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ABSTRACT: Vascular complications are the most frequent adverse events associated with percutaneous coronary interventions (PCIs) leading to an increase in morbidity and mortality. Puncture of the common femoral artery in its middle segment is proved to decrease the risk of procedure-related vascular complications. Real-time ultrasound-guided puncture of the vessel is effective to decrease access site-related vascular complications but complex to perform. We evaluated whether an ultrasonic preinterventional examination of the femoral puncture site and skin marking of anatomic structures and specific vascular characteristics results in a decrease of access site-related vascular complications in PCIs with transfemoral access. Over a period of 12 months we prospectively examined all puncture sites before elective PCIs with transfemoral access (n = 848) using ultrasound. Presence, extent, and location of plaques and stenoses and exact location of bifurcation of the femoral artery were marked by a sonographer on the skin to guide the interventionists in vascular puncture. Postinterventional access site ultrasound was performed to determine possible access site-related complications. Frequency of vascular access site complications was compared to a control cohort (n = 1,027) that did not undergo ultrasound examination before intervention. With ultrasonic vascular access site management the rate of access site-related vascular complications was decreased from 4.2% to 1.9% (odds ratio 0.44, 0.23 to 0.80, p = 0.005). In conclusion, preinterventional ultrasonic access site examination and skin marking decreases the risk of vascular complications in elective PCI with femoral access.
The American journal of cardiology 08/2011; 108(9):1203-6. · 3.58 Impact Factor
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ABSTRACT: This study aimed at exploring access site-related vascular complication rates associated with the use of the vascular closure device (VCD) Angio-Seal™ in an unselected patient population undergoing elective as well as emergency coronary angiography or intervention.
The VCD Angio-Seal™ is widely used to achieve hemostasis after diagnostic and interventional cardiac procedures. There are only little data on the frequency of vascular complications after the use of the VCD Angio-Seal™ in patients in non-elective settings.
In-hospital vascular complications were prospectively assessed in 4,653 consecutive cardiac catheterization procedures, which included 2,772 elective diagnostic and 960 elective percutaneous coronary interventions (PCI), and 921 emergency cardiac catheterizations in patients with NSTEMI/STEMI. In 2,077 procedures manual compression (MC) and in 2,576 procedures VCD was applied. Complication rates for manual compression and VCD use were studied and multivariate analyses performed to disclose predictors for access site-related vascular complications.
Vascular complication rates in patients receiving MC to achieve hemostasis were similar to those receiving a VCD (MC 3.4% vs. VCD 3.2%, p = n.s.). Separate analysis of vascular complication rates for subgroups revealed a significant reduction in vascular complications for the PCI group using a VCD (MC 7.7% vs. VCD 3.2%, p = 0.003). In emergencies VCD use lead to a rise in vascular complications (MC 0.9% vs. VCD 6.3%, p < 0.001).
In contrast to elective settings, the risk of access site-related vascular complications is significantly increased after application of the VCD Angio-Seal™ in patients undergoing emergency catheterizations for NSTEMI/STEMI compared with manual compression.
Clinical Research in Cardiology 04/2011; 100(9):789-95. · 2.95 Impact Factor
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ABSTRACT: Neurally mediated syncope (NMS) is a common disorder that is triggered by orthostatic stress. The circulatory adjustments to orthostatic stress occur just prior to a sudden loss of consciousness. NMS prediction would protect patients from falls or accidents.
Based on simultaneously recorded heart rate (HR) and pulse wave during 70° head-up tilt (HUT) table testing we investigated a syncope warning system. In 14 patients with a history of suspected NMS we tested 2 algorithms based on HR and/or pulse arrival time (PAT). When the cumulative risk exceeded the threshold, which was calculated during the first 2 minutes following the posture change to upright position, a syncope prediction alarm was triggered. All syncopes (n = 7) were detected more than 16 seconds before the onset of dizziness or unconsciousness by using a prediction alarm based on HR and PAT (syncope prediction algorithm 2). No false alarm was generated in patients with negative HUT (n = 7). Syncope prediction was improved by detecting the slope of HR changes as compared with monitoring PAT changes alone (syncope prediction algorithm 1). The duration between the prediction alarm and the occurrence of syncope was 99 ± 108 seconds.
Predicting NMS is feasible by monitoring HR and the onset of the pulse wave at the periphery. This approach might improve NMS management.
