Forearm Blood Flow In Patients Research Articles

Abstract 17927: Acipimox Does Not Improve Endothelial Function and Insulin-Stimulated Vasodilation in Patients With Metabolic Syndrome

Introduction: Insulin resistance increases circulating free fatty acid (FFA) concentrations, which causes the release of inflammatory cytokines and induces endothelial dysfunction. Acipimox reduces FFA efflux and may improve insulin sensitivity and endothelium-dependent microvascular vasodilation. Hypothesis: We hypothesize that acipimox treatment will improve insulin-stimulated forearm blood flow (FBF) compared to placebo in volunteers with metabolic syndrome. Methods: We conducted a randomized, double-blind, placebo-controlled crossover trial (NCT00759291) evaluating 1-week of acipimox 250 mg QID on insulin-stimulated FBF in patients with and without metabolic syndrome. Results: Sixteen patients received acipimox (6 metabolic syndrome and 10 healthy controls). Patients with metabolic syndrome were older (63.8 vs 49.9 years old, p<0.001) with higher baseline insulin levels (15.9 vs 3.5 μU/mL, p=0.002), and trended towards higher BMIs (30.9 vs 24.6 kg/m 2 , p=0.083). Baseline insulin sensitivity by Homeostatic Model Assessment for Insulin Resistance (HOMA IR) differed between controls and those with metabolic syndrome (0.68 vs 3.28, p=0.001) but did not change with acipimox (p=0.540, Panel A). Insulin stimulation increased FBF in patients treated with placebo (p=0.01, Panel B) and acipimox (p=0.03, Panel C) but was not augmented by acipimox in participants with metabolic syndrome or healthy controls (Panel D and E). In multivariable-adjusted regression analysis, acipimox did not increase FBF, even after adjusting for baseline FBF and key baseline differences, including metabolic syndrome. Conclusion: Acipimox did not improve insulin sensitivity and had no effect on microvascular endothelial dysfunction assessed by insulin-stimulated FBF. This suggests that FFA modulation does not reverse microvascular dysfunction in patients with metabolic syndrome.

Abstract 13824: Salsalate Does Not Improve Endothelial Function and Insulin-Stimulated Vasodilation in Patients With Metabolic Syndrome

Background: Insulin resistance accelerates systemic inflammation and vascular dysfunction. Salsalate suppresses inflammation and may improve insulin sensitivity and insulin-mediated, endothelium-dependent vasodilation. Hypothesis: We hypothesized that salsalate treatment would improve insulin-stimulated forearm blood flow (FBF) in volunteers with metabolic syndrome compared to placebo. Methods: We conducted a randomized, double-blind, placebo-controlled crossover trial (NCT00760019) evaluating 4-weeks of salsalate 1.5 grams TID on insulin-stimulated FBF during an insulin clamp in patients with and without metabolic syndrome. Results: Nineteen patients received salsalate (13 metabolic syndrome and 6 healthy controls). Patients with metabolic syndrome were older (36.3 vs 57.1 years old, p=0.002) with higher BMIs (33.9 vs 25.5 kg/m 2 , p=0.001) and higher insulin levels (10.8 vs 4.3 μU/mL, p=0.01). Those with metabolic syndrome had impaired insulin sensitivity by Homeostatic Model Assessment for Insulin Resistance (HOMA IR, 2.66 vs 0.87, p=0.005) and Matsuda Index (MI, 5.81 vs 3.32, p=0.001). After salsalate treatment, insulin sensitivity was unchanged (Panel A & B) and there was no significant reduction in insulin levels (Panel C) or inflammation by C-reactive protein (Panel D). Insulin stimulation increased FBF in patients treated with placebo (p=0.012) and salsalate (p=0.003), but salsalate blunted the FBF response in those with metabolic syndrome (p=0.022, Panel E). In multivariable linear regression, metabolic syndrome, HOMA IR, and MI associated with insulin-stimulated FBF independent of salsalate treatment. Conclusion: Salsalate improved neither insulin sensitivity nor systemic inflammation, and it blunted insulin-stimulated vasodilation in patients with metabolic syndrome. Salsalate does not modulate systemic inflammation and worsens arteriolar endothelial dysfunction in patients with metabolic syndrome.

Effects of inspiratory muscle training combined with aerobic exercise training on neurovascular control in chronic heart failure patients.

