in patients with severe malaria correlated with increasing levels of L-arginine (r = 0.56; P = .008) and decreasing levels of lactate (r = -0.44; P = .001). Recovery of endothelial function in severe malaria is associated with recovery from hypoargininemia and lactic acidosis. Agents that can improve endothelial NO production and endothelial function, such as L-arginine, may have potential as adjunctive therapy early during the course of severe malaria.

Impaired nitric oxide bioavailability and l-arginine–reversible endothelial dysfunction in adults with falciparum malaria

Severe falciparum malaria (SM) is associated with tissue ischemia related to cytoadherence of parasitized erythrocytes to microvascular endothelium and reduced levels of NO and its precursor, l-arginine. Endothelial function has not been characterized in SM but can be improved by l-arginine in cardiovascular disease. In an observational study in Indonesia, we measured endothelial function using reactive hyperemia–peripheral arterial tonometry (RH-PAT) in 51 adults with SM, 48 patients with moderately severe falciparum malaria (MSM), and 48 controls. The mean RH-PAT index was lower in SM (1.41; 95% confidence interval [CI] = 1.33–1.47) than in MSM (1.82; 95% CI = 1.7–2.02) and controls (1.93; 95% CI = 1.8–2.06; P < 0.0001). Endothelial dysfunction was associated with elevated blood lactate and measures of hemolysis. Exhaled NO was also lower in SM relative to MSM and controls. In an ascending dose study of intravenous l-arginine in 30 more patients with MSM, l-arginine increased the RH-PAT index by 19% (95% CI = 6–34; P = 0.006) and exhaled NO by 55% (95% CI = 32–73; P < 0.0001) without important side effects. Hypoargininemia and hemolysis likely reduce NO bioavailability. Endothelial dysfunction in malaria is nearly universal in severe disease, is reversible with l-arginine, and likely contributes to its pathogenesis. Clinical trials in SM of adjunctive agents to improve endothelial NO bioavailability, including l-arginine, are warranted.