Journal of Cardiovascular Electrophysiology 03/2011; 22(9):1042-8. · 3.06 Impact Factor
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ABSTRACT: To evaluate a cardiovascular magnetic resonance imaging (MRI) technique which allows the longitudinal analysis of cardiovascular remodeling in a rodent femoral arteriovenous fistula (AVF) model by means of a clinical scanner.
Eight rats underwent femoral AVF surgery and four rats served as controls. Vascular and cardiac morphology as well as cardiac function was assessed from Week 3 to 12 using contrast-enhanced, time-resolved magnetic resonance angiography (MRA) and cardiac MRI (cine gradient-echo sequence) at 3 T in one imaging session.
Arteriovenous surgery resulted in progressive venous dilation and a subsequent cardiac adaptation. This procedure led to downstream vasodilation of the iliac vein and inferior vena cava of 179% and 188%, respectively (3 weeks). To accommodate the increased returning blood volume, cardiac output (CO) increased significantly (P=.014; 6 weeks). This was caused by increased end-diastolic volume (EDV), stroke volume (SV) and heart rate (HR) consistent with an increased volume load. A continuous increase in heart weight peaked at 12 weeks. This increase combined with a distinct end-diastolic left ventricular dilation implied eccentric hypertrophy.
Small rodent MRI is feasible and clearly depicts fistula maturation and cardiac alterations. This technique proved to be a valuable tool for longitudinal in vivo monitoring in this model, which strongly resembles clinical findings in hemodialysis patients.
Magnetic Resonance Imaging 01/2011; 29(1):57-63. · 1.99 Impact Factor
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ABSTRACT: Diabetes mellitus (DM) leads to accelerated progression of arteriosclerosis with an increased risk of coronary events in comparison to non-diabetic patients with coronary artery disease (CAD). The precise and early detection of DM-induced vascular alterations is crucial to identify patients with high risk for cardiovascular complications. Thus, we aimed at simultaneously characterizing functional, physicomechanical, and structural vascular alterations in diabetic patients using a non-invasive approach.
In CAD patients with and without type 2 diabetes mellitus (n=50), we non-invasively measured flow-mediated dilation (FMD) of the brachial artery as a marker for endothelial function, fractional diameter changes (FDC) as a marker for physicomechanical properties, intima-media thickness (IMT) as a marker for structural properties, and forearm blood flow (FBF) as a marker for microvascular function.
DM was associated with reduced FMD (2.5±0.2 vs 4.8±0.4%; p≤0.001) indicating impaired macrovascular endothelial function. In parallel, reduced FDC (0.024±0.002 vs 0.034±0.004; p≤0.05) and increased IMT (0.38±0.01 vs 0.31±0.01mm; p≤0.001) indicated increased stiffness and enhanced structural alterations. Furthermore, reduced forearm blood flow during reactive hyperemia (10.7±1.0 vs. 15.3±1.4mL/min*100mL; p≤0.05) was found indicating microvascular dysfunction. Plasma glucose and HbA(1c) correlated with FMD (glucose: r=-0.32; HbA(1c): r=-0.45), IMT (glucose: r=0.54; HbA(1c): r=0.48) and FBF (glucose: r=-0.30) suggesting diabetes-specific effects on vascular properties.
In patients with CAD, DM leads to functional and structural vascular alterations of the peripheral vasculature which are determined by the control of the disease underlining the relevance of a strict control of the DM to prevent accelerated atherosclerosis.
American journal of cardiovascular disease. 01/2011; 1(1):68-75.
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ABSTRACT: Microcirculatory dysfunction contributes to morbidity and mortality in vascular diseases. Here, we aimed at establishing a sensitive and valid method to measure microvascular reactivity during post-occlusive reactive hyperemia (PORH) using scanning laser Doppler perfusion imaging (LDPI) of the forearm.
In a first series, LDPI was methodologically evaluated on the volar forearm of healthy volunteers (n = 10) before and after one to five minutes of upper arm occlusion. In a second series, readings were performed in 20 healthy subjects and 20 patients with coronary artery disease (CAD).
Three minutes of forearm occlusion were sufficient to induce maximal vasodilation during PORH as indicated by maximal increase in perfusion unit (PU) amplitude that did not further increase after five-minute occlusion. Five-minute occlusion led to a significant prolongation of PORH with greater area under curve (AUC) suggesting longer lasting vasodilation of microvessels. The five-minute occlusion was associated with lower variability as compared with three minutes (intraindividual variability: 9-17% vs. 12-21%; interindividual variability: 13-24% vs. 14-26%). CAD patients exhibited significantly reduced amplitude (105 +/- 49 vs. 164 +/- 35 PU; p < 0.001), ratio (4.7 +/- 1.8 vs. 7.1 +/- 1.8; p < 0.001), and AUC (1656 +/- 1070 vs. 2723 +/- 864 PU x minutes; p = 0.001).
