How to select a drug for the long-term treatment of chronic heart failure

Abstract First-line drugs for the treatment of chronic congestive heart failure should produce immediate symptomatic benefit, improve exercise tolerance, and thereby improve the quality of life. They should preferentially be active as monotherapy or at least reduce the need for comedication. The drugs must be safe and well tolerated by patients and change, in the end, the natural history of the disease, so that sudden death will be prevented and life expectancy improves. None of the currently available drugs satisfies all these criteria. Diuretics, digitalls, converting-enzyme inhibitors, and ibopamine come close to the described ideal

Congenitale dopamine Beta-hydroxylase deficientie : een nieuw orthostatisch syndroom

Sinds decennia wordt chronische autonome dysfunctie herkend als een belangrijk klinisch probleem hoewel het relatief zeldzaam is. Bradbury en Eggleston beschreven in 1925 het sindsdien naar hen genoemde syndroom als "primary postural hypotension", ook bekend als . "idiopathische orthostatische hypotensie" en "idiopathische autonome dysfunctie" (1). Sindsdien zijn medici zich bewust van het feit, dat een groot aantal medicamenten en systeemziekten het door Bradbury en Eggleston beschreven syndroom kunnen nabootsen. De combinatie van orthostatische hypotensie, hypohydrosis, een relatief gefixeerde polsfrequentie, impotentie en dysfunctie van de urinewegen en het maagdarmkanaal is een complex van symptomen, dat gemakkelijk herkend wordt als dysfunctie van het autonome zenuwstelsel

Congenitale dopamine Beta-hydroxylase deficientie : een nieuw orthostatisch syndroom

Sinds decennia wordt chronische autonome dysfunctie herkend als een belangrijk klinisch probleem hoewel het relatief zeldzaam is. Bradbury en Eggleston beschreven in 1925 het sindsdien naar hen genoemde syndroom als "primary postural hypotension", ook bekend als . "idiopathische orthostatische hypotensie" en "idiopathische autonome dysfunctie" (1). Sindsdien zijn medici zich bewust van het feit, dat een groot aantal medicamenten en systeemziekten het door Bradbury en Eggleston beschreven syndroom kunnen nabootsen. De combinatie van orthostatische hypotensie, hypohydrosis, een relatief gefixeerde polsfrequentie, impotentie en dysfunctie van de urinewegen en het maagdarmkanaal is een complex van symptomen, dat gemakkelijk herkend wordt als dysfunctie van het autonome zenuwstelsel

Comparison of N-terminal pro-atrial natriuretic peptide and atrial natriuretic peptide in human plasma as measured with commercially available radioimmunoassay kits

Atrial natriuretic peptide (ANP) has become an important parameter for assessing the condition of patients with cardia disease. Recently, attention has also focused on N-terminal pro-atrial natriuretic peptide (NtproANP) in this context. NtproANP circulates in plasma in higher concentration, is more stable ex vivo, and may be a better parameter for cardiac function over time. We have evaluated a new commercially available radioimmunoassay kit for NtproANP and compared results and method withthose of ANP measurements. The NtproANP kit was found to be reliable and easy to use (no plasma extraction step is necessary), with good reproducibility (coefficients of variation 7-15%). Normal values in 15 healthy laboratory workers, 25 healthy elderly subjects and 25 patients with heart failure were 207 ± 70, 368 ± 134 and 1206 ± 860 pmol/l, respectively, 8.3, 11.8 and 13.0 times higher, respectively, than corresponding ANP concentrations. NtproANP correlated well with ANP (r 0.64-0.78). We conclude that plasma NtproANP measurement may be a good alternative to plasma ANP measurement: technically, it is easier to perform, and NtproANP is more stable in plasma. Whether NtproANP is a better diagnostic and prognostic parameter than ANP remains to be further established

Beneficial effects of conversion from cyclosporine to azathioprine on fibrinolysis in renal transplant recipients

