Biomedical subjects

V Mitrovic

Publications and source records attributed to V Mitrovic.

At least 19 recordsLinked to original sources

PubMed2006

Prognostic value of N-terminal pro-B-type natriuretic peptide for conservatively and surgically treated patients with aortic valve stenosis.

OBJECTIVE: To evaluate the prognostic value of N-terminal pro-B-type natriuretic peptide (NT-proBNP) in patients with aortic stenosis being treated conservatively or undergoing aortic valve replacement (AVR). METHODS: 159 patients were followed up for a median of 902 days. 102 patients underwent AVR and 57 were treated conservatively. NT-proBNP at baseline was raised in association with the degree of severity and of functional status. RESULTS: During follow up 21 patients (13%) died of cardiac causes or required rehospitalisation for decompensated heart failure. NT-proBNP at baseline was higher in patients with an adverse outcome than in event-free survivors (median 623 (interquartile range 204-1854) pg/ml v 1054 (687-2960) pg/ml, p = 0.028). This difference was even more obvious in conservatively treated patients (331 (129-881) pg/ml v 1102 (796-2960) pg/ml, p = 0.002). Baseline NT-proBNP independently predicted an adverse outcome in the entire study group and in particular in conservatively treated patients (area under the curve (AUC) = 0.65, p = 0.028 and AUC = 0.82, p = 0.002, respectively) but not in patients undergoing AVR (AUC = 0.544). At a cut-off value of 640 pg/ml, baseline NT-proBNP was discriminative for an adverse outcome. CONCLUSION: NT-proBNP concentration is related to severity of aortic stenosis and provides independent prognostic information for an adverse outcome. However, this predictive value is limited to conservatively treated patients. Thus, the data suggest that assessing NT-proBNP may have incremental value for selecting the optimal timing of valve replacement.

Aged↗

PubMed2006

Release pattern of N-terminal pro B-type natriuretic peptide (NT-proBNP) in acute coronary syndromes.

BACKGROUND: Recently it has been found that BNP and NT-proBNP provide independent prognostic information in patients with acute coronary syndromes (ACS). However, little data are available on the time course of NT-proBNP levels in relation to onset of symptoms. METHODS AND RESULTS: We included 765 patients (236 females, aged 64 +/- 11 years) with an ACS (STEMI 42%, NSTEMI 41%, UAP 17%), who were referred for coronary angiography. NT-proBNP was assessed on admission and the next day. NT-proBNP values were related to the time duration from onset of symptoms until blood drawing with lowest values within 3 h and highest values 24-36 h after onset of symptoms (147 (64-436) pg/ml and 1099 (293-3795) pg/ml, respectively, p < 0.001). Highest values for NT-proBNP on admission were found in patients with NSTEMI compared to patients with STEMI and UAP (912 (310-2258) pg/ml) vs 262 (85-1282) pg/ml) vs 182 (74- 410) pg/ml; p < 0.001), but no difference was present between STEMI and NSTEMI the day after admission (1325 (532-2974) pg/ ml vs 1169 (555-3413) pg/ml; p = 0.676). In contrast NT-proBNP values remained unchanged in UAP (182 (74-410) pg/ml) vs 171 (53-474) pg/ml). CONCLUSION: The time interval from onset of symptoms to first blood collection is an important determinant for NT-proBNP values on admission in patients with an ACS and needs to be considered in clinical practice.

Angina, Unstable↗

PubMed2006

Nickel release, a possible indicator for the duration of antiplatelet treatment, from a nickel cardiac device in vivo: a study in patients with atrial septal defects implanted with an Amplatzer occluder.