Scanning LDPI is a feasible and reproducible method for non-invasive assessment of the cutaneous microcirculatory response during PORH.
Microcirculation (New York, N.Y.: 1994) 07/2010; 17(5):358-66. · 2.37 Impact Factor
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Journal of the American College of Cardiology 04/2010; 55(14):1502-3. · 14.16 Impact Factor
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Christian Meyer,
Christian Heiss,
Christine Drexhage,
Eva S Kehmeier,
Jan Balzer,
Anja Mühlfeld,
Marc W Merx, Thomas Lauer,
Harald Kühl,
Jürgen Floege,
Malte Kelm,
Tienush Rassaf
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ABSTRACT: This study sought to characterize the impact of hemodialysis (HD)-induced release of hemoglobin on the bioavailability of nitric oxide (NO) and endothelial function.
Patients on chronic HD suffer from endothelial dysfunction and a massively increased risk for cardiovascular events. Although dialysis-dependent and -independent factors are discussed, the exact mechanisms are not fully understood.
In 14 HD patients (56+/-15 years of age), endothelial function was determined by measuring flow-mediated dilation (FMD) of the brachial artery using high-resolution ultrasound before and after treatment. The NO consumption activity of plasma isolated from patients before and after hemodialysis was studied with an NO-sensitive electrode.
HD impaired FMD (3.5+/-2.6% to 1.7+/-1.4%, p=0.04) without affecting brachial artery diameter (4.7+/-0.6 mm vs. 4.4+/-0.9 mm, p=0.27). This was accompanied by an increase in cell-free plasma hemoglobin (196+/-43 mg/l to 285+/-109 mg/l, p=0.01), which led to a decrease in the bioavailability of free NO by more than 70%. Oxidation of the released plasma ferrous hemoglobin prevented the consumption of NO. The amount of decompartmentalized hemoglobin after HD correlated inversely with the change in FMD (r=-0.65, p=0.041).
Our data support a role of HD-induced release of hemoglobin in the pathogenesis of endothelial dysfunction in patients with end-stage renal disease. Approaches that oxidize free plasma hemoglobin may restore NO bioavailability and may have potential beneficial effects on vascular function. (Influence of Hemodialysis on Endothel-Depending Dilatation of Peripheral Arteries; NCT00764192).
Journal of the American College of Cardiology 02/2010; 55(5):454-9. · 14.16 Impact Factor
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ABSTRACT: The aim of this study was to investigate the effect of diagnostic transradial catheterization on vascular function of upstream brachial artery (BA).
The transradial access has recently become an alternative to transfemoral cardiac catheterization. A potential caveat of this approach lies in possible sustained physical radial artery (RA) damage.
We studied 30 patients (age 61 +/- 11 years) undergoing diagnostic coronary angiography with the transradial access (5-F). Endothelium-dependent, flow-mediated vasodilation (FMD) was measured before and at 6 and 24 h after catheterization of the right-sided RA and BA with high-resolution ultrasound. The left-sided RA served as a control.
Transradial catheterization significantly decreased FMD in the RA (overall mean 8.5 +/- 1.7% to 4.3 +/- 1.6%) and the upstream BA (overall mean 4.4 +/- 1.6% to 2.9 +/- 1.6%) at 6 h. Subgroup analysis showed that FMD of both arteries at 6 h was significantly lower in active smokers and that it only remained impaired at 24 h in this group, whereas nonsmoker FMD fully recovered. The degree of BA but not RA FMD dysfunction was related to the number of catheters used, with no change after 2 catheters, 1.9 +/- 1.2% decrease (6 h) and recovery (24 h) after 3 catheters, and 3.9 +/- 1.2% decrease (6 h) without recovery (24 h) after 4 to 5 catheters. The RA dysfunction correlated with the baseline diameter. The contralateral control RA exhibited no change ruling out systemic effects.
Transradial catheterization not only leads to dysfunction of the RA but also the upstream BA, which is more severe and sustained in smokers and with increasing numbers of catheters.
