Altered bioavailability of epoxyeicosatrienoic acids is associated with conduit artery endothelial dysfunction in type 2 diabetic patients.

BACKGROUND: This pathophysiological study addressed the hypothesis that soluble epoxide hydrolase (sEH), which metabolizes the vasodilator and anti-inflammatory epoxyeicosatrienoic acids (EETs) to dihydroxyeicosatrienoic acids (DHETs), contributes to conduit artery endothelial dysfunction in type 2 diabetes. METHODS AND RESULTS: Radial artery endothelium-dependent flow-mediated dilatation in response to hand skin heating was reduced in essential hypertensive patients (n = 9) and type 2 diabetic subjects with (n = 19) or without hypertension (n = 10) compared to healthy subjects (n = 36), taking into consideration cardiovascular risk factors, flow stimulus and endothelium-independent dilatation to glyceryl trinitrate. Diabetic patients but not non-diabetic hypertensive subjects displayed elevated whole blood reactive oxygen species levels and loss of NO release during heating, assessed by measuring local plasma nitrite variation. Moreover, plasma levels of EET regioisomers increased during heating in healthy subjects, did not change in hypertensive patients and decreased in diabetic patients. Correlation analysis showed in the overall population that the less NO and EETs bioavailability increases during heating, the more flow-mediated dilatation is reduced. The expression and activity of sEH, measured in isolated peripheral blood mononuclear cells, was elevated in diabetic but not hypertensive patients, leading to increased EETs conversion to DHETs. Finally, hyperglycemic and hyperinsulinemic euglycemic clamps induced a decrease in flow-mediated dilatation in healthy subjects and this was associated with an altered EETs release during heating. CONCLUSIONS: These results demonstrate that an increased EETs degradation by sEH and altered NO bioavailability are associated with conduit artery endothelial dysfunction in type 2 diabetic patients independently from their hypertensive status. The hyperinsulinemic and hyperglycemic state in these patients may contribute to these alterations. Trial registration NCT02311075. Registered December 8, 2014.

Evidence that cranberry juice may improve augmentation index in overweight men.

The stiffening of arteries is a key step in atherogenesis leading to cardiovascular disease. It has been suggested that dietary polyphenols may be cardioprotective through possible favorable effects on oxidative stress and vascular function. The present study was undertaken in order to examine the effect of consuming low-calorie cranberry juice cocktail (CJC), a source of polyphenols, on arterial stiffness in abdominally obese men. We hypothesize that regular CJC consumption will reduce circulating oxidized low-density lipoproteins concentrations and have a beneficial impact on endothelial function. Thirty-five men (mean age ± SD: 45 ± 10 years) were randomly assigned to drink 500 mL CJC/day (27% juice) or 500 mL placebo juice (PJ)/day for 4 weeks in a double-blind crossover design. Augmentation index (AIx), an index of arterial stiffness, was measured by applanation tonometry of the radial artery and the cardiometabolic profile was assessed in each participant before and after each phase of the study. We found no significant difference in AIx changes between men who consumed CJC or PJ for 4 weeks (P = .5820). Furthermore, there was no between-treatment difference in changes in AIx responses to salbutamol (P = .6303) and glyceryl trinitrate (P = .4224). No significant difference was noted in other cardiometabolic variables between men consuming PJ or CJC. However, a significant within group decrease in AIx (mean decrease ± SE; -14.0 ± 5.8%, P = .019) was noted following the consumption of 500 mL CJC/day for 4 weeks. Our results indicate that the effect of chronic consumption of CJC on AIx was not significantly different from changes associated with the consumption of PJ. However, the significant within-group decrease in AIx following CJC consumption in abdominally obese men may deserve further investigation.

Effect of Chinese herbal fomentation on arteriovenous fistula maturation.

