Pathophysiology of cardiorenal syndrome in decompensated heart failure: role of lung-right heart-kidney interaction.

Cardiorenal syndrome (CRS) is defined as an interaction of cardiac disease with renal dysfunction that leads to diuretic resistance and renal function worsening, mainly with heart failure (HF) exacerbation. Hemodynamic variables linking heart and kidney are renal blood flow (cardiac output) and perfusion pressure, i.e., the aortic - renal venous pressure gradient. CRS has traditionally been interpreted as related to defective renal perfusion and arterial underfilling and, more recently, to elevation in central venous pressure transmitted back to renal veins. Our suggestion is that in a setting where aortic pressure is generally low, due to heart dysfunction and to vasodrepressive therapy, the elevated central venous pressure (CVP) contributes to lower the renal perfusion pressure below the threshold of kidney autoregulation (≤80mm Hg) and causes renal perfusion to become directly pressure dependent. This condition is associated with high neurohumoral activation and preglomerular vasoconstriction that may preserve pressure, but may decrease filtration fraction and glomerular filtration rate and enhance proximal tubular sodium absorption. Thus, congestion worsens and drives the vicious cycle of further sodium retention and HF exacerbation. Lowering CVP by targeting the lung-right heart interaction that sustains elevated CVP seems to be a more rational approach rather than reducing intravascular volume. This interaction is crucial and consists of a cascade with stepwise development of pulmonary post-capillary hypertension, precapillary arteriolar hypertone, right ventricular overload and enlargement with tricuspid incompetence and interference with left ventricular filling (interdependence). The resultant CVP rise is transmitted to the renal veins, eventually drives CRS and leads to a positive feedback loop evolving towards HF refractoriness.

Tricuspid annular plane systolic excursion and pulmonary arterial systolic pressure relationship in heart failure: an index of right ventricular contractile function and prognosis.

Echo-derived pulmonary arterial systolic pressure (PASP) and right ventricular (RV) tricuspid annular plane systolic excursion (TAPSE; from the end of diastole to end-systole) are of basic relevance in the clinical follow-up of heart failure (HF) patients, carrying two- to threefold increase in cardiac risk when increased and reduced, respectively. We hypothesized that the relationship between TAPSE (longitudinal RV fiber shortening) and PASP (force generated by the RV) provides an index of in vivo RV length-force relationship, with their ratio better disclosing prognosis. Two hundred ninety-three HF patients with reduced (HFrEF, n = 247) or with preserved left ventricular (LV) ejection fraction (HFpEF, n = 46) underwent echo-Doppler studies and N-terminal pro-brain-type natriuretic peptide assessment and were tracked for adverse events. The median follow-up duration was 20.8 mo. TAPSE vs. PASP relationship showed a downward regression line shift in nonsurvivors who were more frequently presenting with higher PASP and lower TAPSE. HFrEF and HFpEF patients exhibited a similar distribution along the regression line. Given the TAPSE, PASP, and TAPSE-to-PASP ratio (TAPSE/PASP) collinearity, separate Cox regression and Kaplan-Meier analyses were performed: one with TAPSE and PASP as individual measures, and the other combining them in ratio form. Hazard ratios for variables retained in the multivariate regression were as follows: TAPSE/PASP

Effects of treatment strategy on endothelial function.

A large body of evidence indicates that endothelial dysfunction is a characteristic of patients with arterial hypertension. As functional abnormalities lead to impaired endothelium-dependent vasodilation, this early step of atherogenesis is potentially reversible. In addition to reducing blood pressure, the major families of anti-hypertensive drugs have a number of pleiotropic effects that could improve endothelial function. In particular, the renin-angiotensin system plays an important role in the pathogenesis of both arterial hypertension and endothelial dysfunction, and so drugs capable of limiting the dangerous effects of this hormonal axis, such as angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers and renin inhibitors, could help prevent/delay/reverse the atherosclerotic process. New third-generation ß-blockers and 5-phosphodiesterase inhibitors may affect endothelial function. Furthermore, the HMGCoA-reductase inhibitors currently used to reduce cholesterol levels have major pleiotropic anti-inflammatory and anti-hypertensive effects. The preservation or recovery of endothelial function in hypertensive patients is crucial to inhibit the development of atherosclerosis and the onset of cardiovascular events. This review focuses on the ancillary effects of hypertensive drugs and HMGCoA-reductase inhibitors that go beyond lowering blood pressure and cholesterol levels.

