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Cardiac dysfunction may be suspected in patients with cardiovascular disease but identifying those with the highest risk is problematic. B-type natriuretic peptide (BNP) is a strong marker of heart failure in un-treated patients. This study evaluates a combined BNP and clinical algorithm for detecting cardiac dysfunction and the risk of death, in patients receiving cardioactive medication.459 stable general practice patients, who were taking typical heart failure drugs for any indication, were included. Echocardiography, ECG, and assay of NT-proANP and BNP (two methods) were performed. Regression models were used to identify items in a Risk Score to detect cardiac dysfunction.A Risk Score based on history of myocardial infarction (1 point), abnormal ECG (2 points), atrial fibrillation (1 point) and raised BNP (1-2 points) detected cardiac dysfunction with an AUC of ROC of 0.85. A Risk Scoreor = 2 had a sensitivity of 90%, specificity of 58%, and positive and negative predictive values of 37% and 96%. Risk Score and LVEF0.36 also predicted mortality. Abnormal BNP defined as either100 pg/ml (Shionogi), or as age and sex related values, had similar predictive value.In patients on cardioactive medication, a structured Risk Score based on raised BNP, history of MI, atrial fibrillation and abnormal ECG was useful for identifying patients for immediate further examination and those who could be evaluated later.

Aims Adrenomedullin is a newly described peptide that has widespread tissue distribution. Its presence in cardiovascular (including vascular endothelial cells, smooth muscle cells, and cardiac atria and ventricles) and renal tissues, together with its vasodilatory and natriuretic properties, suggest a role in blood pressure regulation and fluid and electrolyte balance. Methods Nine normal volunteers were studied to determine whether or not adrenomedullin influenced plasma atrial natriuretic peptide and arginine vasopressin concentrations during systemic angiotensin II infusion. Results A significant (P = 0.02) augmentation of atrial natriuretic peptide concentrations, but no suppression of arginine vasopressin concentrations, was found with coinfusion of adrenomedullin and angiotensin II when compared with vehicle and angiotensin II. Conclusions Despite its vasodilator and natriuretic action, adrenomedullin significantly augmented angiotensin II-stimulated plasma atrial natriuretic peptide concentrations in healthy humans. This provides further evidence of a synergistic interaction between adrenomedullin and atrial natriuretic peptide and suggests that adrenomedullin may have a role in fluid and electrolyte balance and blood pressure regulation.

Background Persistent activation of the renin-angiotensin-aldosterone-system (RAAS) is known to occur in patients with chronic heart failure (CHF) despite treatment with angiotensin-converting enzyme inhibitor (ACE) therapy. When added to ACE inhibitors, angiotensin II type 1 (AT 1 ) antagonists may allow more complete blockade of the RAAS and preserve the beneficial effects of bradykinin accumulation not seen with AT 1 receptor blockade alone. Methods Thirty-six patients with stable New York Heart Association class II-IV CHF receiving ACE inhibitor therapy were randomly assigned in a double-blind manner to receive either eprosartan, a specific competitive AT 1 receptor antagonist (400 to 800 mg daily, n=18) or placebo (n = 18) for 8 weeks. The primary outcome measure was left ventricular ejection fraction (LVEF) as measured by radionuclide ventriculography, and secondary measures were central hemodynamics assessed by Swan-Ganz catheterization and neurohormonal effects. Results There was no change in LVEF with eprosartan therapy (mean relative LVEF percentage change [SEM] +10.5% [9.3] vs +10.1% [5.0], respectively; difference, 0.4; 95% confidence interval [CI], –20.8 to 21.7; P =.97). Eprosartan was associated with a significant reduction in diastolic blood pressure and a trend toward a reduction in systolic blood pressure compared with placebo (–7.3 mm Hg [95% CI, –14.2 to –0.4] diastolic; –8.9 mm Hg [95% CI, –18.6 to 0.8] systolic). No significant change in heart rate or central hemodynamics occurred during treatment with eprosartan compared with placebo. A trend toward an increase in plasma renin activity was noted with eprosartan therapy. Eprosartan was well tolerated, with an adverse event profile similar to placebo, whereas kidney function remained unchanged. Conclusions When added to an ACE inhibitor, eprosartan reduced arterial pressure without increasing heart rate. There was no change in LVEF after 2 months of therapy with eprosartan. (Am Heart J 2001;141:800-7.)

OBJECTIVES This study was designed to compare different proposed methods of assessing adherence with angiotensin-converting enzyme (ACE) inhibitor (ACEI) therapy in chronic heart failure. BACKGROUND The use of ACEIs in chronic heart failure gives us a unique opportunity to assess a patient’s adherence by measuring whether the expected biochemical effect of an ACEI is present in the patient’s bloodstream. In fact, there are several different ways of assessing ACE in vivo: these are serum ACE activity itself, plasma N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP), urine AcSDKP, plasma angiotensin I (AI), plasma angiotensin II (AII), or the AII/AI ratio. METHODS Patients with chronic heart failure (n = 39) were randomized to regimens of ACEI nonadherence for one week, ACEI adherence for one week or two versions of partial adherence for one week, after which the above six tests were performed. RESULTS All six tests significantly distinguished between full nonadherence for one week and full or partial adherence. Only plasma AcSDKP produced a significantly different result between partial adherence and either full adherence or full nonadherence for one week. In terms of their ability to distinguish full nonadherence from full adherence, plasma AcSDKP was 89% sensitive and 100% specific with an area under its ROC of 0.95. Corresponding figures for urine AcSDKP were 92%, 97% and 0.95 and for serum ACE they were 86%, 95% and 0.90. CONCLUSIONS All six tests distinguished full nonadherence from all other forms of adherence. The rank order of performance was plasma AcSDKP, urine AcSDKP, serum ACE, AII/AI ratio and plasma AII followed by plasma AI.