11/2009; 2(11):1067-73. · 1.07 Impact Factor
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Stroke 01/2009; 40(3):670-1. · 5.73 Impact Factor
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ABSTRACT: Conduit arteries respond to increases in flow by dilating, which is mediated by endothelium-derived nitric oxide. The significance of the interaction between microcirculation and macrocirculation in the flow-mediated dilation (FMD) is poorly understood.
We hypothesize that baseline conduit artery vasomotor tone (CAVT) and resting microvascular resistance (MVR) predict FMD.
We investigated resting diameter and FMD of the brachial artery using high-resolution ultrasound and forearm blood flow with plethysmography in 60 healthy individuals. CAVT was calculated as change of the arterial diameter from baseline to maximal dilation expressed as percentage of the maximum dilation. Resting MVR was determined as quotient of mean arterial blood pressure and forearm blood flow.
Mean FMD was 10.7+/-2.0%, indicating normal endothelial function. The extent of brachial artery FMD was not only related to baseline CAVT (r=0.70, P<0.01), but inversely to resting MVR (r=-0.69, P<0.01). Moreover, in a simple regression analysis, baseline CAVT was inversely related to resting MVR (r=-0.82, P<0.01). In a multivariate linear regression analysis, baseline CAVT and MVR were identified as independent predictors of brachial artery FMD.
Our data imply a close interaction of resting microvascular resistance and baseline CAVT modulating flow-mediated conduit artery dilation.
European journal of cardiovascular prevention and rehabilitation: official journal of the European Society of Cardiology, Working Groups on Epidemiology & Prevention and Cardiac Rehabilitation and Exercise Physiology 09/2008; 15(6):677-82. · 2.51 Impact Factor
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ABSTRACT: Nitrite plays an eminent role in cardiovascular physiology and pathology, mediating hypoxic vasodilation, reducing ischemia-reperfusion injury, and regulating cardiac energetics and function. The role of circulating nitrite in critically ill patients has not been examined so far. To investigate whether whole blood nitrite can be determined reproducibly in an intensive care setting, 30 patients from a cardiology intensive care unit were enrolled in this study, no matter what the underlying disease. Blood was drawn from an arterial catheter and whole blood nitrite was determined, using a tri-iodide/ozone-based chemiluminescence assay after incubation with a ferricyanide-containing stabilization solution. Whole blood nitrite levels ranged from 35 to 1193 nmol/L (mean+/-SEM: 220+/-20 nmol/L). Myocardial infarction was associated with lower whole blood nitrite levels (200+/-53 nmol/L for elevated serum CK MB levels vs 432+/-95 nmol/L in the normal CK MB range, p=0.039). Neither impaired kidney function nor an inflammatory state was associated with higher or lower whole blood nitrite levels. In conclusion, whole blood nitrite can be measured easily and reproducibly in critically ill patients, regardless of renal function and inflammation. The origin of decreased nitrite levels in myocardial infarction is currently unclear and needs to be further elucidated.
Free Radical Biology and Medicine 07/2008; 44(11):1945-50. · 5.42 Impact Factor
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Jan Balzer,
Tienush Rassaf,
Christian Heiss,
Petra Kleinbongard, Thomas Lauer,
Marc Merx,
Nicole Heussen,
Heidrun B Gross,
Carl L Keen,
Hagen Schroeter,
Malte Kelm
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ABSTRACT: Our goal was to test feasibility and efficacy of a dietary intervention based on daily intake of flavanol-containing cocoa for improving vascular function of medicated diabetic patients.
Even in fully medicated diabetic patients, overall prognosis is unfavorable due to deteriorated cardiovascular function. Based on epidemiological data, diets rich in flavanols are associated with a reduced cardiovascular risk.
In a feasibility study with 10 diabetic patients, we assessed vascular function as flow-mediated dilation (FMD) of the brachial artery, plasma levels of flavanol metabolites, and tolerability after an acute, single-dose ingestion of cocoa, containing increasing concentrations of flavanols (75, 371, and 963 mg). In a subsequent efficacy study, changes in vascular function in 41 medicated diabetic patients were assessed after a 30-day, thrice-daily dietary intervention with either flavanol-rich cocoa (321 mg flavanols per dose) or a nutrient-matched control (25 mg flavanols per dose). Both studies were undertaken in a randomized, double-masked fashion. Primary and secondary outcome measures included changes in FMD and plasma flavanol metabolites, respectively.