Endothelial dysfunction and pathophysiological correlates in atrial fibrillation.

Endothelial dysfunction (ED) increases oxidative stress and proinflammatory agents, and impairs nitric oxide (NO)-dependent vasorelaxation. Atrial fibrillation (AF) is a risk factor for ED as documented by (1) impaired acetylcholine-mediated blood flow increase; (2) reduced plasma nitrite/nitrate levels; (3) additive impairment of flow-mediated dilatation by comorbidities causing ED; and (4) efficacy of cardioversion. Several possible mechanisms sustain the AF-ED association: (1) An impaired rheology. Endothelial NO release is tightly regulated by laminar shear stress and AF induces a turbulent flow which may impair arterial vessel distension and responsiveness. Specifically, Ca(2+) elicits NO synthase (eNOS) activation, and shear stress application to endothelial cells increases intracellular Ca(2+) primarily in response to regular pulsatile flow at a rate higher than that observed in the presence of oscillatory pulsatile flow. (2) The atrium activity on arterial vessels. The left atrium produces NO and may serve as an endocrine organ releasing nitroso compounds. A disorganised atrial contraction markedly reduces eNOS expression. (3) AF induces atrial inflammation and elevation of C reactive protein and cytokines, exerting a proinflammatory activity on endothelial cells. (4) Systemic factors such as the renin-angiotensin system (RAS) may be prominent. In fact, RAS and inflammation reciprocally "cross-talk". Angiotensin II increases atrial cell death and RAS contributes to myocardial and vascular oxidative stress in AF. RAS inhibition prevents AF. Important clinical correlates of ED in AF patients are muscle underperfusion, premature lactic acidosis and ergoreflex oversignalling during physical activity. This review focuses on the evidence of an association of AF with ED, the possible underlying mechanisms and the pathophysiological correlates.

Regulation of alveolar gas conductance by NO in man, as based on studies with NO donors and inhibitors of NO production.

AIM: Nitric oxide (NO) is a mediator of the pulmonary vessel tone and permeability. We hypothesized that it may also regulate the alveolar-capillary membrane gas conductance and lung diffusion capacity. METHODS: In 20 healthy subjects (age = 23 +/- 3 years) we measured lung diffusion capacity for carbon monoxide (DLco), its determinants (membrane conductance, D(m), and pulmonary capillary blood volume, V(c)), systolic pulmonary artery pressure (PAPs) and pulmonary vascular resistance (PVR). Measurements were performed before and after administration of N(g)-monomethyl-L-arginine (L-NMMA, 0.5 mg kg(-1) min(-1)), as a NO production inhibitor, and L-arginine (L-Arg, 0.5 mg kg(-1) min(1)) as a NO pathway activator. The effects of L-NMMA were also tested in combination with active L-Arg and inactive stereoisomer D-Arg vehicled by 150 mL of 5%d-glucose solution. For L-Arg and L-NMMA, saline (150 mL) was also tested as a vehicle. RESULTS: L-NMMA reduced D(m) (-41%P < 0.01), DLco (-20%, P < 0.01) and cardiac output (CO), and increased PAPs and PVR. In 10 additional subjects, a dose of L-NMMA of 0.03 mg kg(-1) min(1) infused in the main stem of the pulmonary artery was able to lower D(m) (-32%, P < 0.01) despite no effect on PVR and CO. D(m) depression was significantly greater when L-NMMA was vehicled by saline than by glucose. L-Arg but not D-Arg abolished the effects of L-NMMA. L-Arg alone increased D(m) (+14%, P < 0.01). CONCLUSION: The findings indicate that NO mediates the respiratory effects of L-NMMA and L-Arg, and is involved in the physiology of the alveolar-capillary membrane gas conductance in humans. NO deficiency may cause an excessive endothelial sodium exchange/water conduction and fluid leakage in alveolar interstitial space, lengthening the air-blood path and depressing diffusion capacity.