OBJECTIVESThis study was designed to assess the functional importance of endothelin (ET)Breceptors in patients with left ventricular systolic dysfunction (LVSD) by comparing the hemodynamic effects of ET-1, a nonselective ETAand ETBagonist, with ET-3, a selective ETBreceptor agonist.BACKGROUNDKnowledge of the functional importance of ETBreceptors in mediating vasoconstriction in chronic heart failure will help determine whether antagonists at both ETAand ETBreceptors are required to fully prevent vasoconstriction to endogenously produced ET-1.METHODSWe infused ET-1 (5 and 15 pmol/min) and ET-3 (5 and 15 pmol/min) into two separate groups of eight patients with LVSD with similar baseline hemodynamic indices. Hemodynamics were measured using a pulmonary thermodilution catheter and an arterial line.RESULTSEndothelin-1 infusion led to systemic vasoconstriction, with a rise in mean arterial pressure (mean ± SEM 100 ± 3 to 105 ± 3 mm Hg, p < 0.02) and systemic vascular resistance (1,727 ± 142 to 2,055 ± 164 dyn/s/cm−5, p < 0.001) and a fall in cardiac index (2.44 ± 0.21 to 2.22 ± 0.20 liters/min/m2, p < 0.01). Endothelin-3 infusion also led to systemic vasoconstriction, with a rise in mean arterial pressure (99 ± 6 to 105 ± 6 mm Hg, p < 0.01) and systemic vascular resistance (1,639 ± 210 to 1,918 ± 245 dyn/s/cm−5, p < 0.01) and a fall in cardiac index (2.66 ± 0.28 to 2.42 ± 0.24 liters/min/m2, p < 0.05). Pulmonary hemodynamic measurements did not change significantly in either group.CONCLUSIONSBoth ET-1 and ET-3 infusions led to systemic vasoconstriction; the hemodynamic changes observed were of a similar magnitude at the same molar concentration. This suggests that ETBreceptors are functionally important in mediating vasoconstriction, at least in the systemic circulation, in patients with LVSD.

Abstract —Radio-telemetry systems offer the ability to measure blood pressure and heart rate in experimental models of hypertension without the stress artifacts induced by some other methods. We therefore aimed to develop improved, nonparametric regression methods for radio-telemetry data and to use these to assess the effects of pharmacological interventions on cardiac and vascular hypertrophy in the stroke-prone spontaneously hypertensive rat. One control group and 5 groups treated either with losartan (alone or in combination with N G -nitro- l -arginine methyl ester [ l -NAME]), perindopril (also alone or in combination with l -NAME), or hydralazine plus hydrochlorothiazide were monitored for 4 weeks. Cardiac hypertrophy was assessed by the left ventricle plus septum weight to body weight ratio and vascular hypertrophy by flow-cytometry analysis of vascular smooth muscle cell polyploidy. Hemodynamic series were split into trend and cyclic components by the seasonal and trend decomposition procedure based on Loess and compared between groups by Loess regression modeling. Systolic and diastolic blood pressures were reduced systematically by losartan and perindopril ( P −10 ) but to a lesser extent by hydralazine plus hydrochlorothiazide ( P −8 ), and diurnal variation was reduced in the latter group ( P −6 ). l -NAME significantly reduced the hypotensive effect only of losartan. Vascular and cardiac hypertrophy were significantly attenuated with losartan or perindopril, but were unchanged with other treatments. The new analysis proposed here identifies differential effects on trends and cyclic variation and associations with regression of end-organ damage for losartan and perindopril compared with hydralazine plus hydrochlorothiazide. The method offers a powerful tool for detailed investigation of radio-telemetry data.

Background —We have investigated the possible effects of contrasting ACE (I/D) genotypes on the responses to the ACE inhibitor enalaprilat in normotensive men. Methods and Results —Subjects with DD (n=12) and II (n=11) ACE genotypes received an intravenous infusion of enalaprilat or placebo. Pressor responses to stepwise, incremental doses of angiotensin I were measured at 1 and 10 hours after dosing. The dose required to raise mean blood pressure by 20 mm Hg (PD20) was calculated individually, and the ratio of PD20 during enalaprilat to that during placebo (dose ratio, DR) was used for assessment of the extent of ACE inhibition. The pressor response was significantly attenuated at 1 hour after enalaprilat in both groups, but significant attenuation was evident at 10 hours after dose only in the II subjects. The DRs at both 1 hour (median, 5.43 versus 2.82, P =0.0035) and 10 hours (2.06 versus 0.84, P =0.0008) after enalaprilat were significantly higher in II subjects than in DD subjects. Conclusions —The effect of enalaprilat was significantly greater and lasted longer in normotensive men homozygous for the II ACE genotype. By multivariate analysis, ACE (I/D) genotype and plasma angiotensin II levels were predictive of >50% of the variation in response to ACE inhibition.

Objectives : Plasma levels of immunoreactive endothelin-1 (ET-1) are raised in chronic heart failure. Whether plasma ET-1 contributes to the haemodynamic derangement found in chronic heart failure is not known. We investigated the effects of exogenous ET-1 on the pulmonary and systemic vasculature in patients with left ventricular systolic dysfunction (LVD), with or without overt heart failure. Methods : ET-1 was infused at 1, 5 and 15 pmol/min into a distal pulmonary artery of ten patients with LVD to achieve plasma concentrations of ET-1 similar to those found in patients with heart failure and pulmonary hypertension. Haemodynamics were measured using a pulmonary thermodilution catheter and an arterial line. Intravascular Doppler and local pulmonary angiography were used to assess local pulmonary blood flow in the first four patients. Results : Systemic haemodynamic changes occurred with ET-1 infusion: mean arterial pressure (100±3 [standard error of the mean]) to 107±3 mmHg; p