AimsWe tested the hypothesis that the effects of combined inspiratory muscle training and aerobic exercise training (IMT + AET) on muscle sympathetic nerve activity (MSNA) and forearm blood flow in patients with heart failure with reduced ejection fraction are more pronounced than the effects of AET alone.Methods and resultsPatients aged 30–70 years, New York Heart Association Functional Class II‐III, and left ventricular ejection fraction ≤40% were randomly assigned to four groups: IMT (n = 11), AET (n = 12), IMT + AET (n = 9), and non‐training (NT; n = 10). MSNA was recorded using microneurography. Forearm blood flow was measured by venous occlusion plethysmography and inspiratory muscle strength by maximal inspiratory pressure. IMT consisted of 30 min sessions, five times a week, for 4 months. Moderate AET consisted of 60 min sessions, three times a week for 4 months. AET (−10 ± 2 bursts/min, P = 0.03) and IMT + AET (−13 ± 4 bursts/min, P = 0.007) reduced MSNA. These responses in MSNA were not different between AET and IMT + AET groups. IMT (0.22 ± 0.08 mL/min/100 mL, P = 0.03), AET (0.27 ± 0.09 mL/min/100 mL, P = 0.01), and IMT + AET (0.35 ± 0.12 mL/min/100 mL, P = 0.008) increased forearm blood flow. No differences were found between groups. AET (3 ± 1 mL/kg/min, P = 0.006) and IMT + AET (4 ± 1 mL/kg/min, P = 0.001) increased peak oxygen consumption. These responses were similar between these groups. IMT (20 ± 3 cmH2O, P = 0.005) and IMT + AET (18 ± 3 cmH2O, P = 0.01) increased maximal inspiratory pressure. No significant changes were observed in the NT group.ConclusionsIMT + AET causes no additive effects on neurovascular control in patients with heart failure with reduced ejection fraction compared with AET alone. These findings may be, in part, because few patients had inspiratory muscle weakness.

Impaired exercise‐induced forearm blood flow in patients with systemic sclerosis (SSc) is restored after acute tetrahydrobiopterin (BH4) supplementation

Impaired exercise‐induced forearm blood flow in patients with systemic sclerosis (SSc) is restored after acute tetrahydrobiopterin (BH4) supplementation

Effects of the Alpha Glucosidase Inhibitor Acarbose on Endothelial Function after a Mixed Meal in Newly Diagnosed Type 2 Diabetes

Endothelial dysfunction (ED) has been suggested as a possible causal link between postprandial hyperglycemia and cardiovascular events in patients with type 2 diabetes. Recent trials demonstrated a reduction of cardiovascular events by treatment with alpha-glucosidase inhibitor acarbose - a drug which mainly reduces postprandial glucose excursions. We were interested to know whether patients with newly diagnosed type 2 diabetes showed postprandial ED and if so whether acarbose was able to improve this condition. Forearm blood flow (FBF) measurements for assessment of ED were performed in the fasting and postprandial state in 20 newly diagnosed type 2 diabetic patients and 10 healthy control subjects. After baseline examination, patients were randomly assigned to a 20-week treatment of acarbose 100 mg t.i.d or matching placebo, thereafter FBF measurements were repeated. FBF of patients in the fasting state was significantly impaired compared to healthy control subjects (max. FBF 5.3+/-0.7 vs. 8.0+/-0.9 ml/100 ml, p<0.02) and did not change in the postprandial state (max. FBF 5.6+/-0.7 ml/100 ml). In contrast, healthy controls showed a significant improvement of FBF in the postprandial state (11.5+/-1.2 ml/100 ml), which is compatible with postprandial ED in the group of patients. Twenty weeks of acarbose treatment did not affect either fasting or postprandial FBF in patients. Early type 2 diabetes is a state of both fasting and postprandial ED, which is not sensitive to acarbose treatment. Protective cardiovascular effects of acarbose might involve other mechanisms.

Exercise training in heart failure: reduction in angiotensin II, sympathetic nerve activity, and baroreflex control

neurohumoral excitation has been considered the hallmark of heart failure. At the humoral level, cardiac dysfunction has been shown to be associated with increased angiotensin II, aldosterone, and vasopressin levels. The clinical implication for such humoral dysregulation is the increase in salt and

Inducible nitric oxide synthase activity does not contribute to the maintenance of peripheral vascular tone in patients with heart failure

