Pharmacokinetic and pharmacodynamic variability of fluindione in octogenarians.

In the PREPA observational study, we investigated the factors influencing pharmacokinetic and pharmacodynamic variability in the responses to fluindione, an oral anticoagulant drug, in a general population of octogenarian inpatients.Measurements of fluindione concentrations and international normalized ratio (INR ) were obtained for 131 inpatients in whom fluindione treatment was initiated. Treatment was adjusted according to routine clinical practice. The data were analyzed using nonlinear mixed-effects modeling, and the parameters were estimated using MONOLI X 3.2. The pharmacokinetics (PK) of fluindione was monocompartmental, whereas the evolution of INR was modeled in accordance with a turnover model (inhibition of vitamin K recycling). Interindividual variability (II V) was very large. Clearance decreased with age and with prior administration of cordarone. Patients who had undergone surgery before the study had lower IC50 values, leading to an increased sensitivity to fluindione. Pharmacokinetic exposure is substantially increased in elderly patients, warranting a lower dose of fluindione.

[Hormonal theory of heart failure with altered systolic function]. / Théorie hormonale de l'insuffisance cardiaque à fonction systolique altérée.

Heart failure (HF) is a major cause of morbidity and mortality in the developed countries. Hospital discharges and deaths from HF are regularly increasing. Therapies initially aimed at reversing hemodynamic abnormalities in HF, increasing cardiac output, decreasing intracardiac pressures, and blocking vasoconstriction. However, none of these therapies improved survival and some actually increased mortality. Now therapies for HF related to left ventricular systolic dysfunction have focused on counteracting compensatory neurohormonal activation. Several neurohormonal activations are present in HF supporting hemodynamics, but they appear to be deleterious in the long term on the myocardium, increasing progression of the HF and mortality. Blocking the renin-angiotensin-aldosterone system and the sympathetic system are now the mainstay of medical therapy in HF related to systolic dysfunction as they decrease mortality, hospitalisation rate and improve quality of life. Hence, the approach to patient with chronic heart failure should differ from that of patient with acute heart failure.

[Patients with the highest cardiovascular risk are the least compliant with their antihypertensive therapy (DESIR study)]. / Les hypertendus les plus à risque sont les moins observants (étude DESIR).

AIM OF THE STUDY: To identify the sociodemographic and clinical profile of hypertensive patients who are not compliant with their antihypertensive treatment. METHODS: each cardiologist described his or her next 4 hypertensive patients from a clinical standpoint and gave them a self-administered compliance questionnaire developed by the French Committee to Fight Hypertension, which they returned directly to the analysis center using a postage-paid reply envelope. RESULTS: 1965 patients 63.9 +/- 12.1 years old, 55.3% of whom were male, were included in the study. According to the specific questionnaire, compliance is definitely satisfactory in 35.9% of patients, is probably satisfactory in 28.3%, is probably poor in 19.4% and is definitely poor in 16.4%. Poor compliance is more frequent among men (38.1 vs. 33.4%; p < 0.05), overweight or obese patients (35.8 and 43.0% vs. 30.0%; p < 0.001), diabetics (46.7 vs. 32.3%; p < 0.0001), dyslipidemic patients (39.3 vs. 31.8%; p < 0.001), smokers (50.2 vs. 33.8%; p < 0.0001), those whose father died of cardiovascular causes before 55 years of age (51.6 vs. 34.1%; p < 0.0001) or those with a previous history of CV events (40.6 vs. 32.8%; p < 0.001). The rate of poor compliance increases with the number of risk factors: 27.3% with no risk factor other than high BP, 32.2% with one, 37.2 with 2 and 51.5% with 3 or more (p < 0.0001). Multifactorial analyses confirm the independent effect of obesity, diabetes, smoking, and father's CV death before age 55 on patient compliance. CONCLUSION: patients with the highest CV risk are those who are the least compliant with their antihypertensive treatment. These results raise the question of the appropriateness of the prevention information given to the most at-risk patients.

["Diastolic" heart failure and pulsed pressure]. / Insuffisance cardiaque "diastolique" et pression pulsée.