UNLABELLED: The present study was undertaken to evaluate the safety and release of nickel after implantation of a nickel device (Amplatzer occluder) in patients with an atrial septal defect (ASD) receiving antiplatelet therapy. METHODS: Blood and urine samples were obtained from 24 patients with ASD before occluder implantation (baseline) and during a 12-month post closure period. Antiplatelet drugs were administered for the initial 6-month period post implantation. The nickel content in the specimens was determined using electrothermal atomic absorption spectroscopy. The clinical, sonographic and magnetic resonance imaging follow-ups were carried out 1 week, 1 month, 6 months and 12 months post implantation. RESULTS: Mean baseline concentrations of nickel in serum and urine were within normal range with values of 0.6 +/- 0.2 microg/l and 3.1 +/- 1.2 microg/l, respectively. During the 6-week post closure period, the time needed for the formation of neointima on the surface of the graft, nickel levels in serum increased up to 5-fold (p < 0.01 versus baseline). Mean concentrations in serum and urine returned to baseline levels within 4-6 months post implantation. All patients showed satisfactory clinical improvements and there was no sonographic evidence of complications. CONCLUSIONS: The initial dissolution of nickel from the Amplatzer occluder is not a specific cardiovascular risk and is temporarily linked to the formation of the non-thrombogenic neointima on the surface of the graft. The antiplatelet drug regimen used (300 mg aspirin + 75 mg clopidogrel daily for 3 months in the initial phase and 100 mg aspirin daily for a further 3 months) appears to cover the period of neointima formation on the nickel device when nickel levels are significantly elevated. However, further studies in a larger number of patients and over a period greater than 12 months are needed to confirm the validity of these conclusions and to formulate definitive recommendations on the duration of the antiplatelet treatment.

Adult↗

PubMed2005

Left ventricular adaptation after atrial septal defect closure assessed by increased concentrations of N-terminal pro-brain natriuretic peptide and cardiac magnetic resonance imaging in adult patients.

OBJECTIVE: To determine in an observational study whether N-terminal pro-brain natriuretic peptide (NT-proBNP) is raised in patients with an atrial septal defect (ASD) and whether concentrations change after interventional closure. METHODS: 12 patients (6 men, mean (SD) age 44.4 (18.6) years) with a moderate sized ASD type II (23.3 (4.5) mm, pulmonary to systemic flow ratio 2.1 (0.68)) were investigated. In all patients a magnetic resonance imaging (MRI) study was performed and NT-proBNP was assessed at baseline and early (9 (13) days) and late (138 (64) days) after intervention. RESULTS: Concentrations of NT-proBNP were found to be within the normal range at baseline (median 87 pg/ml, interquartile range 65-181 pg/ml) but increased early after the interventional closure (315 pg/ml, 133-384 pg/ml, p = 0.005 versus baseline). The increase of NT-proBNP was associated with an increase in left ventricular dimensions as assessed by MRI (left ventricular end diastolic volume 104 (27) ml to 118 (27) ml, p = 0.003). Late after ASD closure NT-proBNP returned to baseline concentrations (102 pg/ml, 82-188 pg/ml, p = 0.004 versus early follow up). CONCLUSION: These findings suggest the presence of transitory haemodynamic stress during adaptation of the left ventricle after ASD closure, which may contribute to the understanding of the pathological mechanism of acute heart failure and delayed improvement of exercise capacity after ASD closure.

Adult↗

PubMed2005

Influence of the angiotensin converting enzyme inhibitor ramipril on high-sensitivity C-reactive protein (hs-CRP) in patients with documented atherosclerosis.

UNLABELLED: Some medications have been shown to produce reductions in hs-CRP levels after initiating therapy. Whereas the role of the renin-angiotensin system in the inflammatory process has been documented in more detail during the last few years, the impact of an ACE-inhibitor therapy on this process has not been fully understood so far. The aim of this study was to investigate the effect of a therapy with the angiotensin-converting enzyme (ACE) inhibitor ramipril on hs-CRP plasma concentrations in patients with atherosclerosis. METHODS AND RESULTS: A total of 24 patients were enrolled in this prospective, uncontrolled, open-label multicenter study. Inclusion criteria were documented atherosclerosis, baseline high-sensitivity C-reactive protein between 3 and 12 mg/l, LDL-Cholesterol < or =150 mg/dl and no previous treatment with ACE inhibitors or angiotensin receptor blockers. Ten patients, pretreated with statins, and 10 patients not previously treated with statins were eligible for statistical analysis. Baseline high-sensitivity C-reactive protein was significantly decreased from 3.99+/-1.61 mg/l (mean+/-SD) to 2.72+/-1.19 mg/l (-32%) after 3 months treatment with 10 mg ramipril daily (p=0.0002). The decrease was more pronounced in patients who had not been treated with statins previously (-1.50 mg/l+/-1.44 mg/l) compared to those who were pretreated (-0.90 mg/l+/-0.93 mg/l). CONCLUSIONS: The ACE inhibitor ramipril administered in a daily dose of 10 mg to patients with atherosclerosis reduces the high-sensitivity C-reactive protein concentration. This effect may contribute to cardiovascular risk reduction mediated by ramipril aside from the blood pressure lowering effect.

