Paul R. Kalra

Do results of the ENABLE (Endothelin Antagonist Bosentan for Lowering Cardiac Events in Heart Failure) study spell the end for non-selective endothelin antagonism in heart failure?

The last two decades have seen major advances in the treatment of chronic heart failure, primarily as a result of therapeutic manipulation of activated neurohormonal systems. Despite this progress, many patients still suffer significant morbidity and premature death. Antagonism of the biological effects of endothelin, a potent vasoconstrictor, represents a further potential target. To date, positive results from animal models of heart failure have not been translated into clinical practice, perhaps as a consequence of the high doses of drug used. The ENABLE (Endothelin Antagonist Bosentan for Lowering Cardiac Events in Heart Failure) study evaluated the effects of low dose bosentan, a non-selective endothelin receptor antagonist, in patients with severe heart failure (left ventricular ejection fraction <35%, New York Heart Association class IIIb-IV). A total of 1,613 patients were randomized to receive either bosentan (125 mg twice a day) or placebo. The preliminary results were presented at the 51st Annual Scientific Session of the American College of Cardiology (17-20 March 2002, Atlanta, GA, USA). The primary endpoint of all-cause mortality or hospitalization for heart failure was reached in 321/808 patients on placebo and 312/805 receiving bosentan. Treatment with bosentan appeared to confer an early risk of worsening heart failure necessitating hospitalization, as a consequence of fluid retention. It has been suggested that further studies using even lower doses of bosentan or more aggressive concomitant diuretic therapy may avoid this adverse effect. The results from the ENABLE study have, however, thrown further doubt on the potential benefits of non-specific endothelin receptor blockade in heart failure.

Anaemia is an independent predictor of poor outcome in patients with chronic heart failure.

BACKGROUND Mild anaemia frequently occurs in patients with chronic heart failure (CHF), particularly in the advanced stages of the disease. The correction of anaemia with erythropoietin is a therapeutic possibility. The aim of this study was to assess prospectively the relationship between the prevalence of anaemia (haemoglobin level<or=120 g/l) and prognosis in an unselected CHF population. METHODS All consecutive patients with a diagnosis of CHF admitted to our department between January 2000 and April 2000 were considered for the present study. Those with secondary causes of anaemia were excluded. Patients were followed up until November 2001 (>18 months in all survivors), and the end-point of the study was all-cause mortality. RESULTS A total of 176 patients were enrolled (mean age: 63 years, New York Heart Association (NYHA) classification I/II/III/IV: 15/81/51/29; left ventricular ejection fraction (LVEF): 42%, ischaemic aetiology in 62%). In the whole population the mean haemoglobin level was 140+/-15 g/l. Anaemia was found in 18 (10%) patients, and was significantly more common in women than in men (18 vs. 7%, respectively, P=0.02) and in those with most severe CHF symptoms (frequency in NYHA I/II/III/IV: 0/9/10/21%, respectively; NYHA IV vs. I-III, P=0.03), but not related to the other clinical indices. Univariate analysis revealed NYHA class III-IV (hazard ratio 3.8, 95% CI: 1.6-8.9, P=0.003), low LVEF <35% (hazard ratio 2.3, 95% CI: 1.0-4.9, P=0.04) and anaemia (hazard ratio 2.9, 95% CI: 1.2-7.2, P=0.02) as predictors of 18-month mortality. In multivariate analysis, anaemia remained an independent predictor of death when adjusted for NYHA class and LVEF (hazard ratio: 2.6, 95% CI: 1.0-6.5, P=0.04). In anaemic patients, 18-month survival was 67% (95% CI: 45-89%) compared to 87% (81-92%) in patients with a normal haemoglobin level (P=0.016). CONCLUSIONS Mild anaemia is a significant and independent predictor of poor outcome in unselected patients with CHF. Correction of low haemoglobin level may become an interesting therapeutic option for CHF patients.