A single ingestion of flavanol-containing cocoa was dose-dependently associated with significant acute increases in circulating flavanols and FMD (at 2 h: from 3.7 +/- 0.2% to 5.5 +/- 0.4%, p < 0.001). A 30-day, thrice-daily consumption of flavanol-containing cocoa increased baseline FMD by 30% (p < 0.0001), while acute increases of FMD upon ingestion of flavanol-containing cocoa continued to be manifest throughout the study. Treatment was well tolerated without evidence of tachyphylaxia. Endothelium-independent responses, blood pressure, heart rate, and glycemic control were unaffected.
Diets rich in flavanols reverse vascular dysfunction in diabetes, highlighting therapeutic potentials in cardiovascular disease.
Journal of the American College of Cardiology 07/2008; 51(22):2141-9. · 14.16 Impact Factor
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Thomas Lauer,
Christian Heiss,
Jan Balzer,
Eva Kehmeier,
Sarah Mangold,
Thorsten Leyendecker,
Jessica Rottler,
Christian Meyer,
Marc W Merx,
Malte Kelm,
Tienush Rassaf
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ABSTRACT: Age-dependent alterations of the vessel wall may predispose older individuals to increased cardiovascular pathology. Aging is associated with an impaired bioactivity of nitric oxide (NO). Plasma nitrite reflects NO-synthase activity under fasting conditions and is an important storage pool of NO. To test the hypothesis that aging is associated with an impaired capacity of the vasculature to increase plasma nitrite during exercise, 29 young and 28 old healthy individuals (25 +/- 1 years and 58 +/- 2 years; P < 0.001) without major cardiovascular risk factors were enrolled. Exercise stress was similar in both groups. Baseline nitrite did not differ (107 +/- 8 vs. 82 +/- 10 nmol/l, young vs. old; n.s.) although a trend toward higher nitrite levels in young individuals was seen. In young subjects, exercise increased plasma nitrite by 38 +/- 7% (P < 0.001) compared to only 13 +/- 8% (P = n.s.) in older subjects. L-NMMA blocked increases of nitrite. Endothelial function, as defined by flow-mediated-dilation (FMD) of the brachial artery via ultrasound, was impaired in older subjects (5.4 +/- 0.4% vs. 6.7 +/- 0.3%; P < 0.01). Multivariate analysis showed that age (P = 0.007), BMI (P = 0.010), and LDL (P = 0.021) were independent predictors of nitrite increase. The fact that aging is associated with an impaired capacity of the vasculature to adequately increase nitrite to physiological stimuli may contribute to attenuated maintenance and further deterioration of vascular homeostasis with aging.
Archiv für Kreislaufforschung 05/2008; 103(3):291-7. · 7.35 Impact Factor
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Jan Balzer,
Tienush Rassaf,
Christian Heiss,
Petra Kleinbongard, Thomas Lauer,
Marc Merx,
Nicole Heussen,
Heidrun B. Gross,
Carl L. Keen,
Hagen Schroeter,
Malte Kelm
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[hide abstract]
ABSTRACT: Objectives Our goal was to test feasibility and efficacy of a dietary intervention based on daily intake of flavanol-containing cocoa for improving vascular function of medicated diabetic patients. Background Even in fully medicated diabetic patients, overall prognosis is unfavorable due to deteriorated cardiovascular function. Based on epidemiological data, diets rich in flavanols are associated with a reduced cardiovascular risk. Methods In a feasibility study with 10 diabetic patients, we assessed vascular function as flow-mediated dilation (FMD) of the brachial artery, plasma levels of flavanol metabolites, and tolerability after an acute, single-dose ingestion of cocoa, containing increasing concentrations of flavanols (75, 371, and 963 mg). In a subsequent efficacy study, changes in vascular function in 41 medicated diabetic patients were assessed after a 30-day, thrice-daily dietary intervention with either flavanol-rich cocoa (321 mg flavanols per dose) or a nutrient-matched control (25 mg flavanols per dose). Both studies were undertaken in a randomized, double-masked fashion. Primary and sec- ondary outcome measures included changes in FMD and plasma flavanol metabolites, respectively. Results A single ingestion of flavanol-containing cocoa was dose-dependently associated with significant acute increases in circulating flavanols and FMD (at 2 h: from 3.7 0.2% to 5.5 0.4%, p 0.001). A 30-day, thrice-daily con- sumption of flavanol-containing cocoa increased baseline FMD by 30% (p 0.0001), while acute increases of FMD upon ingestion of flavanol-containing cocoa continued to be manifest throughout the study. Treatment was well tolerated without evidence of tachyphylaxia. Endothelium-independent responses, blood pressure, heart rate, and glycemic control were unaffected. Conclusions Diets rich in flavanols reverse vascular dysfunction in diabetes, highlighting therapeutic potentials in cardiovas- cular disease. (J Am Coll Cardiol 2008;51:2141-9) © 2008 by the American College of Cardiology Foundation
Journal of The American College of Cardiology - J AMER COLL CARDIOL. 01/2008; 51(22):2141-2149.