Adult↗

PubMed2004

[Information deficits concerning blood pressure self-measurement].

BACKGROUND AND OBJECTIVE: Blood pressure values resulting from measurements by the patients themselves have greater diagnostic and prognostic significance than those measured by the physician, assuming, however, that measurement is taken correctly. As self-measurement of blood pressure has meanwhile become a widespread practice. The question arises to what extent the rules on exact measurement of blood pressure are known to the patient. PATIENTS AND METHODS: The answers to questions on five rules on self-measurement of blood pressure (resting period prior to measurement, time of measurement and intake of morning medication, left or right arm for measurement, level of measuring point and width of cuff) given by 500 hypertensive patients (373 men, 127 women, mean age 59.2 +/- 10.2 years) were evaluated. RESULTS: Three patients only were in the position to answer all five questions correctly. 19 % were unable to give any right answer. Patients showed highest information levels concerning the resting period before measurement. Approximately half of them (51 %) knew that a pause of three minutes has to be kept. Only one in three, however, was familiar with the fact that morning measurement has to be taken prior to the intake of antihypertensives (32 %) choosing the arm that shows higher blood pressure values. 28 % were informed that the measuring point has to lie at the height of the heart. Only 4 % were able to answer the question on the width of the cuff correctly. CONCLUSION: Our findings show that the rules on correct self-measurement of blood pressure are unknown to most of the hypertensive patients. This may be due to the fact that they are insufficiently informed and trained.

Adult↗

PubMed2004

[Cardiopulmonary exercise capacity increases after interventional ASD-closure].

BACKGROUND: In patients with atrial septal defects of the secundum-type (ASD), exercise tolerance is reduced. Generally, ASD closure is recommended in symptomatic patients and in patients with a relevant left-to-right shunt (Qp/Qs > 1.5). Only few data are available concerning objective parameters of cardiopulmonary exercise capacity. The aim of this study was to evaluate exercise capacity as achieved by ergospirometry in adult patients with an ASD at baseline and in the long-term following transcatheter closure. METHODS AND RESULTS: Thirty consecutive patients (8 male; mean age 43.4 years; defect size 23.5 mm; pulmonary-to-systemic flow ratio (Qp/Qs) 1.94) performed exercise testing on a supine bicycle ergometer. At baseline, oxygen consumption at maximal exercise (VO(2) peak) was 14.3 ml/min kg, oxygen consumption at the anaerobic threshold (VO(2)-AT) was 11.2 ml/min/kg and maximal achieved workload was 86 Watt. At one and six months after ASD-closure, there was no relevant increase of the VO(2) peak, the VO(2)-AT or the maximal workload. After 12 months, there was a significant increase of the VO(2) peak (15.1 ml/min/kg, p = 0.049), the VO(2)-AT (13 ml/min/kg, p < 0.001) and the maximal workload (99 Watt, p < 0.01). An increase of the oxygen consumption at the anaerobic threshold (Delta VO(2) AT) could be seen in 24 out of 30 patients and was independent of shunt volume (Q(p)/Q(s) < or = 2, 1.95 ml/ min/kg; Q(p)/Q(s) > 2, 2.13 ml/min/ kg; ns), defect size (defect < or = 24 mm, 2.0 ml/min/kg; defect > 24 mm, 1.5 ml/min/kg; ns), age (age < or = 44 years, 1.97 ml/min/kg; age >44 years, 1.66 ml/min/kg; ns), gender (female 1.56 ml/min/ kg; male 1.91 ml/min/kg; ns) and of the existence of a residual shunt. Highly symptomatic patients had a tendency to have greater benefit from ASD-closure as compared to mildly symptomatic patients (NYHA 0/I 1.85 ml/min/kg; NYHA II 1.5 ml/min/ kg; NYHA III 2.7 ml/min/kg; ns). There was no correlation between shunt volume, shunt size, pulmonal arterial pressure and increase of the oxygen consumption at the anaerobic threshold (Delta VO(2) AT). CONCLUSION: There is no relevant improvement in exercise capacity early (1-6 months) after interventional ASD-closure, but late after ASD-closure (12 months) exercise capacity improves significantly. This improvement can be found in almost all patients independent of gender, age, symptoms, shunt volume and defect size.