Objectives—To compare the stability of brain natriuretic peptide (BNP) to that of N-terminal atrial natriuretic peptide (NT-ANP) in whole blood and plasma stored under different conditions. To compare a rapid, simple, direct (unextracted) BNP assay to a conventional assay using plasma extraction. Design—Blinded, prospective, comparative study. Setting—Tertiary referral cardiology department. Subjects—Forty two subjects (24 men, 18 women) comprising 28 patients with left ventricular systolic dysfunction (LVSD) ranging from mild to severe and 14 healthy volunteers. Main outcome measures—Stability of NT-ANP and BNP when stored as whole blood or plasma at room temperature over three days. Reproducibility of measurements. Results—BNP was stable in whole blood stored at room temperature for three days; mean change in concentration −7.4% (95% CI 0.6 to −14.8), (direct), −6.3% (5.0 to −16.4), (extracted); whereas a significant decline in BNP concentration was noted in plasma stored at room temperature; −23.2% (−13.7 to −31.6), (direct); −14.4% (−3.2 to −24.3), (extracted). By contrast a small non-significant rise in NT-ANP concentration was noted both in whole blood and plasma stored at room temperature for three days; whole blood +8.6% (+22.3 to −3.5), plasma +6.3%, (23.2 to −8.4). The reproducibility of the BNP measurements, and particularly the rapid, direct, measurement, was superior to that for NT-ANP. Conclusions—BNP is shown to be stable in whole blood for three days and can be measured using a rapid, simple assay. Routine assay of BNP is feasible in ordinary clinical practice and may be of value to general practitioners and hospital based physicians in the diagnosis and management of patients with LVSD. Samples can be sent to a central laboratory without special handling requirements. Keywords: brain natriuretic peptide; atrial natriuretic peptide; heart failure; diagnosis

Potentially harmful stimulation of the neuroendocrine axis occurs in the early hours of myocardial infarction. It has been suggested that this acute neuroendocrine response might be attenuated by early therapeutic reperfusion. To test this hypothesis we measured plasma concentrations of atrial natriuretic factor (ANF), renin, adrenaline (ADR) and noradrenaline (NADR) on admission and at 1 h and 4 h in 32 patients undergoing streptokinase treatment within 6 h of myocardial infarction. Fractional changes (FC) in hormone levels were calculated: e.g. ANFO-ANF4/ANFO. Resolution of ST segment elevation at 4 h was the primary measure of reperfusion. Sixteen patients showed ST segment resolution. There was no difference in hormone levels at baseline between reperfused and non-reperfused patients. Fractional changes in ANF, renin and ADR were similar in both groups. NADR fell from admission to 4 h in reperfused patients but rose in non-reperfused (FC 0.28 vs -0.10; P = 0.054). There was no difference in the changes in pulse rate or blood pressure from admission to 4 h between the two groups. Thus there is no evidence that early reperfusion acutely alters the release of ANF, renin or ADR to myocardial infarction. Although plasma NADR tended to fall acutely in reperfused patients this was not accompanied by other markers of sympathetic withdrawal.

To determine whether induction of arterial hypertension in young normotensive Wistar rats by chronic inhibition of nitric oxide production with NG-nitro-L-arginine methyl ester (L-NAME) produced a form of self-sustained hypertension, and to investigate the role of the renin-angiotensin system and vascular hypertrophy in the hypertensive process.Three-week-old Wistar rats were given 100 or 40 mg/kg per day L-NAME or 40 mg/kg per day L-NAME plus 100 mg/kg per day captopril in their drinking water for between 4 and 7 weeks. Systolic blood pressure was measured by tail-cuff plethysmography both during treatment and after the treatment had been stopped. The effect of treatment on plasma renin was measured and the effect of treatment on mesenteric resistance artery structure was determined using a small-vessel myograph.L-NAME produced a progressive and marked increase in blood pressure during the period of treatment. Hypertension was sustained for 14 weeks after stopping treatment. L-NAME resulted in a fourfold increase in plasma renin which remained elevated after treatment was stopped. Blood pressure was correlated with plasma renin levels. Treatment with L-NAME plus captopril markedly attenuated the rise in blood pressure and captopril also produced a marked fall in blood pressure in rats that developed persistent hypertension. Rats with self-sustained hypertension exhibited both cardiac and mesenteric resistance vessel hypertrophy. The induction of vascular hypertrophy with low-dose L-NAME did not result in the development of self-sustained hypertension.Chronic L-NAME treatment in young rats can produce a form of persistent hypertension which is renin-dependent and which does not seem to involve a vascular amplifier mechanism.

OBJECTIVES--To determine the effects of early treatment with captopril on haemodynamic function, neuroendocrine biochemistry, left ventricular structure, clinical outcome, and exercise capacity over one year from acute myocardial infarction. DESIGN--Randomised, double blind, placebo controlled comparison of captopril and placebo. SETTING--Coronary care units and cardiology departments of two university teaching hospitals in Glasgow. PATIENTS--99 haemodynamically stable patients with acute myocardial infarction, selected on clinical grounds as being at risk of late ventricular dilatation. INTERVENTION--Captopril or identical placebo started between six and 24 hours after start of symptoms and continued for 12 months. Target maintenance dose was 25 mg three times a day. MAIN OUTCOME MEASURES--(a) Acute haemodynamic effects of treatment; (b) neuroendocrine biochemistry from admission to two months; and (c) change in echocardiographic measures of left ventricular size, clinical outcome, and exercise capacity after 12 months of treatment with a separate analysis of the effects of one month of treatment withdrawal on left ventricular volumes. RESULTS--Captopril caused acute reductions in mean (SEM) pulmonary artery pressure (2.48 (0.69) mm Hg) and systemic vascular resistance (260 (103)) dyn.s.cm-5). Over the first 10 hours captopril reduced mean arterial pressure by 12.1 (2.4) mm Hg compared with 3.8 (1.9) mm Hg in the placebo group. No patient had to be withdrawn from the captopril group because of hypotension. From day 1 onwards systolic and diastolic arterial pressures in the captopril treated group were slightly but not significantly lower than on placebo. There was no difference in the incidence of ventricular or supraventricular arrhythmia with treatment. Captopril prevented the day 3 peak in angiotensin II that occurred in the placebo group (peak concentration (interquartile range): 10.1 (4.8-19.4) pg/ml v 16.8 (4.3-46.3) pg/ml)) but had no effect on atrial natriuretic factor, arginine vasopressin, or catecholamines. Plasma atrial natriuretic factor remained above normal in both groups at two months after infarction. After one year left ventricular volume indices had increased less on captopril than on placebo: left ventricular end systolic volume index 5.4 ml/m2 v 14.7 ml/m2 (95% confidence interval (95% CI) of difference -14.6 to -3.9; p = 0.0011); left ventricular end diastolic volume index 8.4 ml/m2 v 19.0 ml/m2 (95% CI of difference, -17.0 to -4.2; p = 0.0016). Withdrawal of captopril for one month did not affect ventricular volumes. There was no difference in exercise capacity. CONCLUSIONS--Captopril started between six and 24 hours after acute myocardial infarction is not associated with significant hypotension. It suppresses activation of the renin angiotensin system but has no effect on plasma concentrations of other neurohormones. Atrial natriuretic factor remains raised at two months after myocardial infarction. Captopril significantly decreases left ventricular dilatation. This effect is not lost after one month of treatment withdrawal and is thus due to an alteration of left ventricular structure and not to a short lived haemodynamic action of captopril. Long-term treatment with captopril does not result in improved aerobic exercise capacity after acute myocardial infarction.