Cardiac failure is the leading cause of hospital admission after 65 years of age. Several studies have confirmed the frequency of cardiac failure with normal systolic function ("diastolic" cardiac failure) in the elderly (nearly half the cases). The cause is commonly isolated systolic hypertension. The pulsed pressure depends on ventricular ejection, arterial rigidity and the precocity of reflected pulse waves. In the elderly, the pulse pressure is a powerful predictive factor for mortality and adverse cardiovascular events (acute coronary syndromes, cardiac failure and cerebrovascular accidents). Patients with isolated systolic hypertension or an increased pulsed pressure usually have left ventricular hypertrophy or concentric remodelling, abnormal relaxation, alteration of hypertrophied myocytes with increased myocardial oxygen consumption and subendocardial ischaemia, especially when the coronary reserve is reduced. The decrease of the diastolic blood pressure reduces the presence of coronary perfusion. Moreover, an increase in the pulsed pressure predisposes to coronary atherosclerosis. These patients are very symptomatic on exercise because they do not have a reserve of preload and easily develop acute pulmonary oedema after a volume overload (increased salt intake, postoperative rehydratation). A recent study showed that the left ventricular ejection fraction was preserved during acute pulmonary oedema of hypertensive patients. The diagnosis of "diastolic" cardiac failure is often suspected by elimination (clinical signs of cardiac failure with a normal left ventricular ejection fraction), and echographers have proposed many criteria to detect abnormal relaxation, filling or distensibility of the left ventricle. Mortality would seem to be half that of systolic cardiac failure. Treatment should normalise the hypertension, ischaemia, tachycardia, and maintain or reestablish sinus rhythm, but it remains empirical.

[Resistance to ACE inhibitors. Myth or reality?]. / Echappement aux inhibiteurs de l'enzyme de conversion. Mythe ou réalité?

Angiotensin Converting Enzyme (ACE) inhibitors represent a major advance in the treatment of: hypertension, and generally speaking, in cardiovascular prevention; myocardial infarction; cardiac failure. They have a cardio and vascular protective action by tending to correct hypertension, left ventricular hypertrophy and remodelling, endothelial dysfunction, arterial smooth muscle proliferation and thrombotic phenomena. However, besides the cough that this therapeutic class engenders, a major question remains unanswered: is there resistance to this family of drugs? In other words, does left ventricular remodelling and arterial smooth muscle proliferation continue with regular treatment at the prescribed dosages? The synthesis of angiotensin II does not only depend on the angiotensin converting enzyme but also on the quality of angiotensin I and the presence of other enzymes such as chymase. A secondary increase of angiotensin II with ACE inhibitor therapy may reflect insufficient blockade of the renin-angiotensin system or a synthesis of angiotensin II by an alternative pathway to the converting enzyme. In vivo measurement of ACE inhibition shows that blockade of the renin-angiotensin system is automatically limited due to the very accurate regulation of angiotensin II concentrations.

Polymorphism in the fractalkine receptor CX3CR1 as a genetic risk factor for coronary artery disease.

Coronary atherosclerosis is a major cause of death in industrialized countries. Monocytes, which play a key role in atherosclerosis, migrate into the vessel wall, presumably guided by specific chemoattractant and adhesion molecules. A compelling candidate for this role is the chemokine receptor CX3CR1, which is expressed on monocytes and acts as either a chemotactic receptor or an adhesion molecule, depending on whether its ligand, fractalkine, is presented free or membrane bound. A common variant of CX3CR1 was recently identified, encoded by the alleles I249 and M280, which form a common I(249)M(280) haplotype. When CX3CR1 genotypes were analyzed in 151 patients with acute coronary syndromes and in 249 healthy controls, CX3CR1 I249 heterozygosity was associated with a markedly reduced risk of acute coronary events, independent of established acquired coronary risk factors (eg, smoking, diabetes). The adjusted odds ratio for this allele was 0.43 (95% confidence interval, 0.26-0.72; P =.001). Consistent with this, functional analysis of peripheral blood mononuclear cells showed that CX3CR1 I249 heterozygosity was associated with a significant decrease in the number of fractalkine binding sites per cell. The results show that CX3CR1 I249 is an independent genetic risk factor for coronary artery disease and that CX3CR1 may be involved in the pathogenesis of atherosclerotic disease. (Blood. 2001;97:1925-1928)

[Heart insufficiency in the elderly]. / Insuffisance cardiaque du sujet âgé.

Congestive heart failure in the elderly differs from the one in the younger. The ageing of the cardiovascular system makes the organism weaker. When a myocardial infarction or an other cardiovascular disease happens, the occurrence of congestive heart failure is precipitated. The symptoms which are often misleading and the polypathologies make the assumption of relationship difficult between a symptom like dyspnea and congestive heart failure. Further examinations are limited because of the reduced physical performances in the elderly (stress test) or because of an increased risk of side-effects (coronary angiogram). The echocardiography has a central role in the exploration of congestive heart failure. The medical treatment has the same principles than in the younger but with cautions especially regarding the renal insufficiency and the multiple treatments that an elderly patient has.