Adolescent↗

PubMed2003

Acute and 3-month treatment effects of candesartan cilexetil on hemodynamics, neurohormones, and clinical symptoms in patients with congestive heart failure.

BACKGROUND: This study evaluated the short-term and long-term effects of the angiotensin II type 1 receptor antagonist candesartan cilexetil on hemodynamics, neurohormones, and clinical symptoms in patients with congestive heart failure (CHF). METHODS: In this multicenter, double-blind, parallel-group study, 218 patients with CHF (New York Heart Association class II or III) with impaired left ventricular function (ejection fraction < or =40%) and pulmonary capillary wedge pressure > or =13 mm Hg were randomly assigned to 12 weeks of treatment with placebo (n = 44) or candesartan cilexetil (2 mg [n = 45], 4 mg [n = 46], 8 mg [n = 39], or 16 mg [n = 44]) once daily after a 2-week placebo run-in period. Hemodynamic measurements were performed by right heart catheterization over a 24-hour period after single (day 1) and repeated (3-month) treatment with the study drug. RESULTS: On regression analysis of the time-response curves, single and multiple doses of candesartan cilexetil produced sustained, significant, and dose-dependent reductions in pulmonary capillary wedge pressure (short-term effect P =.036, long-term effect P =.035) and mean pulmonary arterial pressure (short-term effect P =.031, long-term effect P =.042). Systemic vascular resistance showed a trend toward decreasing with dose on short-term and long-term treatments. No consistent changes were seen in cardiac index. Compensatory increases in plasma renin activity and angiotensin II levels with decreases in aldosterone and atrial natriuretic peptide were dose-dependent and significant. Candesartan cilexetil improved clinical symptoms, stabilized patient New York Heart Association status compared with placebo, and was judged to be an efficacious treatment by the investigators. More patients receiving placebo stopped the trial prematurely because of an adverse event than in any candesartan cilexetil group, and there was no excess of deaths in any treatment group. Candesartan was safe and well tolerated at all dosages. CONCLUSIONS: Candesartan cilexetil demonstrated significant short-term and long-term improvements in hemodynamic, neurohormonal, and symptomatic status and was well tolerated in patients with CHF.

Adolescent↗

PubMed2002

Efficacy and safety of intravenous levosimendan compared with dobutamine in severe low-output heart failure (the LIDO study): a randomised double-blind trial.

BACKGROUND: Levosimendan, a novel calcium sensitiser, improves myocardial contractility without causing an increase in myocardial oxygen demand. We compared the effects of levosimendan and dobutamine on haemodynamic performance and clinical outcome in patients with low-output heart failure. METHODS: Patients were recruited into a multicentre, randomised, double-blind, double-dummy, parallel-group trial. Under continuous haemodynamic monitoring, an initial loading dose of levosimendan of 24 microg/kg was infused over 10 min, followed by a continuous infusion of 0.1 microg kg(-1) min(-1) for 24 h. Dobutamine was infused for 24 h at an initial dose of 5 microg kg(-1) min(-1) without a loading dose. The infusion rate was doubled if the response was inadequate at 2h. The primary endpoint was the proportion of patients with haemodynamic improvement (defined as an increase of 30% or more in cardiac output and a decrease of 25% or more in pulmonary-capillary wedge pressure) at 24 h. Analyses were by intention to treat. FINDINGS: 103 patients were assigned levosimendan and 100 dobutamine. The primary haemodynamic endpoint was achieved in 29 (28%) levosimendan-group patients and 15 (15%) in the dobutamine group (hazard ratio 1.9 [95% CI 1.1-3.3]; p=0.022). At 180 days, 27 (26%) levosimendan-group patients had died, compared with 38 (38%) in the dobutamine group (0.57 [0.34-0.95]; p=0.029). INTERPRETATION: In patients with severe, low-output heart failure, levosimendan improved haemodynamic performance more effectively than dobutamine. This benefit was accompanied by lower mortality in the levosimendan group than in the dobutamine group for up to 180 days.

Cardiac Output, Low↗

PubMed2001

[Effect of the imidazoline receptor agonist moxonidine on hemodynamics, coronary circulation, metabolic ischemia markers and the neurohumoral system in patients with essential hypertension. Effects of moxonidine on coronary circulation].