The clinical importance of cardiopulmonary exercise testing and aerobic training in patients with heart failure: [review] / A importância clínica de testes de exercícios cardiopulmonares e treinamento aeróbico em pacientes com insuficiência cardíaca: [revisão]

INTRODUCTION: The appropriate physiological response to an acute bout of progressive aerobic exercise requires proper functioning of the pulmonary, cardiovascular and skeletal muscle systems. Unfortunately, these systems are all negatively impacted in patients with heart failure (HF), resulting in significantly diminished aerobic capacity compared with apparently healthy individuals. Cardiopulmonary exercise testing (CPX) is a noninvasive assessment technique that provides valuable insight into the health and functioning of the physiological systems that dictate an individual's aerobic capacity. The values of several key variables obtained from CPX, such as peak oxygen consumption and ventilatory efficiency, are often found to be abnormal in patients with HF. In addition to the ability of CPX variables to acutely reflect varying degrees of pathophysiology, they also possess strong prognostic significance, further bolstering their clinical value. Once thought to be contraindicated in patients with HF, participation in a chronic aerobic exercise program is now an accepted lifestyle intervention. Following several weeks/months of aerobic exercise training, an abundance of evidence now demonstrates an improvement in several pathophysiological phenomena contributing to the abnormalities frequently observed during CPX in the HF population. These exercise-induced adaptations to physiological function result in a significant improvement in aerobic capacity and quality of life. CONCLUSIONS: Furthermore, there is initial evidence to suggest that aerobic exercise training improves morbidity and mortality in patients with HF. This paper provides a review of the literature highlighting the clinical significance of aerobic exercise testing and training in this unique cardiac population.

INTRODUÇÃO: A resposta fisiológica aguda ao exercício aeróbio progressivo demanda funcionamento adequado dos sistemas pulmonares, cardiovasculares e músculo-esquelético. Infelizmente, todos estes sistemas estão negativamente afetados em pacientes com insuficiência cardíaca (IC), resultando numa redução significativa da capacidade aeróbia comparada com indivíduos aparentemente saudáveis. O teste de exercício cardiopulmonar (TCP) representa uma técnica não-invasiva de avaliação que fornece compreensão valiosa sobre a saúde e funcionamento dos sistemas fisiológicos que ditam a capacidade aeróbia de um indivíduo. Os valores de várias variáveis-chave obtidas através do TCP, como consumo pico de oxigênio e eficiência ventilatória são encontrados frequentemente como anormais em pacientes com IC. Além da capacidade das variáveis do TCP refletir de maneira aguda os graus variáveis da fisiopatologia, também possuem forte significância prognóstica, aumentando ainda mais o seu valor clínico. A participação num programa de exercícios aeróbios crônicos, anteriormente era contra-indicada em pacientes com IC. Agora é uma intervenção aceitável de estilo de vida. Após um período de treinamento com exercícios aeróbios, durante várias semanas/meses, tem sido evidenciada uma melhora em vários fenômenos fisiopatológicos que contribuem às anormalidades constatadas frequentemente durante TCP na população com IC. CONCLUSÕES: As adaptações fisiológicas induzidas por exercícios aeróbios resultam em uma melhora significativa de capacidade aeróbia e de qualidade de vida. Além disso, há evidências sugerindo que treinamento com exercícios aeróbios melhora a morbidade e a mortalidade em pacientes com IC. Este artigo fornece uma revisão da literatura que destaca a significância clínica dos testes de exercícios aeróbios e treinamento nesta população cardíaca única.

Impaired brachial artery endothelial flow-mediated dilation and orthostatic stress in hemodialysis patients.

