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Biomedical subjects

Malte Kelm

Publications and source records attributed to Malte Kelm.

At least 55 records · Page 3Linked to original sources
PubMed2003

Plasma nitrite reflects constitutive nitric oxide synthase activity in mammals.

Changes in plasma nitrite concentration in the human forearm circulation have recently been shown to reflect acute changes in endothelial nitric oxide synthase (eNOS)-activity. Whether basal plasma nitrite is a general marker of constitutive NOS-activity in vivo is yet unclear. Due to the rapid metabolism of nitrite in blood and the difficulties in its analytical determination literature data on levels of nitrite in mammals are largely inconsistent. We hypothesized that constitutive NOS-activity in the circulatory system is relatively uniform throughout the mammalian kingdom. If true, this should result in comparable systemic plasma nitrite levels in different species. Using three different analytical approaches we determined plasma nitrite concentration to be in a nanomolar range in a variety of species: humans (305 +/- 23 nmol/l), monkeys (367 +/- 62 nmol/l), minipigs (319 +/- 24 nmol/l), dogs (305 +/- 50 nmol/l), rabbits (502 +/- 21 nmol/l), guinea pigs (412 +/- 44 nmol/l), rats (191 +/- 43 nmol/l), and mice (457 +/- 51 nmol/l). Application of different NOS-inhibitors in humans, minipigs, and dogs decreased NOS-activity and thereby increased vascular resistance. This was accompanied by a significant, up to 80%, decrease in plasma nitrite concentration. A comparison of plasma nitrite concentrations between eNOS(-/-) and NOS-inhibited wild-type mice revealed that 70 +/- 5% of plasma nitrite is derived from eNOS. These results provide evidence for a uniform constitutive vascular NOS-activity across mammalian species.

Animals↗
PubMed2003

Direct biochemical evidence for eNOS stimulation by bradykinin in the human forearm vasculature.

OBJECTIVE: Although it has been shown recently that acetylcholine (ACh)-induced vasodilation of forearm resistance vessels is predominantly mediated by nitric oxide, direct biochemical evidence for eNOS stimulation by bradykinin (BK) in the human arterial circulation is still lacking. Therefore, the present study was designed to test the hypothesis that in the human forearm vasculature eNOS stimulation significantly contributes to BK-induced vasodilation. METHODS: BK was infused in the presence and absence of the NOS inhibitor L-NMMA (8 micromol/min) into the brachial artery of 16 healthy volunteers and the effects compared to muscarinergic eNOS stimulation following acetylcholine infusion. Forearm blood flow (FBF) was measured by venous occlusion plethysmography, and plasma nitrite (NO(2)(-)), which represents a sensitive and specific marker of regional eNOS activity, was determined in the antecubital vein and brachial artery by flow injection analysis. Nitric oxide production was calculated as product of the veno-arterial difference of NO(2)(-) concentration times FBF. RESULTS: Kininergic (BK: 20, 60, 200 ng/min) as well as muscarinergic (ACh: 1, 3, 10 microg/min) stimulation resulted in a dose-dependent increase in FBF and NO(2)(-) in each individual. The relationship between FBF and NO production upon BK infusion was comparable to that obtained with ACh (r = 0.98; n = 64, p < 0.01). Moreover, NOS inhibition reduced both flow responses and NO production (BK: 54 and 75 %; ACh: 57 and 72 %) to a similar extent. CONCLUSIONS: These data provide direct biochemical evidence for the involvement of eNOS in bradykinin-induced vasodilation of forearm resistance vessels in humans.

Acetylcholine↗
PubMed2003

The L-arginine-nitric oxide pathway in hypertension.

Nitric oxide is involved in the regulation of resting vascular tone, adaptation of blood flow to metabolic demand of tissue, and adaptation of vessel diameter to volume of inflow, ie, flow-mediated dilation. Arterial hypertension is associated with an increased vascular tone of resistance vessels, a reduced compliance of conduit arteries, along with a thickening of the intima-media leading to vascular remodeling. Dysfunctional endothelium triggers such maladaptive processes. A reduced bioavailability of nitric oxide has been shown in hypertensive individuals dependent on the duration and severity of arterial hypertension. Angiotensin-converting enzyme inhibitors reverse endothelial dysfunction, whereas a concomitant reduction in significant cardiac events due to improved bioavailability has yet to be established. Long-term follow-up studies in individuals with manifest endothelial dysfunction and in offspring from hypertensive patients underscore the prognostic and genetic significance of a reduced nitric oxide bioavailability for the pathophysiology of arterial hypertension.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2003

A prospective study on incidence and risk factors of arteriovenous fistulae following transfemoral cardiac catheterization.