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ABSTRACT: Nitrite is the main oxidation product of nitric oxide (NO) in plasma. It sensitively reflects changes in endothelial NO synthase (eNOS) activity under fasting conditions and serves as an endocrine NO donor, contributing to the regulation of blood flow through reaction with haemoglobin. As NO is necessary to maintain an adequate vascular response to the increased demands of blood flow, it is believed to be important for vasodilation induced by exercise.
To investigate whether the capacity of the vasculature to produce nitrite is associated with exercise performance.
With the use of chemiluminescence detection, nitrite concentrations in 55 healthy subjects (mean (SEM) age 40 (2) years; 22 men) were studied before and after an exercise test, and endothelial function was determined by measuring flow-mediated dilation of the brachial artery using high-resolution ultrasound. In a subset of subjects, the NOS inhibitor, N(G)-monomethyl-L-arginine, was applied to elucidate the effect of eNOS on changes in nitrite.
Exercise significantly (p<0.001) increased plasma nitrite from 97 (6) to 125 (8) nM. The relative increase in plasma nitrite was related to flow-mediated dilation (6.1 (0.3)%; r = 0.36; p = 0.01). N(G)-Monomethyl-L-arginine blocked increases in nitrite. Post-exercise nitrite concentration correlated with exercise performance, as determined by maximally reached stress power (r = 0.37; p<0.007), and inversely with age. Multivariate analysis showed that both age and post-exercise nitrite concentration were independent predictors of stress endurance and power.
The results suggest a role for plasma nitrite in the adaptation of haemodynamics during exercise. An impaired increase in plasma nitrite may limit exercise capacity.
British journal of sports medicine 10/2007; 41(10):669-73; discussion 673. · 2.55 Impact Factor
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ABSTRACT: Nitric oxide (NO) plays a pivotal role in the modulation of multiple physiological processes. It acts as a messenger molecule within the cardiovascular system. NO is a highly unstable free radical in circulating blood and is oxidized rapidly to nitrite and nitrate. Recent studies suggest that nitrite has the potential to function as a surrogate of NO production under physiological and pathophysiological conditions and could therefore be of high relevance as a biochemical parameter in experimental and clinical studies. Under hypoxic conditions nitrite is reduced to bioactive NO by deoxyhemoglobin. This mechanism may represent a dynamic cycle of NO generation to adapt the demand and supply for the vascular system. Because of these potential biological functions the concentration of nitrite in blood is thought to be of particular importance. The determination of nitrite in biological matrices represents a considerable analytical challenge. Methodological problems often arise from pre-analytical sample preparation, sample contamination due to the ubiquity of nitrite, and from lack of selectivity and sensitivity. These analytical difficulties may be a plausible explanation for reported highly diverging concentrations of nitrite in the human circulation. The aim of this article is to review the methods of quantitative analysis of nitrite in the human circulation, notably in plasma and blood, and to discuss pre-analytical and analytical factors potentially affecting accurate quantification of nitrite in these human fluids.
Journal of Chromatography B 06/2007; 851(1-2):106-23. · 2.89 Impact Factor
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ABSTRACT: Attenuation of endothelium-derived nitric oxide (NO) synthesis is a hallmark of endothelial dysfunction. Early detection of this disorder may have therapeutic and prognostic implications. Plasma nitrite mirrors acute and chronic changes in endothelial NO-synthase activity. We hypothesized that local plasma nitrite concentration increases during reactive hyperemia of the forearm, reflecting endothelial function. In healthy subjects (n = 11) plasma nitrite and nitrate were determined at baseline and during reactive hyperemia of the forearm using reductive gas-phase chemiluminescence and flow-injection analysis, respectively. Endothelium-dependent dilation of the brachial artery was measured as flow-mediated dilation (FMD) using high-resolution ultrasound. Results were compared to patients with endothelial dysfunction as defined by reduced FMD (n = 11). Reactive hyperemia of the forearm increased local plasma nitrite concentration from 68 +/- 5 to 126 +/- 13 nmol/L (p < 0.01), whereas in endothelial dysfunction nitrite remained unaffected (116 +/- 12 to 104 +/- 10 nmol/L; n.s.), corresponding to nitrite reserves of 94 +/- 21 and -8 +/- 4%. This was accompanied by a significantly greater increase in brachial artery diameter (FMD: 8.5 +/- 0.4% vs 2.9 +/- 0.5%, for healthy subjects and endothelial dysfunction, respectively; p < 0.001). This observation suggests that nitrite changes reflect endothelial function. Assessment of local plasma nitrite during reactive hyperemia may open new avenues in the diagnosis of vascular function.