OBJECTIVES: The study objectives were to examine the effects of Chinese herbal fomentation on radiocephalic arteriovenous fistula (AVF) maturation. METHODS: All patients' preoperative evaluation, operative procedure, and follow-up information records were reviewed to identify patients undergoing radiocephalic AVF procedures for maintenance hemodialysis. All patients underwent preoperative vessel ultrasound. The ultrasound examinations were repeated every 2 months after the operative procedure. From the day after the operation, the forearm of the patient is fomented with a mixture of Dan Shen and Hong Hua in dry powdered form dissolved in fresh warm water. The fomentation lasted for 60 minutes, once a day for 28 consecutive days. RESULTS: Sixty-four (64) specific access site operations were yielded in 62 patients for analysis. Forty-nine (49; 76.6%) of the 64 fistulas were considered sonographically mature and 15 (23.4%) were deemed sonographically immature. The sonographically mature fistulas (n=46) that were suitable for puncture had blood flow of 655±132 mL/minute, and venous diameter of 4.5±0.3 mm. The most frequent complication was thrombosis before first use, which accounted for 6 AVFs failures to mature (0.16 per patient-year). There were two hospitalizations for fistula-related bacteremia in the group (0.05 per patient-year). CONCLUSIONS: The Chinese herbal fomentation reduced the frequency of early thrombosis of new AVFs and was accompanied by an increase in the proportion of AVFs that were suitable for dialysis.

The effect of a eutectic mixture of local anesthetic cream on wrist pain during transradial coronary procedures.

OBJECTIVE: We sought to evaluate the effects and optimal application time of a eutectic mixture of local anesthetic cream (EMLA-C) in relieving wrist pain during transradial coronary procedures (TRCP). METHODS: The Phase I study enrolled 147 patients to evaluate the efficacy and safety of the EMLA-C during TRCP. The Phase II study was designed to evaluate the optimal preprocedure application time frame of EMLA-C for wrist pain reduction in 400 patients. The EMLA or placebo cream was applied at the puncture site from 2 to 4 hours before the procedure in Phase I, and randomized to 5 time groups according to the time of drug application in Phase II. We evaluated wrist pain by the visual analogue scale (VAS) or verbal rating scale (VRS-4), and evaluated complications as well. RESULTS: EMLA-C demonstrated greater pain relief by VAS (control: 49+/-24, EMLA: 19+/-22; p = 0.001) and VRS-4 (control: 2.3+/-0.5, EMLA: 1.5+/-0.6; p = 0.001), and there was a negative correlation (r = -0.476; p = 0.001) between VAS and the preprocedure application time of EMLA-C. In Phase II, there was a significant difference in pain levels between the control and 1- to 2-hour groups by VAS (control: 49+/-29, EMLA1-2 hours: 32+/-24; p = 0.001) and VRS-4 (control: 2.4+/-0.6, EMLA1-2 hours: 1.9+/-0.6; p = 0.001). Drug-induced local erythema frequently occurred in the 3- to 4-hour group (6.6%) and >4 hours group (11.9%). CONCLUSIONS: EMLA-C can be effective in reducing wrist pain during TRCP without any significant drug-related complications when the application time is 1 to 3 hours before the procedure.

Comparative effects of tolazoline and nitroprusside on human isolated radial artery.