BACKGROUND: A potentially harmful complication of cardiac catheterization is the arteriovenous fistula. Precise knowledge of possible factors predisposing for acquisition of iatrogenic AV-fistulae could enable cardiologists to perform a risk stratification for cardiac patients prior to catheterization. METHODS: Over a period of 2 years, 10,271 consecutive patients who underwent cardiac catheterization were included in this study. Auscultation of a new femoral bruit was followed by a duplex scan to confirm the suspected diagnosis of an AVF. Every patient was investigated on the day after catheterization. RESULTS: The incidence of iatrogenic AVF was 0.86%. A multivariate regression analysis revealed five significant and independent risk factors: (1) procedural heparin dosage >or=12,500 IU (Odds Ratio (OR)=2.88), (2) coumadin therapy (OR=2.34), (3) puncture of the left groin (OR=2.21), (4) arterial hypertension (OR=1.86) and (5) female gender (OR=1.84). Coronary angioplasty (instead of diagnostic procedure), size and number of sheaths, age and body mass index did not significantly affect the incidence of AVF. CONCLUSIONS: The overall incidence of AV-fistulae following cardiac catheterization approximates 1%. Determination of significant risk factors will facilitate identification of patients at risk for iatrogenic arteriovenous fistulae prior to cardiac catheterization and thus help to develop strategies to reduce the incidence of AV-fistulae.

Aged↗
PubMed2003

Effects of right coronary artery PTCA on variables of P-wave signal averaged electrocardiogram.

BACKGROUND: P-wave signal averaged ECG has been used to detect atrial late potentials that were found in paroxysmal atrial fibrillation. Ischemia is supposed to trigger ventricular late potentials, which indicate an elevated risk for ventricular tachycardia. Preexistent ventricular late potentials measured by ventricular signal averaged ECG is supposed to be eliminated by successful PTCA. METHODS: We examined the incidence of atrial late potentials in patients with a proximal stenosis of the right coronary artery and new onset of atrial fibrillation. Furthermore, we investigated the anti-ischemic effect of a successful percutaneous transluminal coronary angioplasty.(PTCA) of the right coronary artery. P-wave signal averaged ECG from 23 patients who had a PTCA of the right coronary artery (group A) were compared to age, sex, and disease-matched control subjects (group B) one day before, one day after, and one month after PTCA. RESULTS: A new appearance of paroxysmal atrial fibrillation was presented in eight patients before PTCA (group A1) of group A. Patients with a stenosis of the right coronary artery had a significantly higher incidence of supraventricular extrasystoles in a 24-hour-Holter ECG (131.1 +/- 45.4 vs 17.1 +/- 18.9, P < 0.0002). The duration of the filtered P wave was longer (124.8 +/- 11.9 vs 118.5 +/- 10.1 ms, P < 0.04) and the root mean square of the last 20 ms (RMS 20) was significantly lower in group A than in group B (2.87 +/- 1.09 vs 3.97 +/- 1.12 micro V, P < 0.01). A successful PTCA caused an increase in RMS 20 (2.87 +/- 1.11 vs 4.19 +/- 1.19 microV, P < 0.02) and a decrease in filtered P-wave duration (124.8 +/- 11.9 vs 118.4 +/- 10.4 ms, P < 0.04). Preexistent atrial late potentials were found among 15 patients before PTCA. After successful PTCA only 3 out of 15 patients were affected (P < 0.0004) after one day, as well as after one month. All patients with a history of atrial fibrillation did not suffer from an arrhythmic recurrence within the following six months after successful PTCA. CONCLUSION: A stenosis of the right coronary artery is associated with atrial late potentials. A successful PTCA of the right coronary artery eliminates preexistent atrial late potentials and may reduce the risk of atrial fibrillation.

Action Potentials↗
PubMed2003

Management of the hypertensive patient with coronary insufficiency but without atherosclerosis.