Free Radical Biology and Medicine 08/2006; 41(2):295-301. · 5.42 Impact Factor
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Tienush Rassaf,
Ludger W Poll,
Paris Brouzos, Thomas Lauer,
Matthias Totzeck,
Petra Kleinbongard,
Putrika Gharini,
Kjel Andersen,
Rainer Schulz,
Gerd Heusch,
Ulrich Mödder,
Malte Kelm
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ABSTRACT: The myocardial effect of tonically released nitric oxide (NO) in humans is still not known. We tested the hypothesis that low-dose NO exerts positive effects on left ventricular (LV) function.
Twelve healthy volunteers, 26+/-4 years, were enrolled in this study. Magnetic resonance imaging was used to precisely measure the direct effects of NO on stroke volume index (SVI). The NO pool was monitored by chemiluminescence. We reduced endogenous NO levels with intravenous infusion of the NO synthase-inhibitor N(G)-monomethyl-l-arginine. Replenishment of the NO pool was achieved with the NO donor S-nitrosoglutathione (GSNO) (0.5 micromol iv). To differentiate load-dependent from the direct effects of NO on LV function, changes in SVI in response to GSNO were compared with changes in the NO-independent vasodilator dihydralazine (2.5 mg iv) at matched arterial pressure and heart rate. Inhibition of NO synthesis was followed by reduction in SVI. Subsequent replenishment of the circulating NO with GSNO significantly increased SVI (39+/-8 to 54+/-7 mL m(-2); P=0.001), whereas no significant changes were observed with the NO-independent vasodilator dihydralazine (39+/-8 to 46+/-8 mL m(-2); P=0.0626).
Inhibition of endogenous NO release reduces, whereas replenishment with exogenous NO increases LV function, pointing towards a positive effect of tonically released NO on LV function in healthy humans.
European Heart Journal 08/2006; 27(14):1699-705. · 10.48 Impact Factor
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Petra Kleinbongard,
Rainer Schulz,
Tienush Rassaf, Thomas Lauer,
André Dejam,
Thomas Jax,
Intan Kumara,
Putrika Gharini,
Svetlana Kabanova,
Burcin Ozüyaman,
Hans-Georg Schnürch,
Axel Gödecke,
Artur-A Weber,
Mirko Robenek,
Horst Robenek,
Wilhelm Bloch,
Peter Rösen,
Malte Kelm
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ABSTRACT: The synthesis of nitric oxide (NO) in the circulation has been attributed exclusively to the vascular endothelium. Red blood cells (RBCs) have been demonstrated to carry a nonfunctional NO synthase (NOS) and, due to their huge hemoglobin content, have been assumed to metabolize large quantities of NO. More recently, however, RBCs have been identified to reversibly bind, transport, and release NO within the cardiovascular system. We now provide evidence that RBCs from humans express an active and functional endothelial-type NOS (eNOS), which is localized in the plasma membrane and the cytoplasm of RBCs. This NOS is regulated by its substrate L-arginine, by calcium, and by phosphorylation via PI3 kinase. RBC-NOS activity regulates deformability of RBC membrane and inhibits activation of platelets. The NOS-dependent conversion of L-arginine in RBCs is comparable to that of cultured human endothelial cells. RBCs in eNOS-/- mice in contrast to wild-type mice lack NOS protein and activity, strengthening the evidence of an eNOS in RBCs. These data show an eNOS-like protein and activity in RBCs serving regulatory functions in RBCs and platelets, which may stimulate new approaches in the treatment of NO deficiency states inherent to several vascular and hematologic diseases.
Blood 05/2006; 107(7):2943-51. · 9.90 Impact Factor