There is activation of the renin angiotensin system after both complicated and uncomplicated myocardial infarction. Angiotensin II increases myocardial oxy gen consumption whilst reducing coronary flow and is also directly toxic to the myocardium. Angiotensin converting enzyme inhibitors produce beneficial haemodynamic and neuroendocrine changes in patients with acute left ventricular failure, and may have a role in selected patients with cardiogenic shock. There is evidence to suggest that they might prevent the development of late cardiac failure by limiting the extent of post infarction ventricular dilation. Further research is necessary to define their role in the treatment of acute myocardial infarction.

1. Cardiovascular reactivity, blood vessel morphology, blood pressure and the activity of the renin—angiotensin system were determined in the 3-week-old spontaneously hypertensive (SHR), Wistar—Kyoto (WKY) and outbred Wistar (WIS) rat. 2. In an isolated perfused mesenteric artery preparation the SHR had a significantly increased maximum response to KCl and noradrenaline (P < 0.02) compared with the WKY. Using a myograph, vascular structure was measured over a range of resistance arteries and showed a significant correlation between lumen diameter and both media cross-sectional area and thickness, with the regression line for the SHR shifted upwards indicating both increased media area and thickness. This was associated with a slight, but significant, narrowing of the lumen (P < 0.01) and an increased media/lumen ratio (0.049 ±0.01, 0.034 ±0.007, 0.036 ±0.008 for SHR, WKY and WIS, respectively, means ±sd P < 0.001). The SHR had a greater heart/body weight ratio than either the WKY or the WIS (P < 0.001). 3. Both mesenteric artery and membrane protein content were higher in the SHR, indicating an increase in cell size or number. 4. Plasma renin activity (means ±sd) was lower in the SHR (1.0 ± 0.7 pmol of angiotensin I h−1 ml−1) than in the WKY (2.2±1.2 pmol of angiotensin I h−1 ml−1, P < 0.001) but not different from that in the WIS (1.2±0.8 pmol of angiotensin I h−1 ml−1). Mesenteric artery vascular renin concentration was also lower in the SHR (P = 0.06). Plasma angiotensin II concentration (mean±sd) was similarly lower in the SHR (11.9 ±3.8 fmol/ml) than in the WKY (18.8 ± 6.2 fmol/ml, P < 0.001) but not different from that in the WIS (14.5 ±5.8 fmol/ml). There was no difference in angiotensin II receptor number or affinity between the three rat strains. 5. Quiescent intra-arterial blood pressure was significantly higher in the SHR both 1 and 2 days after cannula insertion. On day 2 the pressure (mean ± sd) in the SHR was 112.7 ± 19.9 mmHg, in the WKY 81.1 ± 14.4 mmHg and in the WIS 75.1 ± 7.8 mmHg (P < 0.001). 6. These data indicate the presence of marked vascular and cardiac hypertrophy in the SHR at a very early period in its development. Blood pressure is elevated and there is no overactivity of the renin system. We conclude that, at this time, there is no prehypertensive phase nor is there evidence of angiotensin II-mediated pressure-independent mechanism in the hypertrophic development.

Vascular surgery is associated with a substantial risk of cardiovascular events and death.1,2 There is no effective method for determining cardiac risk preoperatively: validated risk prediction instruments are limited by complexity and poor predictive value, and other cardiac investigations such as nuclear stress testing and coronary angiography are limited by time and resources. For these reasons, alternative methods that can predict outcome of at risk patients would be an important advance. Plasma brain natriuretic peptide (BNP) has counter-regulatory vasodilator and natriuretic properties. Plasma BNP concentrations are often increased in cardiac disorders, such as angina and heart failure. The plasma concentrations of BNP are related to prognosis in these conditions.3 Many of these cardiovascular conditions occur in patients with peripheral vascular disease. We investigated the predictive value of preoperative plasma BNP concentration for the occurrence of perioperative fatal or non-fatal myocardial infarction (MI) in high risk vascular surgical patients. We also compared the predictive value of plasma BNP concentration with the Eagle score, a conventional surgical risk assessment instrument.1,2 We screened consecutive patients undergoing major surgery for aortic or peripheral arterial occlusive disease in Gartnavel General Hospital, Glasgow, between April and September 2004. All patients at high risk, defined according to the American Society of Anesthesiology …