Arterial hypertension is a major risk factor for the clinical syndrome of angina pectoris, in which the ECG is abnormal but the coronary arteries are normal. Structural and functional abnormalities in coronary circulation as well as extravascular factors (eg, left-ventricular hypertrophy, fibrosis with diastolic dysfunction) compromise the adequate ratio of coronary blood flow to oxygen demand causing angina, dyspnea, and major cardiac events. Recent studies stress the importance to functional disturbances of coronary microvasculature leading to profound morphologic changes associated with impaired coronary conductance. In patients without epicardial coronary stenosis hypertensive microvascular disease can be qualitatively assessed by noninvasive diagnostic approaches based on new Doppler echocardiography techniques and may also be monitored by widely available stress tests. For ultimate quantitative assessment, invasive procedures are still required. Beyond guidelines to control blood pressure in hypertensive individuals, restoration of functional and structural integrity of the coronary microvasculature represents the ultimate therapeutic goal in hypertensive patients with coronary insufficiency and without angiographic evidence of atherosclerosis. Concomitant factors reducing coronary conductance such as left-ventricular hypertrophy and diastolic dysfunction should be reversed in parallel. Currently, therapeutic intervention in the renin-aldosterone-angiotensin-II-system using ACE inhibitors, angiotensin receptor blockers, and low doses of aldosterone antagonists represent the most promising strategy to achieve these goals. Using the knowledge of these recent results we should refine the overall management of our hypertensive patients with coronary insufficiency but without atherosclerosis.

Antihypertensive Agents↗
PubMed2002

Concomitant presence of N-nitroso and S-nitroso proteins in human plasma.

Nitric oxide (NO)-mediated nitrosation reactions are involved in cell signaling and pathology. Recent efforts have focused on elucidating the role of S-nitrosothiols (RSNO) in different biological systems, including human plasma, where they are believed to represent a transport and buffer system that controls intercellular NO exchange. Although RSNOs have been implicated in cardiovascular disease processes, it is yet unclear what their true physiological concentration is, whether a change in plasma concentration is causally related to the underlying pathology or purely epiphenomenological, and to what extent other nitrosyl adducts may be formed under the same conditions. Therefore, using gas phase chemiluminescence and liquid chromatography we sought to quantify the basal plasma levels of NO-related metabolites in 18 healthy volunteers. We find that in addition to the oxidative products of NO metabolism, nitrite (0.20 +/- 0.02 micromol/l nitrite) and nitrate (14.4 +/- 1.7 micromol/l), on average human plasma contains an approximately 5-fold higher concentration of N-nitroso species (32.3 +/- 5.0 nmol/l) than RSNOs (7.2 +/- 1.1 nmol/l). Both N- and S-nitroso moieties appear to be associated with the albumin fraction. This is the first report on the constitutive presence of a high-molecular-weight N-nitroso compound in the human circulation, raising the question as to its origin and potential physiological role. Our findings may not only have important implications for the transport of NO in vivo, but also for cardiovascular disease diagnostics and the risk assessment of nitrosamine-related carcinogenesis in man.

Adult↗
PubMed2002

Plasma nitrosothiols contribute to the systemic vasodilator effects of intravenously applied NO: experimental and clinical Study on the fate of NO in human blood.

Higher doses of inhaled NO exert effects beyond the pulmonary circulation. How such extrapulmonary effects can be reconciled with the presumed short half-life of NO in the blood is unclear. Whereas erythrocytes have been suggested to participate in NO transport, the exact role of plasma in NO delivery in humans is not clear. Therefore, we investigated potential routes of NO decomposition and transport in human plasma. NO consumption in plasma was accompanied by a concentration-dependent increase in nitrite and S-nitrosothiols (RSNOs), with no apparent saturation limit up to 200 micro mol/L. The presence of red blood cells reduced the formation of plasma RSNOs. Intravenous infusion of 30 micro mol/min NO in healthy volunteers increased plasma levels of RSNOs and induced systemic hemodynamic effects at the level of both conduit and resistance vessels, as reflected by dilator responses in the brachial artery and forearm microvasculature. Intravenous application of S-nitrosoglutathione, a potential carrier of bioactive NO, mimicked the vascular effects of NO, whereas nitrite and nitrate were inactive. Changes in plasma nitrosothiols were correlated with vasodilator effects after intravenous application of S-nitrosoglutathione and NO. These findings demonstrate that in humans the pharmacological delivery of NO solutions results in the transport and delivery of NO as RSNOs along the vascular tree.

