Hanjörg Just

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

BACKGROUNDnLevosimendan, 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.nnnMETHODSnPatients 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.nnnFINDINGSn103 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).nnnINTERPRETATIONnIn 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.

Relation between myocardial function and expression of sarcoplasmic reticulum Ca(2+)-ATPase in failing and nonfailing human myocardium.

Expression of sarcoplasmic reticulum (SR) Ca(2+)-ATPase was shown to be reduced in failing human myocardium. The functional relevance of this finding, however, is not known. We investigated the relation between myocardial function and protein levels of SR Ca(2+)-ATPase in nonfailing human myocardium (8 muscle strips from 4 hearts) and in myocardium from end-stage failing hearts with dilated (10 muscle strips from 9 hearts) or ischemic (7 muscle strips from 5 hearts) cardiomyopathy. Myocardial function was evaluated by the force-frequency relation in isometrically contracting muscle strip preparations (37 degrees C, 30 to 180 min-1). In nonfailing myocardium, twitch tension rose with increasing rates of stimulation and was 76% higher at 120 min-1 compared with 30 min-1 (P < .02). In failing myocardium, there was no significant increase in average tension at stimulation rates above 30 min-1. At 120 min-1, twitch tension was decreased by 59% (P < .05) in dilated cardiomyopathy and 76% (P < .05) in ischemic cardiomyopathy compared with nonfailing myocardium. Protein levels of SR Ca(2+)-ATPase, normalized per total protein or per myosin, were reduced by 36% (P < .02) or 32% (P < .05), respectively, in failing compared with nonfailing myocardium. SR Ca(2+)-ATPase protein levels were closely related to SR Ca2+ uptake, measured in homogenates from the same hearts (r = .70, n = 16, and P < .005).(ABSTRACT TRUNCATED AT 250 WORDS)

Endothelial function in chronic congestive heart failure

There is evidence that the endothelium plays an important role in the control of human vascular tone by releasing endothelium-derived nitric oxide. The hypothesis that an impairment of this mechanism is involved in the increased peripheral vasoconstriction of patients with chronic congestive heart failure (CHF) was tested. Acetylcholine and N-monomethyl-L-arginine (L-NMMA), a specific inhibitor of nitric oxide synthesis from L-arginine, were infused in the brachial artery of healthy volunteer subjects (controls) and patients with severe CHF. The radial artery diameter was determined by a high-precision A-mode ultrasound device, using a 10 MHz probe. Forearm blood flow was calculated from vessel diameter and blood flow velocity measured simultaneously by Doppler. The blood flow response to acetylcholine was blunted in patients with CHF compared with that in control subjects. In contrast, the decrease in blood flow induced by L-NMMA was exaggerated in CHF, and the blood flow response to nitroglycerin was preserved. The changes in radial artery diameter induced by acetylcholine and L-NMMA were not significant in control subjects and CHF patients, but dilation of the radial artery by nitroglycerin was significantly reduced in CHF. The results demonstrate an impaired endothelium-dependent dilation of forearm resistance vessels in CHF, suggesting a reduced release of nitric oxide on stimulation. In contrast, the basal release of nitric oxide from endothelium of forearm resistance vessels is preserved or may even be enhanced, and may play an important compensatory role in chronic CHF by antagonizing neurohumoral vasoconstrictor forces in CHF.

Effect of long-acting nifedipine on mortality and cardiovascular morbidity in patients with stable angina requiring treatment (ACTION trial): randomised controlled trial

BACKGROUNDnCalcium antagonists are widely prescribed for angina pectoris but their effect on clinical outcome is controversial. We aimed to investigate the effect of the calcium antagonist nifedipine on long-term outcome in patients with stable angina pectoris.nnnMETHODSnWe randomly assigned 3825 patients with treated stable symptomatic coronary disease to double-blind addition of nifedipine GITS (gastrointestinal therapeutic system) 60 mg once daily and 3840 to placebo. The primary endpoint was the combination of death, acute myocardial infarction, refractory angina, new overt heart failure, debilitating stroke, and peripheral revascularisation. Mean follow-up was 4.9 years (SD 1.1). Analysis was by intention to treat.nnnFINDINGSn310 patients allocated nifedipine died (1.64 per 100 patient-years) compared with 291 people allocated placebo (1.53 per 100 patient-years; hazard ratio 1.07 [95% CI 0.91-1.25], p=0.41). Primary endpoint rates were 4.60 per 100 patient-years for nifedipine and 4.75 per 100 patient-years for placebo (0.97 [0.88-1.07], p=0.54). With nifedipine, rate of death and any cardiovascular event or procedure was 9.32 per 100 patient-years versus 10.50 per 100 patient-years for placebo (0.89 [0.83-0.95], p=0.0012). The difference was mainly attributable to a reduction in the need for coronary angiography and interventions in patients assigned nifedipine, despite an increase in peripheral revascularisation. Nifedipine had no effect on the rate of myocardial infarction.nnnINTERPRETATIONnAddition of nifedipine GITS to conventional treatment of angina pectoris has no effect on major cardiovascular event-free survival. Nifedipine GITS is safe and reduces the need for coronary angiography and interventions.