Cardiac transplantation is an important treatment option for those patients with end stage heart failure who have failed to respond to disease modifying treatment. However, cardiac transplantation is not without risk, with the one year mortality around 19%,1 and identifying patients at the highest risk of death is notoriously difficult. Brain natriuretic peptide (BNP) and the N-terminal portion of pro-brain natriuretic peptide (NT-proBNP) are now well established diagnostic and adverse prognostic markers in all stages of congestive heart failure. Indeed, we have shown that NT-proBNP is predictive of death before cardiac transplantation.2 Studies have also shown that increasing BNP concentrations precede cardiac allograft rejection and are associated with poor survival late after transplantation.3 However, the prognostic ability of NT-proBNP immediately after cardiac transplantation has not been evaluated. The goal of this study was therefore to assess the short term prognostic ability of NT-proBNP in patients after cardiac transplantation. We prospectively studied 26 consecutive patients undergoing orthotopic cardiac transplantation in the Scottish Cardiopulmonary Transplant Unit between September 2001 and September 2003. The primary end point was all cause mortality. The median follow up was 477 days (range 20–922 days). No patients were lost to follow up. Blood for NT-proBNP was collected in EDTA containing tubes before each routine right ventricular endomyocardial biopsy. The samples were then spun at 3000 rpm for 10 minutes at 0°C. Plasma was extracted and frozen in aliquots at −70°C until analysis. NT-proBNP …

Background: The prognosis of chronic heart failure has improved with modern medical therapy. However, identifying those patients who fail to respond to such therapy and therefore those who remain at high risk is notoriously difficult. The B-type natriuretic peptides are established independent predictors of prognosis in CHF. However, the relevance of a change in NT-proBNP concentration over time in advanced heart failure is unknown. Methods: We prospectively studied 133 patients with advanced CHF referred for consideration of cardiac transplantation. Plasma for NT-proBNP analysis was sampled at baseline and a median of 4months later in the 112 patients surviving without cardiac transplantation. Patients were followed up for a median of 1003days. Results: The primary endpoint of all-cause mortality occurred in 30 (26.8%) patients. Those subjects who had the highest NT-proBNP concentration at 4months were at the greatest risk of death (log rank statistic=10.4, p=0.001). On Cox regression analysis, both a NT-proBNP concentration above the median and an absolute increase in NT-proBNP were independent predictors of mortality (χ2=53, p

Anemia is prevalent in patients with chronic heart failure, the proportion of which increases with deteriorating New York Heart Association functional class. Anemia is also associated with increased symptoms, more frequent hospitalizations, and, in some studies, with an increased mortality rate. We have demonstrated that N-terminal brain natriuretic peptide (NT-proBNP) is a powerful predictor of death in advanced heart failure and is superior to the traditional markers of chronic heart failure (CHF) severity. However, to date, there are no published data that compare the prognostic ability of NT-proBNP with that of hemoglobin and hematocrit in patients with advanced heart failure who are referred for consideration of cardiac transplantation at a time when erythropoietin is under investigation as a treatment option in such a population.We prospectively studied 182 consecutive patients with advanced CHF who had been referred for consideration of cardiac transplantation. Blood samples were taken at recruitment for routine investigation and for NT-proBNP analysis; the patients' condition was followed for a median of 554 days. The primary end point of all-cause death was reached in 30 patients, and the secondary end point of all-cause death or urgent cardiac transplantation was reached in 34 patients. The mean hemoglobin level was 13.9 +/- 2.2 g/dL, and the median concentration of NT-proBNP was 1505 pg/mL (interquartile range, 517-4015). The only multivariate predictor of all-cause death (chi 2 = 14.2; P.001) or the secondary end point of all-cause death or urgent transplantation (chi 2 = 21.8; P.001) was an NT-proBNP concentration above the median value.A single measurement of NT-proBNP in patients with advanced CHF can help to identify patients who are at a higher risk of death and is a better prognostic marker than anemia.

Background: Apelin, the novel endogenous ligand for the G-protein-coupled receptor APJ, has shown positive inotropic, vasodilatory and diuretic properties in animal studies. Differential expression and synthesis of apelin and APJ receptors have been observed in normal and failing human hearts, suggesting a possible role in cardiovascular homeostasis. Changes in plasma apelin concentrations in relation to heart failure have been described in small studies with conflicting results. Our aim was to evaluate plasma apelin concentrations in a large cohort of patients with chronic heart failure (CHF) across a broad spectrum of disease severity. Method and results: Plasma apelin concentrations were measured in 202 patients with CHF secondary to left ventricular systolic dysfunction and 22 age-matched controls. Plasma apelin concentrations were significantly lower in patients with CHF, irrespective of NYHA class, ejection fraction or aetiology when compared to age-matched controls (0.85 [0.53–2.04] versus 3.76 [0.85–5.13] ng/ml, p

The purpose of this multicenter study was to evaluate the technical performance of the automated Elecsys proBNP (brain natriuretic peptide) assay, which is indicated as an aid in the diagnosis of individuals suspected of having congestive heart failure. The Elecsys proBNP assay is an electrochemiluminescent immunoassay employing two polyclonal NT-proBNP-specific antibodies in a sandwich test format. The study was performed on the three Elecsys analyzers (E 1010, E 2010, and E 170) at eight different sites world-wide. Within- and total precision were ≤3%, with total precision slightly higher on the Elecsys E 170 instrument with multiple modules. Reproducibility among sites and platforms was

Objective: To determine whether the plasma concentration of the putative new cardiac hormone relaxin is predictive of clinical outcome in patients with chronic heart failure (CHF). Design: Plasma relaxin and N-terminal pro B type natriuretic peptide (NT pro BNP) concentrations were measured in 87 patients admitted in an emergency with CHF caused by left ventricular systolic dysfunction. These were related to death and death or readmission with CHF over the following year. Setting: Western Infirmary, Glasgow, UK. Main outcome measures: Plasma concentrations of relaxin and NT pro BNP; time to death or hospitalisation caused by heart failure. Results: Plasma concentrations of both relaxin and NT pro BNP were greatly increased. Of the 43 patients with NT pro BNP above the group median concentration, 23 (53%) died and 30 (70%) died or were hospitalised with CHF. Among the 44 with concentrations below the median, these numbers were 5 (11%) and 12 (27%), respectively (p < 0.0001 and p < 0.0001, respectively). Plasma NT pro BNP concentration remained an independent predictor of an adverse clinical outcome in a multivariate analysis. Of the 42 patients with a relaxin concentration above the median, 13 (31%) died and 20 (48%) died or were hospitalised. Below the median, these numbers were 15 of 45 (33%) and 22 of 45 (49%) (p = 0.76 and p = 0.84, respectively). Conclusions: NT pro BNP is a powerful and independent predictor of outcome in CHF, whereas relaxin, also secreted by the heart in increased amounts in CHF, is not.