Effect of anemia on exercise tolerance in chronic heart failure in men

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Haemoglobin concentration and prognosis in new cases of heart failure

Anaemia is common in severe chronic heart failure and is reported to be a predictor of death. We investigated 552 patients (median age 76 years, range 29-95; 54% men [n=296]), in whom the duration of heart failure was sufficiently short that it would be unlikely to affect haemoglobin concentrations. By contrast with studies in established chronic heart failure, haemoglobin was not independently associated with prognosis when age and serum creatinine concentration were included in the analysis. The adverse effects of anaemia on survival might be a consequence of chronic heart failure rather than a separate process causing disease progression.

Left Ventricular Morphology and Function in Patients with Atherosclerotic Renovascular Disease

Atherosclerotic renovascular disease (ARVD) is associated with heart disease. There has been no systematic study of cardiac structure and function in patients with this condition. In this study, the epidemiology of cardiac changes and their relationship to renal function, renovascular anatomy, and BP are delineated. With the use of a cross-sectional design, 79 patients with ARVD and 50 control patients without ARVD underwent echocardiography and 24-h ambulatory BP monitoring. Clinical and biochemical data were collected. Results were analyzed according to renal function, residual renal artery patency, and unilateral or bilateral ARVD. Only 4 (5.1%) patients with ARVD had normal cardiac structure and function. Patients with ARVD (age 70.7 +/- 7.5 yr; estimated GFR 36 +/- 19 ml/min) had significantly more cardiovascular comorbidity (77.2 versus 42.0%; P < 0.001), greater prevalence of left ventricular (LV) hypertrophy (78.5 versus 46.0%; P < 0.001) and LV diastolic dysfunction (74.6 versus 40.0%; P < 0.001), and greater LV mass index (183 +/- 74 versus 116 +/- 33 g/m2; P < 0.001) and LV end-diastolic volume index (82 +/- 35 versus 34 +/- 16 ml/m2; P < 0.001) than control subjects. BP was similar for both patient groups. For patients with ARVD, neither renal function nor renal artery patency predicted a difference in echocardiographic or ambulatory BP monitoring parameters. Patients with bilateral ARVD had greater LV mass index and LV dilation than patients with unilateral disease. Patients with ARVD exhibit a high prevalence of cardiac morphologic and functional abnormalities at early stages of renal dysfunction. Such patients must be identified early in their disease course to allow risk factor modification.

The regulation and measurement of plasma volume in heart failure

Plasma volume, the intravascular portion of the extracellular fluid volume, can be measured using standard dilution techniques with radiolabeled tracer molecules. In healthy persons, plasma volume remains relatively constant as a result of tight regulation by the complex interaction between neurohormonal systems involved in sodium and water homeostasis. Although chronic heart failure (CHF) is characterized by activation of many of these neurohormonal systems, few studies have evaluated plasma volume in this condition under treatment. Untreated edematous decompensated heart failure (HF) is associated with a significant expansion of plasma volume. Patients with stable CHF, receiving conventional therapy, appear to have a contracted plasma volume, a concept that is in contrast to the widely held belief that CHF is associated with long-term hypervolemia. It is likely that significant changes in plasma volume occur during intensification of medical therapy or during transition from the edematous to the stable state. Clinical assessment of plasma volume may be of particular value during treatment in patients with decompensated HF, in whom the plasma volume is contracted despite an increase in total extracellular fluid volume. Under these circumstances, treatment with inotropes or renal vasodilators may be more appropriate than intravenous diuretics alone. Further studies evaluating plasma volume in HF may help to improve our understanding of the pathophysiologic mechanisms occurring in the development and progression of this complex condition.