PURPOSE: Chronic kidney disease (CKD) is associated with an impaired endothelial function, which may contribute to cardiovascular events. Whether impairment in endothelial function is involved in the circulatory response to orthostatic stress is unknown. We assessed endothelial function via brachial artery flow-mediated dilation (BAFMD), an index of endothelial-dependent vasodilation. METHODS: We measured changes in brachial artery diameter (BAD) and blood flow by Doppler ultrasound in 35 CKD patients on hemodialysis, 37 young healthy controls (HC) and 50 non-uremic matched controls (MC), in the supine position and after 60 degrees head-up tilting (HUT). RESULTS: In the supine position, endothelial flow-mediated BAD was significantly increased in HC (p<0.001) and MC (p<0.01) while no significant changes were detected in CKD. Mean percent blood flow changes were HC+323.5%, MC+195.1% and CKD+158.8% (HC vs. CKD p<0.001; HC vs. MC p<0.001; MC vs. CKD p=0.04). Similarly, during HUT mean BAD and blood flow increases were significantly impaired in CKD patients. CONCLUSION: In CKD patients, an impaired response in the physiologic vascular reactivity, suggesting endothelial dysfunction, was found in the supine position and after orthostasis by BAFMD. Our results are in favor of a possible adjunctive role of uremia in the abnormal brachial artery response.

Endothelium-mediated modulation of ergoreflex and improvement in exercise ventilation by acute sildenafil in heart failure patients.

Reflex neural oversignaling sensitive to muscle by-products (ergoreflex) causes exercise hyperventilation in heart failure (HF). We probed whether an improved endothelial function with sildenafil intake may prevent this effect. In 16 chronic heart failure patients and 16 normal subjects, before and after sildenafil intake (50 mg) or placebo, we measured ergoreflex, flow-mediated brachial artery dilation (FMD, an index of endothelial function), and, during maximal exercise, the slope of ventilation to carbon dioxide production (VE/VCO2, an index of ventilatory efficiency), the ratio of changes in O2 uptake (VO2) versus work rate (WR) (deltaVO2/deltaWR, an index of aerobic efficiency). After sildenafil intake, patients, unlike controls, showed a significant decrease in ergoreflex and VE/VCO2 slope and an increase in FMD and deltaVO2/deltaWR. Ergoreflex changes with sildenafil intake correlated with those in FMD and VE/VCO2. Phosphodiesterase-5 inhibition, by improving endothelial activity and muscle perfusion, modulates signaling and improves ventilatory and aerobic efficiencies, potentially indicating a novel pathway in the HF therapeutic management.

Atorvastatin therapy improves exercise oxygen uptake kinetics in post-myocardial infarction patients.

BACKGROUND: Statins represent a modern mainstay of the drug treatment of coronary artery disease and acute coronary syndromes. Reduced aerobic work performance and slowed VO(2) kinetics are established features of the clinical picture of post-myocardial infarction (MI) patients. We tested the hypothesis that statin therapy improves VO(2) exercise performance in normocholesterolaemic post-MI patients. MATERIALS AND METHODS: According to a double-blinded, randomized, crossover and placebo-controlled study design, in 18 patients with uncomplicated recent (3 days) MI we investigated the effects of atorvastatin (20 mg day(-1)) on gas exchange kinetics by calculating VO(2) effective time constant (tau) during a 50-watt constant workload exercise, brachial artery flow-mediated dilatation (FMD) as an index of endothelial function, left ventricular function (echocardiography) and C-reactive protein (CRP, as an index of inflammation). Atorvastatin or placebo was given for 3 months each. RESULTS: Atorvastatin therapy significantly improved exercise VO(2) tau and FMD, and reduced CRP levels. We did not observe changes in cardiac contractile function and relaxation properties during all study periods in either group. CONCLUSIONS: In post-MI patients exercise performance is a potential additional target of benefits related to statin therapy. Endothelial function improvement is very likely implicated in this newly described therapeutic property.