OBJECTIVE—To report the mortality of left ventricular systolic dysfunction (LVD), assessed objectively by echocardiography, and its association with natriuretic peptide hormones in a random sample of 1640 men and women aged 25-74 years from a geographical, urban population. METHODS—Left ventricular function was measured by echocardiography in 1640 attendees studied in 1992-3. LVD was defined as a left ventricular ejection fraction (LVEF) ⩽ 30%. Plasma concentrations of N-terminal atrial natriuretic peptide (N-ANP) and brain natriuretic peptide (BNP) were measured by standard radioimmunoassays. Mortality was documented at four years. RESULTS—The four year all cause mortality rate in the whole cohort was 4.9% (80 deaths). It was 21% (nine deaths) in those with an LVEF ⩽ 30% and 4% in those whose LVEF was > 30% (p

Insulin resistance is of pathogenic importance in several common human disorders including type 2 diabetes, hypertension, obesity and hyperlipidemia, but the underlying mechanisms are unknown. The spontaneously hypertensive rat (SHR) is a model of these human insulin resistance syndromes. Quantitative trait loci (QTLs) for SHR defects in glucose and fatty acid metabolism, hypertriglyceridemia, and hypertension map to a single region on rat chromosome 4. Genetic analysis of an SHR derived from a National Institutes of Health colony led to the identification of a causative mutation in the SHR Cd36. We have investigated glucose and fatty acid metabolism in the stroke-prone SHR (SHRSP). We demonstrate defects in insulin action on 2-deoxy-D-glucose transport (SHRSP 3.3 +/- 1.5 vs. 21.0 +/- 7.4 pmol x min(-1) x [20 microl packed cells](-1), SHRSP vs. WKY, respectively, P = 0.01) and inhibition of catecholamine-stimulated lipolysis (P < 0.05 at all concentrations of insulin) in adipocytes isolated from SHRSP. In contrast, basal levels of catecholamine-stimulated nonesterified free fatty acid (NEFA) release and plasma levels of NEFA are similar in SHRSP and WKY. These results are in agreement with the data on the SHR.4 congenic strain, which suggested that the QTL containing Cd36 mutations accounted for the entire defect in basal catecholamine action but only for approximately 40% of the SHR defect in insulin action. In the SHR, both abnormalities appear consequent of defective Cd36 expression. Because Cd36 sequence and expression are apparently normal in SHRSP, it is likely that the molecular mechanism for defective insulin action in this strain is caused by a gene(s) different than Cd36.

Recently the authors have shown that female stroke-prone spontaneously hypertensive rats (SHRSPs) in proestrus (high endogenous estrogen), sustain more than 20% smaller infarcts after middle cerebral artery occlusion (MCAO) compared with SHRSPs in metestrus (low endogenous estrogen). Because estrogen has vasodilator properties, the authors investigated whether the estrous state influences cerebral blood flow (CBF) after MCAO. CBF was measured 2.5 hours after a distal MCAO by [14C]iodo-antipyrine autoradiography in conscious SHRSPs either in metestrus or in proestrus. There were no significant differences in CBF when analyzed either at predetermined anatomic regions or by cumulative distribution analysis of areas with flow

Objective Adrenomedullin inhibits angiotensin II stimulated aldosterone production in vitro and in vivo in experimental animals. The aim of this study was to investigate the effect of adrenomedullin on angiotensin II and adrenocorticotrophic hormone-stimulated aldosterone production in vivo in healthy humans. Design and Methods Seven volunteers were studied in a quiet, temperature-controlled laboratory. After 35 min of rest, an infusion of placebo or adrenomedullin (3 pmol/kg per min) was given over 60 min; 15 min after starting this first infusion, a second infusion of angiotensin II (0.96 fmol/kg per min) or adrenocorticotrophic hormone (0.1 mIU/kg per min) was co-infused and continued for 45 min. Results Adrenomedullin significantly inhibited angiotensin II stimulated aldosterone production: the increment in aldosterone on the placebo day was 691 pmol/l compared with 552 pmol/l on the adrenomedullin day (P < 0.004). Adrenomedullin did not inhibit adrenocorticotrophic hormone-stimulated aldosterone or cortisol release. Conclusion Adrenomedullin selectively inhibits angiotensin II-stimulated aldosterone production.

In previous studies on the use of natriuretic peptides to detect left-ventricular systolic dysfunction, a higher rate of cardiac disorders in the control groups than in the study groups could have led to bias. We investigated the effectiveness of plasma N-terminal atrial natriuretic peptide (NT-ANP) and brain natriuretic peptide (BNP) concentrations to show left-ventricular systolic dysfunction in a random sample of the general population.We randomly selected 2000 participants aged 25-74 years from family physicians' lists in Glasgow, UK. We sent all participants questionnaires. 1653 respondents underwent echocardiography and electrocardiography. We took a left-ventricular ejection fraction of 30% or less to show left-ventricular systolic dysfunction. NT-ANP and BNP were measured in plasma by RIAs.1252 participants had analysable electrocardiograms and echocardiograms, completed questionnaires, and available blood samples. Median concentrations of NT-ANP and BNP were significantly higher in participants with left-ventricular systolic dysfunction (2.8 ng/mL [IQR 1.8-4.6] and 24.0 pg/mL [18.0-33.0]) than in those without (1.3 ng/mL [0.9-1.8] and 7.7 pg/mL [3.4-13.0]; each p0.001). Among participants with left-ventricular systolic dysfunction, both symptomatic and asymptomatic subgroups had raised NT-ANP and BNP concentrations. A BNP concentration of 17.9 pg/mL or more gave a sensitivity of 77% and specificity of 87% in all participants, and 92% and 72% in participants aged 55 years or older.Measurement of BNP could be a cost-effective method of screening for left-ventricular systolic dysfunction in the general population, especially if its use were targeted to individuals at high risk.