Moxonidine is a new centrally active imidazoline-receptor agonist being effectively applied in the treatment of arterial hypertension due to its sympathicolytic potency. This is the first investigation regarding the effects of moxonidine on coronary and systemic hemodynamics, metabolic markers of ischemia and neurohumoral parameters in patients with essential hypertension (WHO I-II). We studied moxonidine (single dose of 0.4 mg p.o.) in 22 patients with left ventricular (LV) hypertrophy, ST segment depressions during exercise, pectanginal complaints and negative coronarograms. Assessments included arterial blood pressure, cardiac output, pulmonary artery pressure mean (PAPm), pulmonary capillary wedge pressure (PCWP) and coronary sinus flow (CSF) by intravascular Doppler technique. The moxonidine-induced parameter changes 2 hours later were as follows: a decrease in systolic/diastolic pressure by 28/10 mmHg, and in heart rate by 5 bpm, associated with a decline of PAPm by 17% and of PCWP by 26%. LV work was reduced by 26%, MVO2 by 18% and CSF by 16%. Average peak velocity in CS fell by 18% and coronary flow reserve (with adenosine) increased by 12%. CS-O2 saturation rose by 4%, accompanied by an increase in lactate extraction by 17%, a decrease in norepinephrine spillover by 30% and in arterial endotheline by 20%. In conclusion, moxonidine produces clinically relevant sympathicolysis with beneficial effects on hemodynamics, coronary circulation and neurohumoral parameters.

Aged↗

PubMed2001

Activation of the cardiac renin-angiotensin system and increased myocardial collagen expression in human aortic valve disease.

OBJECTIVES: We sought to determine whether the cardiac renin-angiotensin system (RAS) is activated in human aortic valve disease depending on left ventricular function, and we analyzed the concomitant regulation of the extracellular matrix components. BACKGROUND: In animal models with pressure or volume load, activation of the cardiac RAS increases fibrosis. In human aortic valve disease, the ventricular collagen protein content is increased, but only scarce data on the activation state of the cardiac RAS and its effects on collagen and fibronectin messenger ribonucleic acid (mRNA) are available. METHODS: In left ventricular biopsies from patients with aortic valve stenosis (AS) and aortic valve regurgitation and from control subjects, we quantitated mRNAs for angiotensin-converting enzyme (ACE), chymase, transforming growth factor-beta1 (TGF-beta1), collagen I, collagen III and fibronectin by reverse-transcription polymerase chain reaction. Proteins were localized by immunohistochemistry; ACE activity was determined by high performance liquid chromatography; and TGF-beta protein by quantitative enzyme immunoassay. RESULTS: Protein, ACE and TGF-beta1 mRNA were significantly increased in patients with AS and AR (1.5- to 2.1-fold) and correlated with each other. The increase occurred also in patients with normal systolic function. Collagen I and III and fibronectin mRNAs were both upregulated about twofold in patients with AS and AR. In AS, collagen and fibronectin mRNA expression levels were positively correlated with left ventricular end-diastolic pressure and inversely with left ventricular ejection fraction (LVEF). CONCLUSIONS: In human hearts, pressure and volume overload increases cardiac ACE and TGF-beta1 in the early stages. This activation of the cardiac RAS may contribute to the observed increase in collagen I and III and fibronectin mRNA expression. The increase in extracellular matrix already exists in patients with a normal LVEF, and it increases with functional impairment.

Aged↗

PubMed2001

[Actions of standardized extracts of Crataegus berries on exercise tolerance and quality of life in patients with congestive heart failure].