Cyclosporin A (CsA) has been implicated as one of the factors contributing to the high cardiovascular morbidity and mortality after renal transplantation. This may be mediated by either a high prevalence of conventional risk factors for atherosclerosis, such as hypertension, hypercholesterolemia, and diabetes mellitus, or by impairment of the fibrinolytic activity evoked by CsA, possibly through interference with prostanoid metabolism. We therefore assessed the impact of conversion of CsA to azathioprine immunosuppressive treatment on parameters of fibrinolytic activity and plasma concentration of the prostanoids prostaglandin E2 and thromboxane B2 in 18 stable renal transplant recipients. During CsA, mean arterial pressure and serum creatinine were significantly higher than during azathioprine (116+/-15 mm Hg versus 106+/-13 mm Hg, P=0.0003; and 147+/-34 micromol/L versus 127+/-35 micromol/L, P=0.002; mean+/-SD). On conversion, the plasma tissue plasminogen activator activity increased from 1.2 (1.1 to 1.7; median, 95% CI) to 1.8 (1.6 to 2.0) IU/mL (P=0.011), without a significant change of the plasminogen activator antigen concentration. This was associated with a substantial decrease in plasminogen activator inhibitor-1 activity from 10.4 (8.5 to 16.7) to 6.4 (5.6 to 9.2) IU/mL (P=0.009). Furthermore, plasma levels of prostaglandin E2 and thromboxane B2 markedly decreased (from 9.7 [7.4 to 12.9] to 4.6 [4.3 to 8.1] pg/mL, P=0.0006; and from 106.1 [91.7 to 214.2] to 70.2 [50.3 to 85.6] pg/mL, P=0.002, respectively). During CsA, but not azathioprine, plasma tissue plasminogen activator antigen and plasminogen activator inhibitor-1 levels correlated significantly with prostaglandin E2 (r=0.53, P=0.02; and r=0.60, P=0.008, respectively), and thromboxane B2 (r=0.75, P=0.0001; and r=0.77, P=0.0001, respectively) levels. In conclusion, CsA induced substantial impairment of fibrinolytic activity, which recovered after conversion to azathioprine. The impaired fibrinolysis observed during CsA treatment may be caused by modulation of eicosanoid production or metabolism in vascular endothelial cells and possibly contributes to the high incidence of cardiovascular disease after kidney transplantation

Human renal and systemic hemodynamic, natriuretic, and neurohumoral responses to different doses of L-NAME

Experimental evidence indicates that the renal circulation is more sensitive to the effects of nitric oxide (NO) synthesis inhibition than other vascular beds. To explore whether in men the NO-mediated vasodilator tone is greater in the renal than in the systemic circulation, the effects of three different intravenous infusions of NG-nitro-L-arginine methyl ester (L-NAME; 1, 5, and 25 microg. kg-1. min-1 for 30 min) or placebo on mean arterial pressure (MAP), systemic vascular resistance (SVR), renal blood flow (RBF), renal vascular resistance (RVR), glomerular filtration rate (GFR), and fractional sodium and lithium excretion (FENa and FELi) were studied in 12 healthy subjects, each receiving randomly two of the four treatments on two different occasions. MAP was measured continuously by means of the Finapres device, and stroke volume was calculated by a model flow method. GFR and RBF were estimated from the clearances of radiolabeled thalamate and hippuran. Systemic and renal hemodynamics were followed for 2 h after start of infusions. During placebo, renal and systemic hemodynamics and FENa and FELi remained stable. With the low and intermediate L-NAME doses, maximal increments in SVR and RVR were similar: 20.4 +/- 19.6 and 23.5 +/- 16.0%, respectively, with the low dose and 31.4 +/- 26.7 and 31.2 +/- 14.4%, respectively, with the intermediate dose (means +/- SD). With the high L-NAME dose, the increment in RVR was greater than the increment in SVR. Despite a decrease in RBF, FENa and FELi did not change with the low L-NAME dose, but they decreased by 31.2 +/- 11.0 and 20.2 +/- 6.3%, respectively, with the intermediate dose and by 70.8 +/- 8.1 and 31.5 +/- 15.9% with the high L-NAME dose, respectively. It is concluded that in men the renal circulation is not more sensitive to the effects of NO synthesis inhibition than the systemic circulation and that the threshold for NO synthesis inhibition to produce antinatriuresis is higher than the threshold level to cause renal vasoconstriction