BACKGROUND: The radial artery is increasingly being used in coronary revascularization as an alternative conduit to a saphenous vein graft. Its perfect endothelial capacity provides a high patency rate comparable with the internal mammary artery (IMA). However, its spastic characteristics cause difficulties during its intraoperative preparation and may lead to early postoperative graft failure. Thus, treatment and/or prevention of radial artery spasm with an effective vasodilator agent is essential for its longevity. Endogenous vasoconstrictors, including noradrenaline, endothelin-1, and thromboxane A2, are likely to play a role in the pathogenesis of graft spasm. In the present study, we evaluated the vasorelaxant effect of tolazoline, a nonselective alpha-adrenoceptor blocker, against the contractions induced by various spasmogenic agents in an isolated human radial artery. METHODS: Tolazoline (10(-9)-10(-4) M) or sodium nitroprusside (SNP, 10(-9)-10(-4) M) were cumulatively applied on radial artery rings precontracted submaximally with noradrenaline, endothelin-1, thromboxane analogue, U46619, or potassium chloride. In addition, some rings were pretreated with tolazoline (4 x 10(-6) M) for 30 minutes and the contractile response curve to noradrenaline was assessed in its presence. RESULTS: Tolazoline effectively reversed noradrenaline-induced contractions in the radial artery, whereas it failed to produce remarkable relaxations on rings contracted with other spasmogenic agents, while SNP overcame the contractions induced by all spasmogens to a similar extent. In addition, brief pretreatment of radial artery rings with tolazoline significantly inhibited the contractions to noradrenaline. CONCLUSIONS: Tolazoline is not as broadly effective as SNP against all spasmogens investigated; however, it may be effective in counteracting alpha-adrenoceptor-mediated vasospasm in human radial arteries.

Folic Acid does not limit endothelial dysfunction induced by ischemia and reperfusion: a human study.

Nitric oxide synthase (NOS) uncoupling is a condition of increased production of superoxide anion associated with a decreased production of nitric oxide (NO) by this enzyme. Folic acid can prevent and/or reverse NOS uncoupling in the setting of diabetes, smoking, hypercholesterolemia, and nitrate tolerance. Whereas animal studies showed a protective effect of folic acid in ischemia and reperfusion (IR) injury, no study tested whether folic acid administration limits IR-induced endothelial dysfunction in humans. In a double-blind, parallel study, 20 healthy young male volunteers were randomized to receive folic acid, 10 mg/d for 7 days, or matching placebo. At the end of the treatment period, endothelium-dependent, flow-mediated dilation (FMD) of the radial artery was measured before and after IR injury (15 minutes of ischemia at the level of the brachial artery followed by 15 minutes of reperfusion). There was no difference at baseline between groups in any variable. In the placebo group, IR significantly blunted FMD (before IR, 6.7+/-1.0%; after IR, 1.5+/-1.3%, P<0.01). A similar effect was observed in the folic acid group (before IR, 6.3+/-1.1%; after IR, 2.1+/-1.0%, P=ns compared with placebo). As opposed to animal studies, high-dose folic acid does not protect the vascular endothelium from IR injury in humans.

Differential effect of cerivastatin and L-arginine on the vascular function of human radial and left internal thoracic arteries.

BACKGROUND: There are a number of strategies to restore/preserve endothelial function. We have compared the effects of Cerivastatin (CS) to those of L-arginine (L-ARG) supplementation on the endothelial function of human arterial grafts. METHODS: During coronary artery bypass grafting, specimens of radial artery (RA) and left internal thoracic artery (LITA) were obtained. Specimens were divided into vascular rings, which were incubated with either 10(-6) mol/L CS, 10(-3) mol/L L-ARG, or vehicle (control) for 2 or 24 hours. Endothelial function was examined with acethylcholine (10(-9) to 10(-5) mol/L) following contraction by 3 x 10(-8) mol/L endothelin-1. RESULTS: Although no significant differences were observed in the RA at 2 hours, after 24 hours incubation, endothelium-dependent vasodilatation was significantly higher in CS group (68.4 +/- 5.0%; n = 6) compared to L-ARG group (49.9 +/- 5.4%; n = 7, p < 0.05) and control group (33.8 +/- 2.9%; n = 13, p < 0.0001). In addition, there was a significant increase in L-ARG group compared to control (p < 0.01). After 2 hours incubation of the LITA, CS failed to enhance endothelium-dependent vasodilatation compared to control (44.1 +/- 4.9%; n = 9, vs. 40.0 +/- 5.2%; n = 16, respectively, NS), while L-ARG increased it (64.7 +/- 4.9%; n = 7, p < 0.05 vs. CS and p < 0.01 vs. control). However, this increase disappeared at 24 hours although there was a higher trend of endothelium-dependent vasodilatation in CS group (30.3 +/- 3.7%; n = 8 in L-ARG, 56.5 +/- 8.8%; n = 9 in CS and 41.0 +/- 5.5%; n = 18 in control). CONCLUSIONS: CS preserved endothelium-dependent vasodilatation of RA greater than L-ARG. These findings suggest that the use of statins may be an effective therapeutic strategy to preserve endothelial function in the RA grafts, and could have important implications in the clinical practice.