Standardized extracts of Crataegus leaves and blossoms are said to have positive inotropic, positive dromotropic and negative bathmotropic effects. Clinical trials produce evidence for an improvement of symptoms in patients with congestive heart failure (NYHA II). In this trial the efficacy of a standardized extract of fresh Crataegus berries (Rob 10) on exercise tolerance and quality of life was studied in 88 patients. In a three-month placebo-controlled, randomized, double-blind trial these patients were treated with Rob 10 (3 x 25 drops daily). Total exercise time in bicycle ergometry was defined as primary efficacy variable, while quality of life (Minnesota Questionnaire), Dyspnea-Fatigue Index and the assessment of dyspnea by the patient on a visual analogous scale were chosen as secondary parameters. Investigations were performed after a two week placebo run-in period as well as 6 and 12 weeks after the onset of the study. Treatment with Rob 10 led to a increase of exercise time of 38.9 s vs placebo (95% confidence interval 5.7-72.1 s). Quality of life improved accordingly in favour of Rob 10. In the Minnesota Questionnaire, the total score fell by 31% (30.6 vs 44.1) under Rob 10 vs 18% (34.6 vs 42.4) under placebo. The Dyspnea-Fatigue Index demonstrated an increase of the total score of 12% (9.41 vs 8.37) vs 8% (8.92 vs 8.26) under administration of placebo. According to findings of the assessment of dyspnea by the patient, dyspnea decreased by 11% (50.5 vs 56.6 mm) vs 4% (54.8 vs 57.3 mm) under placebo. The present study proves the efficacy and safety of a standardized extract of fresh Crataegus berries (Rob 10) in patients with congestive heart failure (NYHA II) regarding the parameters evaluated.

Aged↗

PubMed2000

Hemodynamic and neurohumoral effects of continuous infusion of levosimendan in patients with congestive heart failure.

OBJECTIVES: We sought to define the therapeutic dose range of levosimendan in patients with New York Heart Association class II-IV heart failure of ischemic origin. BACKGROUND: Levosimendan is a calcium sensitizer for treatment of acute decompensated heart failure. METHODS: A double-blind, placebo-controlled, randomized, multicenter, parallel-group study included 151 adult patients. Levosimendan was given as a 10-min intravenous bolus of 3, 6, 12, 24 or 36 microg/kg, followed by a 24-h infusion of 0.05, 0.1, 0.2, 0.4 or 0.6 microg/kg/min, respectively. Dobutamine, for comparative purposes, was given as an open-label infusion (6 microg/kg/min). The primary efficacy variable was the proportion of patients achieving in each treatment group at least one of the following: 1) a > or =15% increase in stroke volume (SV) at 23 h to 24 h; 2) a > or =25% decrease in pulmonary capillary wedge pressure (PCWP) (and > or =4 mm Hg) at 23 h to 24 h; 3) a > or =40% increase in cardiac output (CO) (with change in heart rate [HR] <20%); 4) a > or =50% decrease in PCWP during two consecutive measurements. RESULTS: The response rate to levosimendan ranged from 50% at the lowest dose to 88% at the highest dose (compared with placebo 14%, dobutamine 70%). A dose-response relationship was demonstrated for levosimendan on increases in CO and SV, and reductions in PCWP during the infusion (for all, p< or =0.001). Headache (9%), nausea (5%) and hypotension (5%) were the most frequently reported adverse events at higher dosages. CONCLUSIONS: Dosing of levosimendan with a 10-min bolus of 6 to 24 microg/kg followed by an infusion of 0.05 to 0.2 microg/kg/min is well tolerated and leads to favorable hemodynamic effects.

Adult↗

PubMed2000

Potassium channel openers and blockers in coronary artery disease. Comparison to betablockers and calcium antagonists.