Adult↗
PubMed2002

Incidence and clinical outcome of iatrogenic femoral arteriovenous fistulas: implications for risk stratification and treatment.

OBJECTIVES: We sought to determine the incidence of arteriovenous fistulas (AVF), identify risk factors for AVF, and follow up the clinical outcome of femoral AVF. BACKGROUND: Arteriovenous fistulas are a potential harmful complication of cardiac catheterization. Incidence and clinical outcome of iatrogenic AVF are unknown so far, although important for risk stratification and treatment. METHODS: A total of 10,271 consecutive patients undergoing cardiac catheterization were followed up prospectively over a period of three years. Diagnosis of AVF was performed by duplex sonography. RESULTS: The incidence of AVF was 0.86% (n = 88). The following significant and independent risk factors for AVF were identified: high heparin dosage (odds ratio [OR]) = 2.88), coumadin therapy (OR = 2.34), puncture of the left groin (OR = 2.21), arterial hypertension (OR = 1.86), and female gender (OR = 1.84). Within 12 months 38% of all AVF closed spontaneously. No signs of cardiac volume overload or limb damage were observed in patients with persisting AVF. None of the risk factors for AVF influenced the incidence or the rate of AVF closure. Only intensified anticoagulation showed a tendency to extend AVF persistence. CONCLUSIONS: Almost 1% of patients undergoing cardiac catheterization acquire femoral AVF, for which patient- and procedure-related risk factors could be identified. One-third of iatrogenic AVF close spontaneously within one year. Cardiac volume overload and limb damage are highly unlikely with AVF persistence. Thus, a conservative management for at least one year seems to be justified.

Aged↗
PubMed2002

Low incidence of paradoxical platelet activation by glycoprotein IIb/IIIa inhibitors.

The human platelet antigen-1 (HPA-1, Pl(A)) polymorphism has been proposed to influence the inhibitory actions of abciximab. Thus, we hypothesized that this polymorphism might also be the cause for paradoxical activation of platelets by GPIIb/IIIa inhibitors. The effects of abciximab (1-10 microg/ml), tirofiban (3-30 nM), or eptifibatide (0.3-3 microg/ml) on basal and ADP (3 microM)-induced CD62P externalization were measured in n=62 healthy blood donors and n=177 patients with stable coronary artery disease. All subjects were genotyped for the human platelet antigen-1 (HPA-1, Pl(A)) polymorphism by GALIOS(R) and fluorescence correlation spectroscopy. Although a significant platelet hyperreactivity was observed in the patients, the HPA-1 genotype did not influence basal or ADP-induced CD62P expression. A moderate (twofold) stimulation of CD62P expression by abciximab but not by tirofiban or eptifibatide was observed in one patient. Interestingly, this patient carried the HPA-1 b/b genotype. In no other subject any activation of platelets by GP IIb/IIIa inhibitors was observed and there were no statistically significant differences between HPA-1 genotypes with respect to the effects of GP IIb/IIIa inhibitors on basal or ADP-stimulated CD62P expression. It is concluded that paradoxical platelet activation by abciximab is a rare (<2%) phenomenon. HPA-1 b/b genotype might be a contributing factor but clearly does not predict platelet activation by GP IIb/IIIa inhibitors.

Abciximab↗
PubMed2002

Concomitant S-, N-, and heme-nitros(yl)ation in biological tissues and fluids: implications for the fate of NO in vivo.