Stent placement for renal arterial stenosis: where do we stand? A meta-analysis

PURPOSE: To perform a meta-analysis of renal arterial stent placement in comparison with renal percutaneous transluminal angioplasty (PTA) in patients with renal arterial stenosis. MATERIALS AND METHODS: Studies dealing with renal arterial stent placement (14 articles; 678 patients) and renal PTA (10 articles; 644 patients) published up to August 1998 were selected. A random-effects model was used to pool the data. RESULTS: Renal arterial stent placement proved highly successful, with an initial adequate performance in 98% and major complications in 11%. The overall cure rate for hypertension was 20%, whereas hypertension was improved in 49%. Renal function improved in 30% and stabilized in 38% of patients. The restenosis rate at follow-up of 6-29 months was 17%. Stent placement had a higher technical success rate and a lower restenosis rate than did renal PTA (98% vs 77% and 17% vs 26%, respectively; P <.001). The complication rate was not different between the two treatments. The cure rate for hypertension was higher and the improvement rate for renal function was lower after stent placement than after renal PTA (20% vs 10% and 30% vs 38%, respectively; P <.001). CONCLUSION: Renal arterial stent placement is technically superior and clinically comparable to renal PTA alone

Hemodynamic changes, plasma catecholamine responses, and echocardiographically detected contractile reserve during two different dobutamine-infusion protocols

We studied hemodynamic changes, catecholamine responses, and the occurrence of improved wall thickening by echocardiography during two different dobutamine-infusion protocols. Forty-three patients were studied by using a stepwise incremental dobutamine dose-infusion protocol (10-40 μg/kg/min, 3-min intervals); a subgroup of 11 patients also underwent a continuous dobutamine-infusion protocol (10 μg/kg/min for 12 min) in random order. No patient used β-blockers. At 3-min intervals, blood pressure, heart rate, and plasma concentrations of dobutamine, epinephrine, and norepinephrine were measured. The echocardiographic improvement of wall thickening was analyzed only in paired protocols by visual assessment in left ventricular regions with normal wall motion at rest. The mean heart rate increased in the continuous and stepwise protocols from 73 to 99 and 74 to 132 beats/min. There was no significant change in blood pressure response between the two protocols. The mean plasma dobutamine concentrations during the continuous and stepwise protocols at 0, 3, 6, 9, and 12 min were 0/0; 31/38; 80/203; 106/448; and 120/692 ng/ml, respectively. In each patient, a response curve was constructed for the plasma dobutamine concentration versus heart rate. The heart rate increment and dobutamine concentration at which wall thickening was detected were similar with both protocols (14 ± 5 vs. 12 ± 7 beats/min) and (8) ± 40 vs. 92 ± 48 ng/ml; mean ± SD). Wall thickening was noted in two of 11 patients b

Time Course and Mechanism of Myocardial Catecholamine Release During Transient Ischemia In Vivo

BACKGROUND: Elevated concentrations of norepinephrine (NE) have been observed in ischemic myocardium. We investigated the magnitude and mechanism of catecholamine release in the myocardial interstitial fluid (MIF) during ischemia and reperfusion in vivo through the use of microdialysis. METHODS AND RESULTS: In 9 anesthetized pigs, interstitial catecholamine concentrations were measured in the perfusion areas of the left anterior descending coronary artery (LAD) and the left circumflex coronary artery. After stabilization, the LAD was occluded for 60 minutes and reperfused for 150 minutes. During the final 30 minutes, tyramine (154 nmol. kg(-1). min(-1)) was infused into the LAD. During LAD occlusion, MIF NE concentrations in the ischemic region increased progressively from 1. 0+/-0.1 to 524+/-125 nmol/L. MIF concentrations of dopamine and epinephrine rose from 0.4+/-0.1 to 43.9+/-9.5 nmol/L and from <0.2 (detection limit) to 4.7+/-0.7 nmol/L, respectively. Local uptake-1 blockade attenuated release of all 3 catecholamines by >50%. During reperfusion, MIF catecholamine concentrations returned to baseline within 120 minutes. At that time, the tyramine-induced NE release was similar to that seen in nonischemic control animals despite massive infarction. Arterial and MIF catecholamine concentrations in the left circumflex coronary artery region remained unchanged. CONCLUSIONS: Myocardial ischemia is associated with a pronounced increase of MIF catecholamines, which is at least in part mediated by a reversed neuronal reuptake mechanism. The increase of MIF epinephrine implies a (probably neuronal) cardiac source, whereas the preserved catecholamine response to tyramine in postischemic necrotic myocardium indicates functional integrity of sympathetic nerve terminals