A new T-287C polymorphism in the 5' regulatory region of the tissue factor pathway inhibitor gene. Association study of the T-287C and C-399T polymorphisms with coronary artery disease and plasma TFPI levels.

Tissue factor pathway inhibitor (TFPI) is an important regulator of the extrinsic blood coagulation pathway. We screened the untranslated 5' region of the TFPI gene for polymorphisms and investigated their possible involvement in arterial thrombosis. The allele frequencies of a new polymorphism, located 287 base pairs upstream of the transcription start site (T-287C), and that of the previously described C-399T polymorphism, were similar in cases and controls. In controls, the -287C allele was associated with significantly higher levels of total TFPI antigen, arguing for an effect of this polymorphism on TFPI gene expression. In controls, the C-399T polymorphism did not alter TFPI levels. In the cases, however, decreased total and post-heparin free TFPI levels and increased F1+2 levels were significantly associated with the -399T allele. These findings suggest that the T-287C and C-399T polymorphisms are not associated with an increased risk of coronary heart disease, a result which should be confirmed by a larger study. However, their influence on outcome, or a link with subtypes of acute coronary syndromes, cannot be excluded.

[Evaluation of a specific French scale of activity in chronic heart failure. A national multicenter study. Group for Cardiac Insufficiency and Cardiomyopathy of the French Society of Cardiology]. / Evaluation d'une échelle d'activité spécifique française de l'insuffisance cardiaque chronique. Etude multicentrique nationale. Groupe insuffisance cardiaque et cardiomyopathie de la Société française de cardiologie.

Many systems have been proposed to evaluate the functional incapacity caused by chronic cardiac failure. The classification of the New York Heart Association (NYHA) is the best known. It is subjective, poorly reproducible and has a poor predictive value on effort. The authors propose a Specific French Scale of Activity with the object of a more accurate functional evaluation of cardiac failure, easier to use by the doctor and more specific to French patients and their life styles. A French multicentre study was set up in hospital departments by the French Society of Cardiology working group on Cardiomyopathy and Cardiac Failure to assess this new classification with respect to the NYHA classification and peak VO2 (Weber's classification). Eight centres participated in the study. A total of 124 patients with chronic cardiac failure and a mean age of 61 years (102 men) were included. Cardiac failure was due to ischaemic heart disease in 72 cases, hypertension in 10 cases, dilated cardiomyopathy in 40 cases and aortic regurgitation in 2 cases. Eighty-two patients underwent a double evaluation using the French Scale: 40 patients by 2 physicians and 42 patients by a physician and a nurse. Good reproducibility was found between the assessment by the 2 physicians in 35 cases (87%) and between the physician and nurse in 30 cases (71%). When compared with peak VO2, the classification was concordant in 47% of cases using the NYHA and in 61% of cases using the French Scale, with variation of one class in 40% of cases with the NYHA and 35% of cases with the French Scale. These results show good reproducibility and correspondence of classification with the exercise test which was better using the French Scale than the NYHA classification.

Acute assessment of microvascular perfusion patterns by myocardial contrast echocardiography during myocardial infarction: relation to timing and extent of functional recovery.

OBJECTIVE: To examine the relation between the initial microvascular perfusion pattern, as assessed by intracoronary myocardial contrast echocardiography (MCE), immediately after restoration of TIMI (thrombolysis in myocardial infarction) (TIMI) grade 3 flow during acute myocardial infarction, and the extent and timing of functional recovery in the area at risk. SETTING: Referral centre for interventional cardiology. METHODS: Intracoronary MCE was performed 15 minutes after TIMI grade 3 recanalisation of the infarct artery in 25 patients. Segmental myocardial contrast patterns were graded semiquantitatively (0, none; 0.5, heterogeneous; 1, homogeneous). Functional recovery was assessed by echocardiography on days 9 and 42. RESULTS: Among 174 myocardial segments in the area at risk, wall motion recovery on day 9 was observed in 40% of MCE grade 1 segments but there was no significant recovery in grade 0 or 0.5 segments. On day 42, recovery had occurred in 56% of MCE grade 1 segments (p < 0. 0001 v MCE grade 0 and 0.5; p = 0.0001 v MCE grade 1 on day 9), and 22% of MCE grade 0.5 segments (p = 0.02 v MCE grade 0; p = 0.0005 v MCE grade 0.5 on day 9); MCE grade 0 segments did not recover. Negative predictive value in predicting recovery by contrast enhancement was 95% and 89% by days 9 and 42, respectively. CONCLUSIONS: Contractile recovery occurs earliest in well reperfused segments. Up to one quarter of segments with heterogeneous contrast enhancement show wall motion recovery within the first six weeks. Myocardial perfusion after recanalisation in acute myocardial infarction, even if heterogeneous, is a prerequisite for postischaemic functional recovery. Thus preservation of acute myocardial perfusion is associated with more complete and early functional recovery.