Cigarette Smoking Potentiates Endothelial Dysfunction of Forearm Resistance Vessels in Patients With Hypercholesterolemia Role of Oxidized LDL

BACKGROUNDnRisk factors for atherosclerosis such as hypercholesterolemia and hypertension are associated with endothelial dysfunction of conduit and resistance vessels; however, the interaction of these risk factors and underlying mechanisms affecting endothelial function remain to be determined. The present study investigated the role of long-term smoking and hypercholesterolemia and their impact on endothelial function of peripheral resistance vessels in relation to plasma levels of autoantibodies against oxidized LDL, which has been implicated in the development of endothelial dysfunction and atherosclerosis.nnnMETHODS AND RESULTSnThe vascular responses to the endothelium-dependent agent acetylcholine (7.5, 15, 30, and 60 micrograms/min) and the endothelium-independent agent sodium nitroprusside (1,3, and 10 micrograms/min) were studied in normal control subjects (n = 10), patients with hypercholesterolemia (n = 15), long-term smokers (n = 15), and hypercholesterolemic patients who smoked (n = 15). Drugs were infused into the brachial artery, and forearm blood flow (FBF) was measured by venous occlusion plethysmography. The FBF responses to acetylcholine were significantly blunted in all three patient groups compared with normal control subjects (P < .05). The acetylcholine-induced increase in FBF was significantly attenuated in patients with hypercholesterolemia who smoked compared with hypercholesterolemic nonsmokers and normocholesterolemic smokers (P < .05 for both). The response to sodium nitroprusside was not statistically different in all four groups. Plasma levels of autoantibody titer against oxidized LDL were inversely related to acetylcholine-induced changes in FBF (r = -.53, P < .002) and were substantially increased in the group with both risk factors.nnnCONCLUSIONSnThese results demonstrate that cigarette smoking and hypercholesterolemia synergistically impair endothelial function and that their combined presence is associated with increased plasma levels of autoantibodies against oxidized LDL. These observations raise the possibility that long-term smoking potentiates endothelial dysfunction in hypercholesterolemic patients by enhancing the oxidation of LDL.

Prognostic significance of right ventricular afterload stress detected by echocardiography in patients with clinically suspected pulmonary embolism.

OBJECTIVE: To investigate the prognostic value of echocardiographic findings in patients who present with symptoms suggestive of acute pulmonary embolism. DESIGN: 317 patients with clinically suspected pulmonary embolism were prospectively evaluated by echocardiography for the presence of right ventricular afterload stress and right heart or pulmonary artery thrombi. Objective confirmation of pulmonary embolism by lung scan or pulmonary angiography was obtained in 164 (52%). The presence of deep venous thrombosis was established in 90 of 158 patients (57%) who underwent phlebographic or Doppler sonographic studies. RESULTS: Right ventricular afterload stress was diagnosed in 87 patients (27%). Objective confirmation of pulmonary embolism and diagnosis of deep venous thrombosis was more common in patients with right ventricular afterload stress than in those without (83% v 40% and 46% v 22%, respectively; P < 0.001). This was also true for the detection of thrombi in the right heart and major pulmonary arteries (12 patients v 1 patient; P < 0.001) as well as for the in-hospital mortality from venous thromboembolism (13% v 0.9%; P < 0.001). One year mortality from pulmonary embolism was 13% in patients with right ventricular afterload stress at presentation compared with 1.3% in those without (P < 0.001). CONCLUSIONS: The presence of right ventricular afterload stress detected by echocardiography is a major determinant of short term prognosis in patients with clinically suspected acute pulmonary embolism.

Contrasting peripheral short-term and long-term effects of converting enzyme inhibition in patients with congestive heart failure. A double-blind, placebo-controlled trial.

To discover the underlying mechanisms involved in the beneficial long-term effects of angiotensin converting enzyme (ACE) inhibitors, we investigated the systemic and peripheral effects of short- and long-term ACE inhibition in patients with chronic heart failure. After assessing the short-term effects and dose titration with cilazapril, a new long-acting ACE inhibitor, 21 patients were randomized to receive either placebo or the ACE inhibitor. Seventeen patients completed the 3-month treatment. Central hemodynamic output, femoral blood flow (measured by thermodilution), oxygen saturation, and lactate and norepinephrine levels were determined simultaneously in the femoral vein and radial artery during treatment and after a 3-month rest and during symptom-limited bicycle exercise. Short-term ACE inhibition improved rest and exercise hemodynamic output, but it did not alter peak femoral blood flow, calculated leg oxygen consumption, or systemic oxygen uptake during exercise, despite significant reduction in femoral norepinephrine extraction and arterial angiotensin levels during exercise. In contrast, long-term ACE inhibition further improved exercise cardiac output and increased leg blood flow (from 2.3 to 2.9 l/min, p less than 0.05), leg oxygen consumption (from 277 to 403 ml/min, p less than 0.05), and systemic oxygen uptake (from 1,133 to 1,453 ml/min, p less than 0.05), whereas these variables remained unchanged with placebo treatment (p less than 0.02 between groups). Moreover, a moderate but significant increase in femoral oxygen extraction occurred after long-term therapy (ACE inhibitor: from 76% to 83%, p less than 0.05; placebo: from 75% to 74%, NS; p less than 0.01 between groups). We conclude that long-term ACE inhibition is clinically beneficial in that it improves blood flow to skeletal muscle during exercise over time. The long-term effects of ACE inhibition are, in part, probably related to peripheral (vascular) mechanisms, for example, by reversing the inability of peripheral vessels to dilate and by improving oxygen utilization.