Potassium channel openers and blockers, which belong to a novel class of vasodilator drugs and to the class of specific bradycardic substances, are potential new antianginal drugs. Experimental findings in vivo suggest that bimakalim is a new substance characterized as ATP-sensitive K+ channel openers, since it exerts preferential vasodilation of the collateral circulation of the coronary vasculature and both leads to increase blood flow to ischemic areas and to attenuate the ST segment elevation caused by regional ischemia in the canine heart. Opening of KATP increases the conductivity of potassium ions which results in hyperpolarization of smooth muscle membranes, thus producing vasodilation. Tedisamil is a new bradycardic agent proven to exert antiischemic and antiarrhythmic effects by blockade of the cellular cardiac repolarization K+ currents as well as of multiple neuronal and vascular K+ currents (Ito, Ik, and K+ATP). Using right heart catheterization and exercise tolerance tests, we investigated the hemodynamic, antiischemic and neurohumoral effects of bimakalim and tedisamil in patients with angiographically proven coronary artery disease, stable angina pectoris and reproducible ST segment depression during exercise. In 50 patients with coronary artery disease, the hemodynamic and antiischemic effects of a single oral dose bimakalim of 0.1 mg, 0.3 mg and 0.6 mg were compared to placebo. In a dose-finding baseline-controlled study, a comparable collective was examined for the effects of acute i.v. administration of tedisamil 0.1, 0.2, 0.3 and 0.4 mg/kg bw. A subgroup of 8 patients receiving 0.3 mg/kg bw tedisamil i.v. was compared with a similar group of 14 patients who had received esmolol (i.v. bolus of 500 micrograms/kg, maintenance dose 200 micrograms/kg/min) and gallopamil (initial dose 0.025 mg/kg, maintenance dose 0.0005 mg/kg/h) in a second intra-individual comparison. Furthermore, in 48 patients, short-term (6 days) effects of tedisamil, 2 times 100 mg orally, were compared to 2 times 50 mg atenolol treatment. With a single oral dose of bimakalim antianginal and/or antiischemic effects were lacking, increased doses, however, induced changes in hemodynamics typical of vasodilation, i.e., a significant decrease in systolic blood pressure and a secondary chronotropic response. In contrast to bimakalim, tedisamil produced antiischemic effects and was found to have favorable hemodynamic, neurohumoral and antiischemic effects in comparison to the betablocker esmolol and atenolol in patients with coronary artery disease. Tedisamil induced a dose-dependent decrease in both heart rate and the index of myocardial oxygen consumption associated with an improvement in ST segment depression. Tedisamil as well as esmolol and atenolol showed almost equipotent antiischemic effects at the doses administered. Compared with gallopamil, both tedisamil and esmolol were superior in their effects on myocardial oxygen consumption and ST segment depression, whereas plasma lactate concentrations were more reduced by tedisamil and gallopamil.

Adrenergic beta-Antagonists↗

PubMed2000

Acute hemodynamic and neurohumoral effects of selective ET(A) receptor blockade in patients with congestive heart failure. ET 003 Investigators.

OBJECTIVES: To investigate the hemodynamic effects of the selective endothelin (ET)A receptor antagonist LU135252 in patients with congestive heart failure (CHF). BACKGROUND: Nonselective ET(A/B( receptor antagonists improve hemodynamics in patients with CHF. Since ET(B( receptors mediate the release of nitric oxide and the clearance of ET-1, selective ET(A) antagonists are of special interest. METHODS: The hemodynamic effects of a single oral dose of the selective ET(A) receptor antagonist LU135252 (1, 10, 30, 100 or 300 mg) were investigated in a multicenter study involving 95 patients with CHF (New York Heart Association II-III) with an ejection fraction < or = 35%. RESULTS: Baseline ET-1 positively correlated with pulmonary vascular resistance, pulmonary capillary wedge pressure (PCWP), and mean pulmonary artery pressure (MPAP, r = 0.37-0.50, p < 0.0004) but were inversely related to cardiac index (CI; r = -0.36, p = 0.0004). LU135252 dose dependently increased CI and decreased mean arterial pressure and systemic vascular resistance (p < 0.03-0.0002), while heart rate remained constant or decreased slightly. Pulmonary capillary wedge pressure, MPAP, pulmonary vascular resistance and right atrial pressure also decreased significantly (p < 0.035- < 0.0001). Two hours after LU135252, plasma ET-1 did not significantly increase after 1 mg but did so by 23% (p = 0.003), 29% (p = 0.0018), 56% (p < 0.0001) and 101% (p < 0.0001) after 10, 30, 100 and 300 mg, respectively, while plasma catecholamines remained constant. CONCLUSIONS: In patients with CHF, a single oral dose of the selective ET(A) receptor antagonist LU135252 improves hemodynamics in a dose-dependent manner without activation of other neurohumoral systems and is well tolerated over a wide dose range.

Catecholamines↗

PubMed2000

Hemodynamic, antiischemic, and neurohumoral effects of tedisamil and atenolol in patients with coronary artery disease.