Polymorphisms of the tissue factor pathway inhibitor (TFPI) gene in patients with acute coronary syndromes and in healthy subjects : impact of the V264M substitution on plasma levels of TFPI.

-Mutations of the gene encoding tissue factor pathway inhibitor (TFPI), an inhibitor of TF-induced activation of the coagulation cascade, were screened for in 130 patients and 142 healthy controls to determine whether these variants contribute to acute coronary syndromes or modify plasma TFPI levels. The following 3 new polymorphisms were identified: 384T-->C in exon IV, which does not change the corresponding amino acid (tyrosine 57); -33C-->T in intron 7 (the T/T, C/T, and C/C genotypes were found in approximately 50%, 40%, and 10% of subjects in both groups); and 874G-->A in exon IX (GTG-->ATG), which predicts a valine to methionine change (V264M) in the carboxy-terminus tail of TFPI. The V264M polymorphism was found in 9.2% of the cases and 4.9% of the controls; the associated odds ratio (OR) for acute coronary syndromes was 2.0 (95% confidence interval [CI], 0.7 to 5.1). The OR increased to 3.6 (95% CI, 0.8 to 15.7) and 3.2 (95% CI, 0.9 to 11.8) in nonsmokers and patients without other risk factors, respectively. The possible link between the V264M polymorphism and coronary heart disease was checked in a large case-control study of myocardial infarction (Etude Cas-Témoins de l'Infarctus du Myocarde [the ECTIM Study]). The results showed no link between the V264M polymorphism and coronary syndromes. Interestingly, however, 5 patients heterozygous for the V264M polymorphism had significantly lower plasma TFPI levels than did 13 patients with the most common genotype. Although our present results do not support an association between TFPI polymorphisms and acute coronary syndromes, the possibility that 1 of them, especially the exon IX polymorphism, is associated with subtypes of myocardial infarction or to evolutive particularities that were not assessed in this study, cannot be excluded and is currently being evaluated.

[Thrombocytopenia after cardiac surgery due to anti-platelet allo-immunization. Apropos of a case]. / Thrombopénie après chirurgie cardiaque par allo-immunisation antiplaquettaire. A propos d'un cas.

Thrombocytopaenia is rare after cardiac surgery but carries a very high risk of bleeding and thrombotic complications. It is generally due to heparinisation but may be secondary to the surgical procedure itself (cardiopulmonary bypass, sepsis, platelet consumption by the prosthesis), or associated factors (massive blood transfusion, drug reaction, rare antiplatelet allo-immunisation). One case of post-transfusion thrombocytopenia with antiplatelet anti-HPA-la allo-antibodies with a favourable outcome with high dose polyvalent gammaglobulins is reported. The authors describe the diagnostic and therapeutic approaches to this problem.

[Evaluation of the cost of a systematic early reperfusion of the infarction artery by primary or salvage angioplasty]. / Evaluation du coût d'une stratégie de reperfusion systématique prècoce de l'artère de l'infarctus par angioplastie primaire ou de sauvetage.

In order to evaluate the cost of a strategy designed to ensure a maximal early patency rate of the coronary artery responsible for acute myocardial infarction, we retrospectively studied 112 unselected, consecutive patients, treated during the 6 hours following onset of symptoms, either by intravenous thrombolysis (group 1, n = 57) followed by coronary angiography at the 90 th minute, and if necessary rescue angioplasty, or by primary angioplasty (group 2, n = 49), or finally by simple conventional medical treatment (group 3, contraindications to thrombolysis and catheterization, n = 6). The costs of medical treatment were expressed as standard mean costs, and were compared with total hospital expenditure. The overall hospital mortality was 8.0%: 3.5% in group 1, 8.2% in group 2, and 50% in group 3. The total cost of medical procedures during the initial hospital stay was 16,684 F, identical in groups 1 and 2 (17,985 F and 16,780 F, respectively). Total hospital expenditure was 36,254 F, with no significant difference between groups 1 and 2 (34,086 F and 41,670 F, respectively), despite a tendency towards a higher cost in group 2. This tendency reflected that of a longer hospital stay for patients in group 2, due to their more severe condition, but the proportion of medical cost within the total hospital expenditure was lower than in group 1 (40% and 53%, respectively). After one year of follow-up, only one other death from a cardiac cause was reported: the supplementary expenditure amounted to 14,617 F. This maximal reperfusion strategy during the acute phase of myocardial infarction achieved a low hospital mortality and one-year mortality, without a marked excess medical cost compared to previously published estimations. Primary angioplasty appears to have allowed a certain reduction of this cost compared to thrombolysis, but the heterogeneity of the study population does not allow direct comparison of the costs of the 2 reperfusion methods. One half of the total expenditure remains directly dependent on the duration of the hospital stay.