Enhanced iNOS (inducible nitric oxide synthase) activity may contribute to vascular dysfunction in patients with heart failure. In the present study, we aimed to determine whether iNOS activity contributes to the maintenance of vascular tone in patients with symptomatic heart failure with the use of the highly selective iNOS inhibitor 1400W {N-[3-(aminomethyl)benzyl] acetamidine}. Bilateral forearm blood flow was measured using venous occlusion plethysmography in 12 patients with New York Heart Association class II-IV heart failure and eight matched healthy control subjects during intra-brachial infusion of 1400W (0.1-1 micromol/min), L-NMMA (N(G)-monomethyl-L-arginine; a non-selective NOS inhibitor; 2-8 micromol/min) and noradrenaline (control vasoconstrictor; 60-480 pmol/min). In both patients and controls, intra-brachial infusion of L-NMMA and noradrenaline caused a dose-dependent reduction in infused forearm blood flow (P<0.05 for both): peak reduction of 32+/-6% and 37+/-4% during L-NMMA and 52+/-6% and 49+/-5% during noradrenaline respectively (P values were not significant when patients were compared with controls). In contrast, 1400W had no effect on blood flow at 1 micromol/min [-3+/-4% in patients (95% confidence intervals, -11 to 5%) and 3+/-8% in controls; P value was not significant]. In conclusion, we have demonstrated that intrabrachial selective iNOS inhibition does not influence forearm blood flow in patients with heart failure. We conclude that iNOS activity does not contribute to peripheral vascular tone in patients with symptomatic heart failure.

Effects of folinic acid on forearm blood flow in patients with end-stage renal disease

Abnormalities of endothelial function are likely to contribute to the accelerated atherosclerotic risk in subjects with end-stage renal disease (ESRD). While folates can improve endothelial function, their role in ESRD has not been fully studied. The objective was to determine the acute and 12 week-effect of folinic acid on endothelium-dependent vasodilation in subjects with ESRD. Forearm blood flow (FBF) was assessed by strain gauge plethysmography at baseline and after 12 weeks in 34 ESRD patients (57 +/- 14 years). Vascular function was assessed with acetylcholine (ACh), and sodium nitroprusside (SNP). Patients were randomized to receive folinic acid (50 mg i.v. once weekly) or a matching placebo. A subset of 25 subjects also received folinic acid (500 microg/min intra-arterially) or placebo to determine the acute effect on ACh and SNP mediated dilation at the time of the baseline vascular study. Folinic acid acutely improved the maximum change in ACh mediated FBF (10.0 +/- 2.4 to 12.8 +/- 2.2 ml/min/100 ml, P = 0.017), but did not change SNP responses. Chronic active therapy did not change ACh or SNP-mediated increases in FBF. Folinic acid resulted in a non-significant decrease in homocysteine (21 +/- 6 vs 28 +/- 18 micromol/l, P = 0.16) and diastolic blood pressure was significantly reduced (P = 0.05). The present study demonstrated that folinic acid acutely improved endothelium-dependent vasodilatation in patients with ESRD suggesting a direct vascular effect. Chronic treatment with folinic acid did not show benefit in endothelial function, but did lower diastolic blood pressure. Further work is required to determine the optimal regime to protect vascular health in subjects with ESRD.

Sodium Nitrite Increases Regional Blood Flow in Patients with Sickle Cell Disease.

Patients with sickle cell disease have decreased nitric oxide bioavailability, and studies from several groups have confirmed a blunted response to various NO donors in humans and mice with sickle cell disease. Recently published studies show that nitrite induces vasodilation in humans, apparently mediated by conversion of nitrite to NO.This study is designed to determine the potential therapeutic effect of intra-arterial nitrite infusion to restore nitric oxide dependent blood flow in the forearms of patients with sickle cell disease.Venous occlusion strain gauge plethysmography is used to measure the change of forearm blood flow in patients with sickle cell disease, before and after sequential brachial artery infusions of increasing doses of sodium nitrite. In addition, NO responsiveness before and after nitrite infusion is measured by test doses of the NO donor sodium nitroprusside (SNP). Six patients have completed the study and enrollment is continuing.These data indicate that nitrite promotes regional blood flow in patients with sickle cell disease, albeit with a blunted response compared to our healthy control subjects, in whom we previously have found increased blood flow up to 187% with comparable dosing. The significant but blunted response is consistent with the state of nitric oxide resistance to NO donors that has been seen by several groups in patients and mice with SCD. Additionally, we find in these patients that nitrite partially restores SNP responsiveness, with baseline maximal SNP responses more than doubling on average following nitrite infusion, although this finding is preliminary. No adverse effects of nitrite were seen in these six patients.Our early results support a role for nitrite as an NO donor effective in restoring NO-dependent blood flow in patients with sickle cell disease. Additional translational studies are warranted to evaluate the therapeutic effects of systemic nitrite dosing.Table 1Forearm Blood Flow Response to Nitrite InfusionNitrite Dose (micromole/min)Sickle Cell DiseaseHistorical Controls0.45 +/−7.2% N=622 +/−3.2% N=10415 +/− 11% N=6Not infused4049 +/− 8.9% N=6187 +/− 16%N=18P< .0001 (ANOVA)Table 2Nitrite Effect on Nitroprusside ResponsivenessSNP Dose (micrograms/min)Pre-NitritePost-Nitrite0.8+21 +/− 5.6%+33 +/− 8.3%1.6+15 +/− 5.9%+62 +/− 15.1%3.2+29 +/− 6.3%+67 +/− 11.5%P= .02 (RM-ANOVA) N=6