Clinical drawbacks of beta-blocker treatment in stable angina have motivated researchers to provide alternative heart-rate-lowering agents, such as tedisamil, which additionally exerts antiischemic and antiarrhythmic effects by blockade of cellular repolarizing K+ currents. Forty-eight patients with stable angina pectoris were investigated (doubleblind, randomized, parallel grouped) comparing the hemodynamic, antiischemic, metabolic and neurohumoral effects of tedisamil 100 mg b.i.d. and atenolol 50 mg b.i.d. after a single dose and over 6 days of treatment. Tedisamil and atenolol produced a decrease in heart rate both at rest [day 1:-13.6 versus - 15.4 bpm; day 6: - 14.8 versus - 22.2 bpm, resp.; p > 0.05] and exercise [day 1: - 9.1 versus - 18.3 bpm; p = 0.001; day 6: - 12.0 versus - 24.8 bpm, resp.; p = 0.001], while anginal threshold increased. Cardiac output decreased with tedisamil and atenolol at rest [day 1: -1.01 versus -1.19 l/min; p > 0.05; day 6: - 0.86 versus - 1.10 l/min, resp.; p > 0.05] and exercise [day 1: - 0.82 versus - 1.28 l/min; p > 0.05; day 6: - 0.65 versus - 2.68 l/min, resp.; p = 0.03], while stroke volume remained unchanged. Right atrial pressure changed during exercise only: it decreased with tedisamil (-1.7 mmHg) and increased with atenolol (+ 3.7 mmHg) (p < .001). Mean pulmonary capillary wedge pressures decreased both at rest (- 0.5 mmHg) and exercise (- 6.9 mmHg) in the tedisamil group but tended to increase with atenolol on day 6 of treatment [rest: + 1.7; exercise: + 3.7 mmHg) (p = 0.03). Arterial pressure decreased under atenolol treatment only. Exercise-induced plasma norepinephrine levels were reduced by tedisamil (- 93 pg/ml) but elevated by atenolol (+ 172 pg/ml) (p = 0.001). As compared to atenolol, tedisamil produced a prolongation of QTc interval [+ 31 versus 8 ms] at initial values of 0.408 +/- 0.018 s with PQ and QRS remaining unaltered. In patients with stable angina, tedisamil (100 mg b.i.d.) as compared to atenolol (50 mg b.i.d.) generated similar hemodynamic, neurohumoral and antiischemic effects. The antiischemic efficacy of tedisamil, as measured by ST segment depression and angina threshold, was comparable to that of atenolol.

Administration, Oral↗

PubMed2000

Neurohumoral blockade in CHF management.

Is heart failure an endocrine disease? Historically, congestive heart failure (CHF) has often been regarded as a mechanical and haemodynamic condition. However, there is now strong evidence that the activation of neuroendocrine systems, like the renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system, as well as the activation of natriuretic peptides, endothelin and vasopressin, play key roles in the progression of CHF. In this context, agents targeting neurohormones offer a highly rational approach to CHF management, with ACE inhibitors, aldosterone antagonists and beta-adrenergic blockade improving the prognosis for many patients. Although relevant improvements in clinical status and survival can be achieved with these drug classes, mortality rates for patients with CHF are still very high. Moreover, most patients do not receive these proven life-prolonging drugs, partially due to fear of adverse events, such as hypotension (with ACE inhibitors), gynaecomastia (with spironolactone) and fatigue (with beta-blockers). New agents that combine efficacy with better tolerability are therefore needed. The angiotensin II type 1 (AT(1))-receptor blockers have the potential to fulfil both these requirements, by blocking the deleterious cardiovascular and haemodynamic effects of angiotensin II while offering placebo-like tolerability. As shown with candesartan, AT(1)-receptor blockers also modulate the levels of other neurohormones, including aldosterone and atrial natriuretic peptide (ANP). Combined with its tight, long-lasting binding to AT(1)-receptors, this characteristic gives candesartan the potential for complete blockade of the RAAS-neurohormonal axis, along with the great potential to improve clinical outcomes.

Aldosterone↗

PubMed2000

Homocysteine and arteriosclerosis: established risk factor or new illusion?

Homocysteine is an amino acid and a product of methionine metabolism that is metabolized through two different enzymatic pathways: transsulfuration and remethylation. Vitamin B6 is important in homocysteine transsulfuration, whereas folate and vitamin B12 play significant roles in homocysteine remethylation. The hyperhomocysteinemia offers an explanation for observations on human arteriosclerosis that are difficult to explain by the cholesterol/fat approach. However, hyperhomocysteinemia can influence cognitive functions in the elderly. The causes of hyperhomocysteinemia are inherited and acquired. The treatment of hyperhomocysteinemia varies with underlying cause; generally, vitamin supplementation (with folic acid and vitamins B6 and B12) is effective in reducing homocysteine concentrations. Also, specific recommendations, food fortification with folic acid, and preventive strategies in European countries (as in United States) are necessary to decrease cardiovascular morbidity and mortality.

Arteriosclerosis↗