Pathophysiologic quantities of endotoxin-induced tumor necrosis factor-alpha release in whole blood from patients with chronic heart failure

Bacterial endotoxin activity is elevated in patients with decompensated chronic heart failure (HF) and acts as a potent stimulus for immune activation. We sought to determine whether endotoxin, at an activity level seen in vivo (around 0.6 EU/ml), is sufficient to stimulate the secretion of tumor necrosis factor-alpha (TNF-alpha) and TNF-alpha soluble receptor (sTNFR2) in ex vivo whole blood from patients with HF. We studied 15 patients with HF (aged 65 +/- 1.9 years, New York Heart Association class 2.1 +/- 0.3, left ventricular ejection fraction 31 +/- 5%; mean +/- SEM), of whom 5 had cardiac cachexia, and 7 healthy control subjects (59 +/- 5 years, p = NS). Reference endotoxin was added to venous blood at concentrations of 0.6, 1.0, and 3.0 EU/ml, and was incubated for 6 hours. Endotoxin induced a dose-dependent increase in TNF-alpha release (p <0.05 in all groups). Patients with noncachectic HF produced significantly more TNF-alpha compared with controls after stimulation with 0.6, 1.0, and 3.0 EU/ml of endotoxin (113 +/- 46 vs 22 +/- 4 [p = 0.009], 149 +/- 48 vs 34 +/- 4 [p = 0.002], and 328 +/- 88 vs 89 +/- 16 pg/ml [p = 0.002], respectively; mean +/- SEM). Patients with cardiac cachexia produced significantly less TNF-alpha compared with patients without cardiac cachexia for all given concentrations (all p <0.05, analysis of variance p = 0.02). Production of sTNFR2 was greater at all concentrations of endotoxin versus controls (all p <0.05, analysis of variance p = 0.002). Plasma endotoxin levels were higher in patients with cardiac cachexia (4.3 times higher than in control subjects, p <0.005). Thus, low endotoxin activity, at levels seen in vivo in patients with HF, induces significant TNF-alpha and sTNFR2 production ex vivo. These results suggest that elevated plasma endotoxin activity observed in patients with HF is of pathophysiologic relevance.

Role of Cardiovascular Magnetic Resonance as a Gatekeeper to Invasive Coronary Angiography in Patients Presenting With Heart Failure of Unknown Etiology

Background— In patients presenting with new-onset heart failure of uncertain etiology, the role of coronary angiography (CA) is unclear. Although conventionally performed to differentiate underlying coronary artery disease from dilated cardiomyopathy, CA is associated with a risk of complications and may not detect an ischemic cause resulting from arterial recanalization or an embolic episode. In this study, we assessed the diagnostic accuracy of a cardiovascular magnetic resonance (CMR) protocol incorporating late gadolinium enhancement (LGE) and magnetic resonance CA as a noninvasive gatekeeper to CA in determining the etiology of heart failure in this subset of patients. Methods and Results— One hundred twenty consecutive patients underwent CMR and CA. The etiology was ascribed by a consensus panel that used the results of the CMR scans. Similarly, a separate consensus group ascribed an underlying cause by using the results of CA. The diagnostic accuracy of both strategies was compared against a gold-standard panel that made a definitive judgment by reviewing all clinical data. The study was powered to show noninferiority between the 2 techniques. The sensitivity of 100%, specificity of 96%, and diagnostic accuracy of 97% for LGE-CMR were equivalent to CA (sensitivity, 93%; specificity, 96%; and diagnostic accuracy, 95%). As a gatekeeper to CA, LGE-CMR was also found to be a cheaper diagnostic strategy in a decision tree model when United Kingdom–based costs were assumed. The economic merits of this model would change, depending on the relative costs of LGE-CMR and CA in any specific healthcare system. Conclusion— This study showed that LGE-CMR is a safe, clinically effective, and potentially economical gatekeeper to CA in patients presenting with heart failure of uncertain etiology.