OBJECTIVES: To determine whether plasma concentrations of inactive and active renin in adult life are related to foetal development. DESIGN: A follow-up study of a group of men and women whose weight and other measurements of body size had been recorded at birth. SETTING: Sheffield, England. SUBJECTS: In total 148 men and women born in the Jessop Hospital, Sheffield, during 1939-40 and now aged 50-53 years. MAIN OUTCOME MEASUREMENT: Plasma concentrations of inactive and active renin in adult life. RESULTS: Plasma concentrations of inactive and active renin in adult life tended to be higher in people who had been large at birth. The strongest relationship was between concentrations of inactive renin and abdominal circumference at birth; the median plasma concentration of inactive renin was 88.5 mu/ml in people whose abdominal circumference at birth had been 13 inches (33.02 cm) or more compared with 61 mu/ml in people whose abdomens had measured 11.5 inches (29.21 cm) or less. CONCLUSION: Impairment of foetal growth is associated with lower plasma concentrations of inactive renin in adult life. Alterations in the activity of the renin-angiotensin system may be a mechanism by which reduced foetal growth leads to raised adult blood pressure.

Much of the information concerning angiotensin II (ANG II) and its effects on cardiovascular hypertrophy derives from therapy studies in experimental models of hypertension, particularly the spontaneously hypertensive rat (SHR). Angiotensin-converting enzyme (ACE) inhibitors seem to be particularly effective in that they have persistent effects on blood pressure after treatment is stopped. More recently, similar findings have been found using the angiotensin AT1 receptor antagonist losartan. It has been suggested that the persistent effects of these agents might be related to their ability to modify vascular structure by blocking a direct tropic effect of ANG II on blood vessels. Many questions remain, however, concerning the mechanism involved. In particular, the precise role played by ANG II remains to be clarified.

BACKGROUND--Endothelin is an extremely potent vasoconstrictor that may have a role in the pathogenesis of acute myocardial ischaemia. Atrial natriuretic factor is an endogenous antagonist of endothelin. To find the pattern and possible importance of circulating endothelin in ischaemic heart disease, concentrations in normal controls and those in patients with stable and unstable angina, acute myocardial infarction, and chronic cardiac failure were compared. The relation between circulating concentrations of endothelin and atrial natriuretic factor in the aftermath of myocardial infarction was also examined. METHODS--Eighteen patients with acute myocardial infarction, 10 with unstable angina, 10 with stable angina, 12 with chronic cardiac failure, and 10 normal controls were studied. Endothelin concentration was measured in venous plasma by radioimmunoassay. In patients with acute myocardial infarction simultaneous concentrations of endothelin and atrial natriuretic factor were measured on admission and at one, four, and 24 hours. RESULTS--Mean concentrations (SEM) of endothelin were 5.72 (0.19) fmol/ml in controls, 6.56 (0.48) fmol/ml in stable angina, 6.41 (0.48) fmol/ml in unstable angina, and 13.83 (0.95) fmol/ml in chronic cardiac failure. In acute myocardial infarction concentrations were 8.81 (0.69) fmol/ml on admission, 11.85 (1.02) fmol/ml at one hour, 11.88 (1.10) fmol/ml at four hours, and 7.30 (0.49) fmol/ml at 24 hours. Concentrations of atrial natriuretic factor at the same times were 68.1 (13.1) pg/ml, 8.4 (1.5) pg/ml, 24.4 (4.1) pg/ml, and 42.0 (6.9) pg/ml. CONCLUSIONS--Plasma endothelin is raised in chronic heart failure and in the aftermath of acute myocardial infarction but not in stable or unstable angina. After myocardial infarction endothelin concentrations are raised whereas concentrations of atrial natriuretic factor are relatively low. The role of endothelin in the pathogenesis of acute myocardial infarction and its interactions with other humoral factors require further investigation.

Measurement of plasma concentrations of the natriuretic peptides has recently been recognised as a potentially useful means of identifying patients with left ventricular systolic dysfunction (LVSD). Most studies, including our own,1 suggest that brain natriuretic peptide (BNP) may be superior to N-terminal atrial natriuretic peptide for diagnostic purposes. The widespread applicability of BNP would, nevertheless, be greatly diminished if the blood sample required special storage or handling. We have previously shown in a mixed population—including patients with LVSD and healthy volunteers—that endogenous BNP is stable in whole blood at room temperature for three days.2However, other groups have published conflicting results, which at first sight cast doubt on our data3; therefore, our results have not gained universal acceptance.4-6 We, therefore, repeated our study and confirmed our original findings. Interestingly, our study is …

Male Sprague-Dawley rats were uninephrectomized and given either deoxycorticosterone (DOC) pivalate (12.5 mg three times weekly) and 1% NaCl/0.2% KCl to drink for 4 weeks (DOC-treated), after which DOC was stopped and tap water substituted (post-DOC), or tap water to drink throughout (controls), DOC treatment increased blood pressure, serum sodium, plasma atrial natriuretic peptide (P-ANP) and plasma deoxycorticosterone (P-DOC) (P less than 0.05), while serum potassium, plasma renin and plasma angiotensin II were lower (P less than 0.05) than in control animals. Plasma vasopressin (P-AVP) was also raised but not significantly. These changes persisted for up to 4 weeks post-DOC and, in the case of plasma renin, plasma angiotensin II, P-AVP and P-ANP, for up to 12 weeks. Total body sodium was also increased at 2 weeks post-DOC (P less than 0.05). Rats which were adrenalectomized after 4 weeks of DOC treatment in which DOC injections were stopped, then drank either NaCl/KCl or tap water; blood pressure and P-DOC remained elevated while plasma renin remained suppressed. There were more deaths in rats given NaCl/KCl (five of six) than in the group given water (one of six). Rats treated with a subcutaneous DOC silastic implant had a comparable rise in blood pressure to rats given DOC injections. However, after removal of the implant, while blood pressure remained elevated, P-DOC levels were not raised and plasma renin rose to control levels after 4 weeks. These findings indicate that, in rats given DOC injections, post-DOC hypertension results from sodium and fluid retention as a consequence of chronic hangover of exogenously administered DOC.