Sildenafil reduces L-NAME-induced severe hypertension and worsening of myocardial ischaemia-reperfusion damage in the rat.

BACKGROUND AND PURPOSE: Phosphodiesterase-5 inhibitors are beneficial in pulmonary hypertension and congestive heart failure, the two conditions associated with coronary heart disease and ischaemia. We investigated whether sildenafil counteracts the cardiovascular alterations induced by N -nitro-L-arginine methyl ester (L-NAME) in the rat. EXPERIMENTAL APPROACH: Sildenafil was given orally to rats at doses of 0.37, 0.75 or 1.5 mg kg-1day-1 for four weeks, either alone or with L-NAME (35-40 mg kg-1 day-1 in the drinking water). Systolic blood pressure and urinary parameters (6-keto-prostaglandin F1alpha, thromboxane B2, 8-isoprostane-prostaglandin F2 and nitrite/nitrate) were measured in conscious rats. Isolated hearts were subjected to low flow ischaemia-reperfusion, and myocardial levels of guanosine 3', 5'cyclic monophosphate (cGMP) were determined. Endothelial vascular dysfunction was examined in aortic rings. KEY RESULTS: Sildenafil dose-dependently prevented the rise in systolic blood pressure in L-NAME-treated rats. This activity was associated with a normalization of urinary 8-isoprostane-prostaglandin F2alpha and other biochemical parameters. In perfused hearts, the post-ischaemic ventricular dysfunction was worse in preparations from L-NAME-treated rats than in controls. Sildenafil dose-dependently reduced this effect, and creatine kinase and lactate dehydrogenase release were lower too. cGMP levels, which were low in myocardial tissue from L-NAME-treated rats, were restored by sildenafil. In noradrenaline-precontracted aortic rings from L-NAME-treated rats acetylcholine lost its vasorelaxant effect, and sildenafil restored it. CONCLUSION AND IMPLICATIONS: In a rat model of chronic nitric oxide deprivation, where hypertension and aggravation of post-ischaemic ventricular dysfunction are associated with loss of vascular endothelium-relaxant function, sildenafil provided significant cardiovascular protection, primarily by maintaining tissue cGMP levels.

Effects of cardioversion of atrial fibrillation on endothelial function in hypertension or diabetes.

BACKGROUND: Cardioversion (CV) to sinus rhythm corrects endothelial dysfunction secondary to atrial fibrillation (AF). As AF often complicates hypertension and diabetes (disorders associated with impaired endothelial function) the study probed whether these comorbidities to AF produced an additive effect and to what extent CV might be advantageous. MATERIALS AND METHODS: Brachial artery flow-mediated dilatation (FMD) was evaluated before and after CV in 17 lone AF patients (group 1), 16 patients with AF + hypertension (group 2) and 17 patients with AF + diabetes type II (group 3), while in supine and head-up tilting (HUT) positions, as this is when endothelial vasodilation is emphasized as a counterbalance to neurogenic vasoconstriction. RESULTS: After 2 weeks, CV in group 1 increased (P < 0.01) supine FMD (from 7.22-->9.50%) and restored its HUT potentiation (from 9.31-->17.22%). In group 2, FMD also improved significantly with CV (supine from 4.92-->7.11% and HUT from 5.29-->11.83%; P < 0.01). In group 3, CV did not promote significant FMD changes (supine from 5.12-->4.92% and HUT from 4.98-->4.73%). After 3 months, FMD improvement persisted in groups 1 and 2 with enduring sinus rhythm, but not in those with AF relapse. In group 3, FMD remained unchanged regardless of cardiac rhythm. CONCLUSIONS: Cardioversion persistently increases supine shear stress endothelial responsiveness and restores the orthostatic modulation in AF alone or in association with hypertension, but not with diabetes. Differences in background endothelial impairment may explain the presence (hypertension) or the absence (diabetes) of an additive AF effect in comorbidities, as well as CV results.

The behaviour of the flow-mediated brachial artery vasodilatation during orthostatic stress in normal man.