There is growing evidence for the involvement of nitric oxide (NO) -mediated nitrosation in cell signaling and pathology. Although S-nitrosothiols (RSNOs) have been frequently implicated in these processes, it is unclear whether NO forms nitrosyl adducts with moieties other than thiols. A major obstacle in assessing the significance of formation of nitrosated species is the limited reliability of available analytical techniques for measurements in complex biological matrices. Here we report on the presence of nitrosated compounds in plasma and erythrocytes of rats, mice, guinea pigs, and monkeys under basal conditions, in immunologically challenged murine macrophages in vitro and laboratory animals in vivo. Besides RSNOs, all biological samples also contained mercury-stable nitroso species, indicating the additional involvement of amine and heme nitros(yl)ation reactions. Significant differences in the amounts and ratios of RSNOs over N- and heme-nitros(yl)ated compounds were found between species and organs. These observations were made possible by the development of a novel gas-phase chemiluminescence-based technique that allows detection of nitroso species in tissues and biological fluids without prior extraction or deproteinization. The method can quantify as little as 100 fmol bound NO and has been validated extensively for use in different biological matrices. Discrimination between nitrite, RSNOs, and N-nitroso or nitrosylheme compounds is accomplished by use of group-specific reagents. Our findings suggest that NO generation in vivo leads to concomitant formation of RSNOs, nitrosamines, and nitrosylhemes with considerable variation between rodents and primates, highlighting the difficulty in comparing data between different animal models and extrapolating results from experimental animals to human physiology.

Animals↗
PubMed2002

Left ventricular remodeling impairs coronary flow reserve in hypertensive patients.

BACKGROUND: In arterial hypertension, changes in both left ventricular mass and geometry may occur. Concentric left ventricular remodeling (i.e. an increased wall thickness relative to end diastolic diameter) has been implicated as an independent cardiovascular risk factor in hypertensive patients. The influence of concentric remodeling on the coronary microcirculation is not known. OBJECTIVE: To investigate the impact of left ventricular geometry on coronary flow reserve in patients with arterial hypertension and angiographically normal coronary arteries. METHODS: Following exclusion of coronary artery disease by cardiac catheterization, coronary flow reserve (dipyridamole, 0.5 mg/kg body weight intravenously; argon gas-chromatographic method) was measured in 49 patients with arterial hypertension and in six age-matched controls. Hypertensive patients were grouped by echocardiographic findings according to left ventricular mass and relative left ventricular wall thickness (i.e. left ventricular posterior wall plus septal thickness divided by end diastolic diameter): seven patients had normal left ventricular mass and geometry, 19 had eccentric hypertrophy (i.e. normal relative wall thickness but increased mass), concentric remodeling (i.e. normal mass but increased relative wall thickness) was present in nine patients, and 14 patients had concentric hypertrophy. RESULTS: There was a marked reduction in coronary flow reserve in all hypertensive groups as compared with control values (4.2 +/- 0.5). Within the hypertensive subgroups, the coronary flow reserve was differentially reduced in the following rank order: concentric remodeling (2.0 +/- 0.7) approximately concentric hypertrophy (2.3 +/- 0.8) < eccentric hypertrophy (2.9 +/- 0.6) mu normal geometry (2.7 +/- 0.4). Multi-factorial regression analysis showed that the relative wall thickness but not left ventricular mass was independently linked to the coronary flow reserve. CONCLUSIONS: Concentric left ventricular remodeling is an independent predictor of the coronary flow reserve in hypertensive patients with chest pain and normal coronary angiogram. The impairment of the coronary microcirculation may contribute to the excess cardiovascular event rate associated with hypertensive concentric left ventricular remodeling.

Adult↗
PubMed2002

No evidence for an influence of the human platelet antigen-1 polymorphism on the antiplatelet effects of glycoprotein IIb/IIIa inhibitors.

This study investigated the hypothesis that the human platelet antigen-1 (HPA-1) polymorphism may influence the antiplatelet effects of glycoprotein (GP)IIb/IIIa inhibitors. Adenosine diphosphate (30 micro mol)-induced fibrinogen binding was measured by flow cytometry. Abciximab (0.03-3 micro g/ml), tirofiban (0.3-30 nmol/l) or eptifibatide (0.01-1 micro g/ml) were incubated for 15 min with the samples prior to stimulation. IC(50) values for the inhibition of fibrinogen binding were determined from each experiment. All subjects were genotyped by GALIOS and automated fluorescence correlation spectroscopy. Although a marked variability in the inhibitory effects of all three GPIIb/IIIa inhibitors was confirmed, there were no significant differences between the genotypes with respect to the inhibition of fibrinogen binding. Thus, the present study does not provide evidence for an effect of HPA-1 polymorphism on the inter-individual variability in the platelet inhibitory effects of the three GPIIb/IIIa inhibitors approved for clinical use.

Abciximab↗