Ascorbic acid reduces blood pressure and arterial stiffness in type 2 diabetes.

Experimental evidence suggests that acute parenteral administration of high-dose ascorbic acid has beneficial vascular effects in type 2 diabetes. We studied the hemodynamic effects of chronic oral supplementation in this condition. Thirty patients, 45 to 70 years of age, with type 2 diabetes, were randomly assigned in a double-blind manner to receive 500 mg ascorbic acid daily by mouth or placebo. Patients were studied at baseline and after 4 weeks of assigned treatment. The central aortic augmentation index (AgIx) and the time to wave reflection (Tr) were derived from radial artery pulse wave analysis data. AgIx and Tr were used as measures of systemic arterial stiffness and aortic stiffness, respectively. Ascorbic acid decreased brachial systolic blood pressure from 142.1+/-12.6 (SD) to 132.3+/-12.1 mm Hg (difference [95% CI] 9.9 [4.7, 15.0]; P<0.01), brachial diastolic pressure from 83.9+/-4.8 to 79.5+/-6.0 mm Hg (4.4 [1.8, 7.0]; P<0.01), and AgIx from 26.8+/-5.5% to 22.5+/-6.8% (4.3 [1.5, 7.1]; P<0.01). Tr increased from 137.1+/-12.6 to 143.4+/-9.2 ms (-6.3 [-10.1, -2.5]; P<0.01). Placebo had no hemodynamic effects, and this difference between treatments was significant (P<0.01 for blood pressure and Tr, P=0.03 for AgIx). We have therefore shown that after 1 month, oral ascorbic acid lowered arterial blood pressure and improved arterial stiffness in patients with type 2 diabetes. As strict control of blood pressure reduces cardiovascular risk in diabetes, ascorbic acid supplementation may potentially be a useful and inexpensive adjunctive therapy. Larger and longer studies now need to be performed.

Nitric oxide and endothelium-derived hyperpolarizing factor in human arteries and veins.

BACKGROUND: We have investigated and compared nitric oxide (NO) release and endothelium-derived hyperpolarizing factor (EDHF)-mediated hyperpolarization in the human internal mammary artery (IMA), radial artery (RA), saphenous vein (SV), and coronary artery. MATERIALS AND METHODS: Vessel segments taken from coronary artery bypass grafting or heart transplantation patients were placed in an organ chamber. NO-sensitive electrode or intracellular glass microelectrode was used to study NO or EDHF in response to acetylcholine (ACh) and bradykinin (BK). RESULTS: The resting membrane potential of the smooth muscle cells of IMA, RA, and SV was -58 +/- 0.84 (n = 61), -61 +/- 1.3 mV (n = 46, p = 0.03), and -62 +/- 0.9 mV (n = 23, p = 0.0001) respectively. BK- (10(-7) M) induced EDHF-mediated hyperpolarization (-10.9 +/- 1.5 mV, n = 7) in the IMA was significantly greater than that in RA (-5.8 +/- 0.9 mV, n = 6, p = 0.04) and SV (-5.1 +/- 0.5 mV, n = 8, p < 0.01). The basal release of NO in IMA (16.8 +/- 1.9 nM) was significantly higher than that in RA (11.1 +/- 1.0 nM, n = 12, p = 0.02) and in SV (9.9 +/- 2.8 nM, n = 13, p < 0.001). The stimulated release of NO to BK in IMA was significantly greater than that in RA (44.3 +/- 4.0 vs 25.8 +/- 3.6 nM, n = 8, p = 0.004). The duration of NO release was longer in IMA than in RA or in SV. CONCLUSIONS: The basal and stimulated release of NO and EDHF-mediated hyperpolarization in the IMA are significantly greater than that in the RA and SV. EDHF exists in all these human vessels. This study reveals the differences among human vessels regarding the endothelial function that have implications in vasospasm, coronary protection, or long-term graft patency.