Water and sodium regulation in chronic heart failure: the role of natriuretic peptides and vasopressin

Time for primary review 28 days. Chronic heart failure (CHF) is a complex syndrome characterised by objective evidence of ventricular dysfunction and associated clinical symptoms [1]. Activated neurohormonal mechanisms play an important role in the maintenance of circulatory homeostasis. They can be divided into the vasoconstrictive, sodium retaining and the opposing vasodilatory, natriuretic systems. Vasoconstrictive and sodium retentive actions are provided by the renin–angiotensin–aldosterone system, the sympathetic nervous system, vasopressin, thromboxane and endothelin [2–5]. Initially, in patients with heart failure, these act as important compensatory mechanisms maintaining blood pressure and adequate tissue perfusion. However, prolonged activation of these systems has deleterious effects on haemodynamics and directly on the heart itself. Enhanced vasoconstriction and fluid retention result in adverse loading conditions in the failing ventricle, whilst high levels of angiotensin II directly induce cardiac myocyte necrosis and adversely alter the myocardial matrix structure [6–9]. Angiotensin II also potentiates sympathetic drive by direct stimulation and by impairing its control by the baroreceptors [10]. In view of these adverse effects, it might be anticipated that measurement of plasma levels of neurohormones would be a helpful adjunct during prognostic assessment and even in the tailoring of therapy in CHF. Several studies have demonstrated an impaired prognosis in patients with CHF who have elevated plasma levels of norepinephrine and endothelin-1 [11,12]. Cardiac cachexia is a wasting condition that occurs in a significant percentage of patients with CHF, and is associated with a particularly poor prognosis [13]. This group appears to have marked neurohormonal abnormalities, with patients demonstrating elevated levels of norepinephrine and a reduction in plasma sodium concentration [14]. However, drugs that reduce plasma catecholamine levels are not necessarily associated with an improved prognosis, suggesting that the mechanisms involved in blunting the effects of the sympathetic nervous system … *Corresponding author. Tel.: +44-207-351-8127; fax: +44-207-351-8733 p.kalra{at}ic.ac.uk

Studies on bacterial endotoxin and intestinal absorption function in patients with chronic heart failure

BACKGROUND Small intestinal function may be altered in decompensated chronic heart failure (CHF) and translocating LPS may contribute to systemic inflammation observed in CHF. METHODS We measured intestinal permeability (melibiose and rhamnose), active (3-O-methyl-d-glucose (3-OMG)) and passive (d-xylose) carrier-mediated absorption in 20 CHF patients (12 edematous and 8 non-edematous) and 8 controls by saccharide absorption technique assessing urinary recovery of orally administered sugars. We additionally measured LPS concentrations in 42 patients with decompensated heart failure and after recompensation. RESULTS CHF patients had a 54% reduction of active carrier-mediated intestinal transport compared to controls (p<0.0001). This reduction was strongest in edematous compared to non-edematous patients and controls (recovery in urine: 13.2±2.0% vs. 20.8±2.4% vs. 36.0 ± 3.7%, all p ≤ 0.05). Patients showed a 34% reduction of passive carrier-mediated transport, strongest in edematous patients (p=0.006). A greater impairment of active carrier-mediated transport remained significant after adjustment for non-mucosal factors in CHF (p=0.0004). Non carrier-mediated intestinal permeability was not altered. Data from 42 decompensated patients showed a decrease in LPS after recompensation (p=0.004). Edematous patients had highest blood concentrations of LPS, TNF and sTNF-R1 (p<0.04). CHF patients with abnormal LPS concentrations >0.50EU/mL (n=7) had the highest concentrations of TNF (7.0 ± 1.6 vs. 3.1 ± 0.3pg/mL, p<0.02), and sTNF-R1 (3499 ± 52 vs. 1599±219 pg/mL, p=0.02). CONCLUSION Active carrier-mediated intestinal transport is reduced in decompensated CHF indicating epithelial dysfunction possibly as a consequence of intestinal ischemia. Higher LPS concentrations in edematous CHF relate to inflammation. LPS decreased after recompensation. This suggests a cause/effect relationship between edematous gut wall, epithelial dysfunction and translocating LPS.