AIMS: Flow-mediated brachial artery vasodilatation is an index of endothelial function. Published literature describes only supine data and no study has been performed during vertical displacement. This subject deserves investigation for two main reasons: humans spend the larger part of their life in the upright position; this position has significant effects on neural vascular regulation. METHODS: In 21 healthy men (25 +/- 2 years) the flow-dependent brachial artery vasodilating response to distal circulatory arrest was assessed by Doppler ultrasound imaging, while supine and during 20 degrees and 60 degrees head-up tilting (HUT). In 11 of these subjects the vasodilating response to nitroglycerine was also explored. RESULTS: Absolute and percentage increments in brachial calibre during hyperaemia after deflation of the occluding cuff became increasingly greater at 20 degrees (+0.44 mm) and 60 degrees (+0.92 mm) HUT (P < 0.01), compared with the horizontal position (+0.27 mm), and the arterial dilatation for an increase in flow (0.98 +/- 0.08 and 1.68 +/- 0.06 mm mL(-1) min(-1) x 1000, respectively) was larger (P < 0.01) than occurred while supine (0.41 +/- 0.05 mm mL(-1) min(-1) x 1000). Nitroglycerine-mediated vasodilatation at 60 degrees HUT was similar to that in the supine position. CONCLUSION: The orthostatic stimulus is associated with an increase of the flow-mediated brachial artery vasodilatation, which is proportional to the degree of displacement. The mechanism of this effect does not consist of changes in nitric oxide sensitivity.

Does lung diffusion impairment affect exercise capacity in patients with heart failure?

OBJECTIVE: To determine whether there is a relation between impairment of lung diffusion and reduced exercise capacity in chronic heart failure. DESIGN: 40 patients with heart failure in stable clinical condition and 40 controls participated in the study. All subjects underwent standard pulmonary function tests plus measurements of resting lung diffusion (carbon monoxide transfer, TLCO), pulmonary capillary volume (VC), and membrane resistance (DM), and maximal cardiopulmonary exercise testing. In 20 patients and controls, the following investigations were also done: (1) resting and constant work rate TLCO; (2) maximal cardiopulmonary exercise testing with inspiratory O2 fractions of 0.21 and 0.16; and (3) rest and peak exercise blood gases. The other subjects underwent TLCO, DM, and VC measurements during constant work rate exercise. RESULTS: In normoxia, exercise induced reductions of haemoglobin O2 saturation never occurred. With hypoxia, peak exercise uptake (peak O2) decreased from (mean (SD)) 1285 (395) to 1081 (396) ml/min (p < 0.01) in patients, and from 1861 (563) to 1771 (457) ml/min (p < 0.05) in controls. Resting TLCO correlated with peak O2 in heart failure (normoxia < hypoxia). In heart failure patients and normal subjects, TLCO and peak O2 correlated with O2 arterial content at rest and during peak exercise in both normoxia and hypoxia. TLCO, VC, and DM increased during exercise. The increase in TLCO was greater in patients who had a smaller reduction of exercise capacity with hypoxia. Alveolar-arterial O2 gradient at peak correlated with exercise capacity in heart failure during normoxia and, to a greater extent, during hypoxia. CONCLUSIONS: Lung diffusion impairment is related to exercise capacity in heart failure.

Alveolar--capillary membrane gas conductance: a novel prognostic indicator in chronic heart failure.