Distinguishing between acute and subacute massive pulmonary embolism by conventional and Doppler echocardiography.

OBJECTIVE--To determine the ability of conventional and Doppler echocardiography to distinguish between minor, acute massive, and subacute massive pulmonary embolism in patients with confirmed pulmonary embolism. DESIGN--Prospective study of a consecutive series of 47 patients with confirmed pulmonary embolism. SETTING--Department of internal medicine, university clinic. PATIENTS--11 patients (23%) had minor, 23 patients (49%) had acute massive, and 13 patients (28%) had subacute massive pulmonary embolism. RESULTS--Dilatation of the right ventricular cavity (33 (92%)) and asynergy of the right ventricular free wall (29 (81%)) were seen only in patients with acute and subacute massive pulmonary embolism (n = 36). 23 (64%) with pulmonary hypertension had tricuspid regurgitation. The velocity of the tricuspid regurgitant jet correlated with the pulmonary arterial pressure (r = 0.88, SEE = 11.6 mm Hg) and was significantly lower in patients with acute massive pulmonary embolism (3.0 (0.4) m/s, n = 12) than in patients with subacute massive pulmonary embolism (4.2 (0.6) m/s; n = 11) (p < 0.001). The use of predefined indices (right ventricular free wall thickness > 5 mm; tricuspid regurgitant jet velocity > 3.7 m/s; and the occurrence of both a dilated right ventricular cavity with normal interventricular septal motion, or an inspiratory collapse of the inferior vena cava, or both) correctly identified 11 of 13 patients (85%) with subacute massive pulmonary embolism. CONCLUSION--Conventional and Doppler echocardiography were successful in evaluating the haemodynamic consequences of pulmonary embolism.

Comparison of alteplase versus heparin for resolution of major pulmonary embolism

Complete resolution of major pulmonary embolism (PE) treated with heparin alone can often take > 3 weeks. Thrombolytic agents effectively resolve pulmonary artery thrombi within a few hours. However, the effect of the 2 types of treatment on recovery of right ventricular function has not yet been followed for periods of > 24 hours. We prospectively examined 40 consecutive patients with documented major PE (symptoms being present for < or = 8 weeks). After diagnosis, 27 patients (68%) were treated with alteplase plus heparin and 13 (32%) with heparin alone. There was no significant difference between the 2 groups with regard to baseline parameters. At 12 hours, systolic pulmonary artery pressure decreased from 56 +/- 20 to 37 +/- 21 mm Hg in the alteplase group, and from 50 +/- 11 to 46 +/- 12 mm Hg in the heparin group (significantly more; p = 0.016). On echocardiographic follow-up, a decrease in end-diastolic dimensions of the right ventricle and an increase in left ventricular dimensions was significantly more pronounced in the alteplase group (p <0.001 and p = 0.05, respectively). The incidence of right ventricular dilation and paradoxical septal wall motion decreased significantly only in the thrombolyis group. However, at 1-week follow-up, no difference was seen between the 2 groups regarding the overall change in right or left ventricular dimensions or the final values of other echocardiographic parameters. Thus, echocardiography is particularly useful for hemodynamic follow-up of major PE. Thrombolysis may rapidly reduce pulmonary artery pressure, but resolution of right ventricular pressure overload also occurs within 1 week in patients treated with heparin alone.

Haemodynamic effects of intracoronary pyruvate in patients with congestive heart failure: an open study.

BACKGROUNDnPyruvate, as an intermediate in the Krebs cycle, is an important source of energy for myocardium and improves contractility of normal, hypoxic, and postischaemic animal myocardium. We investigated the effect of intracoronary pyruvate in patients with congestive heart failure.nnnMETHODSnHaemodynamic measurements were done in eight patients with dilated cardiomyopathy after two 15 min infusions of pyruvate into the left main coronary artery and after saline washout of pyruvate.nnnFINDINGSnThere were no significant differences between the two pyruvate concentrations. Application of pyruvate resulted in a 23% increase in cardiac index (p<0.05), a 38% increase in stroke-volume index (p<0.05), and a 36% decrease in pulmonary capillary wedge pressure (p<0.05). Heart rate decreased significantly by 11%. Mean aortic pressure and systemic vascular resistance did not change. Most of the effects of pyruvate were reversed 15 min after the infusion stopped.nnnINTERPRETATIONnPyruvate has the profile of a favourable inotropic substance. Other modes of administration need to be studied.