An inhibitor of inducible nitric oxide synthase decreases forearm blood flow in patients with congestive heart failure

OBJECTIVESThe functional activation of inducible nitric oxide synthase (iNOS) was evaluated as a source of nitric oxide (NO) in the forearm of patients with heart failure.BACKGROUNDAlthough endogenous NO is normally produced by constitutive NO synthase (cNOS) in patients with congestive heart failure (CHF), expression of iNOS provides an additional source of NO. However, there are no in vivo studies showing functional activation of iNOS in humans.METHODSA nonselective NOS inhibitor, NG-monomethyl-L-arginine (L-NMMA), and a selective inhibitor of iNOS, aminoguanidine, were administered intra-arterially in graded doses into the brachial arteries of 13 patients with CHF and 10 normal control subjects. Forearm blood flow (FBF) was measured simultaneously in the infused and noninfused arms by plethysmography. Arterial and venous plasma concentrations of nitrite/nitrate (NOx) were measured at baseline and at the highest dose of each drug.RESULTSL-NMMA significantly reduced the FBF ratio between the infused and noninfused arms in both the control and patient groups (35 ± 12% and 34 ± 10%, respectively; both p < 0.001). Aminoguanidine at the same concentration significantly reduced the ratio in the patient group (15 ± 9%, p < 0.01), with no change in the control group. The arterial NOx concentration was not affected by either drug; however, venous NOx concentrations were significantly decreased in both the control and patient groups by L-NMMA (18 ± 5% and 18 ± 17%, respectively; both p < 0.05) and in the patient group only by aminoguanidine (7 ± 6%, p < 0.05).CONCLUSIONSThese findings suggest that NO production in the forearms of patients with CHF is induced partly by iNOS activation, whereas in normal subjects, it can be ascribed to cNOS activation.

Non-invasive assessment of vascular function; paradoxical vascular response to intravenous glucose in coronary heart disease.

In healthy individuals, insulin administration causes an increase in forearm blood flow which is dependent on the effects of insulin on the vascular endothelium. Glucose, administered as an intravenous bolus, produces a transient hyperinsulinaemic response. We hypothesized that the insulin response to an intravenous glucose challenge during the intravenous glucose tolerance test might lead to increases in forearm blood flow in healthy individuals, and that such a response might be altered in patients with coronary heart disease. Healthy individuals (n=10, aged 41.6+/-3. 0 years, mean+/-SEM) and patients with angiographically proven coronary heart disease (n=13, aged 65.5+/-2.4 years) underwent an intravenous glucose tolerance test with simultaneous measurement of right forearm blood flow at 28 time points, using mercury-in-silastic venous occlusion plethysmography. In controls, forearm blood flow increased to a mean of 31.7% above baseline values at 7 min and remained above baseline up to 180 min after intravenous glucose. In contrast, patients with coronary heart disease exhibited an opposite response, with forearm blood flow decreasing to a mean of -16.2% below baseline values at 7 min and -25.8% at 180 min. Marked group differences emerged in net changes from baseline in forearm blood flow throughout the intravenous glucose tolerance test, expressed as incremental areas under the forearm blood flow profiles (controls: +351.3+/-121.7; coronary heart disease patients: -244.3+/-72.4 min ml(-1). 100 ml(-1), P=0. 001). We have demonstrated for the first time that in healthy individuals forearm blood flow increases after an intravenous bolus of glucose, and that paradoxically, this response is reduced below baseline forearm blood flow in patients with coronary heart disease. Further studies are needed to determine whether plethysmographic measurement of forearm blood flow after an intravenous bolus of glucose could provide a clinically useful non-invasive test for the diagnosis of occult coronary heart disease.

Quantitative measurement of oxygen consumption and forearm blood flow in patients with mitochondrial myopathies.

Five patients with chronic progressive external ophthalmoplegia (CPEO) and 27 healthy controls were examined by near-infrared spectroscopy (NIRS) for the non-invasive and direct quantitative measurement of muscle oxygen consumption during rest as well as during static isometric handgrip exercise at 10% of their maximum voluntary contraction. In patients with CPEO, we found a significantly decreased oxygen consumption during exercise, but more remarkably already during rest. Our results suggest that NIRS is able to discriminate between CPEO patients and healthy controls, which makes NIRS a promising tool in the diagnostic work-up of patients suspected of a mitochondrial myopathy.