Effects of storage solutions on in vitro vasoreactivity of radial artery conduits.

OBJECTIVES: Surgical preparation of coronary conduits for coronary artery bypass grafting may affect their early and long-term patency; one mechanism may involve endothelial damage. We investigated the effect of 3 commonly used solutions-Ringer's solution, normal saline solution, and heparinized whole blood-on in vitro endothelial and contractile functions of the human radial artery. METHODS: Radial artery segments were harvested, cut into 3-mm rings, and stored in unoxygenated Ringer's solution, normal saline solution, or heparinized whole blood for 45 minutes. Rings stored in Krebs solution were used as controls. The rings were then mounted and stretched to an optimal resting tension in oxygenated Krebs solution at 37 degrees C. Contraction responses to potassium, norepinephrine, and serotonin and relaxation responses to acetylcholine, verapamil, and nitroprusside were evaluated. RESULTS: Fifty-six radial artery ring segments from 14 patients (n = 7 rings for each contraction-relaxation curve) were studied. Equilibrated resting tension was 9.6 +/- 0.3 mN (5.9 +/- 0.2 g), and resting internal circumference was 6.4 +/- 0.2 mm. Absolute maximum contraction to potassium was significantly less in rings stored in normal saline solution than in rings stored in control solution (10.7 +/- 0.6 g vs 14.5 +/- 0.6 g, P <.01; 95% confidence intervals, 0.9-6.9). There was no difference in the contraction to norepinephrine (P =.11) and serotonin (P =.25) among the 3 solutions compared with the control solution. Rings stored in heparinized whole blood had significantly greater endothelium-dependent relaxation to acetylcholine (P <.007), whereas those stored in normal saline solution had reduced responses. Endothelium-independent relaxation to verapamil and nitroprusside were similar among the 3 solutions. CONCLUSION: Heparinized whole blood is a better physiologic medium for preservation of radial artery endothelial and contractile functions during storage before grafting.

Correction of endothelial dysfunction in chronic heart failure: additional effects of exercise training and oral L-arginine supplementation.

OBJECTIVES: The aim of this study was to analyze whether L-arginine (L-arg.) has comparable or additive effects to physical exercise regarding endothelium-dependent vasodilation in patients with chronic heart failure (CHF). BACKGROUND: Endothelial dysfunction in patients with CHF can be corrected by both dietary supplementation with L-arg. and regular physical exercise. METHODS: Forty patients with severe CHF (left ventricular ejection fraction 19 +/- 9%) were randomized to an L-arg. group (8 g/day), a training group (T) with daily handgrip training, L-arg. and T (L-arg. + T) or an inactive control group (C). The mean internal radial artery diameter was determined at the beginning and after four weeks in response to brachial arterial administration of acetylcholine (ACh) (7.5, 15, 30 microg/min) and nitroglycerin (0.2 mg/min) with a transcutaneous high-resolution 10 MHz A-mode echo tracking system coupled with a Doppler device. The power of the study to detect clinically significant differences in endothelium-dependent vasodilation was 96.6%. RESULTS: At the beginning, the mean endothelium-dependent vasodilation in response to ACh, 30 microg/min was 2.54 +/- 0.09% (p = NS between groups). After four weeks, internal radial artery diameter increased by 8.8 +/- 0.9% after ACh 30 microg/min in L-arg. (p < 0.001 vs. C), by 8.6 +/- 0.9% in T (p < 0.001 vs. C) and by 12.0 +/- 0.3% in L-arg. +/- T (p < 0.005 vs. C, L-arg. and T). Endothelium-independent vasodilation as assessed by infusion of nitroglycerin was similar in all groups at the beginning and at the end of the study. CONCLUSIONS: Dietary supplementation of L-arg. as well as regular physical exercise improved agonist-mediated, endothelium-dependent vasodilation to a similar extent. Both interventions together seem to produce additive effects with respect to endothelium-dependent vasodilation.