1. Blood pressure, left ventricular mass and platelet cytosolic free calcium concentrations were measured in 23 patients with untreated primary hyperparathyroidism, 30 normotensive control subjects and 23 control subjects matched for age, sex and blood pressure. In 12 patients measurements were repeated after parathyroidectomy. 2. Patients with primary hyperparathyroidism had significantly elevated blood pressures (139 ± 6/86 ± 3 mmHg, mean ± sem) compared with control subjects (125 ± 2/78 ± 1 mmHg), but high values persisted after hypercalcaemia was corrected. 3. Despite chronic extracellular hypercalcaemia, intracellular free calcium levels were lower in patients with hyperparathyroidism than in controls matched for age, sex and blood pressure (median concentrations 81.5 nmol/l vs 93 nmol/l, 95% confidence interval 0.1 to 20.1; P < 0.05) and values tended to increase after parathyroidectomy. 4. Left ventricular mass index was increased in the primary hyperparathyroid group as compared with control subjects matched for age, sex and blood pressure (123 g/m2 vs 100 g/m2, 95% confidence interval −36.1 to −3.1; P = 0.03). Parathyroidectomy resulted in a small reduction of the left ventricular mass index (123.5 g/m2 vs 104 g/m2, 95% confidence interval 46.5 to 2.5; P = 0.1) but no change in blood pressure. 5. Hypertension and left ventricular hypertrophy in primary hyperparathyroidism are associated with relatively low levels of free calcium in platelets.

To determine whether endothelin is extracted from plasma during passage through the pulmonary circulation, we measured its concentration at several points, including the pulmonary artery and the left superior pulmonary vein in seven patients undergoing cardiac surgery. Endothelin concentrations were very similar at all sites sampled. In patients undergoing coronary artery bypass grafting, there is no net pulmonary clearance of endothelin.

The physiological response to a chronically failing heart is the implementation of compensatory mechanisms intended to support blood pressure. These mechanisms, which are not fully understood, increase peripheral vascular tone, thus increasing the strain on the weakened myocardium. This study investigated the structure and function of small arteries from heart failure patients and controls without heart failure in an attempt to identify abnormalities associated with heart failure which may be related to these mechanisms. Small arteries were dissected from gluteal biopsies and studied using wire myography. Arterial morphological parameters were measured and concentration–response curves constructed for a number of vasoconstrictor and vasodilator agonists. Plasma concentrations of neuroendocrine hormones were also measured. There were no morphological differences between small arteries from control subjects and those from patients with chronic heart failure. In heart failure patients, vasoconstrictor responses to endothelin-1 were significantly reduced, although plasma endothelin-1 levels were increased. Arteries from heart failure patients also showed evidence of an impaired neuronal uptake mechanism, since blockade by cocaine had no effect on noradrenaline-induced vasoconstriction in these vessels. These results suggest that small-artery structure is not altered in chronic heart failure and so cannot account for the heightened vascular resistance in this syndrome. However, abnormal neuronal uptake and impaired vasoconstriction in response to endothelin-1 may be associated with the complex compensatory phenomenon involved in heart failure.

Objective To quantify vascular smooth muscle polyploidy and growth kinetics in aortic cells from stroke-prone spontaneously hypertensive rats (SHRSP) and from normotensive Wistar-Kyoto (WKY) rats, and to examine the effects of treatment with the angiotensin converting enzyme (ACE) inhibitor perindopril on these parameters. Design The following experimental groups were used: young (age 20 weeks) untreated WKY rats and untreated SHRSP; SHRSP treated with perindopril, and age- and sex-matched control SHRSP; and SHRSP treated with hydralazine and hydrochlorothiazide and age- and sex-matched control SHRSP. The effects of treatment of the SHRSP with perindopril for 30 days on vascular smooth muscle polyploidy and growth kinetics were measured and compared with the effects of equivalent antihypertensive doses of hydralazine and hydrochlorothiazide. Methods Vascular smooth muscle polyploidy was measured using flow-cytometry DNA analysis of freshly harvested cells. Growth curves were performed on cultured aortic cells. Plasma renin activity was measured by an antibody-trapping method, plasma angiotensin II (Ang II) by radioimmunoassay and plasma ACE activity by a colorimetric method. Cardiac hypertrophy was evaluated by measuring the heart weight:body weight and left ventricle + septum weight:body weight ratios. Results The SHRSP had markedly and significantly elevated G2 + M phase of the cell cycle. Treatment with perindopril resulted in a significant reduction in polyploidy in the SHRSP, whereas treatment with hydralazine and hydrochlorothiazide had no effect on the percentage of cells in the G2 + M phase of the cell cycle. The regression of polyploidy after treatment with perindopril was associated with a significant reduction in the concentration of Ang II and ACE activity, and with a significant regression of cardiac hypertrophy. Increased mitogenesis of cultured vascular smooth muscle cells from the SHRSP was not altered by treatment with perindopril. Conclusions ACE inhibition reduces vascular smooth muscle polyploidy in large conduit arteries. This type of vascular protection is mediated by the reduced Ang II and possibly by increased kinins level, rather than by the hypotensive effect alone.