[Secondary prevention after myocardial infarction; rôle of platelet antiaggregants and hypolipemic agents]. / Prévention secondaire de l'infarctus du myocarde; place des antiagrégants plaquettaires et des hypolipémiants.

The goals of secondary prevention after myocardial infarction are to avoid the complications of infarction itself, to prevent reinfarction, to detect and treat ischaemic episodes and to slow the progression of atherosclerosis. Antiplatelet therapy, especially with aspirin, has a clearcut beneficial effect decreasing cardiovascular mortality and of non-fatal reinfarction. A metaanalysis of ten trials has shown a 25% decrease in vascular events in the long-term, irrespective of age, gender, blood pressure blood glucose level, and dosage whether low (75 to 160 mg) or moderate (160 to 325 mg/day). Apart from the irreversible inhibition of cyclooxygenase, a beneficial effect on remodelling may be observed. Lipid lowering therapy has made significant advances since the introduction of the statimes. Compared with fibrates, statines have the advantage of reducing total mortality in addition to coronary mortality, whereas the fibrates, though reducing the latter, have been reported to increase total mortality and non-coronary mortality, but in a non-significant manner. Fibrates remain the drugs of choice for the treatment of pure hypertriglyceridaemia. The mechanisms of action of the statine are diverse: effects on endothelium-dependent relaxation, haemostasis, stabilisation of the atheromatous plaque and prevention of its rupture. The cost/effectiveness ratio of aspirin and statines is very high, the latter being much more cost-effective than, for example, the treatment of mild hypertension.

Iliac artery patency before and immediately after percutaneous transluminal angioplasty: assessment with time-of-flight MR angiography.

PURPOSE: To assess the efficacy of magnetic resonance (MR) angiography of iliac arteries before and immediately after percutaneous transluminal angioplasty (PTA). MATERIALS AND METHODS: In 14 patients with 22 diseased iliac artery segments (external or common), axial two-dimensional time-of-flight MR angiography was performed. Images were reconstructed with a maximum-intensity-projection (MIP) algorithm. MR angiography was performed 1-4 days after diagnostic digital angiography and 6-24 hours after PTA. Findings obtained before and immediately after PTA were compared for number and location of significant (ie, > 50%) stenoses, length and diameter of balloon to be employed, and diameter of the stenotic artery after PTA. Linear regression analysis was performed. RESULTS: Sensitivity and specificity of MR angiography for determination of significant stenoses were 95% and 97%, respectively. Before PTA, balloon dimensions depicted on MR angiograms and digital angiograms were well correlated (r = .76, P < .05). After PTA, MR angiograms and digital angiograms provided similar findings in all but one case. CONCLUSION: MR angiography helped determine if PTA is indicated and depicted iliac artery patency after PTA.

Relationship between Rap1 protein phosphorylation and regulation of Ca2+ transport in platelets: a new approach.