Role of endothelium in control of forearm bloodflow in patients with heart failure

We studied the role of endothelium in control of forearm blood flow during reactive and exercise hyperemia in patients with heart failure as well as in normal subjects. First, endothelium-dependent forearm vasodilation in response to acetylcholine (ACh), substance P, and endothelium-independent forearm vasodilation in response to sodium nitroprusside (SNP) were examined in patients with heart failure and in normal subjects. Endothelium-dependent forearm vasodilation in response to ACh but not to substance P was impaired in patients with heart failure. Endothelium-independent forearm vasodilation to SNP was also preserved in patients with heart failure. Second, the role of nitric oxide (NO) in reactive hyperemia and exercise hyperemia was examined in normal subjects using NG-monomethyl-L-arginine (L-NMMA), a blocker of NO synthesis. Results suggest that NO plays a minimal role in peak reactive hyperemia and exercise hyperemia in normal human forearm vessels. Finally, we determined if L-arginine, a precursor of NO, improves impaired endothelium-dependent vasodilation due to ACh and reactive and exercise hyperemia in patients with heart failure. L-Arginine augmented impaired ACh-induced vasodilation as well as reactive and exercise hyperemia in patients with heart failure. Our results suggest that defective endothelial function may contribute to abnormal control of forearm blood flow in patients with heart failure.

Calf and forearm blood flow in patients with primary hyperparathyroidism and in control subjects

Using a venous occlusion air-filled plethysmograph we measured the blood flow in the limbs in 10 patients with established primary hyperparathyroidism and control subjects. The patients had highly raised ionized calcium and immunoreactive parathormone levels, and the diagnosis was verified at operation. In all patients resting blood flow values in the limbs were increased compared with control subjects. Peak blood flow after 5 min of ischemia was also increased, however, not significantly. This clinical study supports previous studies on a vasoactive effect of parathormone.

Regulation of forearm blood flow in patients with bordline essential hypertension

Regulation of forearm blood flow in patients with bordline essential hypertension

Effects of alpha- and beta-adrenergic antagonists on plasma apolipoproteins and forearm blood flow in patients with mild hypertension

To study the mechanisms by which adrenergic antagonists affect blood pressure and plasma lipid levels, the effects of alpha-blockade with prazosin were compared with those of beta-blockade with propranolol in 23 normolipidemic, mildly hypertensive patients. Plasma lipoprotein composition, apolipoproteins, and some of the processes involved in lipid synthesis and clearance from plasma were investigated also. Patients entered an eight-week placebo period during which they were free of all antihypertensive medications. They were then randomly assigned under double-blind conditions to treatment with either prazosin (mean dose, 5 mg per day) or propranolol (mean dose, 133 mg per day) for eight weeks. Doses of both drugs were titrated to achieve either a decrease in diastolic blood pressure of 10 mm Hg or more or a reduction of diastolic blood pressure to less than 85 mm Hg, whichever was lower. Total plasma cholesterol decreased by 9 percent during prazosin treatment and increased by 7 percent during propranolol treatment (p <0.005 between treatments). Low-density lipoprotein cholesterol decreased by 12 percent with prazosin and increased by 12 percent with propranolol (p <0.005). Apolipoprotein B decreased by 17 percent with prazosin and increased by 15 percent with propranolol (p <0.005). There were no significant changes in total high-density lipoprotein cholesterol, its subfractions high-density lipoprotein 2 or high-density lipoprotein 3, or in apolipoprotein A 1 and apolipoprotein A 2. Plasma very low-density lipoprotein and low-density lipoprotein triglycerides were not significantly affected by either treatment. Plasma post-heparin lipase activities, which clear triglyceride and high-density lipoprotein cholesterol from plasma, were not altered significantly. Since regional blood flow could affect the clearance of plasma lipoproteins, measurements were taken of forearm blood flow, forearm vascular resistance, and maximal forearm vasodilatory potential during reactive hyperemia. The adrenergic antagonists had no effect on these measurements, nor did they affect cellular cholesterol synthesis as measured by the activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase in blood mononuclear cells. The results of this study demonstrate differing actions between alpha- and beta-adrenergic antagonism. Alpha-blockade produced significantly lower levels of plasma low-density lipoprotein cholesterol and apolipoprotein B than beta-adrenergic antagonism without changes in high-density lipoproteins.