AIMS: Lung dysfunction occurring in chronic heart failure worsens clinical status and exercise performance. The prognostic value of airway and alveolar function measurements in chronic heart failure has not been explored. We aimed to evaluate the prognostic value of lung function tests in a population of patients with stable chronic heart failure. METHODS AND RESULTS: One hundred and six stable chronic heart failure patients (whose left ventricular ejection fraction averaged 33 +/- 1%) underwent echocardiography, metabolic stress testing, assessment of pulmonary function at rest (by spirometry), of alveolar diffusing capacity (DLco) (with carbon monoxide technique) and of its membrane (DM) and capillary blood volume (Vc) components. Prognostic relevance of pulmonary variables was assessed by the Kaplan-Meier approach with log-rank testing and by Cox regression analysis. Cut-off values of lung parameters were based on the 33rd and 66th centiles. Seventeen patients died for cardiac reasons. Non-survivors compared to survivors showed lower forced expiratory volume in 1 s (2 X 1 +/- 0 X 1 vs 2 X 4 +/- 0 X 1 l; P<0 X 01), forced vital capacity (2 X 6 +/- 0 X 1 vs 2 X 9 +/- 0 X 1 l; P<0 X 01), maximal voluntary ventilation (80 X 7 +/- 2 X 5 vs 95 X 4 +/- 2 X 7 l; P<0 X 01), DLco (16 X 5 +/- 1 X 1 vs 19 X 3 +/- 0 X 6 ml . min(-1) . mmHg(-1); P<0 X 01) and DM (25 X 1 +/- 1 X 8 vs 31 X 9 +/- 1 X 5 ml . min(-1) . mmHg(-1); P<0 X 01). They also exhibited a smaller peak VO2 (14 X 6 +/- 0 X 7 vs 15 X 9 +/- 0 X 6 ml . min(-1) . kg(-1); P<0 X 05) and a steeper VE/VCO2 slope (45 X 0 +/- 1 X 7 vs 41 X 9 +/- 1 X 5; P<0 X 01). Multivariate analysis revealed that DM was the only independent predictor of cardiac death. Cases at high risk for adverse outcome were identified by a DM<24 X 7 ml . min(-1) . mmHg(-1). Patients receiving ACE-inhibitors presented with a higher DM (32 X 1 +/- 1 X 7 vs 27 X 9 +/- 1 X 7 ml . min(-1) . mmHg(-1), P<0 X 05) as well as a better Cox estimated survival rate. CONCLUSIONS: Impaired DM is a powerful independent predictor of worse prognosis in stable chronic heart failure and may be considered an additional index of disease severity, as well as a specific therapeutic target.

Comparison of enoxaparin and unfractionated heparin on thrombin generation in acute coronary syndromes without ST-segment elevation.

Recent clinical trials have demonstrated a better ability of low-molecular-weight heparin, compared to unfractionated heparin, in reducing ischemic cardiac events in patients with acute coronary syndromes without ST-segment elevation. No data are available concerning the in-vivo comparison of enoxaparin and unfractionated heparin on thrombin generation in patients with unstable angina or non-Q-wave myocardial infarction. We measured the plasma levels of prothrombin fragment 1+2 (a marker of prothrombin activation) and thrombin/antithrombin complex (a marker of thrombin generation) in 45 patients with non ST-elevation acute coronary syndromes who were randomized to receive enoxaparin, 3000 IU anti-Xa as an i. v. bolus, followed by 70 IU anti-Xa/Kg every 8 h for 3 days (23 pts. Group 1) or a bolus of 100 IU/kg of unfractionated heparin followed by infusion for 3 days titrated to maintain the aPTT between 70 and 90 s (22 pts, Group 2). Plasma levels of prothrombin fragment 1+2 reduced significantly at 3rd h of treatment in both groups (-42% in Group 1 and -45% in Group 2), reached the lowest plasma concentration at the 24th h and exhibited a slight increase at the 72nd h; no differences were observed between the two groups at any time points. Plasma thrombin/antithrombin complex levels had a similar behaviour: reduced markedly in both groups at the 3rd h (-52% in Group 1 and -46% in Group 2), remained lower during the first two days and slightly rose at 72nd h. No differences between the two groups in plasma levels of this marker were apparent during drug infusion. In Group 1 the aPTT did not show significant changes: in Group 2 the mean value of aPTT doubled the basal value at any time point of determination. Both enoxaparin and unfractionated heparin produced a marked and similar reduction of thrombin generation. Other unknown mechanisms might explain the different clinical effects of the two heparins.