Although the interrelationship between the two messengers Ca2+ and cyclic AMP in platelet function is well documented, its mechanism of action still remains to be established. We investigated here the question of the regulation of platelet Ca(2+)-ATPases by cyclic AMP through the phosphorylation of the Rap1 protein using a pathological model. We first found experimental conditions where Ca(2+)-transport by platelet membrane vesicles appeared to be dependent on the phosphorylation of the Rap1 protein. Then, we studied platelets of patients with congestive heart failure for their expression of the potential 97 kDa Ca(2+)-ATPase target of regulation through the Rap1 protein as well as the phosphorylation of the Rap1 protein using the catalytic subunit of the cyclic AMP-dependent protein kinase (C. Sub.). In the first patients studied, we found no significant modification in the expression of the 97 kDa Ca(2+)-ATPase by Western blotting using the PL/IM 430 monoclonal antibody which specifically recognized this isoform. In contrast, the Rap1 protein was differentially phosphorylated when using 15 micrograms/ml of the C. Sub. These results allowed us to use these pathological platelets to study the relationship between the expression of Rap1 protein and the regulation of Ca2+ transport by selecting a patient with severe heart failure. We could show a decrease in the expression as well as in the phosphorylation of Rap1 protein and demonstrate a lower effect of C. Sub. on Ca2+ transport. Finally, by studying a further series of patients, we could confirm that the decrease in Rap1 protein expression in heart failure, whatever its extent, was variable, and could strictly correlate the expression of Rap1 protein with the stimulatory effect of C. Sub. on Ca2+ transport. Besides the evidence for regulation of the expression of the Rap1 protein in platelets from patients with heart failure, these findings constitute a new approach in favour of the regulation of platelet Ca2+ transport through the phosphorylation of the Rap1 protein.

[Baroreflexes and congestive heart failure]. / Baroréflexes et insuffisance cardiaque.

Abnormal responses are found in the early stages of heart failure with increased sympathetic and decreased parasympathetic activity, causing peripheral arteriolar vasconstriction and tachycardia respectively. The cardiopulmonary baroreflex may be studied by decreasing venous return ("low body negative pressure") and by measuring vascular resistance forearm. The arterial baroreflex may be studied by changing aortic pressures (by intravenous phenylephrine or nitroglycerin). Orthostatism and the tilt test deactivate the cardiopulmonary and arterial baroreflexes simultaneously. These baroreflexes are impaired in patients with heart failure. Their activation does not cause the usual sympatho-inhibition so contributing to increased sympathetic tone. This dysfunction may result from a change at any point on the reflex pathway: the baroreceptors themselves, the afferent, central and efferent pathways. It is selective as during the cold pressor test, the vasoconstrictor response remains intact. One of the possible mechanisms of baroreflex dysfunction in heart failure is loss of sensitivities of the baroreceptors. This may be multifactorial: structural abnormalities, changes in compliance or functional abnormality. Even if the loss of sensitivity is partially related to a change in compliance, other factors play a role. It is more functional than structural abnormalities because, after cardiac transplantation, the baroreceptors regain their sensitivity within 2 to 3 weeks. Excessive Na-K dependent ATPase activation of the smooth muscle cells of the carotid sinus could lead to hyperpolarization of the cell membrane, so reducing the excitability of the receptor. Aldosterone is one of the factors which could activate the Na-K ATPase, as this hormone directly increases pump activity and favorizes the synthesis of new pumps in the vascular smooth muscle cells.(ABSTRACT TRUNCATED AT 250 WORDS)

[Classic treatment of chronic heart insufficiency. What if new?]. / Le traitement classique de l'insuffisance cardiaque chronique. Quoi de neuf?

The aims of treatment of chronic heart failure are to improve the symptoms and the quality of life, reduce mortality and prevent left ventricular dysfunction. Before the first symptom occurs, neurohormonal activation takes place (increased catecholamines and atrial natriuretic peptide levels). Diuretics improve symptoms and are irreplaceable for the elimination of salt and water overload. Loop diuretics are used more often than the thiazides. Their deleterious effects on electrolyte balance are well known. The fact that they activate the renin angiotensin system is a more recent acquisition; the increase in plasma renin activity is a poor prognostic factor. Diuretics potentialize the vasodilator effect of angiotensin converting enzyme inhibitors which inhibit the neurohumoral activation induced by the diuretics. This therapeutic association is very logical, effective and allows reduction in the dosage of the diuretic. To date, there are no large scale controlled studies of the effects of diuretics on mortality. Spironolactone corrects hypokalaemia and hypomagnesaemia induced by loop diuretics. Moreover, it has been shown experimentally in renovascular hypertension and in hyperaldosteronism, that this molecule can prevent myocardial fibrosis, a factor which leads to ventricular dysfunction. The RALES study will analyse the effect of associating spironolactone to diuretic and ACE inhibitor therapy on the mortality of patients in NYHA classes III-IV. The value of digitalis in heart failure patients with sinus rhythm is a classical controversy. Digitalis has a positive inotropic effect (inhibition of NaK-dependent ATPase). More recently, a favourable neurohormonal effect has been reported; digitalis decreases the activation of the sympathetic and renin-angiotensin systems.(ABSTRACT TRUNCATED AT 250 WORDS)