Short term effects of omega-3 fatty acids on the radial artery of patients with coronary artery disease.

Long-term dietary omega-3 fatty acids improve coronary endothelial function in CAD patients, heart transplant recipients and diabetics. This study assessed whether short term omega-3 fatty acids affect radial artery function in CAD patients. A high resolution A-mode echotracking device (NIUS 02) was used to measure continuously, radial artery internal diameter at rest, during flow mediated vasodilation (FMD), during cold pressure test (CPT), and after sublingual glyceryl trinitrate (GTN). We studied 18 male CAD patients in a randomized, double blind, placebo controlled design. Between pre- and post-intervention measurements 24 h apart, nine subjects received 18 g fish oil concentrate (6.4 g eicosapentaenoic acid and 3.9 g docosahexaenoic acid) and nine subjects 18 g placebo. In the placebo group correlation between both baseline diameters was 0.98; P < 0.001. Pre-intervention FMD was 7.5+/-5.6%, CPT mediated vasoconstriction was 3.8+/-2.5%, and GTN induced vasodilation was 15.7+/-9.8%. Vascular responses post-intervention showed no significant difference to pre intervention, there was no significant difference between both treatment groups. The radial artery does not seem to be an immediate target for vasodilatory actions of omega-3 fatty acids.

Cardiovascular effect of oral calcium supplementation: echocardiographic study in patients with essential hypertension.

Oral calcium (Ca) supplementation mildly reduces blood pressure. The authors studied the effects of Ca supplementation on the cardiovascular system in patients with mild to moderate essential hypertension. Twelve patients aged forty-nine to seventy years (7 men and 5 women, mean age with 60.3 +/- 7.2 years) participated. The investigators orally administered Ca (1.0 g/day for one week) under hospitalization, adding to a dietary intake of Ca (0.6 g/day). Left ventricular function and systemic arterial compliance were evaluated by M-mode and pulsed Doppler echocardiographies before and after seven days of Ca supplementation. Left ventricular contractility and afterload were not changed. Preload indicated by end-diastolic volume was significantly decreased after Ca supplementation (109.6 +/- 8.5 vs 107.3 +/- 8.2 mL, P < 0.05). Myocardial relaxation evaluated by IIa-mitral valve opening time (87.7 +/- 6.7 vs 82.1 +/- 6.2 ms, P < 0.01) and maximum descending rate of the left ventricular posterior wall (10.6 +/- 1.0 vs 12.4 +/- 1.0 cm/s, P < 0.01), and atrioventricular net compliance assessed by the descending slope of rapid filling flow in the left ventricular inflow tract (2.63 +/- 0.24 vs 2.26 +/- 0.17 m/s2, P <0.05), as well as systemic arterial compliance (2.05 +/- 0.20 vs 2.73 +/- 0.26 mL/mmHg, P < 0.01) were significantly improved by Ca supplementation. Oral Ca supplementation improved the disturbed left ventricular diastolic function and systemic arterial compliance.

Alteration of pulse in human subjects by three Chinese herbs.

Human subjects were fed with extract of three Chinese herbs, Panax ginseng, Panax quinquefolium roots and Ganoderma lucidum. Pulse of the radial artery was examined. Our results indicate that each herb has a specific effect on the Fourier components of the pulse, and is in agreement with traditional Chinese medical descriptions.